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Chemical
11-22-2015, 06:01 AM
Hi all, I've been doing some research on MBP for the pat few weeks and I thought I'd share some of the interesting insights on this topic, its a long read but you can skip the abstracts and articles for my conclusions. Please do not hesitate to ask questions and I strongly encourage people to dispute this research, as this will lead to a beneficial discussion on points that I havent considered.

Lets look at how DHT works to cause MBP - in depth.



The Anticancer Testosterone Metabolite 3β-Adiol (http://meridianvalleylab.com/testosteron-metabolite-3b-adiol)

Since DHT is generally agreed to be carcinogenic, the thought was that reducing the transformation of testosterone into DHT would reduce cancer risk. In the Prostate Cancer Prevention Trial (PCPT), 18,882 men over age 55 years with normal prostate examinations and a PSA below 3.0 were randomly assigned finasteride or placebo for seven years.
Slightly Lower Cancer Risk, Much Higher Killer Cancer Risk
The results were a surprise to the researchers, who found – as they expected – a lower rate of cancer in the finasteride group than in the placebo group (18.4% versus 24.4%). What surprised them was the considerably higher number of significantly aggressive cancers – for the technically inclined, higher Gleason scores – among those in the finasteride group with cancer versus those with cancer in the placebo group (37% versus 22.3%). That’s why you never saw a television commercial about finasteride preventing prostate cancer. To be accurate it would have to say, “Take finasteride! It lowers your risk of prostate cancer, but if you do get prostate cancer, you’re more likely to die of it!”
The PCPT researchers concluded, “finasteride prevents or delays the appearance of prostate cancer, but this possible benefit and a reduced risk of urinary problems must be weighed against sexual side effects and the increased risk of high-grade prostate cancer.” A separate meta-analysis published as a Cochrane Review found that 5a-reductase inhibitors, including finasteride, have inadequate evidence to say that these patent medicines reduce mortality, in terms of prostate cancer.
It’s true that if DHT alone is considered, elevated levels of DHT might be thought to increase your prostate cancer risk, as DHT is a procarcinogenic (for the technically inclined, dedifferentiating) meta¬bolite.
However, thanks to evolution and Nature has developed a natural way of counter acting the procarcinogenic effects of DHT! If we take the metabolites of DHT into consideration, too, elevated DHT may or may not have this effect. One of these metabolites may actually offset or even reduce any DHT-increased risk. How does that happen?
After testosterone is converted to DHT, DHT is in turn normally metabolized into a relatively smaller quantity of 5a-androstane-3a,17b-diol (abbreviated as 3a-Adiol), and a usually larger amount of 5a-androstane-3b,17b-diol (abbreviated as 3b-Adiol). These same researchers also report that while nearly all the 3a-Adiol is converted back to DHT (which presumably makes 3a-Adiol a “pre-procarcinogen”), the 3b-Adiol does not convert back to 5a-DHT. Very importantly, they report that 3b-Adiol is an anticarcinogen (for the technically inclined, a redifferentiating agent) that activates estrogen receptor beta, an anticarcinogenic estrogen receptor present in large numbers in the prostate gland.5 (Estrogen receptor beta is present in many other tissues in both sexes, but that’s a topic to be explored at another time.)
http://www.lmreview.com/images/sized/assets/images/article_images/testosterone_metabolism_flowchart_2-21-11-590x443.JPG

Here are some studies in support of the DHT metabolite 3Beta diol being a potent activator of Estrogen Receptor Beta.

5α-Androstane-3β,17β-diol (3β-diol), an estrogenic metabolite of 5α-dihydrotestosterone, is a potent modulator of estrogen receptor ERβ expression in the ventral prostrate of adult rats (http://www.sciencedirect.com/science/article/pii/S0039128X07001365)
An endocrine pathway in the prostate, ERβ, AR, 5α-androstane-3β,17β-diol, and CYP7B1, regulates prostate growth (http://www.pnas.org/content/99/21/13589.long)

Back to the original article on DHT’s effect on the prostate.


In a letter to the editor of the New England Journal of Medicine, Otabek Imamov, MD, et al. state, “[DHT] is the fulcrum in this balance. It suggests that finasteride, by blocking the conversion of testosterone to [DHT], inhibits the production of [3b-Adiol] thus suppressing [the anticarcinogenic activity of] ERb and preventing the [re]-differentiation of epithelium. This mechanism could account for the higher incidence of poorly differentiated tumors in the finasteride group in the Prostate Cancer Prevention Trial.”6
A review in the Biology of Reproduction Journal states, “We believe that a higher incidence of low-differentiated [more aggressive] tumors in the finasteride-treated arm observed in the PCPT is caused by altering the normal differentiation of prostatic epithelium in the environment lacking the natural ERb ligand – [3b-Adiol].”7
Research has found some very specific things that 3b-Adiol does to inhibit prostate cancer growth. According to the title of a 2005 research report: “The androgen derivative 5a-androstane-3b, 17b-diol [3b-Adiol] inhibits prostate cancer cell migration through activation of the estrogen receptor beta subtype.”8 Other researchers reported that “3b-Adiol not only inhibits PC3-Luc cell [a specific type of prostate cancer cell] migratory properties, but also induces a broader antitumor phenotype [type of cell] by decreasing the proliferation [growth] rate, increasing cell adhesion [cancer cells don’t “stick” as normal cells do] and reducing invasive capabilities in vitro.”9 But these researchers went beyond test-tubes to living mice, writing “In vivo, continuous administration of 3b-Adiol reduces growth of established tumors and counteracts metastasis formation when PC3-Luc cells are engrafted subcutaneously in nude mice or are injected into the prostate.”
The conclusion to this research article was very encouraging: “Since 3b-Adiol has no androgenic activity, and cannot be converted to androgenic compounds, the effects here described entail a novel potential application of this agent against human PC.”9 A novel potential application of 3b-Adiol, a totally natural human testosterone, against human prostate cancer! Where are the headlines? This article was published in 2010!
For the really technically inclined, here are several “mechanisms of action” of 3b-Adiol, all of which come from stimulation of estrogen receptor beta:
- repression of VEGF-A (vascular endothelial growth factor A) expression
- destabilization of HIF-1a (hypoxia-inducible factor 1a)
- reduction of “Snail1″ relocation from the cytoplasm to the nucleus of cancer cells

According to the researchers who published the above mechanisms of action, “… high Gleason grade cancers … exhibit significantly more HIF-1a and VEGF-A and Snail1 nuclear localization compared to low Gleason grade cancers.”


It appears VEGF expression is crucial for hair follicle anagen induction and maintenance as described by this study:


The murine hair follicle undergoes pronounced cyclic expansion and regression, leading to rapidly changing demands for its vascular support. Our study aimed to quantify the cyclic changes of perifollicular vascularization and to characterize the biological role of VEGF for hair growth, angiogenesis, and follicle cycling. We found a significant increase in perifollicular vascularization during the growth phase (anagen) of the hair cycle, followed by regression of angiogenic blood vessels during the involution (catagen) and the resting (telogen) phase. Perifollicular angiogenesis was temporally and spatially correlated with upregulation of VEGF mRNA expression by follicular keratinocytes of the outer root sheath, but not by dermal papilla cells. Transgenic overexpression of VEGF in outer root sheath keratinocytes of hair follicles strongly induced perifollicular vascularization, resulting in accelerated hair regrowth after depilation and in increased size of hair follicles and hair shafts. Conversely, systemic treatment with a neutralizing anti-VEGF antibody led to hair growth retardation and reduced hair follicle size. No effects of VEGF treatment or VEGF blockade were observed in mouse vibrissa organ cultures, which lack a functional vascular system. These results identify VEGF as a major mediator of hair follicle growth and cycling and provide the first direct evidence that improved follicle vascularization promotes hair growth and increases hair follicle and hair size.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC199257/


This shows that VEGF is crucial for hair follicle survival and a reduction in VEGF mediated angiogenesis (formation of new blood vessels to supply hair follicles) could prevent the transition from telogen to anagen.

Heres a study demonstrating the role of hif-1 in VEGF regulation:


Transcriptional Regulation Controls Angiogenesis in Hypoxia
One important HIF-1 function is to promote angiogenesis; HIF-1 directs migration of mature endothelial cells toward a hypoxic environment [2,5]. This is done via HIF-1 regulation of vascular endothelial growth factor (VEGF) transcription. VEGF is a major regulator of angiogenesis, which promotes endothelial cell migration toward a hypoxic area. During hypoxia, HIF-1 binds the regulatory region of the VEGF gene, inducing its transcription and initiating its expression [12,15,16]. Such endothelial cells ultimately help to form new blood vessels, supplying the given area with oxygenated blood [14].
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2140184/
Androgens actually enhances the expression of HIF-1 via Androgen Receptor mediated signalling which explains the procarcinogenic effect of androgens in prostate cancer:
http://www.ncbi.nlm.nih.gov/pubmed/24035332

Androgens stimulate hypoxia-inducible factor 1 activation via autocrine loop of tyrosine kinase receptor/phosphatidylinositol 3'-kinase/protein kinase B in prostate cancer cells. (http://www.ncbi.nlm.nih.gov/pubmed/12855613)
Dihydrotestosterone (DHT) activates HIF-1alpha nuclear protein expression in LNCaP cells but not in androgen receptor-negative PC-3 cells. HIF-1alpha expression is correlated with the transactivation of a hypoxia-responsive element-driven reporter gene and with the production of VEGF protein. The effect of DHT on HIF-1 was blocked by nonsteroidal antiandrogens, flutamide and bicalutamide. DHT does not affect HIF-1alpha mRNA levels but regulates HIF-1alpha protein expression through a translation-dependent pathway. PC-3 cells when incubated with increasing amounts of conditioned medium from LNCaP cells treated with DHT experienced a dose-dependent increase in HIF-1alpha. This induction was not seen either when LNCaP cells were treated with flutamide or conditioned medium were pretreated with antibody to the epidermal growth factor (EGF). HIF-1 activation by DHT was blocked by LY294002, a potent inhibitor of the phosphatidylinositol 3'-kinase signaling pathway, whereas HIF-1 activation by EGF, as ligand, was not inhibited by flutamide. In contrast, HIF-2alpha protein was not affected by androgens or antiandrogens.
This could explain the vellus to terminal transition of follicles all over the body in males, especially facial hair. We can conclude from this that it is indeed possible for vellus hair follicles to become terminal given the right environmental conditions (local growth promoting agents) and time. Males require a significant number of years of exposure to androgens to develop thick facial and body hair.
Evolution could be responsible for this DHT driven inhibition of androgen's procarcinogenic effects i.e the males with higher androgens were physically and mentally (androgen increases grey matter/spatial ability) stronger but were also susceptible to early cancer related deaths, so the males that ended up surviving were the ones that had the AR related edge and developed a feedback loop that canceled out the negative effects of androgens. Some of these biological feedback loops have been refined over thousands of years an as a result have become increasingly complex due to natural selection (survival of the fittest/most adaptable).
This is all interesting with regards to the prostate but what about the scalp?
First lets take a look at how exactly 3 beta diol is synthesized.

5α-Androstane-3β,17β-diol, also called 3β-androstanediol, and often shortened to 3β-diol, is an endogenous steroid hormone. It is a 5α-reduced and 17β-hydroxylated metabolite of dehydroepiandrosterone (DHEA) as well as a 3β-hydroxylated metabolite of dihydrotestosterone (DHT). Similarly to DHEA, 3β-diol is a high-affinity full agonist of the ERβ, and hence, an estrogen.
https://en.wikipedia.org/wiki/5%CE%B1-Androstane-3%CE%B2,17%CE%B2-diol

3 beta diol can be synthesized from either DHEA or DHT via the respective enzymes. An important bit of information to note is that both 3 beta diol and DHEA activate ERbeta.

Regional scalp differences of the androgenic metabolic pattern in subjects affected by male pattern baldness. (http://www.ncbi.nlm.nih.gov/pubmed/2091154)
Regional differences in the androgen metabolism were established in alopecic and non alopecic areas of patients affected by male pattern baldness (MPB). 5-alpha-reductase (5-alpha-R) activity was measured by the formation of dihydrotestosterone (DHT), using 3H-testosterone as substrate: this activity was higher in the alopecic areas (3.4 pmol/g tissue/h) than in the non alopecic skin (1.5 pmol/g tissue/h). 3-alpha,beta-hydroxysteroid oxoreductase (3-alpha, beta-HO) was studied using 3H-DHT as precursor and measuring the corresponding formed 3-alpha- and 3-beta-androstanediols (alpha DIOL and beta DIOL). The beta DIOL was the predominant metabolite and total 3-alpha, beta-HO activity was higher in alopecic skin (12.4 pmol/g tissue/h) than in non alopecic areas (8.4 pmol/g tissue/h). Also 17, beta-hydroxysteroid oxoreductase was measured using either testosterone or DHT as substrates: androstenedione formed from testosterone was higher in hairy skin (12 pmol/g tissue/h) than in alopecic areas (6 pmol/g tissue/h); androstanedione formed from DHT was also higher in non alopecic areas (8.1 pmol/g tissue/h) than in alopecic skin (2.8 pmol/g tissue/h). The greater formation of beta DIOL in the sebaceous glands-enriched alopecic skin supports the hypothesis for a specific role of this metabolite in the control of the sebaceous activity.

This study is incredibly crucial to understanding the regional differences in Androgen metabolism and how the hairline is affected the most. We know that 5ar is elevated in balding regions but furthermore, the enzymes responsible for catalyzing the conversion of DHT to 3beta diol are also elevated in alopecic regions, whereas the enzymes responsible for synthesizing anrostanedione were higher in non alopecic regions.

When I read this I immediately recalled a compound that is commonly used for treating Androgenetic Alopecia: Ketoconazole (nizoral).
Ketoconazole is actually a really effective inhibitor of androgen synthesis, and a weak inhibitor of Androgen receptor.


In vitro inhibition by ketoconazole of human testicular steroid oxidoreductases. (http://www.ncbi.nlm.nih.gov/pubmed/2214784)
An oral antimycotic agent, ketoconazole has been demonstrated to be an inhibitor of cytochrome P-450-dependent monooxygenases. To investigate its effect on steroid oxidoreductases, in vitro studies were carried out using subcellular fractions of human testes. Ketoconazole competitively inhibited activities of 3 beta-hydroxy-5-ene-steroid oxidoreductase/isomerase and NADH-linked 20 alpha-hydroxysteroid oxidoreductase for steroid substrate and the Ki values were 2.9 and 0.9 microM, respectively. In contrast, ketoconazole inhibited neither 17 beta-hydroxysteroid oxidoreductase nor NADPH-linked 20 alpha-hydroxysteroid oxidoreductase, indicating that the two 20 alpha-hydroxysteroid oxidoreductases are distinct. Further, ketoconazole inhibited non-competitively the above enzyme activities for the corresponding cofactors of NAD and NADH. From the binding mode of ketoconazole to cytochrome P-450 and the present findings, it appears likely that the agent binds to a site which is different from that of steroids or pyridine nucleotides.
3 beta-hydroxy-5-ene-steroid oxidoreductase = 3 beta HSD (https://en.wikipedia.org/wiki/3-beta-HSD#Nomenclature)

Hydroxylation of 5 alpha-androstane-3 beta,17 beta-diol by rat prostate microsomes: potent inhibition by imidazole-type antimycotic drugs and lack of inhibition by steroid 5 alpha-reductase inhibitors. (http://www.ncbi.nlm.nih.gov/pubmed/1632630)
5 alpha-Dihydrotestosterone, the principal androgen mediating prostate growth and function in the rat, is formed from testosterone by steroid 5 alpha-reductase. The inactivation of 5 alpha-dihydrotestosterone involves reversible reduction to 5 alpha-androstane-3 beta,17 beta-diol by 3 beta-hydroxysteroid oxidoreductase followed by 6 alpha-, 7 alpha-, or 7 beta-hydroxylation. 5 alpha-Androstane-3 beta,17 beta-diol hydroxylation represents the ultimate inactivation step of dihydrotestosterone in rat prostate and is apparently catalyzed by a single, high-affinity (Km approximately 0.5 microM) microsomal cytochrome P450 enzyme. The present studies were designed to determine if 5 alpha-androstane-3 beta,17 beta-diol hydroxylation by rat prostate microsomes is inhibited by agents that are known inhibitors of androgen-metabolizing enzymes. Inhibitors of steroid 5 alpha-reductase (4-azasteroid analogs; 10 microM) or inhibitors of 3 beta-hydroxysteroid oxidoreductase (trilostane, azastene, and cyanoketone; 10 microM) had no appreciable effect on the 6 alpha-, 7 alpha-, or 7 beta-hydroxylation of 5 alpha-androstane-3 beta,17 beta-diol (10 microM) by rat prostate microsomes. Imidazole-type antimycotic drugs (ketoconazole, clotrimazole, and miconazole; 0.1-10 microM) all markedly inhibited 5 alpha-androstane-3 beta,17 beta-diol hydroxylation in a concentration-dependent manner, whereas triazole-type antimycotic drugs (fluconazole and itraconazole; 0.1-10 microM) had no inhibitory effect. The rank order of inhibitory potency of the imidazole-type antimycotic drugs was miconazole greater than clotrimazole greater than ketoconazole. In the case of clotrimazole, the inhibition was shown to be competitive in nature, with a Ki of 0.03 microM. The imidazole-type antimycotic drugs inhibited all three pathways of 5 alpha-androstane-3 beta,17 beta-diol hydroxylation to the same extent[B], which provides further evidence that, in rat prostate microsomes, a single cytochrome P450 enzyme catalyzes the 6 alpha-, 7 alpha-, and 7 beta-hydroxylation of 5 alpha-androstane-3 beta,17 beta-diol. These studies demonstrate that certain imidazole-type compounds are [B]potent, competitive inhibitors of 5 alpha-androstane-3 beta,17 beta-diol hydroxylation by rat prostate microsomes, which is consistent with the effect of these antimycotic drugs on cytochrome P450 enzymes involved in the metabolism of other androgens and steroids.

So for clarification:

Ketoconazole/miconzole inhibit 3 Beta HSD
3 beta HSD converts DHT to 3beta diol.
3beta diol activates ERbeta.
ERbeta destabilizes HIF-1 and results in loss of VEGF expression.
Hair follicles fail to enter anagen due to lack of bood supply.
This is a potential explanation of the mechanism behind ketoconazoles hair growth/hair loss prevention effects.

I also wanted to talk a bit about PGD2. Specifically it’s metabolite:



15-dPGJ2 and PGD2 inhibit hair growth in mouse and human hair follicles
Given the temporal peak of PGD2 before the apoptotic catagen stage, the published ability of its metabolite 15-dPGJ2 to induce apoptosis in other cell types, we tested the effects of the prostaglandins on primary cell culture of keratinocytes isolated from neonatal foreskin. 15-dPGJ2 induces apoptosis (fig. S2A), as evidenced by plasma membrane blebbing and cell retraction/shrinkage. 15-dPGJ2 also decreased cell density, cell division, and live-cell numbers (fig. S2, B to D). Perhaps because the origin of these keratinocytes was not the hair follicle, PGD2 had no such effect on the cells. However, 15-dPGJ2 did increase sub-G1 DNA quantities and activated caspase 3 in human keratinocytes, which are features of apoptotic cell death (fig. S2, E to G). We therefore hypothesized that at least 15-dPGJ2, if not also PGD2, could directly inhibit hair growth in vivo.
15-dPGJ2 was applied topically to dorsal back skin of C57BL/6 mice that had been depilated to synchronize the hair follicle cycle. Starting on day 8 after depilation and continuing every other day, we applied 10 μg of 15-dPGJ2 or acetone vehicle. Hair length was measured on days 4, 12, 14, and 16 after depilation. On days 12 to 16, hair at the site of treatment was shorter than in vehicle-treated animals (Fig. 6A). To determine a minimal effective dose, we tested the application of 1 μg of both PGD2 and 15-dPGJ2 as above and measured hair length on day 20 after depilation. PGD2 inhibited hair growth, but to a lesser extent than 15-dPGJ2 (Fig. 6B). We found no evidence of changes in hair follicle cycling grossly or by histologic examination.


http://i64.tinypic.com/ou1t8w.jpg (http://www.spandidos-publications.com/article_images/etm/1/2/ETM-01-02-0257-g00.jpg)

http://www.spandidos-publications.com/etm/1/2/257

I’m still doing research on this by product of PGD2 as it may hold more relevance than PGD2 itself.

Another very crucial effect of DHT is the elevation Dickkopf-1 (DKK1).


Dihydrotestosterone-inducible dickkopf 1 from balding dermal papilla cells causes apoptosis in follicular keratinocytes.
Abstract
Recent studies suggest that androgen-driven alteration to the autocrine and paracrine factors produced by scalp dermal papilla (DP) cells may be a key to androgen-potentiated balding. Here, we screened dihydrotestosterone (DHT)-regulated genes in balding DP cells and found that dickkopf 1 (DKK-1) is one of the most upregulated genes. DKK-1 messenger RNA is upregulated in 3-6 hours after 50-100 nM DHT treatment and ELISA showed that DKK-1 is secreted from DP cells in response to DHT. A co-culture system using outer root sheath (ORS) keratinocytes and DP cells showed that DHT inhibits the growth of ORS cells, and neutralizing antibody against DKK-1 significantly reversed the growth inhibition of ORS cells. Analysis of co-cultured ORS cells showed a significant increment of sub-G1 apoptotic cells in response to DHT. Also, recombinant human DKK-1 inhibited the growth of ORS cells and triggered apoptotic cell death. In addition, DHT-induced epithelial cell death in cultured hair follicles was reversed by neutralizing DKK-1 antibody. Moreover, immunoblotting showed that the DKK-1 level is up in the bald scalp compared with the haired scalp of patients with androgenetic alopecia. Altogether, our data strongly suggest that DHT-inducible DKK-1 is involved in DHT-driven balding.

So how exactly does dkk1 work?


DKK1 is a high affinity antagonistic ligand for LRP6, which is a Wnt coreceptor that acts together with the Frizzled serpentine receptor to initiate Wnt signal transduction. Two different models have been proposed to account for the mechanism by which DKK1 antagonizes LRP6 function. One model suggests that DKK1 binding to LRP6 disrupts Wnt-induced Frizzled-LRP6 complex formation, whereas the other model proposes that DKK1 interaction with LRP6 promotes LRP6 internalization and degradation, thereby reducing the cell surface LRP6 level.


Lets take a look at the importance of LRP6.

http://www.nature.com/nrm/journal/v13/n1/images/nrm3244-f2.jpg



WNT - Canonical pathway
The canonical Wnt pathway (or Wnt/β-catenin pathway) is the Wnt pathway that causes an accumulation of β-catenin in the cytoplasm and its eventual translocation into the nucleus to act as a transcriptional coactivator of transcription factors that belong to the TCF/LEF family. Without Wnt signaling, the β-catenin would not accumulate in the cytoplasm since a destruction complex would normally degrade it. This destruction complex includes the following proteins: Axin, adenomatosis polyposis coli (APC), protein phosphatase 2A (PP2A), glycogen synthase kinase 3 (GSK3) and casein kinase 1α (CK1α).[14] It degrades β-catenin by targeting it forubiquitination, which subsequently sends it to the proteasome to be digested.[11][15] However, as soon as Wnt binds Fz and LRP5/6, the destruction complex function becomes disrupted. This is due to Wnt causing the translocation of the negative Wnt regulator, Axin, and the destruction complex to the plasma membrane.Phosphorylation by other proteins in the destruction complex subsequently binds Axin to the cytoplasmic tail of LRP5/6. Axin becomes de-phosphorylated and its stability and levels are decreased. Dsh then becomes activated via phosphorylation and its DIX and PDZ domains inhibit the GSK3 activity of the destruction complex. This allows β-catenin to accumulate and localize to the nucleus and subsequently induce a cellular response via gene transduction alongside the TCF/LEF (T-cell factor/lymphoid enhancing factor)[16]transcription factors.[15]


So without LRP6, the canonical WNT pathway cannot be activated. This means Beta Catenin will be degraded by GSK3.
It’s very clear that without Beta Catenin hair will not form:



Further analysis demonstrates that β-catenin is essential for fate decisions of skin stem cells: in the absence of β-catenin, stem cells fail to differentiate into follicular keratinocytes, but instead adopt an epidermal fate.

The real question is how does DHT actually increase DKK1? This is something that I’ve been struggling to figure out. Finding an effective and feasible way to prevent the increase of DKK1 as a result of DHT may allow us to focus our attention away from DHT inhibitors, and also allow other hair promoting agents to work better (although even without agonists the body’s natural wnt proteins can have a chance to bind to the LRP6 and do their job).

I’ve come across mainly dead ends and no studies to date actually document how Dkk1 is regulated.

http://www.nature.com/jid/journal/v128/n2/full/5700999a.html

We know that L-ascorbic acid 2-phosphate and L-threonate, an ascorbate metabolite inhibits DHT induced DKK-1.
Dkk-1 is also induced by p53: http://www.ncbi.nlm.nih.gov/pubmed/10777218

DHT increases p53 and p21 significantly: http://www.ncbi.nlm.nih.gov/pubmed/22859066
This is a weak connection at best.

Other possible links include:
http://carcin.oxfordjournals.org/content/28/9/1877.full.pdf



The Wnt antagonist DICKKOPF-1 gene is induced by 1a,25-dihydroxyvitamin D3
The Wnt–b-catenin pathway is aberrantly activated in most colon cancers. DICKKOPF-1 (DKK-1) gene encodes an extracellular Wnt inhibitor that blocks the formation of signalling receptor complexes at the plasma membrane. We report that 1a,25- dihydroxyvitamin D3 [1,25(OH)2D3], the most active vitamin D metabolite, increases the level of DKK-1 RNA and protein in human SW480-ADH colon cancer cells. This effect is dose dependent, slow and depends on the presence of a transcription-competent nuclear vitamin D receptor (VDR). Accordingly, 1,25(OH)2D3 activates a 2300 bp fragment of the human DKK-1 gene promoter. Chromatin immunoprecipitation assays revealed that 1,25(OH)2D3 treatment induced a pattern of histone modifications which is compatible with transcriptionally active chromatin. Exogenous expression of E-cadherin into SW480-ADH cells results in a strong adhesive phenotype and a 17-fold increase in DKK-1 RNA. In contrast, an E-cadherin blocking antibody inhibits 1,25(OH)2D3-induced differentiation of SW480-ADH cells and DKK-1 gene expression. Remarkably, in vivo treatment with the vitamin D analogue EB1089 induced DKK-1 protein expression in SW480-ADH cells xenografted in immunodeficient mice, and a correlation was observed in the expression of VDR and DKK-1 RNA in a series of 32 human colorectal tumours. These data indicate that 1,25(OH)2D3 activates the transcription of the DKK-1 gene, probably in an indirect way that is associated to the promotion of a differentiated phenotype. DKK-1 gene induction constitutes a novel mechanism of inhibition of Wnt signalling and antitumour action by 1,25(OH)2D3.


It appears VDR (Vitamin D receptor) mediates DKK-1 protein expression in the presence of E cadherin by binding to a promoter region on Dkk1 gene.
Furthermore, DHT has been shown to upregulate VDR via - wait for it – ERBeta!



Sex steroids induced up-regulation of 1,25-(OH)2 vitamin D3 receptors in T 47D breast cancer cells.

Abstract
There is evidence indicating that 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] through binding to its specific receptor (VDR) exerts an antiproliferative effect on breast cancer cells. Considering the importance of receptor regulation in modulating the target cell responsiveness to hormones, the effect of dihydrotestosterone (DHT) and estradiol-17 beta (E2) on the regulation of VDR number was investigated in T 47D human breast cancer cells that also express androgen and estrogen (ER) receptors. Exposure to 10(-7) M DHT for 72 h resulted in a significant increase in VDR levels. Similar results were obtained with 10(-7) M E2. DHT- and E2-induced up-regulation was completely suppressed by 10(-6) M tamoxifen (TAM) addition but unaffected by 10(-6) M flutamide. TAM treatment alone produced a significant dose-dependent increase in VDR content, that was maximal at 10(-6) M. Our data strongly suggest, for the first time, an up-regulation of VDR by DHT and E2 via an ER-mediated mechanism.


Although this study’s focus is on breast cancer cells, it’s still points us in the right direction.

Vitamin D has been shown to have a biphasic effect on hair growth:



http://www.ncbi.nlm.nih.gov/pubmed/8077696
At higher concentrations of 1,25(OH)2D3, there was a dose-dependent inhibition of both follicle and fiber growth (IC50 values of 100 nM), in part due to reduction in the growth periods. There was a marked delay between the onset of 1,25(OH)2D-induced hair follicle and hair fiber growth inhibition.


This exactly inline with the oxford study:



Time-course and dose-curve experiments showed that 1,25(OH)2D3 (107 M) caused a slow 3- to 5-fold induction of DKK-1 RNA at 24–48 h upon treatment. The effect of 1,25(OH)2D3 was specific, as several hormones (dexamethasone, retinoic acid, progesterone and oestradiol) acting through members of the superfamily of nuclear receptors similar to VDR did not induce DKK-1. The induction of DKK-1 was confirmed at the protein level and in another colon cancer cell line. Immunofluorescence studies confirmed the increase in DKK-1 protein expression following 1,25(OH)2D3 exposure and showed its preferential localization in the cell periphery, Golgi apparatus and vesicles of the exocytic route. These results confirmed that 1,25(OH)2D3 induces DKK-1 expression with slow kinetics, which precluded the use of translation inhibitors such as cycloheximide to investigate whether the induction is direct or indirect.


So to conclude, it’s quite apparent there are a multitude of factors involved in the prognosis of MBP, but certain pathways have been overlooked which I believe has stagnated potential progress.

I strongly believe that inhibiting DKK-1 or reducing it will enable other treatments to work far more effectively, along with mitigating the detrimental effects of downstream DHT pathways i.e the actual effect instead of the overall mediator. The answer lies in the details, we must fully understand the mechanisms – the how and why before trying to exploit the pathway for our own gain. This is the key to hacking and efficient problem solving, you find the weakest link and plan your attack on that.
In the next post I will discuss therapeutic applications of these findings and some experiments I’ve been conducting (with interesting results), after all, what good is theory without application?

bananana
11-22-2015, 12:38 PM
Very interesting, I found some wiki pages that confirm your theory...

I got ONE QUESTION:

DKK-1 - How do we kill it?

Chemical
11-23-2015, 12:32 PM
Very interesting, I found some wiki pages that confirm your theory...

I got ONE QUESTION:

DKK-1 - How do we kill it?


This is the million dollar question.

One way is to inhibit DHT, but that is a difficult task especially using topical agents.

Another is l-threonate/ascorbate derivatives.



We recently reported that DHT inhibits the growth of co-cultured ORS keratinocytes using this in vitro co-culture system and demonstrated that the growth suppression is largely due to DKK-1 (11). Consistent with this, the growth of cocultured ORS cells was significantly suppressed in the presence of 100 nM DHT. Since L-threonate repressed DHT-induced DKK-1 expression, we investigated whether or not L-threonate attenuates DHT-induced growth suppression of co-cultured keratinocytes. We indeed observed that L-threonate reversed the DHT-induced growth inhibition of co-cultured keratinocytes. In summary, our data demonstrates that L-threonate repressed DHT-induced DKK-1 expression in cultured DPCs and attenuated DHT-induced growth inhibition of co-cultured keratinocytes. Although further investigation is needed to elucidate the mechanism of L-threonate-mediated repression of DHT induced DKK-1 expression, our data in this study strongly suggest that L-threonate has an inhibitory effect on androgen-driven balding (Fig. 4).

L threonate or Ascorbate derivatives but they do not last long or work effectively as topical treatments. (I also havent seen any supporting evidence)

Another way could be completely inhibiting Estrogen Receptor Beta to prevent the DHT -> VDR -> DKK-1 pathway with topical tamoxifen which has a moderately long tissue half life (7 days when applied topically to breast tissue), there currently isnt any topical available but it shouldnt be too hard to make a formulation. The study used off the shelf inregredients to make their own topical - I'll have to dig it out if anyones interested as it could combat all the negative effects of DHT if it works, including:

-stabilizing HIF-1 alpha, disinhibiting VEGF, and inhibiting DKK1.

Here's some more evidence on why DKK1 is of the main culprits:



The neutralizing antibody against DKK-1 reverses the DHT-induced cell death in cultured hair follicles
To further investigate the role of DHT-inducible DKK-1 in hair growth, we employed a hair-follicle organ culture system (Philpott et al., 1994). Significant cell death was observed in epithelial cells surrounding DP in response to 100 nm DHT compared with control follicles (Figure 6a and b). The neutralizing antibody against DKK-1 reversed the DHT-induced cell death in epithelial cells (Figure 6c), demonstrating that the cell death is due largely to DKK-1.

DKK-1 level is up in the balding scalp compared with the haired scalp of patients with AGA
To strengthen the argument that our in vitro observations translate to a significant role for DKK-1 in AGA, we examined DKK-1 expression in balding and non-balding scalp of patients. Immunoblots showed a strong band around 35 kDa from balding scalp, whereas we observed a weak signal from non-balding scalp (Figure 7). This result clearly shows that DKK-1 is upregulated in the balding scalp compared with the haired scalp of patients with AGA.


However, a working, and readily available supplement that moderately inhibits DKK1 and enhances a myriad of other growth factors is: oleuropein. I'll be making an in-depth post on oleuropein this weekend, how it works, supporting evidence, and results of my own experiments with this compound in a topical formulation (very very exciting results).

BaldingEagle
11-23-2015, 01:30 PM
Quality post.

Thanks for taking the time. Very interesting theory.

bananana
11-23-2015, 02:41 PM
Sounds good, oleuropein is basically extract of olive leaf?

Seems a bit farfetched because I see bunch of ORAL supplements selling on ebay, so probably a lot of people using them already,
and no remarks of hair growth... Or you think it should be applied topically?

regards

tiktok
11-23-2015, 03:07 PM
Solid work so far!
I'm partial the idea that heightened estrogen levels are a likely cause of propecia not working for some people (couples sometimes with a burning/flushed scalp, another symptom of elevated estrogen), and your research seems to back this up.

Regarding topical Tamoxifen, Afimoxifene (4-hydroxytamoxifen) looks like a great candidate as it works topically and doesn't seem to increase much in serum (http://clincancerres.aacrjournals.org/content/20/14/3672.abstract).

burtandernie
11-24-2015, 08:45 PM
Yeah good work with piecing all that together but its a bit over my head. How do you put this to practical use? How do you stop DKK-1?
The complexity of all this is what makes me not want to try propecia. I really never liked the idea of screwing this big complicated system up, but what choice do you have. Nothing else seems to work

jamesst11
11-24-2015, 08:48 PM
Yeah good work with piecing all that together but its a bit over my head. How do you put this to practical use? How do you stop DKK-1?
The complexity of all this is what makes me not want to try propecia. I really never liked the idea of screwing this big complicated system up, but what choice do you have. Nothing else seems to work

You don't... this is a nice regurgitation, and a lot of effort and that's awesome but molecular biologists have been trying to sort this out for years. when we are 60, perhaps they will have a solution.

Magster
11-25-2015, 09:49 PM
Looking forward to your experiments with topical oleuropein, Chemical. I am interested in doing similar.

Chemical
11-29-2015, 11:08 AM
In this post I’ll be describing the effects of Oleuropein on hair follicles and just how awesome this herb is.
I’ll start off with the main study which luckily is a free pubmed article:

Topical Application of Oleuropein Induces Anagen Hair Growth in Telogen Mouse Skin (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4462586/)

I’m not going to bother with the cliffs, we’re going to look at the findings in depth because that’s where the devil lives.



Recently, we observed that oleuropein reduced body weight gain and visceral adiposity in high-fat diet (HFD)-fed mice. The protective effect of oleuropein against HFD-induced adiposity in mice appeared to be mediated through the upregulation of genes involved in Wnt10b-mediated signaling cascades [11]. In the present study we investigated whether oleuropein could induce anagenic hair growth in C57BL/6N mice and explored the underlying mechanism.


What does WNT10b do?



Here, we showed that in response to prolonged ectopic Wnt10b-mediated β-catenin activation, regenerating anagen hair follicles grew larger in size. In particular, the hair bulb, dermal papilla and hair shaft became enlarged, while the formation of different hair types was unaffected. Interestingly, we found that the effect of exogenous WNT10b was mainly on Zigzag and less on the other kinds of hairs. We observed dramatically enhanced proliferation within the matrix, DP and hair shaft of the enlarged AdWnt10b-treated hair follicles compared with those of normal hair follicles at P98. Furthermore, expression of CD34, a specific hair stem cell marker, was increased in its number to the bulge region after AdWnt10b treatment. Ectopic expression of CD34 throughout the ORS region was also observed. Many CD34-positive hair stem cells were actively proliferating in AdWnt10b-induced hair follicles. Importantly, subsequent co-treatment with the Wnt inhibitor, DKK1, reduced hair follicle enlargement and decreased proliferation and ectopic localization of hair stem cells. Moreover, injection of DKK1 during early anagen significantly reduced the width of prospective hairs. Together, these findings strongly suggest that Wnt10b/DKK1 can modulate hair follicle size during hair regeneration.

http://www.ncbi.nlm.nih.gov/pubmed/24750467


We have our first evidence that oleuropein has the potential to significantly stimulate hair growth in the absence of DKK1.



We investigated the effect of oleuropein on the proliferation of DPCs. DPCs were treated with various concentrations of oleuropein (10, 20, and 50 μM), and cell proliferation after day 5 was assessed by using an MTT assay and trypan blue exclusion assay. Outcomes from trypan blue assay were highly consistent with that from MTT assay (Fig 1B). Treatment with oleuropein significantly increased DPC proliferation relative to untreated controls (Fig 1). The highest degree of proliferation was achieved using 20 μM oleuropein. The effect of 20 μM oleuropein on increasing cell proliferation was significantly higher than that of minoxidil at 100 μM.


http://i65.tinypic.com/nx6vdd.jpg

Strangely the optimal concentration that achieved the highest percentage of cells with increased proliferation was 20um, instead of the 50um, perhaps theres a biphasic effect? Or maybe a statistical/extraneous anomaly because the two concentrations have similar efficacy. I’ll come back to this.



To investigate whether oleuropein modulates the Wnt/β-catenin pathway in DPCs, we examined the expression of nuclear β-catenin by western blotting analysis. As shown in Fig 2A, the protein level of nuclear β-catenin was significantly increased in oleuropein-treated DPCs (a 212% increase) compared with control cells treated with dimethyl sulfoxide (DMSO). Cells treated with oleuropein for 24 h were evaluated for expression of Wnt/β-catenin signaling target genes by using RT-PCR. We found that compared with control cells treated with DMSO, cells treated with oleuropein showed significantly increased expression of LEF1 (P = 0.0027) and Cyc-D1 (P = 0.0034) (Fig 2C). In addition, cells treated with oleuropein showed significantly increased nuclear accumulation of β-catenin and mRNA expression of LEF1 and Cyc-D1 relative to those treated with minoxidil.


(Cyc d1 is an indicator of cell cycle progression and correlates with proliferation)
Oleuropein increases BetaCatenin which as we know is a very good thing.



To determine whether oleuropein promoted hair growth, we measured the length of 10 hairs plucked from the dorsal skin center area of each mouse at 0, 7, 14, 21, and 28 days. As shown in Fig 3B, the hairs in the oleuropein-treated group were significantly longer than those in the control group. Moreover, the hairs in the oleuropein-treated group were observed to be longer than those in the minoxidil-treated group.
---
In the representative longitudinal sections, the number and size of hair follicles were significantly increased in the oleuropein-treated group compared to the control group (Fig 4). In addition, the number and size of hair follicles in the oleuropein-treated group were significantly greater than those of minoxidil-treated group.

The hairs were physically longer than the tried and proven minoxidil! And there were more follicles in anagen (up from telogen). I’m curious as to what concentration of minoxidil they used and if using higher concentration would’ve yielded better results.



Mice treated with oleuropein exhibited a significant increase in the mRNA levels of IGF-1 (P = 0.0008), hepatocyte growth factor (HGF, P = 0.0021), vascular endothelial growth factor (VEGF, P = 0.0062), and keratocyte growth factor (KGF, P = 0.0052) in their skin tissues compared with mice treated with vehicle (Fig 5A). The effect of oleuropein on increasing mRNA levels of these growth factors was significantly greater than that of minoxidil. ELISA analysis revealed that dermal IGF-1 levels were significantly increased in mice treated with oleuropein (71% increase) compared with mice treated with vehicle only (Fig 5B). The oleuropein-treated mice demonstrated significant increases in dermal IGF-1 level and immunohistochemical expression compared with control mice (Fig 5B and 5C).



http://i64.tinypic.com/2d7irgi.jpg

Oleuropein somehow manages to increase IGF1 (by a lot) and VEGF too. This study (http://www.ncbi.nlm.nih.gov/pubmed/25860333) shows that oleuropein can increase VEGF via WNT10b, however I’m not sure how IGF-1 was elevated. The figure clearly shows just how much these growth factors are elevated, but I’m surprised minoxidil didn’t come anywhere near close enough to oleuropein in increasing VEGF.



DPC incubated with increasing minoxidil concentrations (0.2, 2, 6, 12 and 24 mumol/L) induced a dose-dependent expression of VEGF mRNA. Quantification of transcripts showed that DPC stimulated with 24 mumol/L minoxidil express six times more VEGF mRNA than controls. Similarly, VEGF protein production increases in cell extracts and conditioned media following minoxidil stimulation. These studies strongly support the likely involvement of minoxidil in the development of dermal papilla vascularization via a stimulation of VEGF expression, and support the hypothesis that minoxidil has a physiological role in maintaining a good vascularization of hair follicles in androgenetic alopecia.


The oleuropein study used 3mg of minoxidil – not sure howthat translates to mumol, maybe someone an help?


and the minoxidil group received vehicle containing 3 mg of minoxidil.

Anyways, now comes the best part:



Mice treated with oleuropein exhibited a significant increase in the mRNA levels of WNT10b (P = 0.0045), LRP5 (P = 0.0004), FZDR1 (P = 0.0123), and the Wnt-responsive transcription factor LEF1 (P = 0.0142), along with its target genes, such as Cyc-D1 (P = 0.009), in their skin tissues compared with mice treated with the control vehicle (Fig 6A). In addition, oleuropein-treated mice showed a significant decrease in the mRNA level of DKK1 (P = 0.0003) in their skin tissues compared with control vehicle-treated mice. The oleuropein-treated mice showed significant increases in the mRNA levels of Wnt signaling-related genes (Wnt10b, LRP5, FZDR1, LEF1, and Cyc-D1) relative to minoxidil-treated mice. This effect of oleuropein on increasing protein levels of β-catenin in hair follicles was greater than that of minoxidil.


http://i66.tinypic.com/9ghws0.jpg

THIS IS THE ****ING HOLY GRAIL. The rare SYNERGY. When you decrease an inhibitory protein and boost an agonist protein you achieve synergy, where 2 + 2 does not equal 4 (additive) but rather 7. You can see that DKK1 was reduced from control levels. They did not elucidate the actual pathway but if oleuropein targets the gene expression or transcription then this could mean DHT can no longer exert its effects on the hair follicle via DKK1. I am still trying to figure out how this inhibition works because I don’t like believing studies that do not have supporting evidence from other sources. If someone can assist with research I’d be very very grateful.
Lets talk about the dosages and how it translates to human doses.



Based on our preliminary study involving different oleuropein dosages (0.4 to 3.0 mg/mous), 0.4 mg of oleuropein per mouse was found to be the minimal effective dose for anagen hair induction in C57BL/6N mice.


0.4mg as in 10um? Or 20um? probably 20 as the minimum EFFECTIVE dose. 3mg might have resulted in diminishing returns since they didn’t see dose dependant growth. I believe theres a plateau of diminishing returns and oleuropein isn’t biphasic but that’s still open to debate.



Each mouse received 200 μL of the reagent applied topically with a plastic spatula to the shaved dorsal skin daily for 28 days. The control group received vehicle alone, the oleuropein group received vehicle containing 0.4 mg of oleuropein, and the minoxidil group received vehicle containing 3 mg of minoxidil. All reagents used for the hair growth test were dissolved in a vehicle composed of 50% (v/v) ethanol, 30% water, and 20% propylene glycol.


Nothing fancy here, just your standard 50% ethanol, water and propylene glycol. Which means anyone can make an oleuropein vehicle very cheaply. Heck, you could even dissolve it in minoxidil (which is what I’ve been doing).
To conclude the study:



Li et al. reported that Wnt10b could induce the biological switch of hair follicles from the telogenic phase to the anagenic phase in mouse skin [31]. In addition, they showed that siRNA suppression of β-catenin inhibited hair follicle regeneration, even when Wnt10b was overexpressed [31]. Recently, Choi et al. reported that β-catenin-deleted and DKK1-expressing hair follicles showed greatly diminished expression of Cyc-D1, a direct Wnt/β-catenin target gene that helps initiate the transition from late G1 to S phase of the cell cycle, likely contributing to decreased hair follicle matrix proliferation [32]. In the present study, in parallel to the significant upregulation of Wnt10b, LRP5, FZDR1, β-catenin, LEF1, and Cyc-D1, a prominent decrease of DKK1 levels was observed in skin tissue of oleuropein-treated mice compared with the control group. On the basis of these results, we propose that oleuropein may cause premature entry of telogenic follicles into the anagen phase via activation of the Wnt10b/β-catenin signaling pathway.

------

Imagine what would happen if we combined Minoxidil with this.
A decrease in DKK1 -> more LRP6 available to bind -> the body's natural WNTs can finally work.
Oleuropeins WNT10b upregulation -> increased IGF-1, VEGF, KGF -> BetaCatenin
An increase in VEGF both from oleuropein AND Minoxidil -> more blood vessels to hair follicle, which as I’ve discussed in my first post, leads to increased hair follicle size and growth.
A ridiculous amount of beta catenin from oleuropein and minoxidil combined – does anyone see where I’m going with this?

Thats the agonist side covered, and not to forget:

ketoconazole and miconazole nitrate for 3 beta HSD suppression -> less DHT converted to 3 Beta diol – which is a potent ERBeta agonist -> disinhibition of VEGF pathways and stabilization of HIF-1.
Throw in topical saw palmetto just for safe measure and you’ve got yourself a serious stack.

Bringing me to the part that is most important.
My experiments. First a little bit about myself:

My hairline started receding when I was 17 because I stupidly decided to mess with anabolic steroids (which is where I got my biology knowledge). I used emu oil, and nizoral but didn’t touch minoxidil or fin, saw a slight improvement but nothing significant. My father started receding at 30, so I’ve definitely got the genes and would’ve receded eventually even if I hadn’t messed around with my androgens.

I became a NW2 at 18, after using letrozole to boost testosterone to suraphysical levels not realizing it would **** up my hairline. I started using seakelp bioferment, microneedling, emu oil, folligen, and some other supplements. Saw slight improvements but nothing too great.

Then I became a NW3 at 19 when I had the worst shed of my life after a car accident. I was in icu for 2 months and the stress really destroyed my hair. I used emu oil, folligen and microneedling but still wasn’t seeing any significant growth.
Fast forward this year april. I was desperate. So I took the plunge. I decided to go on fin, minoxidil (everyday), and ketoconazole cream (everyday). I used emu oil religiously to help with absorption. 2 months in and I saw great regrowth, increased density and I became a NW2.2 ish.
I took the fin every 3 days because I didn’t want it to affect my pregnenolone levels too much (I’ve got anxiety and fin ED made it worse). I stopped after the 2 month mark. I incorporated iodine into te minoxidil thinking it would help. didn’t do shit. Kept using minoxidil mixed with emu oil with minor improvements in hair density and decreased shedding.

August 2015, I started putting the pieces together and I had a few breakthroughs in terms of research.

Bought myself Oleuropein capsules from amazon (extra strength), and mixed it with minoxidil. I had one bottle left so I dissolved like 5 capsules into the liquid and gave it a good shake. I also added a few saw palmetto capsules which I regret because it did not dissolve at all. I let it sit for 24 hour then shook it again.
I then used the dropper to mix around 10ml into my emu oil dispenser which was half full (25ml). And that was my treatment. I used it most nights but it was a real pain to keep looking at the ceiling to prevent it from pouring down my forehead. In the morning it would all be absorbed thanks to the minoxidil but there’d be a few remnants of the undissolved saw palmetto and the oleuropein.

Every week I kept adding more drops of the minoxidil (with the dissolved oleuropein and saw) because I wanted to see what would happen. I also used ketoconazole cream 2% (Janssen pharma) twice a day non stop because it was easy to apply.

6 weeks in and I could feel stubble, small prickly hairs. I was ****ing ecstatic. My existing hairs became thicker especially the vertex area, and shedding stopped – (almost completely) but I was still skeptical, I thought it must’ve been a delayed reaction to minoxidil and ketoconazole. My frontal hairline grew a few hairs initially because that’s where I was using it the most, but I wanted to see if this solution actually did anything so I started using it only on my left side and tilting my head to the right to make it pour down to the other side and the backwards to reach the rest of my scalp.
I regret not taking enough pictures before starting although I wasn’t really planning to share this until I genuinely saw an improvement. I’ve got a few shitty pictures taken with a potato before the regimen:

43348

( 6 weeks into the regimen):

43349

43350

The left side was the same as the first pic before the regimen:

43351

43352

The past few weeks I’ve been really busy with work and have only been using the solution heavily on the weekends (3-5 times a day) to make up for not using it on the weekdays. I've been feeling more stubble, mainly on the left side, and thicker vertex hair. I also got carried away with the oleuropein and now the solution leaves a hard residue after drying so I’ve had to buy more minoxidil and emu oil which should be here this week. I ran out of ketoconazole also so I’ll be starting a proper log with decent pictures now that I’ve got a better phone.

I'll be posting more recent pics tomorrow.

I would strongly recommend people get some ketoconazole in cream form and maybe miconazole too to apply everyday, as often as possible. The reason being, testosterone is always present in the blood, which means DHT is being converted all the time by the hair follicles. You need to keep the hair follicles saturated with antagonists and agonists to keep them from being slowly killed by DKK1/DHT. Agonists like minoxidil and your body's own WNT proteins WILL NOT work if DKK1 has internalized the LRP6 receptors.

I'd also suggest people not to take finasteride systematically because the body will naturally increase testosterone to offset the negative feedback loop, and since finasteride only inhibits ~60%, that increase in testosterone will give 5AR additional substrate to convert into DHT, defeating the whole purpose of fin. I'd like to see people try this with RU as an augmentation, since theoretically there should be less DKK1 as a result of impaired AR signalling.

Sorry for the long read.

karxxx
11-29-2015, 12:20 PM
hi Chemical
What is your diet?
How to apply with us?
thanks...

Ulti1
11-29-2015, 12:27 PM
Great stuff man!

Few questions:

Where do you get your miconzole nitrate? And can I mix it into ru/neo.

Which brand of oleuropeim do you use on amazon?

Seuxin
11-29-2015, 12:51 PM
Hello,

I use miconazole once a day since 5 months...no result at all !
I use Nizoral (Ketoconazole) 2%, twice a week, and Stemoxydine, Adenosine, Zinc Sulphate.

All this since 5 month, no result !

I just added fin !

Using ketoconazole, even as a cream is not dangerous once a day???

bornthisway
11-29-2015, 01:42 PM
Why 5 caps, and not say 10 into a bottle of minox? Would more capsules being dissolved into the mix yield greater effects or is there a point of diminishing return / maximum number of caps that can be dissolved into your standard minox bottle (60 ml)?

Dench57
11-30-2015, 05:05 AM
Very nice post. Thanks for the info.

Chemical
11-30-2015, 12:08 PM
hi Chemical
What is your diet?
How to apply with us?
thanks...

I eat junk food. And I take calcium + 10,000iu weekdays, L-theanine, and tryptophan supplements. Diets cant really fight androgenetic alopecia imo.


Great stuff man!

Few questions:

Where do you get your miconzole nitrate? And can I mix it into ru/neo.

Which brand of oleuropeim do you use on amazon?

I recently bought daktarin 2% which has miconazole nitrate, cant wait to start using it alongside keto.

I use swansons superior herbs 750mg oleuropein capsules (http://www.amazon.co.uk/Swanson-Superior-Extract-Strength-Capsules/dp/B0056Z7IMC/ref=sr_1_1?ie=UTF8&qid=1448908308&sr=8-1&keywords=oleuropein)

thats the highest dose I could find. And it was the most cost effective.

Mix the oleuropein and keto/mico wih ru/neo? I wouldnnt recommend it solely because I like to use creams by themselves and wait a few minutes before using the emu oil solution. It just appears to absorb better that way.


Hello,

I use miconazole once a day since 5 months...no result at all !
I use Nizoral (Ketoconazole) 2%, twice a week, and Stemoxydine, Adenosine, Zinc Sulphate.

All this since 5 month, no result !

I just added fin !

Using ketoconazole, even as a cream is not dangerous once a day???

I would scrap the stemoxydine, I've seen zero studies regarding it and I get the feeling its a snake oil marketed by a big brand which somehow makes it legit. Keep the adenosine, not sure bout the zinc.

You've probably got DHT and DKK1 preventing the WNTs from working, if you dont inhibit the antagonists the agonists will most probably have little effect.

I've no reason to believe ketoconazole is detrimental in cream form, the shampoo on the other hand may be an irritant hence why people recommend 3 days a week max.


Why 5 caps, and not say 10 into a bottle of minox? Would more capsules being dissolved into the mix yield greater effects or is there a point of diminishing return / maximum number of caps that can be dissolved into your standard minox bottle (60 ml)?

the caps I bought were 750mg, and I had 60ml of minoxidil. 0.4mg is what the study used, so 3750 seemed like alot. I was also curious to see if there really was a biphasic effect (little being more). And the oleuropein wasnt dissolving completely so I guessed it was saturated enough. I did however keep adding 2-3 capsules every week, with most of the powder just clumping up at the bottom.

43361

I've noticed the most regrowth in the green regions, especially in the region circled because thats where I use the regimen the most. I use the emu oil solution mainly there and tilt my head to the otherside so it reaches the other areas. The dotted black regions are thickening up slowly although I've not been diligent in these areas for the past few weeks hence my slow progress.

For those of you that have missed the analysis, its at the bottom of page 1: here (https://www.baldtruthtalk.com/threads/22104-Updated-Research-and-Knowledge-Cutting-Edge?p=224344&viewfull=1#post224344)

Chemical
12-01-2015, 01:10 PM
@Chemical

Thank you. See where I'm heading at though? Let's hypothetically assume that these factors are indeed deeply implicated in AGA. How does one work around that? Direct modulation of these factors for instance is something you can't really do I guess due to very serious safety concerns. I find it also interesting that 17b-estradiol can regrow hair to great extent sometimes but not always. I have seen pictures of people that have regrown a very big amount of hair due to being on anti-androgen therapy + estrogen. I think Cotsarelis puts this nicely again;

When you look at what estrogen actions are on the hair follicle it's quite broad; http://press.endocrine.org/doi/full/10.1210/er.2006-0020. Awesome study in relation to estrogen and the hair follicle. Some targets seem to be the likes of Cyclin D1, AP-1 (c-fos , c-jun proto-oncogenes), SHH, WNT's etc.

Does something stand out for you there? It does for me. All these targets of estrogen seem to be factors that control cell proliferation positively. And to no surprise estrogen is classified as a carcinogen and formulations of estrogen have a black box warning; http://www.cancer.org/cancer/cancercauses/othercarcinogens/generalinformationaboutcarcinogens/known-and-probable-human-carcinogens.

When we look at AP1 for example induction of it can repress (antagonize) other factors like P53, P16 , P21 etc;

And all these factors P53, pRB, P21 etc. seem to act negatively on cell proliferation generally. Studies that I have shown that show these factors to be implicated in AGA.

Now there is way more to read upon these pathways how they interact with each other obviously. So this begs the question how do we fix this problem? Well I can only think that you can guinea pig yourself and start modulating these factors directly. But as one can imagine that would be incredibly dangerous due to obvious reasons.

To finish it off here are some examples where estrogen has regrown hair;

And there are more cases. On another forum a transgender also is regrowing hair from NW5 to NW2. Doesn't happen always but it can happen. Estrogen is obviously no option though for any men ;). It's interesting nonetheless I guess. Perhaps you might find something.


Yes! I was planning to make another in depth post on estrogen receptor signalling and the effects on hair growth (specifically in males).

I'm so glad you found that article because it concisely sums up alot of the research that are scattered around the internet.

First of all, Estrogen acts through two receptors, ER alpha and ER beta. These receptors have different roles - sometimes even contradictory, depending on the tissue localisation and agonist binding affinity. Estrogen is not the only hormone that bind to these receptors, there can be other agents with much higher binding affinities and much much powerful activation. 3 Beta Diol can activate ER beta and it is way more potent than Estrogen itself. 3Beta Diol is actually a DHT derivative, in males, since we have less Estrogen floating around, the body has developed alternative ways of activating ER beta.

One clear frustration when analyzing the biochemichal pathways of Estrogen is the massive discrepancy f ER mediated pathways between genders and species. In females, ER beta in the hair follicles has a completely different distribution to males, and actually inhibits hair growth. The same in male mice. ER alpha inhibits hair growth and ER beta silences ER alpha.




The wide distribution of ERβ in human pilosebaceous unit suggests that estrogens play an important role in the maintenance and the regulation of the hair follicle and provides further evidence for estrogen action in nonclassic target tissues. Recently, it was reported that in cultured dermal papilla cells from nonbalding male donors, both ERα and ERβ showed a consistently higher expression, both at the RNA and protein levels, in occiput dermal papilla cells compared with vertex dermal papilla cells (258). With respect to ERβ immunoreactivity, we found that, in anagen VI follicles microdissected from frontotemporal skin, there was a remarkable distribution difference between male and female hair follicles from frontotemporal scalp skin: ERβ immunoreactivity was found in male scalp hair follicles predominantly in the matrix keratinocytes, whereas in female hair follicles, ERβ immunoreactivity was predominantly found in the dermal papilla fibroblasts (10). These data not only highlight substantial, previously underappreciated sex-dependent differences in ERβ expression of an important peripheral E2 target organ, but also underscore the importance of investigating whether E2 effects on the human hair follicle are location-dependent, as is well-recognized for the paradoxical hair growth effects of androgens (64, 259, 260).
Conflicting data have been presented concerning ER expression patterns in murine hair follicles. It has been reported that ERα was expressed only in the dermal papilla and outer root sheath of telogen and early anagen mouse hair follicles and that ERβ was undetectable (26, 250). Recently, however, we could show that both ERα and ERβ as well as the splice variant ERβ ins are expressed throughout the entire, depilation-induced murine hair cycle at both the protein and RNA levels (28). In addition, hair follicles in late anagen (anagen VI) were highly sensitive to regulation by topically applied E2, which rapidly induced premature catagen entry. Therefore, anagen VI mouse pelage hair follicles must express fully functional ERs (28).
ERα immunoreactivity peaks in murine telogen follicles within the dermal papilla and the sebaceous gland, whereas the inner root sheath and outer root sheath show weaker immunoreactivity. In anagen VI, ERα immunoreactivity (IR) is detectable in the outer root sheath and the dermal papilla, whereas in early catagen it is restricted to the dermal papilla and the secondary hair germ. In anagen VI follicles, ERβ is weakly positive in hair matrix and outer root sheath, whereas in catagen and telogen follicles, ERβ is expressed in the dermal papilla, inner root sheath, outer root sheath, and the sebaceous gland. By RT-PCR, ERα and ERβ transcripts can be detected in telogen, anagen V and VI, and late catagen skin mRNA extracts. Investigation of ERβ knockout mice showed an accelerated catagen development along with an increase in the number of apoptotic hair follicle keratinocytes (28). Taken together, this suggests that the catagen-promoting properties of E2 in murine skin are mediated by ERα and that ERβ mainly functions as a silencer of ERα action in murine hair biology. (An additional list on reported expression of estrogen signaling components is provided in Table 2).


In males, Estrogen - I'm struggling to find any evidence of which receptor specifically - actually stimulates significant hairshaft elongation in a time dependant manner:

Estrogens and Human Scalp Hair Growth—Still More Questions than Answers (http://www.nature.com/jid/journal/v122/n3/full/5602254a.html)

This study found further discrepancies in In-Vitro and In-Vivo effects of ER Beta:



We found only two corresponding reports in the published literature, one using human anagen hair follicles from an unspecified scalp skin location of what appears to be two male individuals aged 17 and 35 y (Kondo et al, 1990), and one recent meeting abstract based on the use of female occipital scalp skin follicles (Nelson et al, 2003). Both studies report that E2 (Kondo et al: 18 nM; Nelson et al: 10 nM), significantly inhibits human scalp hair shaft elongation in vitro.

Here theyre saying E2 inhibted hair in-vitro. This only adds to the confusion. They also did a study themselves on female hair:



Recently, we have also studied the effects of E2 (1 nM–1 muM, Sigma St. Louis, MO) on female occipital scalp hair follicles, and have essentially confirmed hair shaft elongation-inhibitory properties of E2, which were maximal at 1 muM

In females, Estrogen inhibits hair growth.

Then theres this:



Therefore, we have investigated in a single, large, frontotemporal scalp skin sample (healthy male individual, no medications, 46 y; how E2 addition to the medium (1–100 nM, Sigma, diluted in serum-free William's E medium, supplemented with l-glutamine, penicillin, streptomycin, insulin, and hydrocortisone) affected hair shaft elongation, anagen duration, hair follicle pigmentation and hair matrix keratinocyte proliferation in microdissected, organ-cultured male anagen VI hair follicles from the frontotemporal scalp skin region.

Surprisingly, compared to the vehicle control, the hair shaft elongation of male frontotemporal scalp hair follicles was significantly stimulated by 1–100 nM E2 already as early as 1 d after the start of organ culture, and this stimulation became even more pronounced at the end of organ culture (days 7 and 9) Figure 1. This stimulation of hair shaft formation (which is the result of stringently coordinated proliferation and differentiation of hair matrix keratinocytes (Stenn and Paus, 2001) corresponded to a significant stimulation of hair matrix keratinocyte proliferation by 10 nM E2 at day 9 (average number of Ki-positive-cells: in the control group 14 cells (SEM 3.21) and 26 cells in the E2-treated (10 nM) group (SEM 4.38); level of significance: pless than or equal to0.05, Mann–Whitney test). While no evident differences were noted by H&E or Fontana–Masson histochemistry between E2- and vehicle-treated hair follicles in the hair follicle pigmentary unit or in the degree of hair follicle degeneration during organ culture (data not shown), a slight, though not statistically significant, anagen-prolonging effect of E2 was seen in E2-treated test hair follicles as compared to vehicle controls (data not shown).

There was a time dependant increase in hair follicle growth in frontotemporal hair follicles in 46 year old male, I presume with a full head of hair.

The question is, how does estrogen do this? Since there are no clear studies outlining which receptor mediates the hair growth promoting effects of Estrogen in males, nor are there any consistent animal studies with similar receptor actions, we are left to deduce.

ER beta is known to inhibit Hif-1 and VEGF as a means of counteracting the pro-carcinogenic effects of androgens on the prostate, which Ivee covered in more detail in my first post. And the prostate is more closely related to the scalp than female scalp tissue or mice skin. furthermore, this study (http://www.impactjournals.com/oncotarget/index.php?journal=oncotarget&page=article&op=view&path%5B%5D=2820) shows how ER alpha enhances prostate cancer cell proliferation:



ABSTRACT

While high doses of estrogen, in combination with androgens, can initiate prostate cancer (PCa) via activation of the estrogen receptor α (ERα), the role of ERα in PCa cells within established tumors is largely unknown. Here we show that expression of ERα is increased in high grade human PCa. Similarly, ERα is elevated in mouse models of aggressive PCa driven by MYC overexpression or deletion of PTEN. Within the prostate of PTEN-deficient mice, there is a progressive pattern of ERα expression: low in benign glands, moderate in tumors within the dorsal, lateral and ventral lobes, and high in tumors within the anterior prostate. This expression significantly correlates with the proliferation marker Ki67. Furthermore, in vitro knockdown of ERα in cells derived from PTEN-deficient tumors causes a significant and sustained decrease in proliferation. Depletion of ERα also reduces the activity of the PI3K and MAPK pathways, both downstream targets of non-genomic ERα action. Finally, ERα knockdown reduces the levels of the MYC protein and lowers the sensitivity of cellular proliferation to glucose withdrawal, which correlates with decreased expression of the glucose transporter GLUT1. Collectively, these results demonstrate that ERα orchestrates proliferation and metabolism to promote the neoplastic growth of PCa cells.

There are studies talking briefly about the interaction between ER alpha and IGF-1R including upregulation, which the anabolic steroid stanozolol activates to increase muscle IGF1 levels.

This brings me back to the theory of using topical tamoxifen, which is a ER alpha agonist and ER beta antagonist. DHT seems to activate ER beta in the prostate via the 3Beta Diol metabolite and 3beta Diol is elevated in balding scalp as a result of increased 3 Beta HSD (which ketoconazole inhibits).

Topical tamoxifen has been shown to have minimal systematic absorbtion if used in doses up to 1mg with similar efficiency in blocking ER beta and activating ER alpha as higher doses.

There is also the theory that Estrogen receptors interact with Androgen metabolism (suppressing their activity), but I havent seen any significant links.

Trouse5858
12-01-2015, 03:49 PM
I find the bit about estrogen receptors to be particularly interesting. I'm currently taking a SERM to reduce the effects of gyno I got after taking RU for several months. It's 30 mg of Raloxifene, said to be stronger than tamoxifen, that I am taking now every other day. It's not topical but I'll certainly try to keep my eye on any noticeable results, as unlikely as they are.

baldybald
12-02-2015, 01:23 AM
This guy knows what he is talking about,won't be surprised if he got a cure for baldness!

Medium
12-02-2015, 10:40 AM
Do you think that it's possible to mix the oleuropein capsules into castor oil instead of minox?

Chemical
12-02-2015, 01:11 PM
I find the bit about estrogen receptors to be particularly interesting. I'm currently taking a SERM to reduce the effects of gyno I got after taking RU for several months. It's 30 mg of Raloxifene, said to be stronger than tamoxifen, that I am taking now every other day. It's not topical but I'll certainly try to keep my eye on any noticeable results, as unlikely as they are.

You probably wont notice any hair growth since any agonistic activity of raloxifene on ERa will be negated by DKK1 that is strongly induced by DHT. I'm more interested in seeing you use oleuropein with raloxifene since that'll address both ends of spectrum, and I plan to mix tamoxifen with a separate minox bottle to test out this theory in the next two weeks or so.


This guy knows what he is talking about,won't be surprised if he got a cure for baldness!

Why thank you baldybald, but I believe a cure can be found if we work together, combining our knowledge and trying novel approaches instead of just waiting for these big drug companies to give us false hope. These companies are just people motivated by money, with their time and resources they should be trying to figure out how the complex biomechanics work (like DKK1 and how it' actually induced or that there are might be other factors like 3Beta-Diol inhibiting hair follicle blood vessel formation) instead of blindly trying to create single compounds that will miraculously cure baldness in a vaccuum. The human body isn't black and white, its not just a few simple interactions either, its ridiculously complex with feedback loops designed to adapt and requires an approach that will tackle all the factors. "Igf-1 increases hair growth - lets spend millions trying to create compound that can deliver igf-1 to hair follicles, it worked in-vivo and in-vitro, so it will definitely work if we put in the necessary R&D". Its a system that can be exploited if you're brave enough to take calculated risks. Just my 2 cents that I'd wanted to share.


Do you think that it's possible to mix the oleuropein capsules into castor oil instead of minox?

I tried that, it did not go well. You end up with oleuropein still in its powder form and when the oil dries up it leaves a hard residue of oleuropein that is a nightmare, especially since I recommend applying the solution as often as possible to keep tissue concentrations high. You want the oleuropein to dissolve as much as possible so it can be carried through the skin layers by emu oil. Emu oil also helps with imflammation allowing you to use keto/mico and minox without irritation. I also dissolved saw palmetto, not sure if that actually did anything.

And here are some more recent pictures of my hairline. I've noticed alot less stubble since I stopped using it everyday (I'm just waiting for minoxidil to come through to make a new 3 month batch).

2 weeks ago:

43388

You can see my most recent pictures here: http://imgur.com/a/g6TdQ

Medium
12-02-2015, 01:16 PM
Great,
Thanks for the response.
My only concern is that I don't want to get on minox, so would dissolving the oleuropein capsules in emu oil still be effective?

tiktok
12-02-2015, 06:24 PM
I plan on trying to use http://www.nowfoods.com/Olive-Leaf-Glycerite-18-percent-Vegetarian-2oz.htm with emu oil.

Swooping
12-03-2015, 10:21 AM
Chemical thanks :). I’ll get in on this discussion on a later point (busy atm). But here is what I think about androgenetic alopecia (AGA) as a whole. Hopefully it can help you.

First of all AGA is androgen and AR dependent right (Androgens > AR)? This begs the question; Why does AR activation lead to hair loss?
Well we don’t know, but to simplify it I would just like to call that AR activation causes cellular stress in AGA.

We can already maintain hair simply by castration. So we know that castration removes the “stress” right? So is it really beneficial for us to search for other “stress” factors beside the AR? One could argue it is because of possible better therapies that could give someone maintenance of their hair state. For instance let’s assume hypothetically that pathway “X” is implicated after AR activation in AGA. This would make the pathway chain; Androgens > AR > X. So if that was the case we could modulate X too and provide someone with maintenance of hair just like removing the AR would provide or castration does. Perhaps modulation of X would be something better because of a better side effect profile. This is exactly what Kythera (Cotsarelis) their hypothesis is made of. Instead of X however they argue that PGD2 functions highly upstream after AR activation and this leads to hair loss. So in their hypothesis modulation of PGD2 should work too (I don't think that is even the case but we will see.).

However will that bring back our hair? No right? I mean castration doesn't do it either. That is why I think in terms of reversal of AGA it’s less important to understand what causes the damage but rather what happens because of the damage. So let’s assume it is Androgens > AR > X. That causes the damage or “stress”. But what happens in response to that ? I have showed you the studies that points out to rather major pathways that seem to be implicated in AGA. And the thing is they seem to be implicated in stress responses like ROS and DNA damage. In this sense we can perhaps broaden the damage factor to DNA damage or ROS. So because of what happens in AGA these pathways react to the damage and this can be for example DNA damage or ROS. To make a example one might argue that Androgens > AR causes DNA damage and because of the DNA damage pathways come into action that react to this cellular stress.

Really I believe it all originates from the dermal papilla cells too. They are the master cells of the hair follicle. Dermal papilla numbers correlate with hair follicle size. A decline of dermal papilla is seen in AGA as the hair follicle continues to miniaturize. Several studies have pointed this out. Not only that we know that in bald scalp we lack progenitor cells. Well guess what? The dermal papilla regulates these progenitor cells. So if the dermal papilla cells get stressed and altered it could easily lead to a lack of progenitors. Studies have pointed out that the dermal papilla regulates progenitors as recently confirmed again by a abstract on the hair congress;


Getting It Right: Coordinating Progenitors and Their Niche to Specify Hair Size and Structure

ABSTRACT: The size and shape of the hair shaft is dependent on the number and activity of hair progenitor cells, which is in turn dependent on the number and activity of the dermal papilla cells that comprise their niche

http://s24.postimg.org/6tvb31g3p/thinning.jpg

Anyway back to the original point again. I have shown you the papers that point out the evidence of the pathways that seem to be implicated in AGA . And as you can see it is these pathways, exactly these pathways that react to cellular stress. I would like to simply call AGA cellular stress. Then they decide what action to take with a cell. Is it apoptosis? Is it senescence? Is it cell cycle arrest? Is it repair? What action is taken in AGA that leads to a miniaturized hair follicle? It might be even a combination for instance there might be a wave of apoptosis first before cell cycle arrest or senescence. For instance as seen here in a animal model;

http://s22.postimg.org/iojfxcpu9/senescne6.jpg


“Activation of P14, but not of P16, also caused a rapid but transient wave of apoptosis prior to the generation of senescent cells”.

As you can see it displays the multi-facetted role these pathways can take upon this stress and the several actions they can take."

What sort of stress or damage is it furthermore in AGA? Is it ROS or DNA damage? Maybe something else. I guess we don’t understand the specifics details yet. In my opinion the picture is becoming clear though. To no wonder, more and more researchers and studies are starting to point out in the same direction.

Finally here are some related pictures that go with this all.

Senescence (note how they mention that it causes SASP (inflammatory response, would explain the inflammation in AGA and also how they mention that it may not only affect differentiated cells but also stem and progenitor and limit the regenerative capacity of tissues):

http://s1.postimg.org/ywbmxp03z/senescence.jpg
http://s9.postimg.org/jwsl5d5wf/senes.jpg

Cell cycle (arrest):

http://www.pathophys.org/wp-content/uploads/2012/10/Cell-cycle-copy.jpg

Swooping
12-03-2015, 10:44 AM
Forgot this one. Shows some pathways that are implicated in senescence due to different stress causes (DNA damage, ROS etc.);

http://s27.postimg.org/yjmacf0fn/senescc.jpg

Chemical
12-03-2015, 02:31 PM
Great,
Thanks for the response.
My only concern is that I don't want to get on minox, so would dissolving the oleuropein capsules in emu oil still be effective?

I'm terribly sorry, I had a feeling you wanted to avoid minoxidil altogether, in which case you can make vehicle to dissolve the oleuropein with the following:



50% (v/v) ethanol, 30% water, and 20% propylene glycol.


You really need to dissolve the oleuropein so that it gets absorbed effectively.


I plan on trying to use http://www.nowfoods.com/Olive-Leaf-Glycerite-18-percent-Vegetarian-2oz.htm with emu oil.

The oleuropein extract would be ideal, and I wouldnt encourage anything else. You need the extract, not the leaf. Theres not a whole lot of brands out there that make oleuropein in extract form. Its a pain but it's worth it imo.


You probably wont notice any hair growth since any agonistic activity of raloxifene on ERa will be negated by DKK1 that is strongly induced by DHT. I'm more interested in seeing you use oleuropein with raloxifene since that'll address both ends of spectrum, and I plan to mix tamoxifen with a separate minox bottle to test out this theory in the next two weeks or so.



I'd also like to add that SERMs are especially useful for increasing testosterone by negating the negative feedback loop of estrogen on the pituitary, thus increasing LH and subsequently testosterone. More testosterone = more DHT and more DKK1. This is why its also important to have a serm that acts locally vith little systematic absorbtion, and raloxifene is very very potent stuff, along with tamox.

@Swooping

It seems you're a better researcher than me. This community needs more people like yourself.

Those diagrams are excellent. And I like your philosophy of targeting the root cause instead of damage control.

I'll keep this brief and to the point but I'll expand later.

Like you've pointed out, the DPC control the Mesenchymal stem cells, possibly by HGF/c-met, WNTs, and IGF1 which acts as a pro-survival cytokine. In short, if the DPC need to grow hair, they will signal to the progenitor cells to maintain their pluripotency. They stop growing, the progenitor no longer needs to be kept pluripotent and they may start to differentiate. This could explain why its hard for nw5s to grow back hair without aggressive treatment. However, these stem cells can be reactivated with consistent agonist activity and stimulation from IGF-1, EGF, or HGF/KGF. The AR is the cause of all of this. But I've given on this avenue because its notoriously difficult to inhibit AR locally and feasibly.

The pathways that induce senescence are not exactly a switch, they're actually on all the time. Its when they start winning the tug of war that bad stuff happens, like aging and hair loss. I'm also aware that ROS activates P53 and from the diagram it appears p16 and p21 too. I posted a study on my first post about L-threonate an Ascorbic Acid derivative abolishing the inhibitory effect of DHT-induced DKK1, where L-threonate completely prevented the growth inhibition. DHT is known to increase P53, and this study (http://www.ncbi.nlm.nih.gov/pubmed/24658017) I found after a quick search does confirm the hypothesis that Androgens do increase reactive oxygen species generation (mitochondria dependant pathway in that study). ROS is a clear mediator of cellular apoptosis and senescence.



In aerobic organisms the energy needed to fuel biological functions is produced in the mitochondria via the electron transport chain. In addition to energy, reactive oxygen species (ROS) with the potential to cause cellular damage are produced. ROS can damage DNA, RNA, and proteins, which, in theory, contributes to the physiology of ageing.

ROS are produced as a normal product of cellular metabolism. In particular, one major contributor to oxidative damage is hydrogen peroxide (H2O2), which is converted from superoxide that leaks from the mitochondria. Catalase and superoxide dismutase ameliorate the damaging effects of hydrogen peroxide and superoxide, respectively, by converting these compounds into oxygen and hydrogen peroxide (which is later converted to water), resulting in the production of benign molecules. However, this conversion is not 100% efficient, and residual peroxides persist in the cell. While ROS are produced as a product of normal cellular functioning, excessive amounts can cause deleterious effects.[14] Memory capabilities decline with age, evident in human degenerative diseases such as Alzheimer's disease, which is accompanied by an accumulation of oxidative damage. Current studies demonstrate that the accumulation of ROS can decrease an organism's fitness because oxidative damage is a contributor to senescence.



And guess what, Ascorbic Acid and its derivates are known to be powerful ROS scavengers. So perhaps we need an effective ROS scavenger. The other tumor suppressor proteins could be ignored since we cannot and shouldnt trying to eliminate them, but preventing ROS generation will most definitely reduce the amount of DNA damage cause by androgens.

I'd like to hear your thoughts on this too.

Trouse5858
12-03-2015, 08:46 PM
@ Chemical you're obviously very well informed on a lot of these topics. I was wondering if I could get your opinion on taking Raloxifene. I read somewhere that it can have a detrimental effect on libido, even though at the same time it is raising testosterone production. I was wondering if you could shed any light on this whatsoever. I may be feeling this side effect right now but it could also be a placebo..any insight on safe dosages or long term implications for men? Thanks

Chemical
12-04-2015, 11:39 AM
@ Chemical you're obviously very well informed on a lot of these topics. I was wondering if I could get your opinion on taking Raloxifene. I read somewhere that it can have a detrimental effect on libido, even though at the same time it is raising testosterone production. I was wondering if you could shed any light on this whatsoever. I may be feeling this side effect right now but it could also be a placebo..any insight on safe dosages or long term implications for men? Thanks

Libido actually heavily depends on estrogen converted from testosterone via aromatase. The brain is quite sensitive to estrogen receptor changes, and among the steroid users who use ralox or tamox or even letro like I did, some notice a sharp decline in libido/sex drive, and a select few not so much. Its not a placebo effect if you're feeling it, but its short term so as soon as you stop you'll be fine. It also reduces sperm count temporarily. As for dosages, Ralox has a 27 hr half life, you're better off taking it everyday to reduce the gyno quicker, and you'll be able to come off it sooner. Its good for your HDL levels and unlike letro it wont **** up your bone mineral density so you dont have to be extra cautious when using it for more than 2 months, and I'd say its the best SERM out there to treat gyno.

TheKingofFighters
12-04-2015, 12:29 PM
Libido actually heavily depends on estrogen converted from testosterone via aromatase. The brain is quite sensitive to estrogen receptor changes, and among the steroid users who use ralox or tamox or even letro like I did, some notice a sharp decline in libido/sex drive, and a select few not so much. Its not a placebo effect if you're feeling it, but its short term so as soon as you stop you'll be fine. It also reduces sperm count temporarily. As for dosages, Ralox has a 27 hr half life, you're better off taking it everyday to reduce the gyno quicker, and you'll be able to come off it sooner. Its good for your HDL levels and unlike letro it wont **** up your bone mineral density so you dont have to be extra cautious when using it for more than 2 months, and I'd say its the best SERM out there to treat gyno.

Wow thx for ur hard work! Can u check profile? Would oleupein help me in activating stem cells? Im using minoxidil but it has only grown some tiny baby hairs thst nv seem to terminal. Would oleupein turn them terminal?

Trouse5858
12-04-2015, 04:44 PM
Yeah that was an even more in depth answer than I was anticipating, I appreciate the information.

tiktok
12-04-2015, 08:33 PM
The oleuropein extract would be ideal, and I wouldnt encourage anything else. You need the extract, not the leaf. Theres not a whole lot of brands out there that make oleuropein in extract form. Its a pain but it's worth it imo.


It's a standardized extract without all the filler of other pills, so less chance of precipitate - seems ideal.

karxxx
12-05-2015, 12:24 AM
hi Chemical

What , medicine, please can I use ?
Oleuropein into the liquid mixture containing minoxidil ?
How oleuro mg daily pill ?
Additional additives ?finastreid,avodard,peptipe...?

Chemical
12-05-2015, 12:34 AM
I just clicked the link and saw that it is standardised extract. It's perfect. And it's in frickin liquid form! Next time I'll reply when I'm sober - sorry about that.

@medium

If you can get your hands on the liquid form or a ready made tincture, you can mix it with emu oil instead of buying ethanol + propylene glycol.

Medium
12-07-2015, 08:26 AM
Thanks, Chemical.
I'll definitely get this solution. I can take it emu oil works much better than castor oil for dissolving the stuff?

potato1987
12-07-2015, 10:41 AM
Can someone explain in simple terms what this product might achieve?

Chemical
12-07-2015, 12:10 PM
hi Chemical

What , medicine, please can I use ?
Oleuropein into the liquid mixture containing minoxidil ?
How oleuro mg daily pill ?
Additional additives ?finastreid,avodard,peptipe...?

Oleuropein mixed into the liquid minoxidil solution. Only the liquid.
No oral oleuropein. Emu oil mixed with the oleuropein + minoxidil helps the minoxidil absorb better and is easier to apply. I'd avoid finasteride and any other drugs/medication for hair loss. Unless of course you know what youre doing and want to experiment.


Thanks, Chemical.
I'll definitely get this solution. I can take it emu oil works much better than castor oil for dissolving the stuff?

Emu oil doesnt help for dissolving but does supposedly permeate the skin better and acts as a carrier/vehicle. Its also an anti-inflammatory/(mild 5ar inhibitor?) which means you can stack it with ketoconazole/mico if you're using them frequently.


Can someone explain in simple terms what this product might achieve?

This helps you regrow hair if you're lucky.
It works by reducing DKK1. DKK1 prevents your hair from growing. And it increases growth factors like IGF-1, KGF, HGF and BetaCatenin. I wouldnt recommend this stack for beginners as it does require you to mix stuff.

update:

I've officially stopped the treatment since two weeks ago because I cant be bothered to wash my hair everytime I use the mixture. It dries up into a semi hair wax consistency that is a pain to wash out. I also got my miconazole nitrate a week ago, which I've been using 3 time a day, toothpaste sized amounts, and I've noticed my left side where I've been concentrating the regimen is seeing a dozen or so stubble follicles. When I touch that area its like I'm touching my beard.

This could be a residual effect of the treatment or it could be mico, I cant tell. If it is the mico then the theory that Estrogen Receptor inhibiting hair growth is plausible and tamoxifen will definitely work. This warrants further investigation. I'm still waiting for my minox, which is taking ages to arrive. I'm going to dissolve only 2 oleuropein capsules in the minox this time around and I'll try that for a month straight just to see if there really is a biphasic effect. Last time I got carried away thinking more was better.

InBeforeTheCure
12-07-2015, 03:26 PM
This may interest you.


Hair follicles have characteristic sizes corresponding to their cycle specific stage. However, how the anagen hair follicle specifies its size remains elusive. Here, we show that in response to prolonged ectopic Wnt10b-mediated β-catenin activation, regenerating anagen hair follicles grow larger in size. In particular, the hair bulb, dermal papilla and hair shaft become enlarged. While the formation of different hair types (Guard, Awl, Auchene, and Zigzag) is unaffected. Interestingly, we found the effect of exogenous WNT10b was mainly on Zigzag and less on the other kinds of hairs. We observed dramatically enhanced proliferation within the matrix, DP and hair shaft of the enlarged AdWnt10b-treated hair follicles compared with those of normal hair follicles at P98. Furthermore, expression of CD34, a specific hair stem cell marker, was increased in its number to the bulge region after AdWnt10b treatment. Ectopic expression of CD34 throughout the ORS region was also observed. Many CD34 positive hair stem cells were actively proliferating in AdWnt10b-induced hair follicles. Importantly, subsequent co-treatment with the Wnt inhibitor, DKK1, reduced hair follicle enlargement, decreased proliferation and maintained proper hair stem cell localization. Moreover, injection of DKK1 during early anagen significantly reduced the width of prospective hairs. Together, these findings strongly suggest that a balance of Wnt10b/DKK1 governs reciprocal signaling between cutaneous epithelium and mesenchyme to regulate proper hair follicle size.

Link to paper: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4383245/

potato1987
12-07-2015, 04:19 PM
Thanks for the response,
Would it do any good without minox? minox (and I know there are doubters, gave me puffy eyes and reduced collagen). I wouldn't lie about it and nor would others. I didn't know it was a symptom I just thought it was lack of sleep but the bags got darker and my skin got thinner the longer the weeks went on.

SriHanuman
12-08-2015, 03:13 PM
The mice study seems great! I am going to go ahead and use
http://www.amazon.co.uk/Herb-Pharm-Extract-Liquid-29-6ml/dp/B001E0X2EG/ref=sr_1_1?ie=UTF8&qid=1449612675&sr=8-1&keywords=herb+pharm+olive+leaf+extract+liquid+29.6 ml+1floz

with tretinoid as it increases absorption. If it works similar on humans I can expect great results...

SriHanuman
12-08-2015, 03:13 PM
F****** double post :(

potato1987
12-08-2015, 03:46 PM
Sorry what does this mean?

Eire1980
12-09-2015, 12:51 PM
The mice study seems great! I am going to go ahead and use
http://www.amazon.co.uk/Herb-Pharm-Extract-Liquid-29-6ml/dp/B001E0X2EG/ref=sr_1_1?ie=UTF8&qid=1449612675&sr=8-1&keywords=herb+pharm+olive+leaf+extract+liquid+29.6 ml+1floz

with tretinoid as it increases absorption. If it works similar on humans I can expect great results...

Can someone confirm that the liquid in the amazon link is the stuff to use..if so how much would you use daily..appreciate the feedback

SriHanuman
12-09-2015, 01:13 PM
Sure it is, it is olive leaf extract, so it contains oleuropein. I will use it enough so it covers the area. This is test and trial... Will report in few months.

Eire1980
12-09-2015, 02:23 PM
Sure it is, it is olive leaf extract, so it contains oleuropein. I will use it enough so it covers the area. This is test and trial... Will report in few months.

Thanks much appreciated :D

I see others have asked before but in simple terms how is this meant to work? ..thanks :cool:

joshuk
12-10-2015, 06:21 AM
hi just posted to say thanks to chemical for an indepth look at wnt/dkk1 channels and also do you think this http://www.amazon.co.uk/gp/product/B00B2U9MW4?psc=1&redirect=true&ref_=oh_aui_detailpage_o00_s00 would be suitable to use as a topical im also using CB-03-01 which would help with DKK1 if i read it properly.

Chemical
12-10-2015, 11:51 AM
This may interest you.

Link to paper: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4383245/

I read that study before but I missed some of the discussion they went over. Turns out WNT10b and possibly other WNTs have the ability to signal to the mesenchyme via the DPC to increase the progenitor pool + promote differentiation towards keratinocytes. In other words, Oleuropein can stimulate the stem cells to start proliferating so that the DPC have enough cells to grow hair. Without these stem cells the DPC will not be able to build the follicles. Thanks for bringing this to my attention, excellent stuff InBeforeTheCure.


Thanks for the response,
Would it do any good without minox? minox (and I know there are doubters, gave me puffy eyes and reduced collagen). I wouldn't lie about it and nor would others. I didn't know it was a symptom I just thought it was lack of sleep but the bags got darker and my skin got thinner the longer the weeks went on.

Yes! I've just come to realise that minox stimulates a 40% increase in 17BHD.



Minoxidil increases 17 beta-hydroxysteroid dehydrogenase and 5 alpha-reductase activity of cultured human dermal papilla cells from balding scalp.
Abstract
Minoxidil is known to induce hair growth in male pattern baldness, for which development androgen plays a central role. We studied the effect of minoxidil on testosterone metabolism by cultured dermal papilla cells from balding or nonbalding scalp and dermal fibroblasts. In all three groups, 17beta-hydroxysteroid dehydrogenase activity was much higher than 5alpha-reductase activity. Minoxidil increased 17beta-hydroxysteroid dehydrogenase activity by nearly 40% (P < 0.001) in dermal papilla cells of balding scalp, whereas the effect was less marked in dermal papilla cells from nonbalding scalp and dermal fibroblasts. 5alpha-Reductase activity was also slightly increased by minoxidil in dermal papilla cells from balding scalp. Again, the effect on 5alpha-reductase activity was insignificant in the other two groups of cells. Whether such modification of testosterone metabolism in dermal papilla cells of balding scalp by minoxidil is related to its therapeutic effect remains unknown.

I've shown before that the 17BHD, 3BetaHSD family facilitate the conversion of DHT to 3Beta Diol which negatively affects hair growth. And although miconazole/keto reduce those proteins, this increase from minoxidil might just negate the positive effects of mico/keto. I'm not sure if the Adenosine receptor activation (how minoxidil actually increases VEGF and grows hair) is worth the increase in ER beta activation. I'm going to think about this a bit more. But if you want to avoid minox, then you should definitely try the ethanolic solution or even make your own. You MUST dissolve the oleuropein.


The mice study seems great! I am going to go ahead and use
http://www.amazon.co.uk/Herb-Pharm-Extract-Liquid-29-6ml/dp/B001E0X2EG/ref=sr_1_1?ie=UTF8&qid=1449612675&sr=8-1&keywords=herb+pharm+olive+leaf+extract+liquid+29.6 ml+1floz

with tretinoid as it increases absorption. If it works similar on humans I can expect great results...

Not too sure about this brand. If you're buying from amazon uk then I'd suggest the one joshuk linked below, that ones got numbers and its an ethanolic mixture which is perfect as is. I will advise you to get yourself some emu oil as that will help with application rather than tretinoin. Yes, tretinoin can increase skin permeability, but its a keratinocyte proliferation stabilizer - good for acne, but hair rely on the proliferation of kerainocytes. There are studies which demonstrate the negative effect of the tretinoid receptors on hair follicles, I'll have to dig them up. Here a study that shows even small amount of tretinoin with minoxidil produced sub par results in comparison to minox alone.



Tretinoin was reported to increase percutaneous absorption of Minoxidil by increasing the stratum corneum permeability [32]. Our study demonstrated that Tretinoin in combination with Minoxidil caused a significant increase in hair growth and a significant increase in hair follicle diameter. However, in this study the results obtained from the combination of Minoxidil with low dose Tretinoin are less than that of Minoxidil alone and this warrants further studies to evaluate the role of Tretinoin in combination with Minoxidil in the treatment of hair loss.


Can someone confirm that the liquid in the amazon link is the stuff to use..if so how much would you use daily..appreciate the feedback

Thanks much appreciated :D

I see others have asked before but in simple terms how is this meant to work? ..thanks :cool:

I'd recommend this link: http://www.amazon.co.uk/gp/product/B00B2U9MW4?psc=1&redirect=true&ref_=oh_aui_detailpage_o00_s00

Courtesy of joshuk.

In simple terms:

DHT increases DKK1
DKK1 inhibits hair growth
Oleuropein inhibits DKK1, thus allowing your hair to growth

DHT also increases 3BetaDiol
3BetaDiol activates ER Beta
ER Beta cuts off the blood supply to your hair follicles
Ketoconazole and miconazole prevent DHT from increasing 3BetaDiol

Hair grows faster with WNT10b
Oleuropein increases WNT10b

I'm going to make a diagram to make it easier to visualise. I really want people to understand the science because I dont want people blindly trying whatever they see on the internet. Knowledge is power, if you do not understand, do not make reckless decisions. Ask first, I will try to clarify, and only then should you make informed decisions.


hi just posted to say thanks to chemical for an indepth look at wnt/dkk1 channels and also do you think this http://www.amazon.co.uk/gp/product/B00B2U9MW4?psc=1&redirect=true&ref_=oh_aui_detailpage_o00_s00 would be suitable to use as a topical im also using CB-03-01 which would help with DKK1 if i read it properly.

Thank you Josh! That brand is perfect. CB should definitely help and I want to see how oleuropein augments AR antagonists. Keep us posted.

Seuxin
12-10-2015, 12:03 PM
Awesome work ! Thanks a lot !
So you think oleuropein is better than minox ?
We definitively have to make a trial for this ! I need regrowth :)
i'm looking for buying a the right Vitamine C Form in order to inhibe dkk1 too ;)

joshuk
12-10-2015, 12:14 PM
ok thanks for that chemical just wanted to make sure that was ok to use, ive droped minox due to side effects so im just going to use that Oleuropein mixture with Adenosine and my CB mixed into neogenic with nizoral 3 times a week ive taken base photos so ill give this go

SriHanuman
12-10-2015, 02:48 PM
Chemical, first of all thank you for your effort, really appreciate it.

As it concerns tretinoin there are many studies that support its use in hair growth. Would not women using it for years report healthier skin and less hair, and it would be all the rave? If we are talking keratin...

scooterboy
12-10-2015, 02:53 PM
Hi everyone . This is my first post here .
I have two questions for ChemicaL about mixing emu with minox and oleuropein . I am no sure how you or using emu with minox and oleuropein . In post 10 you say to add 5 750 mg oleuropein capsules and mix them in a bottle of minoxidil.
Then use the dropper to mix around 10ml of minox and oleuropein with 25ml of emu oil . is this right or am I misunderstanding your instructions ? I am not sure how much emu to mix .

One more question . Instead ov emu oil can I put some DMSO in the bottle ? It works great for penetrating in to the scalp .

HMDWN
12-10-2015, 07:05 PM
Ok so, what's the equivalent of the Olive Leaf Extract Liquid Ethanolic Tincture 100ml Concentrate (3.5 oz) (contains approx. 9X more Oleuropein than popular Glycerine extracts per ml & 2-5X more Oleuropein than 1:2 and 1:5 ethanolic tinctures) > > > in the USA Amazon site???
As all I'm seeing is this...http://www.amazon.com/Olive-europaea-Liquid-Extract-Tincture/dp/B008A7EAHO/ref=sr_1_fkmr0_1?ie=UTF8&qid=1449799465&sr=8-1-fkmr0&keywords=Olive+Leaf+Extract+Liquid+Ethanolic+Tinct ure+100ml+Concentrate

TubZy
12-10-2015, 07:46 PM
Dissolved one cap of olive leaf extract (25% oleuropein) into neogenic

http://i.imgur.com/AypJTb2.jpg

Eire1980
12-11-2015, 11:54 AM
I read that study before but I missed some of the discussion they went over. Turns out WNT10b and possibly other WNTs have the ability to signal to the mesenchyme via the DPC to increase the progenitor pool + promote differentiation towards keratinocytes. In other words, Oleuropein can stimulate the stem cells to start proliferating so that the DPC have enough cells to grow hair. Without these stem cells the DPC will not be able to build the follicles. Thanks for bringing this to my attention, excellent stuff InBeforeTheCure.



Yes! I've just come to realise that minox stimulates a 40% increase in 17BHD.



I've shown before that the 17BHD, 3BetaHSD family facilitate the conversion of DHT to 3Beta Diol which negatively affects hair growth. And although miconazole/keto reduce those proteins, this increase from minoxidil might just negate the positive effects of mico/keto. I'm not sure if the Adenosine receptor activation (how minoxidil actually increases VEGF and grows hair) is worth the increase in ER beta activation. I'm going to think about this a bit more. But if you want to avoid minox, then you should definitely try the ethanolic solution or even make your own. You MUST dissolve the oleuropein.



Not too sure about this brand. If you're buying from amazon uk then I'd suggest the one joshuk linked below, that ones got numbers and its an ethanolic mixture which is perfect as is. I will advise you to get yourself some emu oil as that will help with application rather than tretinoin. Yes, tretinoin can increase skin permeability, but its a keratinocyte proliferation stabilizer - good for acne, but hair rely on the proliferation of kerainocytes. There are studies which demonstrate the negative effect of the tretinoid receptors on hair follicles, I'll have to dig them up. Here a study that shows even small amount of tretinoin with minoxidil produced sub par results in comparison to minox alone.





I'd recommend this link: http://www.amazon.co.uk/gp/product/B00B2U9MW4?psc=1&redirect=true&ref_=oh_aui_detailpage_o00_s00

Courtesy of joshuk.

In simple terms:

DHT increases DKK1
DKK1 inhibits hair growth
Oleuropein inhibits DKK1, thus allowing your hair to growth

DHT also increases 3BetaDiol
3BetaDiol activates ER Beta
ER Beta cuts off the blood supply to your hair follicles
Ketoconazole and miconazole prevent DHT from increasing 3BetaDiol

Hair grows faster with WNT10b
Oleuropein increases WNT10b

I'm going to make a diagram to make it easier to visualise. I really want people to understand the science because I dont want people blindly trying whatever they see on the internet. Knowledge is power, if you do not understand, do not make reckless decisions. Ask first, I will try to clarify, and only then should you make informed decisions.



Thank you Josh! That brand is perfect. CB should definitely help and I want to see how oleuropein augments AR antagonists. Keep us posted.

http://www.amazon.co.uk/gp/product/B00B2U9MW4?psc=1&redirect=true&ref_=oh_aui_detailpage_o00_s00[/url][/B]
[/B] Thanks chemical..so this I can use on its own without mixing:confused:

Chemical
12-12-2015, 05:54 AM
Awesome work ! Thanks a lot !
So you think oleuropein is better than minox ?
We definitively have to make a trial for this ! I need regrowth :)
i'm looking for buying a the right Vitamine C Form in order to inhibe dkk1 too ;)

Minox is definitely an effective agent for stimulating hair growth, and there are indications that it might turn off Androgen Receptor signalling (although I'm not fully convinced). The only concern I have with minox is the effect it has on 17BetaHSD, if you look at the diagram below you see it will work against mico/keto. Oleuropein works differently, it inhibits DKK1 and increases other growth factors that greatly improve hair growth.It comes down to personal preference at the moment.


ok thanks for that chemical just wanted to make sure that was ok to use, ive droped minox due to side effects so im just going to use that Oleuropein mixture with Adenosine and my CB mixed into neogenic with nizoral 3 times a week ive taken base photos so ill give this go

Why are you guys using neogenic? I've not seen any documentation of how stemoxydine supposedly works. I would much rather people try treatments which have some form of documented mechanism.

If you're going to be buying from amazon uk you might as well get ketoconazole (and mico if you want) in cream form

Daktarin Ketoconazole Cream 2% (http://www.amazon.co.uk/s/ref=nb_sb_ss_i_2_6?url=search-alias%3Daps&field-keywords=ketoconazole+cream&sprefix=ketoconazole+cream%2Caps%2C167)
Daktarin miconazole Cream 2% (http://www.amazon.co.uk/s/ref=nb_sb_noss_1?url=search-alias%3Daps&field-keywords=miconazole+cream&rh=i%3Aaps%2Ck%3Amiconazole+cream)

This will help suppress the effects of 3Beta diol as shown below. The shampoo can be quite irritating I find, if you use anymore than twice a day.


Chemical, first of all thank you for your effort, really appreciate it.

As it concerns tretinoin there are many studies that support its use in hair growth. Would not women using it for years report healthier skin and less hair, and it would be all the rave? If we are talking keratin...

I've actually used tretinoin and it does wonders for skin. It works by causing an initial increase in keratinocyte turnover then gradually reducing proliferation over time. It also increases collagen which makes your skin look good. Women generally use it on their face, most women dont have any visible facial hair so I dont think they'd be able to tell if it was decreasing hair growth. Yes some studies have shown that certain doses increase hair growth, but this is due to initial increase in proliferation I was just talking about. Even if you use a tiny amount you still wont achieve 1nm tissue concentration, and in a few weeks your hair will stop growing as the therapeutic effects of tretinoin kick in. I used tretinoin 0.5% on my hairline with emu oil and I couldnt tell if it was working, but I saw the emu oil by itself did make a difference after a few weeks.


Hi everyone . This is my first post here .
I have two questions for ChemicaL about mixing emu with minox and oleuropein . I am no sure how you or using emu with minox and oleuropein . In post 10 you say to add 5 750 mg oleuropein capsules and mix them in a bottle of minoxidil.
Then use the dropper to mix around 10ml of minox and oleuropein with 25ml of emu oil . is this right or am I misunderstanding your instructions ? I am not sure how much emu to mix .

One more question . Instead ov emu oil can I put some DMSO in the bottle ? It works great for penetrating in to the scalp .

Good question. Each cap contains 20% standardized oleuropein, which means 150mg per capsule.

Swanson Super Strength Olive Leaf Extract is standardised to 20% oleuropein concentration to deliver an impressive 150 mg oleuropein per capsule.

The minox solution had 750mg of oleuropein in 60ml. Thats 12.5mg per ml. Granted that most of the oleuropein didnt dissolve I'd say 10mg per ml.

10ml of this solution yields 100mg. Combined with 25ml of Emu oil, thats 100mg/35ml = 2.8mg per ml. The study used a maximum of 3mg.

This time I used 2 caps in 30ml of minox. Nearly all the oleuropein was dissolved. 300mg / 30ml = 10mg per ml. I used around 60ml of Emu oil this time = 300mg/90ml = 3mg/ml. I started off on this last time but kept adding more oleuropein (i cap every week) which wasnt consistent. I typically use 1ml per application and I'm going to stick to this dose just too see how a lower dose works. I suggest everyone else do the same because you can always increase the concentration of oleuropein gradually. There shouldnt be a plateau since the more time your follicles have active WNT signalling the greater the chance they'll fully regrow, with increased thickness.


Ok so, what's the equivalent of the Olive Leaf Extract Liquid Ethanolic Tincture 100ml Concentrate (3.5 oz) (contains approx. 9X more Oleuropein than popular Glycerine extracts per ml & 2-5X more Oleuropein than 1:2 and 1:5 ethanolic tinctures) > > > in the USA Amazon site???
http://www.amazon.com/Olive-europaea-Liquid-Extract-Tincture/dp/B008A7EAHO/ref=sr_1_fkmr0_1?ie=UTF8&qid=1449799465&sr=8-1-fkmr0&keywords=Olive+Leaf+Extract+Liquid+Ethanolic+Tinct ure+100ml+Concentrate

You're better off making your own solution because you'll have to have the liquid shipped from UK. You should be okay with this vehicle if you dont want to use minox: 50% v/v ethanol (50% water + 50% ethanol), 20% propylene glycol, and 30% water.


Dissolved one cap of olive leaf extract (25% oleuropein) into neogenic


Can you link me to this product? I'd like to see what's inside. Not sure if it'll be an appropriate vehicle atm.


http://www.amazon.co.uk/gp/product/B00B2U9MW4?psc=1&redirect=true&ref_=oh_aui_detailpage_o00_s00[/url]
[/B] Thanks chemical..so this I can use on its own without mixing:confused:

I'd recommend mixing with emu oil. But you can use itself.

Heres a digram I've made to help everyone understand the pathways that contribute to hairloss and how the treatments work:

http://i.imgur.com/7y3Q8kch.png

jamesst11
12-12-2015, 08:31 AM
Chemical, I don't know if you've covered this already, but what are your opinions on Spiro (s-5 cream) applied topically to the balding scalp?

scooterboy
12-12-2015, 08:35 AM
Is 10mg of the minox and oleuropein solution mixed with 25ml of emu used for just one application ?

Seuxin
12-12-2015, 10:16 AM
Spiro cream is totally bullshit guy !

TheKingofFighters
12-12-2015, 10:33 AM
.

scooterboy
12-12-2015, 10:42 AM
Is 10mg of the minox and oleuropein solution mixed with 25ml of emu used for just one application ?I reread your answers you sent me and seen that one application is 1 ml . Thanks for your help

Seuxin
12-12-2015, 10:57 AM
Chemical : For information, Stemoxydine creates hypoxia, so it increase VEGF. If i'm not wrong it increase too CD200.

Chemical
12-12-2015, 12:02 PM
I'm looking for buying a the right Vitamin C Form in order to inhibit dkk1 too

I forgot to address this question.

Alot of women on skin forums tend to use vitamin C topically and report having positive effects on skin firmness and elasticity.

This study shows that even 5% Vit.C demonstrates a clinically significant improvement in photodamaged skin. I'm a bit disappointed they didnt talk much about the vehicle...



Topical ascorbic acid on photoaged skin. Clinical, topographical and ultrastructural evaluation: double-blind study vs. placebo.

Vitamin C is known for its antioxidant potential and activity in the collagen biosynthetic pathway. Photoprotective properties of topically applied vitamin C have also been demonstrated, placing this molecule as a potential candidate for use in the prevention and treatment of skin ageing. A topically applied cream containing 5% vitamin C and its excipient were tested on healthy female volunteers presenting with photoaged skin on their low-neck and arms in view to evaluate efficacy and safety of such treatment. A double-blind, randomized trial was performed over a 6-month period, comparing the action of the vitamin C cream vs. excipient on photoaged skin. Clinical assessments included evaluation at the beginning and after 3 and 6 months of daily treatment. They were performed by the investigator and compared with the volunteer self assessment. Skin relief parameters were determined on silicone rubber replicas performed at the same time-points. Cutaneous biopsies were obtained at the end of the trial and investigated using immunohistochemistry and electron microscopy. Clinical examination by a dermatologist as well as self-assessment by the volunteers disclosed a significant improvement, in terms of the 'global score', on the vitamin C-treated side compared with the control. A highly significant increase in the density of skin microrelief and a decrease of the deep furrows were demonstrated. Ultrastructural evidence of the elastic tissue repair was also obtained and well corroborated the favorable results of the clinical and skin surface examinations. Topical application of 5% vitamin C cream was an effective and well-tolerated treatment. It led to a clinically apparent improvement of the photodamaged skin and induced modifications of skin relief and ultrastructure, suggesting a positive influence of topical vitamin C on parameters characteristic for sun-induced skin ageing.

Luckily this study gives us a starting point to achieve an optimal way of delivering Vit.C topically:

--------------------------------

http://www.ncbi.nlm.nih.gov/pubmed/12823436

Vit. C is available in the market as a variety of creams, serum and transdermal patches. Of these, only the serum contains active Vit. C in an almost colorless form. It is unstable and, on exposure to light, gets oxidized to Dehydro Ascorbic Acid (DHAA), which imparts a yellow color. The stability of Vit. C is controlled by maintaining a pH of less than 3.5. At this pH, the ionic charge on the molecule is removed and it is transported well across the stratum corneum.[3,5,9]

From a clinical point of view, it is important to note that the efficacy of the Vit. C serum is proportional to the concentration, but only up to 20%.[3] The half-life in the skin after achieving maximum concentration is 4 days. A persistent reservoir of Vit. C is important for adequate photoprotection, and can be achieved by regular 8-hourly applications.[1,5] As UV light lowers tissue Vit. C levels, topical Vit. C is best used after exposure to UV light and not prior.[1–3] A combination of tyrosine, zinc and Vit. C has been shown to increase the bioavailability of Vit. C 20-times vis-ŕ-vis using just Vit. C.[2]

Note: You probably dont want to just mix these up randomly. I'll find a formulation with the optimal concentrations of each and if this is actually true

A variety of creams with Vit. C derivatives are available in the market. As a dermatologist, it is important to know that not all preparations are physiologically effective. Some are not delivered into the dermis in an adequate quantity, while others do not chemically convert to the biologically active form of Vit. C in the skin.[1,2,4]

Note: This is the most crucial part. I'll do more research on this.

Magnesium ascorbyl phosphate (MAP) is the most stable and preferred ascorbyl ester. This lipophilic molecule is easily absorbed into the skin, and the rate-limiting step for absorption is its release from the vehicle, and not the rate of diffusion across the stratum corneum as one might suppose. MAP has a hydrating effect on the skin and decreases transepidermal water loss. It is also a free radical scavenger that is photoprotective and increases collagen production under laboratory test conditions.[1,3] Other useful stable esterified derivatives are:

------------------------------

MAP might be a better alternative to Vit C seeing as its more stable and readily used by skin cells.

Also:



A combination of 0.5% ferulic acid (a potent antioxidant of plant origin) with 15% Vit. C and 1% Vit. E can increase the efficacy of Vit. C eight-fold.[3] It was noted that this triple combination was very useful for the reduction of acute and chronic photodamage, and could be used for prevention of skin cancer in the future.

Maybe ferulic acid can increase efficiency of MAP?

This is could be helpful in reducing androgen mediated/ROS induced oxidative damage . I've got more questions than answers so I'll look into this a bit more.



Why are you guys using neogenic? I've not seen any documentation of how stemoxydine supposedly works. I would much rather people try treatments which have some form of documented mechanism.


Found a lead:



Stemoxydine (active ingredient in Neogenic) = diethyl pyridine-2,4-dicarboxylate

A bit more info on the molecule...

https://www.caymanchem.com/app/template/Product.vm/catalog/71200




2,4-Diethylpyridine dicarboxylate
The pro-angiogenic factor HIF-1α is targeted for destruction in normoxic environments by the hydroxylation of a specific proline residue, P564, by the oxygen-sensing enzyme HIF-α prolyl hydroxylase (HIF-PH).1 2,4-DPD is a cell permeable, competitive inhibitor of HIF-PH. 2,4-DPD inhibits the hydroxylation of P564 by acting as a competitive inhibitor of the HIF-PH cofactor α-keto glutarate, with effective concentrations in the low µM range.2 2,4-DPD is therefore expected to act as a pro-angiogenic compound, via the HIF-1α system.3,4

A conserved family of prolyl-4-hydroxylases that modify HIF. (http://www.ncbi.nlm.nih.gov/pubmed/11598268)

HIFalpha targeted for VHL-mediated destruction by proline hydroxylation: implications for O2 sensing. (http://www.ncbi.nlm.nih.gov/pubmed/11292862)

Those studies are the references that describe the pro-HIF-1alpha effects of stemoxydine. HIF-1 stimulates VEGF, and an increase in DPC blood supply actually increases hair diameter and growth rate (check first post for more info). I'm going to do some more reading when I have time, this might be interesting.


Chemical, I don't know if you've covered this already, but what are your opinions on Spiro (s-5 cream) applied topically to the balding scalp?

Topical spiro is a tricky one. There are a handful of people that seen improvements and others that claim it goes systemic (leading to gyno). Theoretically, inhibition of systemic AR results in the HPTA pumping out more testosterone to satisfy negative feedback loop, so you shouldnt experience serious gyno. There is only one study that tested spiro for systemic absorption and they only measured hormone levels over 72hrs, which wouldnt be greatly affected anyway since its an AR blocker. They also saw no increase in the metabolite which is sketchy imo. Plus it was a while ago. http://www.ncbi.nlm.nih.gov/pubmed/3411088

This hamster study: http://www.ncbi.nlm.nih.gov/pubmed/7608379
shows that topical spiro blunted exogenous testosterone induced sebaceous gland growth, which means its doing something.

Its also been used to treat female pattern hairloss with vary degrees of success, but female scalp is not exactly the same as male scalp physiologically (gender dependant receptor and protein expression variability). Then theres the side effects (https://en.wikipedia.org/wiki/Spironolactone#Side_effects) - although typical low doses shouldnt be a problem if it indeed doesnt go systemic.

I wanted to try spiro and thought it would be an ideal candidate to block AR. Flutamide has better physiological responses but its got considerable hepatotoxicity risks. Bicalutamide seems like a better canditate since its got a ridiuculous half life, but theres still not enough information on topical administration and systemic effects, I suspect it'll most probably go systemic using standard skin penetration vehicles. Personally? I wouldnt advocate spiro with insufficient evidence on its efficacy.

scooterboy
12-12-2015, 12:16 PM
What do you think of DMSO instead of emu ? It works great for penetrating in to the scalp .

Seuxin
12-12-2015, 12:32 PM
And p53 is decreased by hypoxia...and Stemoxydine induce hypoxia.

TheKingofFighters
12-12-2015, 12:45 PM
using ascorbic acid and its derivatives on the balding scalp are gonna further upregulate already-upregulated immunity genes there.

solaeg
12-12-2015, 12:52 PM
I am currently using oleuropein since it seems to have great potential when using it topically, but also internally in terms of body-recomposition and various health related effects (e.g. http://suppversity.blogspot.dk/2012/09/on-short-notice-250-more-testosterone.html and http://www.ergo-log.com/oleuropein-boosts-testosterone-lowers-cortisol-stimulates-anabolism.html)

This thread is great for trying to understand the effects using it topically .
As I understand, some of it's fat loss effects comes from being an PPAR Gamma antagonist. Meanwhile, PPAR Gamma agonists stimulates adipogenesis. And a thickening fat layer in the scalp is good for hair (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3992657/ - "In each case, the thickness of the fat layer was decreased by 50% in the regions of hair loss"), while it is otherwise replaced by fibrotic tissue (collagen).
If I understand it correctly, activation of PPAR Gamma also has anti-fibrotic effects (maybe due to regulating adipogenesis?): http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3733781/

Considering the above, are there any issues when using Oleuropein topically and/or internally?

And what is the role of oleuropein and adipogenesis in the scalp?
"Wnt/β-catenin signaling stimulates adipocyte differentiation in vivo and in vitro": http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3992657/
On the other hand, Wnt6, Wnt10a and Wnt10b seem to do the opposite:
http://www.ncbi.nlm.nih.gov/pubmed/21872687
And I guess we don't want osteoblast in the scalp?

Is oleuropein activating wnt10b which upregulates wnt/β-catenin signaling which positively regulates adipogenesis in the scalp? Or is it likely to not have an effect on adipogenesis?

TheKingofFighters
12-12-2015, 01:09 PM
oleuropein inhibits COX2

All tested polyphenols reduced endothelial cell tube formation on matrigel and migration in wound healing assays. The reduced angiogenesis was associated with the inhibition of PMA-induced COX-2 protein expression and prostanoid production, as well as MMP-9 protein release and gelatinolytic activity. These effects were accompanied by a significant reduction in the stimulated intracellular reactive oxygen species levels and in the activation of the redox-sensitive transcription factor nuclear factor (NF)-κB. Our findings reveal that olive oil and red wine polyphenols reduce inflammatory angiogenesis in cultured endothelial cells, through MMP-9 and COX-2 inhibition, supporting a potential protective role for dietary polyphenols in atherosclerotic vascular disease and cancer.

http://www.ncbi.nlm.nih.gov/pubmed/22595400



Khalatbary et al. demonstrated that oleuropein treatment significantly attenuates the expression of TNF-α and IL-1β, and, consequently, the expression of iNOS and COX-2 [43].

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4227229/

Seuxin
12-12-2015, 01:27 PM
If Oleuropein inhibe cox-2 , we just need another coumpound in order to increase PEG2 !

TheKingofFighters
12-12-2015, 02:36 PM
btw, i do agree that vit c is good on areas u want fair, smooth, hairless and collagen-filled

UNBEAT
12-13-2015, 05:08 AM
Hey chemical, thanks for what you are doing.. i wanted to know if oleuropein can help with seborreah severe hair loss .i have lost 50% of my hair because of it. thank you

Chemical
12-13-2015, 07:23 AM
What do you think of DMSO instead of emu ? It works great for penetrating in to the scalp .

Some people have noticed that when using DMSO as a vehicle they had increased shedding. I think I saw some posts on btt and ***. Avoid DMSO and go with a different vehicle.


And p53 is decreased by hypoxia...and Stemoxydine induce hypoxia.

Apparently so! http://www.nature.com/cddis/journal/v2/n5/full/cddis201148a.html

But hypoxia has also been frequently found to elevate p53 levels as elucidated in the study. So not that straightforward it seems.


using ascorbic acid and its derivatives on the balding scalp are gonna further upregulate already-upregulated immunity genes there.

This is true that ascorbic acid derivatives will increase immunity markers but AGA is not an autoimmune condition. The saying: "correlation does not equal causuality" applies here. Just because immunity genes are elevated in balding scap (I've seen studies talk about this) does not mean those genes cause baldness. It could be a reaction to either one of many pathways, tumor suppressors, ros, dna damage, anything.


btw, i do agree that vit c is good on areas u want fair, smooth, hairless and collagen-filled

Its not Vit.c specifically that we're after, we need a good ROS scavenger, since the studies I posted in my first page show that ROS scavengers like ascorbate completely reverse the effects of DHT mediated hair growth inhibition. Your statement implies vitamin C does not help with hair growth/or causes hair to stop growing, which I disagree with for the aformentioned reasons.


oleuropein inhibits COX2
These effects were accompanied by a significant reduction in the stimulated intracellular reactive oxygen species levels and in the activation of the redox-sensitive transcription factor nuclear factor (NF)-κB. Our findings reveal that olive oil and red wine polyphenols reduce inflammatory angiogenesis in cultured endothelial cells, through MMP-9 and COX-2 inhibition, supporting a potential protective role for dietary polyphenols in atherosclerotic vascular disease and cancer.

http://www.ncbi.nlm.nih.gov/pubmed/22595400

Khalatbary et al. demonstrated that oleuropein treatment significantly attenuates the expression of TNF-α and IL-1β, and, consequently, the expression of iNOS and COX-2 [43].
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4227229/

A reduction in COX-2 does mean there will be less arachidonic acid for PGHS to convert to PGE2, and also PGD2. A decrease in PGE2 does not necessarily mean hair will affected detrimentally, this may be the case in people who do not use exogenous hair growth agents. We are manually controlling the protein/receptor expression for a net increase in hair growth, so although there might factors trying to inhibit hair growth, the pro growth factors will win the tug of war. I'd like to people to get out of this black and white mindset, this is a complex model and the body is designed to have alternate pathways in case one fails. This is both a good thing and a bad thing because it means we have to take everything into account when targeting certain paths.


If Oleuropein inhibe cox-2 , we just need another coumpound in order to increase PEG2 !

Minoxidil is your answer. http://www.ncbi.nlm.nih.gov/pubmed/9008235
Although there probably wont be much arachidonic acid if COX-2 is significantly inhibited by oleuropein. DHT is a known stimulator of COX-2 via IL-1B, so thers still a chance oleuropein only cancel this to normal levels.


I am currently using oleuropein since it seems to have great potential when using it topically, but also internally in terms of body-recomposition and various health related effects (e.g. http://suppversity.blogspot.dk/2012/09/on-short-notice-250-more-testosterone.html and http://www.ergo-log.com/oleuropein-boosts-testosterone-lowers-cortisol-stimulates-anabolism.html)

This thread is great for trying to understand the effects using it topically .
As I understand, some of it's fat loss effects comes from being an PPAR Gamma antagonist. Meanwhile, PPAR Gamma agonists stimulates adipogenesis. And a thickening fat layer in the scalp is good for hair (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3992657/ - "In each case, the thickness of the fat layer was decreased by 50% in the regions of hair loss"), while it is otherwise replaced by fibrotic tissue (collagen).
If I understand it correctly, activation of PPAR Gamma also has anti-fibrotic effects (maybe due to regulating adipogenesis?): http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3733781/

Considering the above, are there any issues when using Oleuropein topically and/or internally?

And what is the role of oleuropein and adipogenesis in the scalp?

"Wnt/β-catenin signaling stimulates adipocyte differentiation in vivo and in vitro":
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3992657/

On the other hand, Wnt6, Wnt10a and Wnt10b seem to do the opposite:
http://www.ncbi.nlm.nih.gov/pubmed/21872687
And I guess we don't want osteoblast in the scalp?

Is oleuropein activating wnt10b which upregulates wnt/β-catenin signaling which positively regulates adipogenesis in the scalp? Or is it likely to not have an effect on adipogenesis?

Really thought provoking questions!

The Japanese study (http://www.ncbi.nlm.nih.gov/pubmed/19001767) from ergo log shows a strange result:



The content of uncoupling protein 1 (UCP1) in IBAT and urinary noradrenaline and adrenaline excretions were significantly higher in rats fed the 0.1 or 0.2% oleuropein diet, as compared with those of rats fed with the control diet, although there were no significant differences in rats fed the 0.4% oleuropein diet

(Nor/adrenaline increases T via α1-adrenergic receptor mediated LH increase (http://www.ncbi.nlm.nih.gov/pubmed/6096749))

Oleuropein has a biphasic effect!? So it is true.

WNT10b inhibits adipogenesis (http://www.ncbi.nlm.nih.gov/pubmed/25104077) via a mechanism I dont fully understand, along with WNT6 and 10a like you pointed out. You wont have progenitor cells differentiate into osteoblasts in the skin so thats nothing to worry about, but WNT10b will promote the keratinocyte lineage.

Oleuropein is a known inhibitor of PPARγ, and adipocytes differentiate/mature via PPARγ (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3896615/)

The question now is like you've pointed out, what happens if the fat layer in scalp reduced? Does the fat layer cause hair regrowth? These studes are excellent and help us understand the underlying mechanics.

Epidermal Wnt/β-catenin signaling regulates adipocyte differentiation via secretion of adipogenic factors (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3992657/)

Unraveling hair follicle-adipocyte communication (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3507425/)

The adipocyte precursors actually promotes anagen development via PDGF (not to be confused with PGD2)



In addition to the requirement of adipocytes in the skin for anagen induction, adipocyte lineage cells are sufficient to induce the hair follicle cycle. Transplantation of adipocyte progenitor cells intradermally into the backskin of shaved mice at the extended 3–4 week telogen stage of the hair follicle cycle that occurs around 7 weeks of age resulted in adipocyte graft formation and corresponding precocious hair growth. Anagen was induced in these mice injected with the enriched adipocyte progenitor cells from WT or AZIP, but not with cells of the entire stromal vascular fraction (SVF), supporting that the hair-inducing activity was specific for immature adipocyte lineage cells [7].

The mechanism behind this interaction is not completely understood, but PDGF signaling may play a role [7] (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3298746/). PDGFA mRNA is significantly elevated in adipocyte precursor cells, and mice lacking PDGFA show a delay in hair follicle stem cell activation that mirrors the phenotype of Ebf1−/− mice [27,28].

Based on the expression of PDGF ligands by adipocyte lineage cells, the activation of the PDGFR in the DP during anagen, and the ability of PDGF-coated beads to rescue hair cycling defects in Ebf1 null mice, we propose that adipocyte precursor cells secrete PDGF to promote hair growth. Mice lacking PDGF-A display similar hair follicle defects as Ebf1 null mice, namely a lack of anagen entry

Only the precursor adipocytes produce PDGF, not the mature differentiated hypertrophic cells.

How does PDGF do this? look at this:



Involvement of platelet-derived growth factor receptor-alpha in hair canal formation. (http://www.ncbi.nlm.nih.gov/pubmed/8875964)

Hair follicles develop and are maintained by multiple rounds of inductive events involving interactions among various cell types within the follicles and the adjacent mesenchyme. In this study, we established the antagonistic monoclonal antibody APA5 against platelet-derived growth factor (PDGF) receptor-alpha (PDGFR-alpha) and used it to investigate the role of PDGFR-alpha in neonatal skin development. In addition to the dermal mesenchyme, a known site of PDGFR-alpha expression, immunohistologic staining of neonatal skin detected transient expression of PDGFR-alpha in the perinatal epidermis for several days. On the other hand, ligands for PDGFR-alpha were detected in epithelial cells and sebaceous glands of hair follicles. To determine whether this contiguous expression of PDGF and PDGFR-alpha in neonatal skin plays a functional role, we injected APA5 into neonates to block the function of PDGFR-alpha. Consistent with the PDGF/PDGFR-alpha expression in the neonatal skin, two defects were induced by this procedure. First, hair canal formation in the epidermis was severely suppressed. Second, the growth of dermal connective tissues and of hair follicles of pelage hairs was suppressed. These results indicate that PDGF signals are involved in both the epidermis-follicle interaction and the dermal mesenchyme-follicle interaction required for hair canal formation and the growth of the dermal mesenchyme, respectively.


So the adipocyte precursors (mesenchymal stem cells?) actually signal to the hair follicle canal to prepare for the new anagen cycle. This is the kick that telogen hairs need to actually form the follicle canal before the DPC can start proliferating.

Effect of IGF-I on Hair Growth Is Related to the Anti-Apoptotic Effect of IGF-I and Up-Regulation of PDGF-A and PDGF-B (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3283847/)

Oleuropein upregulated IGF-1 significantly, so the DPC should be more receptive to PDGF signals.

This is incredible stuff! Okay, so what controls adipogenesis fate?



The growth of the intradermal adipose depot could occur through adipocyte hypertrophy or adipogenesis. While adipocyte hypertrophy involves lipogenesis, adipogenesis requires the proliferation and specification of adipocyte precursor cells into preadipocytes, which exit from the cell cycle and differentiate into mature, lipid-laden adipocytes (Rodeheffer et al., 2008; Rosen and Spiegelman, 2000). Adipogenesis requires the upregulation and transcriptional activity of the nuclear receptor, PPARγ in preadipoctyes

Perhaps this could explain the sudden increase in dozen or so new follicles when I stopped the oleuropein? This could mean that you need to cycle the oleuropein, using 2-4 weeks on then 2 weeks off. Then again, immature adipocytes only help with anagen induction and do not play a huge part in maintenance (Beta Cetenin does that (http://www.ncbi.nlm.nih.gov/pubmed/15084463/)). Mature adipocytes actually secrete factors that inhibit hair growth. This inhibition is probably weak since females hair ridiculously long anagen cycles even though they have a normal scalp fat layer. The adipocytes also have estrogen receptors which could explain their hypertrophy during anagen (http://www.ncbi.nlm.nih.gov/pubmed/14761887):



Mature adipocytes also express signaling molecules that can modulate hair cycling. Intradermal adipocytes express BMP2 maximally in late anagen and early telogen, causing follicles to be refractory to activation cues [30]. Given that BMP signaling blocks anagen induction [33–36], these data suggest that adipocyte derived BMPs may promote and maintain follicular stem cell quiescence. Thus, when BMP signals are reduced in the macroenvironment, the hair follicles are open to activation signals, enter into a competent telogen phase and the follicles can re-enter anagen. The contribution of adipocyte derived BMP proteins is unknown since the dermal papillae also express BMP mRNAs [37].

Delving deeper:


Analysis of BrdU incorporation within adipocyte precursor cells revealed that prior to anagen ~50% of adipocyte precursor cells are proliferating. However, once anagen was initiated, the percentage of proliferative adipogenic cells was reduced to ~25% (Figure 2C). Thus, adipocyte precursor cells are stimulated to proliferate during late catagen to generate an increased population of adipogenic cells during anagen induction. These data correlate with the timing of de novo adipocyte generation after anagen induction (Figure 1C).

Thus, these three mouse models with diminished or absent intradermal adipocytes affect different stages of adipogenesis in the skin. The Ebf1 null mouse lacks adipocyte precursor cells suggesting that this mutation acts at the adipocyte precursor cell to block postnatal intradermal adipogenesis. PPARγ antagonists do not block the formation of adipocyte precursor cells in the skin but disrupt the formation of PPARγ+, preadipocytes, resulting in a loss of postnatal intradermal adipogenesis.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3298746/


This is already becoming complex. I suspect whats happening here is that once hairs enter anagen they start secreting factors that reduce PPARy signalling, hence the reduction in adipocyte precursors. WNT10b, 10a, and WNT6 could be elevated in anagen hairs, and when the catagen phase kicks in, the adipocyte precursors are free to proliferate, then once the hair follicle is recreated the precurors have done their job. The increase in the fat layer is caused by the growing hair follicles:



During activation of hair growth, the expansion of the intradermal adipocyte layer in the skin doubles the skin’s thickness (Butcher, 1934; Chase et al., 1953; Hansen et al., 1984).

This means the balding skin is primed for growth, and just needs that kick. The follicles need to be stimulated with WNT/BetaCatenin to start the adipocyte precursor proliferation and then once the hair canal is formed, you need sustained BetaCatenin to maintain hair follicle which is a hard job because theres multiple pathways working against you.

I think I'll cycle the Oleuropein 4 weeks on, 2 weeks off. I'm also going to look into ROS scavengers to prevent the rise in DKK1 when not using oleuropein.

Seuxin
12-13-2015, 07:33 AM
In order to increase PGE2, you shoud look at Vitamine E Succinate studies ;)
By the way, i use adenosine since 7 month with really no results :(

Seuxin
12-13-2015, 08:17 AM
Hello,

I have difficutlies to find a good oleuropein supplement to buy which can be shipped to France...
Better is to buy as liquide, ethanol based right ?

Any link for Europe please ?

Thanks a lot :)

TheKingofFighters
12-13-2015, 07:14 PM
Ascorbic acid =

COX2 inhibitor
Prolactin activator
Hypoxia inhibitor
CD34 inhibitor

upregulates these genes that are already overexpressed in balding scalp:

1) ifi27: Promotes cell death. Mediates IFN-induced apoptosis characterized by a rapid and robust release of cytochrome C from the mitochondria and activation of BAX and caspases 2, 3, 6, 8 and 9. http://www.genecards.org/cgi-bin/carddisp.pl?gene=IFI27
2) IGF-1(not an immune marker- but it is already overupregulated in balding scalp)
3)c-FOS apoptotic gene
4)CTSK(this gene breaks down bones- and hair):
Closely involved in osteoclastic bone resorption and may participate partially in the disorder of bone remodeling. Displays potent endoprotease activity against fibrinogen at acid pH. May play an important role in extracellular matrix degradation
Tocris Summary for CTSK Gene

http://www.genecards.org/cgi-bin/carddisp.pl?gene=CTSK&keywords=ctsk

5)CXCL9:
Cytokine that affects the growth, movement, or activation state of cells that participate in immune and inflammatory response. Chemotactic for activated T-cells. Binds to CXCR3

6)C3:
C3 plays a central role in the activation of the complement system. Its processing by C3 convertase is the central reaction in both classical and alternative complement pathways. After activation C3b can bind covalently, via its reactive thioester, to cell surface carbohydrates or immune aggregates
Derived from proteolytic degradation of complement C3, C3a anaphylatoxin is a mediator of local inflammatory process. In chronic inflammation, acts as a chemoattractant for neutrophils (By similarity). It induces the contraction of smooth muscle, increases vascular permeability and causes histamine release from mast cells and basophilic leukocytes.
C3-beta-c: Acts as a chemoattractant for neutrophils in chronic inflammation.
Acylation stimulating protein: adipogenic hormone that stimulates triglyceride (TG) synthesis and glucose transport in adipocytes, regulating fat storage and playing a role in postprandial TG clearance. Appears to stimulate TG synthesis via activation of the PLC, MAPK and AKT signaling pathways. Ligand for C5AR2. Promotes the phosphorylation, ARRB2-mediated internalization and recycling of C5AR2 (PubMed:8376604, PubMed:2909530, PubMed:9059512, PubMed:10432298, PubMed:15833747, PubMed:16333141, PubMed:19615750).

Sorry but If u're claiming that these immunity genes are not the 1s causing balding- then what is? MpB is not an atuimmune condition? do u have any idea what does CRTh2 stands for?

A reduction in COX-2 does mean there will be less arachidonic acid for PGHS to convert to PGE2, and also PGD2. A decrease in PGE2 does not necessarily mean hair will affected detrimentally, this may be the case in people who do not use exogenous hair growth agents. We are manually controlling the protein/receptor expression for a net increase in hair growth, so although there might factors trying to inhibit hair growth, the pro growth factors will win the tug of war. I'd like to people to get out of this black and white mindset, this is a complex model and the body is designed to have alternate pathways in case one fails. This is both a good thing and a bad thing because it means we have to take everything into account when targeting certain paths.

We are 'manually' controlling which protein and receptor? a net increase in hair growth by what mechanism? what are the factors that you are talking about? What's the altenative pathway? I can only see a long detour here

woodnor
12-14-2015, 04:34 AM
Hey Chemical I think that what youre doing is great and its nice that you try to answer every question thoroughly :)
Now I have a question, though im not sure if it is too stupid but here it goes... i always though there was no point in taking things that stimulate growth like minox or now Oleuropein if you dont take something that halts or slows down the balding process. The explanation that I had read for this was that it didnt matter if your hair was thicker (because of minox/Oleuropein) because the follicles were gonna die anyway, as you werent attacking the root of the problem (and supposedly finasteride would attack the 'root' as it lowers dht).

Maybe i got everything wrong, but it would be great if you could explain this to me, as i dont really understrand why would you take something like Oleuropein (which from what i understand only stimulates growth) without taking something that would stop or slow the death of the follicle? Does this question make sense? Its like why would you want to make your hair thicker if its going to fall off anyway.
Thanks for your time i really appreciate what youre doing :)

paleocapa89
12-14-2015, 09:32 AM
Hey Chemical, I was wondering, can oleuropein penetrate the skin without problem, given that it is a fairly large molecule?

tiktok
12-14-2015, 06:27 PM
Hey Chemical, I was wondering, can oleuropein penetrate the skin without problem, given that it is a fairly large molecule?

Looks like it's right around the 500 dalton limit (http://www.ncbi.nlm.nih.gov/pubmed/10839713) at 540.52 Daltons (http://www.biocyc.org/META/NEW-IMAGE?type=COMPOUND&object=CPD-17784&orgids=ECOLI)

Seuxin
12-15-2015, 01:28 AM
540 daltons oO ? Is it possible to use it properly ???

Chemical
12-16-2015, 01:02 PM
In order to increase PGE2, you should look at Vitamine E Succinate studies. By the way, i use adenosine since 7 month with really no results :(

I have difficutlies to find a good oleuropein supplement to buy which can be shipped to France... Better is to buy as liquide, ethanol based right ?

Any link for Europe please ?

Thanks a lot :)

Do you remember the names of any particular studies that show vitamin E succinate increasing pge2? (because I cant seem to find any or I'm just being lazy)

You can try contacting this seller to see if they ship their liquid oleuropein to france http://www.amazon.co.uk/gp/aag/main?ie=UTF8&asin=&isAmazonFulfilled=&isCBA=&marketplaceID=A1F83G8C2ARO7P&orderID=&protocol=current&seller=ADU6XUILJRJRO&sshmPath=

As a last result you can make your own oleuropein solution, it'll be a bit more expensive and time consuming to mix the liquids in the right amounts but unfortuneately thats the best option you have. Its still ridiculously cheap if you think about how long it will last you. I'm reducing my application dose to 0.5ml because I'm starting to think that less might be more effective.


Ascorbic acid =

COX2 inhibitor
Prolactin activator
Hypoxia inhibitor
CD34 inhibitor

upregulates these genes that are already overexpressed in balding scalp:

2) IGF-1(not an immune marker- but it is already overupregulated in balding scalp)
3)c-FOS apoptotic gene
4)CTSK(this gene breaks down bones- and hair):
Closely involved in osteoclastic bone resorption and may participate partially in the disorder of bone remodeling. Displays potent endoprotease activity against fibrinogen at acid pH. May play an important role in extracellular matrix degradation
Tocris Summary for CTSK Gene

http://www.genecards.org/cgi-bin/carddisp.pl?gene=CTSK&keywords=ctsk

5)CXCL9:
Cytokine that affects the growth, movement, or activation state of cells that participate in immune and inflammatory response. Chemotactic for activated T-cells. Binds to CXCR3

6)C3: C3-beta-c: Acts as a chemoattractant for neutrophils in chronic inflammation.

Sorry but If u're claiming that these immunity genes are not the 1s causing balding- then what is? MpB is not an atuimmune condition? do u have any idea what does CRTh2 stands for?

We are 'manually' controlling which protein and receptor? a net increase in hair growth by what mechanism? what are the factors that you are talking about? What's the altenative pathway? I can only see a long detour here

Ah, I see now why you think Vitamin C is bad. You hold the belief that Androgenetic Alopecia/MBP is an autoimmune condition. I'll tell you straight, its not. AGA is not Alopecia Areata. It is androgen dependent, and Androgens are the cause of baldness. The androgen receptor and DHT both reduce hair growth via AR mediated signalling pathways including: Beta Catenin suppression (I'll go into this), DKK1, and 3BetaDiol which is a metabolite of DHT. I'm not sure where you got your theory that immunity markers cause T cells to attack DPC and cause baldness. You will have to explain this to me if you think I'm not understanding it.

CRTH2 is the Prostaglandin DP2 receptor (https://en.wikipedia.org/wiki/Prostaglandin_DP2_receptor) correct? I'm not sure what youre suggesting here with this. PGD2 elevation might be a causative factor but I believe its more of a side effect rather than the initiator. Immunity markers are simply markers. They are indicative of other agents causing these markers to be expressed. Like inflammation.

Furthermore, IGF-1 is NOT elevated in the balding scalp, it is reduced. IGF-1 is good for hair and actually stimulates regrowth. Coming back to Ascorbic Acid, I did say this:


Its not Vit.c specifically that we're after, we need a good ROS scavenger, since the studies I posted in my first page show that ROS scavengers like ascorbate completely reverse the effects of DHT mediated hair growth inhibition. Your statement implies vitamin C does not help with hair growth/or causes hair to stop growing, which I disagree with for the aformentioned reasons.

You might have missed it or maybe I wasnt clear enough. Ascorbic Acid was merely an example that gave us a starting point in finding a suitable ROS scavenger. If we disregard your assumption that AGA is an autoimmune condition, Vitamin C could be therapeutic as it increases hair growth (http://www.ncbi.nlm.nih.gov/pubmed/19416266).

Addressing your question of the pathways:

http://i.imgur.com/7y3Q8kch.png

It seems as though you've not read any of my posts about the treatments available to use to against hair loss. Minoxidil, oleuropein, ketoconazole, emu oil. They all have mechanisms that target different pathways. Look at the diagram.


I always though there was no point in taking things that stimulate growth like minox or now Oleuropein if you dont take something that halts or slows down the balding process. The explanation that I had read for this was that it didnt matter if your hair was thicker (because of minox/Oleuropein) because the follicles were gonna die anyway, as you werent attacking the root of the problem (and supposedly finasteride would attack the 'root' as it lowers dht).

Maybe i got everything wrong, but it would be great if you could explain this to me, as i dont really understrand why would you take something like Oleuropein (which from what i understand only stimulates growth) without taking something that would stop or slow the death of the follicle? Does this question make sense? Its like why would you want to make your hair thicker if its going to fall off anyway.
Thanks for your time i really appreciate what youre doing :)

This question hasnt been asked before and it's a very valid question that I havent directly addressed. In short, unless you can deactivate the Androgen Receptor permanently or permanently interfere with the Androgen signalling pathway, you will not be able to come off treatment. Alternatively if a treatment can reduce AR with a long half life, you can kind of call that a semi permanent cure, since you dont need to use it everyday. The root cause is the AR, and the various extension pathways that reduce hair growth like DHT metabolites and DHT induced DKK1 which act in a paracrine manner (cells that release proteins that bind to nearby cells surface). Yes, the hair will fall out if you stop the treatment, but it will stop the shedding, AND regrow hair. So long as you stay on the treatment, you'll keep your hair. Its a battle against on your genes. Furthermore, not many people know this but minoxidil dose dependantly inhibits AR activity by around 50% in the presence of DHT (and this is with 5% minoxidil with an assumed absorption rate of ~1.7%). Imagine if you bumped up the dose to 10% or used it along side emu oil for enhanced skin penetration. How does it do this? Minoxidil binds to the AR and interferes with its co-activators rendering most of the AR useless, but not completely. The androgen receptor on the other hand competes with TCF for BetaCatenin. If TCF cannot bind with Beta Catenin, you wont see any hair growth, and instead the DPC will secrete factors that will inhibit the growth of nearby DPC in a paracrine manner that I just mentioned earlier. We need to find agents that will interfere with Androgen Receptor signalling, or co-activators, that way we can avoid Anti-androgens and still achieve Androgen receptor inhibition.

Funnily enough, Beta Catenin has been found to inhibit Filamin A which Androgen Receptors require to function. So if you increase BetaCatenin, which you need to anyway to regrow and keep hair, you can also shut down the AR. Now the challenge is to find something that increases betacatenin consistently and can cause a prolonged increase.

Regarding your question about what oleuropein will do stop the root cause, if you look the diagram above you can see that oleuropein inhibits DKK1, which DHT increases via P53. This is one of the ways that DHT kills hair follicles. Oleuropein also stimulates BetaCatenin via WNT10b, and IGF-1 which has the potential to regrow hair via PDGF-a/b upregulation. I'm using minoxidil, and I advocate minox for its androgen receptor suppressing effects.

Heres the science behind all of what I just said, feel free to skip this part:

Minoxidil may suppress androgen receptor-related functions (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4039155/)

All of the above data were obtained in prostate cancer cell lines or in in vitro studies. To extend these findings to skin cells, we tested whether minoxidil has similar effects in HHDPCs (human hair dermal papilla cells) using an AR reporter assay. AR expression in HHDPCs was confirmed at mRNA (Fig. ​(Fig.4A)4A) and protein (Fig. ​(Fig.4B)4B) levels. As shown in Fig. ​Fig.4C,4C, minoxidil suppressed AR transcriptional activity in a concentration-dependent manner (compare lanes 4 and 5 to lane 2). We further tested minoxidil effects on AR protein stability in HHDPCs. As shown in Fig. ​Fig.4D,4D, minoxidil induced a concentration-dependent reduction in AR protein stability. These data provide further evidence that the efficacy of minoxidil in treating AGA may involve suppression of AR-related functions.

http://i.imgur.com/uV5EPqQ.png

Interestingly, our structural studies demonstrated that minoxidil is chelated at a novel, previously unreported groove in the AR. The residues surrounding the groove provide hydrophobicity at the surface, whereas the inner core exhibits hydrophilic properties, implying selectivity for binding factors. Moreover, the groove is also located opposite to and at a distance from AF-2 and BF-3 sites [48]; accordingly, it may represent a new candidate site for the interaction of AR coregulators (Fig. ​(Fig.3D).3D). To date, there have been few reports on AR structure and none has described the role of the groove identified here in AR action. Mutation of a nearby residue, Cys784, to Tyr784 in the α8 helix was reported to cause the loss of transactivation activity in a female patient [49]. In our model, variations in this region resulted in steric clashes or changes in secondary structure. By occupying this grove, minoxidil may hinder the physical association of interacting proteins, thereby disrupting downstream regulation of AR transactivation. Taken together with mutagenesis data, our structural findings suggest that this groove may be important for binding of AR-interacting proteins during transactivation. The minoxidil-AR-LBD co-crystal model thus may provide a platform for the further development of drugs for the treatment of AGA and other androgen-AR pathway-related diseases

-----------------------


The Androgen Receptor Antagonizes Wnt/β-Catenin Signaling in Epidermal Stem Cells (http://www.nature.com/jid/journal/v135/n11/full/jid2015242a.html)

Conversely, Filamin A (FlnA), which is required for AR activation in response to androgen stimulation (Castoria et al., 2011; Mooso et al., 2012), was significantly downregulated by β-catenin activation, an effect that was antagonized by testosterone (Supplementary Figure S5c online). The observation that testosterone increased FlnA expression in the presence of 4-OHT is consistent with the conclusion that AR signaling antagonized β-catenin signaling. As 4-OHT treatment led to a major reduction in FlnA, it is not surprising that there was no further effect of bicalutamide.

As a side note they reported the same finding of BetaCatenin stimulating PDGF-a expression which we know causes the formation of new hair follicles.


Sustained β-catenin activation in combination with AR inhibition led to an increase in platelet-derived growth factor receptor-α-positive (Figure 5a) and Vimentin-positive (Figure 5d) fibroblasts adjacent to ectopic HFs.


Functional localization and competition between the androgen receptor and T-cell factor for nuclear beta-catenin: a means for inhibition of the Tcf signaling axis. (http://www.ncbi.nlm.nih.gov/pubmed/12944908)

BCT = beta-catenin-T-cell factor (Tcf) signalling pathway

These data suggest that in steady-state conditions, AR has the ability to compete out Tcf binding for beta-catenin. Finally, using SW480 cells, we show that AR-mediated repression of the BCT pathway has implications for cell cycle progression and in vitro growth. Using FACs analysis, we observed a 26.1% increase in accumulation of cells in the G1 phase of the cell cycle, while in vitro growth assays showed a 35% reduction in viable cells transfected with AR+DHT treatment. Together, our data strongly suggest that a reciprocal balance of nuclear beta-catenin facilitates AR-mediated repression of BCT-driven transcription and cell growth.


Ligand-dependent inhibition of beta-catenin/TCF signaling by androgen receptor. (http://www.nature.com/onc/journal/v21/n55/full/1206049a.html)

Importantly, this TCF4 construct was unable to prohibit ligand-dependent repression of CRT (Figure 8e), implying that TCF4 competes with AR for beta-catenin. Thus, the pivotal factor underlying ligand-dependent inhibition of CRT by AR could be beta-catenin. This outcome with wildtype TCF4 over-expression (Figure 8e, full length) may represent a general property of all TCF/LEF family members, as ectopic expression of LEF1 likewise mollifies the effects of androgen signaling on CRT (Figure 8f). Noticeably, LEF1 synergized with mutant beta-catenin to potentiate CRT.

Also, Genistein Combined Polysaccharide is an effective Filamin A inhibitor.But its quite pricy: http://www.amazon.com/GeniKinoko-500-vcaps-Quality-Life/dp/B002YE8232


Hey Chemical, I was wondering, can oleuropein penetrate the skin without problem, given that it is a fairly large molecule?

I completely missed this fact. Could this mean oleuropein cant do anything?

I did however see this article:


https://www.futurederm.com/what-exactly-is-the-500-dalton-rule/

Molecules that are of a small enough weight are able to penetrate through the layers of the skin and be absorbed. This weight is generally considered to be 500 Daltons (Experimental Dermatology). After review, researchers found that there were no ingredients that were effective when much larger than 500 Daltons, though there are some that are still effective at slightly larger than 500 Daltons. Common allergens also tend to be under 500 Daltons.

And, yet, there are still some exceptions to this rule. For example, atopic dermatitis can be treated with derivatives tacrolimus, which is 822 Daltons, and ascomycin, which is 811 Daltons. But, generally speaking, researchers suggest that anything intended for medicinal purposes be smaller than 500 Daltons to assure absorption.

I wonder if mouse skin has a different limit?

TheKingofFighters
12-16-2015, 01:47 PM
Ah, I see now why you think Vitamin C is bad. You hold the belief that Androgenetic Alopecia/MBP is an autoimmune condition. I'll tell you straight, its not. AGA is not Alopecia Areata. It is androgen dependent, and Androgens are the cause of baldness. The androgen receptor and DHT both reduce hair growth via AR mediated signalling pathways including: Beta Catenin suppression (I'll go into this), DKK1, and 3BetaDiol which is a metabolite of DHT. I'm not sure where you got your theory that immunity markers cause T cells to attack DPC and cause baldness. You will have to explain this to me if you think I'm not understanding it.

Theory? it's From Dr Cotsareli's patent page 91-92 under 'IMAGES' http://www.google.com/patents/US20110021599



CRTH2 is the Prostaglandin DP2 receptor (https://en.wikipedia.org/wiki/Prostaglandin_DP2_receptor) correct? I'm not sure what youre suggesting here with this. PGD2 elevation might be a causative factor but I believe its more of a side effect rather than the initiator. Immunity markers are simply markers. They are indicative of other agents causing these markers to be expressed. Like inflammation.

Initiator of what? Side effect of what? So u're saying 'inflammation' is what is causing the rise of PGD2 n not the other way around? Not to mention that PGD2 is not the only factor for all the inflamamtion is MPB- based on Dr Cotsareli's patent


Furthermore, IGF-1 is NOT elevated in the balding scalp, it is reduced. IGF-1 is good for hair and actually stimulates regrowth. Coming back to Ascorbic Acid, I did say this:

IGF-1 is not elevated in balding scalp??? Take a look yourself page 81 under 'IMAGES' http://www.google.com/patents/US20110021599 by Dr Cotsarelis


You might have missed it or maybe I wasnt clear enough. Ascorbic Acid was merely an example that gave us a starting point in finding a suitable ROS scavenger. If we disregard your assumption that AGA is an autoimmune condition, Vitamin C could be therapeutic as it increases hair growth (http://www.ncbi.nlm.nih.gov/pubmed/19416266).

So what's your assumption based on that MPB is not an autoimmune disorder? you clearly meant to suggest that Ascorbic acid was effective at addressing MPB- and AS upregulates at least 6 genes unbeneficially in bald scalp.


Addressing your question of the pathways:

It seems as though you've not read any of my posts about the treatments available to use to against hair loss. Minoxidil, oleuropein, ketoconazole, emu oil. They all have mechanisms that target different pathways. Look at the diagram.

what makes u think i have not read or USED for that matter(in fact, i've used 3 of that 4 items u have just listed out in that paragraph)


This question hasnt been asked before and it's a very valid question that I havent directly addressed. In short, unless you can deactivate the Androgen Receptor permanently or permanently interfere with the Androgen signalling pathway, you will not be able to come off treatment. Alternatively if a treatment can reduce AR with a long half life, you can kind of call that a semi permanent cure, since you dont need to use it everyday. The root cause is the AR, and the various extension pathways that reduce hair growth like DHT metabolites and DHT induced DKK1 which act in a paracrine manner (cells that release proteins that bind to nearby cells surface). Yes, the hair will fall out if you stop the treatment, but it will stop the shedding, AND regrow hair. So long as you stay on the treatment, you'll keep your hair. Its a battle against on your genes. Furthermore, not many people know this but minoxidil dose dependantly inhibits AR activity by around 50% in the presence of DHT (and this is with 5% minoxidil with an assumed absorption rate of ~1.7%). Imagine if you bumped up the dose to 10% or used it along side emu oil for enhanced skin penetration. How does it do this? Minoxidil binds to the AR and interferes with its co-activators rendering most of the AR useless, but not completely. The androgen receptor on the other hand competes with TCF for BetaCatenin. If TCF cannot bind with Beta Catenin, you wont see any hair growth, and instead the DPC will secrete factors that will inhibit the growth of nearby DPC in a paracrine manner that I just mentioned earlier. We need to find agents that will interfere with Androgen Receptor signalling, or co-activators, that way we can avoid Anti-androgens and still achieve Androgen receptor inhibition.


Funnily enough, Beta Catenin has been found to inhibit Filamin A which Androgen Receptors require to function. So if you increase BetaCatenin, which you need to anyway to regrow and keep hair, you can also shut down the AR. Now the challenge is to find something that increases betacatenin consistently and can cause a prolonged increase.

that's what any1 with some decent knowledge in hairloss mechansims would say too.

Regarding your question about what oleuropein will do stop the root cause, if you look the diagram above you can see that oleuropein inhibits DKK1, which DHT increases via P53. This is one of the ways that DHT kills hair follicles. Oleuropein also stimulates BetaCatenin via WNT10b, and IGF-1 which has the potential to regrow hair via PDGF-a/b upregulation. I'm using minoxidil, and I advocate minox for its androgen receptor suppressing effects.


Really? even the title of the study says that the authors are'nt exactly conclusive of that purported effect of minoxidil. If it's true- i guess those using Minoxidil concomitantly with RU or Dut while should stop wasting money on the latter 2.

'Minoxidil may suppress androgen receptor-related functions'

Dkk1 could be upregulated not by just p53- it could also be done so by BMP4, Hairless, VDR and Retinoic acid receptors

tiktok
12-16-2015, 03:59 PM
I completely missed this fact. Could this mean oleuropein cant do anything?




Strangely Ketoconazole has a weight of 531 daltons, so if the theory were exact, then it should not be effective either.

Also worth noting that limit changes based on the condition and type of skin:

http://i.imgur.com/9X0fUbQ.png

I'd say it's a prime candidate for use with light dermarolling (which is how I intend on using it).

FeelsBad
12-16-2015, 10:16 PM
Anyone have a US source for oleupurein? Preferably an alcohol tincture.

potato1987
12-17-2015, 12:06 AM
Does emu oil help absorption at all? It's a shame Foillicept don't just sell the vehicle they created.

Chemical
12-17-2015, 12:08 PM
Theory? it's From Dr Cotsareli's patent page 91-92 under 'IMAGES' http://www.google.com/patents/US20110021599

Initiator of what? Side effect of what? So u're saying 'inflammation' is what is causing the rise of PGD2 n not the other way around? Not to mention that PGD2 is not the only factor for all the inflamamtion is MPB- based on Dr Cotsareli's patent

IGF-1 is not elevated in balding scalp??? Take a look yourself page 81 under 'IMAGES' http://www.google.com/patents/US20110021599 by Dr Cotsarelis

So what's your assumption based on that MPB is not an autoimmune disorder? you clearly meant to suggest that Ascorbic acid was effective at addressing MPB- and AS upregulates at least 6 genes unbeneficially in bald scalp.

what makes u think i have not read or USED for that matter(in fact, i've used 3 of that 4 items u have just listed out in that paragraph)

Really? even the title of the study says that the authors are'nt exactly conclusive of that purported effect of minoxidil. If it's true- i guess those using Minoxidil concomitantly with RU or Dut while should stop wasting money on the latter 2.

'Minoxidil may suppress androgen receptor-related functions'

Dkk1 could be upregulated not by just p53- it could also be done so by BMP4, Hairless, VDR and Retinoic acid receptors

I think we're going to have to agree to disagree on these topics. If you think you're right and I'm wrong then thats fine too, I'll continue in my ignorance. You're not posting any real evidence (I couldnt find anything in that patent supporting what you've said - I might just be blind) and aren't contributing anything meaningful or constructive to this discussion.

You were right about PGD2 leading to inflammation via the CRTH2 receptor, but it can also reduce inflammation:


Collectively, these results show that when hematopoietic PGD synthase is overexpressed, tissue resident cell-derived PGD2 suppresses skin inflammation via DP in the early phase, but hematopoietic lineage cell-derived PGD2 stimulates CRTH2 and promotes inflammation during the late phase. DP-mediated vascular barrier enhancement or CRTH2-mediated neutrophil activation may be responsible for these effects. Thus, PGD2 represents opposite roles in inflammation, depending on the disease phase in vivo.

Also:


Insulin-like growth factor-1: roles in androgenetic alopecia.

Abstract
Of all the cytokines or growth factors that have been postulated to play a role in hair follicle, insulin-like growth factor-1 (IGF-1) is known to be regulated by androgens. However, how IGF-1 is altered in the balding scalp has not yet been investigated. In this study, expressions of IGF-1 and its binding proteins by dermal papilla (DP) cells obtained from balding versus non-balding hair follicles were quantified using growth factor array. DP cells from balding scalp follicles were found to secrete significantly less IGF-1, IGFBP-2 and IGFBP-4 (P < 0.05) than their non-balding counterparts. Our data confirmed that the downregulation of IGF-1 may be one of the important mechanisms contributing to male pattern baldness.

So this study is bullshit according to Dr Cotsarelis?

Moreover, the title is not the conclusion. Theres a difference:


Minoxidil also suppressed AR-responsive reporter activity and decreased AR protein stability in human hair dermal papilla cells. The current findings provide evidence that minoxidil could be used to treat both cancer and age-related disease, and open a new avenue for applications of minoxidil in treating androgen-AR pathway-related diseases.

VDR is there in the diagram. DHT upregulates VDR via ER Beta too. DHT is known to increase DKK1 in the scalp: Dihydrotestosterone-inducible dickkopf 1 from balding dermal papilla cells causes apoptosis in follicular keratinocytes. (http://www.ncbi.nlm.nih.gov/pubmed/17657240)
If you know of any other pathways then please contribute evidence.

I shouldnt be the one to support your own claims with evidence, thats your job. Telling people to go and google it or find it isnt useful, you dont see me doing that do you? If you're going to continue with this behaviour then dont waste your time, or my time too because it just pollutes the thread. I wont be responding to your posts because you seem to be trying to evoke a reaction from me.


Strangely Ketoconazole has a weight of 531 daltons, so if the theory were exact, then it should not be effective either.

Also worth noting that limit changes based on the condition and type of skin:

I'd say it's a prime candidate for use with light dermarolling (which is how I intend on using it).

http://i.imgur.com/ejzq8Ja.png

From that graph, it looks like oleuropein and keto have a 70% absorption rate. Its not too bad and theres still potential.


Does emu oil help absorption at all? It's a shame Foillicept don't just sell the vehicle they created.

Apparently Emu Oil aids with skin permeation but that might just be for itself.

Interestingly:


Relative influence of ethanol and propylene glycol cosolvents on deposition of minoxidil into the skin.
Abstract
Minoxidil, a potent antihypertensive, is moderately effective in the treatment of hair loss when it is applied to the scalp as a 2% solution in 60% ethanol, 20% propylene glycol and 20% water. Important questions remain concerning both the mechanism of delivery and the pathway of penetration of this drug from its ternary solvent system. Since preliminary studies in our laboratory indicated that water in the formulation influenced permeation far less than the other two solvents, we examined the relative deposition and penetration influences of binary combinations of ethanol and propylene glycol. When 50 microL/cm2 of the formulations was spread over hairless mouse skin sections mounted in Franz diffusion cells, only small amounts of minoxidil were actually recovered from the receiver compartments. Nevertheless, more minoxidil penetrated the skin as the proportion of ethanol in the mixtures was increased. To determine if these in vitro results formed a representative picture of the in vivo behaviors of these vehicles, selected deposition experiments were performed on live, anesthetized mice under experimental conditions similar to those used in the diffusion cell work. The good agreement between in vivo and in vitro studies may be a result of the relatively fast partitioning of the drug into the skin as compared to its diffusion through the skin.

Ethanol disrupts the lipid barrier of the stratum corneum:


In conclusion, 80% EtOH/20% PG enhanced the percutaneous absorption of aspirin by perturbing the macroscopic barrier integrity of the stratum corneum and through a loss of stratum corneum lipids.

Continuing on the research for AR antagonism, I've found some leads:


Green tea polyphenol EGCG blunts androgen receptor function in prostate cancer.
(http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3058706/)
To explain its antigrowth effect on PCa cells, we found that EGCG physically interacts with the AR-LBD and competes with natural agonist DHT (IC50 0.4 μM). The cell growth assay was also in concordance with this result, and EGCG in fact abrogated the proliferative effect of strong synthetic agonist R1881 on PCa cells, and hence serves as a functional antagonist. It is important to mention here that the most widely used AR antagonists have been the steroidal drug cyproterone and the nonsteroidal drugs flutamide and bicalutamide, which are all competitive antagonists of androgen binding.

Another study:



Effects of topical application of EGCG on testosterone-induced hair loss in a mouse model (http://onlinelibrary.wiley.com/enhanced/doi/10.1111/j.1600-0625.2011.01353.x/)

These results suggest that T injection in this mouse model can induce hair loss through apoptosis of hair follicles. EGCG can reduce the T-induced hair loss by down-regulating the apoptosis of follicular epithelial cells and even stimulate hair re-growth.

Effect of T injection and EGCG on AR, 17β- and 3β-hydroxysteroid dehydrogenase (HSD) expression of hair follicles

We examined the effect of T on AR expression by IHC staining. IHC of AR demonstrated that the T + vehicle group had 50–70% staining intensity in follicular epithelial cells as well as sebaceous glands, whereas the T + EGCG group had <10% staining in follicular epithelial cells (Figure S1 and Table S1). IHC staining for 17β- and 3β-HSD was also performed to determine whether there were changes in the androgen pathway by T or EGCG. However, there was no difference in 17β- and 3β-HSD expression among the T-injected and T + EGCG groups (unpublished data). These results demonstrate that EGCG can down-regulate T-induced AR expression of hair follicular cells but has no effect on 17β- and 3β-HSD expression.

Testosterone increased AR activity, hence the 50-70% staining. However, when EGCG was present, there was less than 10%.

EGCG has a molecular weight of 458 which is good.

Topical absorption shows promise:


In vivo human skin penetration of (-)-epigallocatechin-3-gallate from topical formulations.
Abstract
The aim of the study was to examine the effect of topical vehicles on the in vivo human stratum corneum penetration of the antioxidant and skin photoprotective agent (-)-epigallocatechin-3-gallate (EGCG). Model oil-in-water (o/w) emulsion and gel formulations containing 1 % (m/m) EGCG were prepared and subjected to photodegradation studies in order to select excipients that minimize the light instability of EGCG. The optimized emulsion and gel were applied to human volunteers and the EGCG percutaneous permeation was evaluated in vivo by the tape- -stripping technique. No significant differences in the percentage of the applied EGCG dose diffused into the stratum corneum were observed between the o/w emulsion (36.1 ± 7.5 %) and gel (35.5 ± 8.1 %) preparations. However, the amount of EGCG permeated into the deeper region of human stratum corneum was significantly larger for the o/w emulsion compared to the gel. Therefore, the emulsion represents a suitable vehicle for topical delivery of EGCG.

They didnt notice a huge difference using the oil in water emulsion vehicle on the diffusion rate, but it did enhance stratum corneum permeation.

The mice study used 10% EGCG and ethanol:


Histologic findings of the upper dorsal skin stained with haematoxylin and eosin (a–f), and TUNEL staining (g–l). Topical application of 10% EGCG (a, g), testosterone (T)’s vehicle injection (b, h), T injection (c, i), T injection + topical application of EGCG vehicle (ethanol) (d, j), T injection + topical application of 10% cyproterone acetate (e, k) and T injection + topical application of EGCG (f, l). [(a–f) × 100, (g–l) × 400].

Since ethanol reduces the barrier function of the SC, EGCG might be readily absorbed. I'm going to try this after christmas break because it could be the an effective agent to use alongside minox to inhibit AR.

pilipili
12-18-2015, 08:01 AM
Thank you for your amazing work. It’s worth giving it a try. But If I may, do you think mixing ginkgo and olive tincture is a good idea ? And what If I also use adenosine, azelaic acid and vitamin E succinate in my regimen. thank you for your advices

scooterboy
12-20-2015, 04:56 PM
Chemical. are you applying this once or twice a day ?

solaeg
12-21-2015, 05:01 AM
Thank you for your contributions, Chemical.

I'm not sure whether it has been covered but this suggests that specifically hydroxytorosol (oral intake in men) inhibits PGF2a: http://www.ncbi.nlm.nih.gov/pubmed/11095986
I believe bim works as an PGF2 analogue. Could the topical (or oral) intake of olive leaf extract countereffect that? Or maybe one that is standardized to hydroxytorosol, thus inhibiting PGF2a? Or is that perhaps why PGE1/2 is needed besides oleuropein?

solaeg
12-21-2015, 05:02 AM
Double post

Keeper
12-21-2015, 06:37 AM
Hey Chemical!


I like your way of approaching things !
So i decide to support you a little bit and to talk to a huge german company which is specialized in production of oleuropein extract (for around 20 years) in all possible concentrations and also Emu Oil.
After some conversation they said: if we can show them a summary of your theory that makes kind of sense and we have a plan how to conduct a study they would probably produce a liquid in a concentration we want (also with emu oil or what else is necessary) and send free samples to us to try it for an amount of time (probably 50-100 people). Of course we would have to make pictures and give protocols about our experience and so on but I think this should stop us. She said to start it before christmas would be unrealistic, but very soon in the new year!!!!

Sounds not that bad or?

Keeper
12-21-2015, 07:03 AM
I know its not that easy.
But would be nice if we could all cooperate together and figure out a plan and also with the help of experienced members about how to design a survey based on this.

trunks
12-21-2015, 07:32 AM
They should do preclinical trial with ~60 ppl on their own, with professional tools, documentation and so on.

Oleuropein, Minoxidil and placebo would be the best.

I probably couldnt participate even remotely becouse I dont want to drop my current regimen.

HMDWN
12-21-2015, 09:53 AM
I'm currently on no regimen...I'm up for it!

Chemical
12-21-2015, 10:25 AM
Thank you for your amazing work. It’s worth giving it a try. But If I may, do you think mixing ginkgo and olive tincture is a good idea ? And what If I also use adenosine, azelaic acid and vitamin E succinate in my regimen. thank you for your advices

I wouldnt mix them unless you know what you're doing. Theres only one study on ginkgo's effects on hair: http://www.ncbi.nlm.nih.gov/pubmed/8254481
Its not too reassuring imo.


Chemical. are you applying this once or twice a day ?

My current protocol is:

1/5 of a oleuropein cap dissolved in 30ml minox. (1mg/ml) ~0.5mg absorption per the molecular mass.

I use this minox solution in the morning, 0.5ml. Then once its dried, I use emu oil (just emu oil). Helps rehydrate the skin after the ethanol dries up. If I feel like it I'll use miconazole 2%.

At night, same thing, but I use the emu oil with the oleuropein and minox mixed in.

The stubble hairs that I noticed a week ago are actually getting longer, i tried to take some pictures but my stupid camera over exposures the pictures so you cant see jack. I'll have to invest in a camera or wait for the area to fill in properly so I can see the difference in the before and after pics. Right now I'm 80% sure the oleuropein is augmenting the minox. I never saw this many vellus to anagen transition this quickly. The region where I concentrate the treatments is actually turning grey, the same colour as when you shave facial hair to the skin. Frontal shedding has completely stopped. I cannot explain how excited I am about, but I'm trying to stay skeptical and critical because this is not just about me. Theres alot of people out there sufferring from this stupid condition, its wrecks havoc on a persons self esteem - I know first hand.

The task now is to find something that will keep hair. I've ordered some EGCG:

http://www.amazon.co.uk/Swanson-Superior-Caffeine-Vegetarian-Capsules/dp/B0031XEF2M/ref=sr_1_1?ie=UTF8&qid=1450716253&sr=8-1&keywords=teavigo

The highest potency I could find. I'll be mixing a cap with minox, I'll get it when I go back to work on Jan 4. Theoretically EGCG should increase the rate of hair regrowth and shaft elongation by inhibiting AR protein, downregulating it, and preventing the paracrine action of TGF-beta (which causes nearby follicles to stop proliferating).


Thank you for your contributions, Chemical.
I'm not sure whether it has been covered but this suggests that specifically hydroxytorosol (oral intake in men) inhibits PGF2a: http://www.ncbi.nlm.nih.gov/pubmed/11095986
I believe bim works as an PGF2 analogue. Could the topical (or oral) intake of olive leaf extract countereffect that? Or maybe one that is standardized to hydroxytorosol, thus inhibiting PGF2a? Or is that perhaps why PGE1/2 is needed besides oleuropein?

Its a marker of oxidative stress, so a reduction doesnt really tell us much, especially since its measured via urine. Prostaglandins can promote hair growth when overpresssed/stimulated, but theyre not the main factors that actually control hair growth in people who arent affected by AGA. Its the WNTs.

I'm doing some research on WNT3a which is known to stimulate hair growth, so if we can find an agonist, it'll be deadly in combination with oleuropein.


They should do preclinical trial with ~60 ppl on their own, with professional tools, documentation and so on.

Oleuropein, Minoxidil and placebo would be the best.

I probably couldnt participate even remotely becouse I dont want to drop my current regimen.


Hey Chemical!

I like your way of approaching things !
So i decide to support you a little bit and to talk to a huge german company which is specialized in production of oleuropein extract (for around 20 years) in all possible concentrations and also Emu Oil.
After some conversation they said: if we can show them a summary of your theory that makes kind of sense and we have a plan how to conduct a study they would probably produce a liquid in a concentration we want (also with emu oil or what else is necessary) and send free samples to us to try it for an amount of time (probably 50-100 people). Of course we would have to make pictures and give protocols about our experience and so on but I think this should stop us. She said to start it before christmas would be unrealistic, but very soon in the new year!!!!

Sounds not that bad or?

I know its not that easy.
But would be nice if we could all cooperate together and figure out a plan and also with the help of experienced members about how to design a survey based on this.


I think this is an excellent idea! Great stuff Keeper! The only issue I have is, when involving commercial companies I fear they will let their greed take over. IF it works on a preliminary group of people, this'll become a market. I don't like the idea of people paying companies for something they can make themselves, or companies trying to make money off something that should be non-profit. On the other hand this will allow people to actually test this to see if it works on the general population, before investing in overseas shipping and whatnot. We need to verify their ingredients and where they're sourcing the extracts. I like this idea, We'll have to talk more about this.

I've made some changes to my own formulation, so emu oil isnt actually necessary. Its only good for keeping irritation/inflammation at bay when using propylene glycol and ethanol. A pure formulation of ethanol + propylene glycol (some people are sensitive to this) + oleuropein, 3mg/ml max would be the ideal formulation. If people want to see a trial then I will have to insist that people wait a few more weeks while I test the EGCG or discover anything else that might help or warrant modifications. It would be nice to run a full blown study with controls but oleuropein is not a cure and it requires additional treatments like (minox, keto/mico, AR suppressors) to fully maximise its benefits. I've been concentrating the treatment only on side, and I can definitely see the difference. The right side hasnt improved as much as the left. Perhaps this would be better than having controls on placebo, the local untreated skin can act as the control which should give a better indication on its efficacy since everyones got different feedback loops and environments working against hair follicles.

The studies that I've read showed that it takes sustained dosing for 2 weeks straights to see any change in WNT10b expression, my own observation isnt valid because I was inconsistent but I guess 30 days is sufficient to see any change. The dose is also another concern because I'm pretty sure its got a biphasic effect i.e too much and it wont work as good, plus its got around 70% absorption rate through skin due to it 540 molecular weight. Having a fixed dose for everyone may or may not be optimal, theres just too many variables at play.

Keeper
12-21-2015, 01:57 PM
Hey Chemical, glad you like the idea. Just some thoughts of me. I talked to a nice woman, she didn't seem to be greedy. She said its a funny idea we have and she likes it. She was also talking about mixing oleuropein and emu oil and so on. They are not a big pharma company (she was talking about that oleuropein is shown to be effective for so reducing so many issues in health and they have evidence about it but its sad, that the "school medicine says: take this and this medicament". And even if they take advantage of our survey. Why not ? IT can not be mich more expensive than now. They already have a lot of different combinations of ingredients. It won't change too much I guess. And even if it works, they will be really quick really much competition and since you can not really have a patent about oleuropein and emu oil they is not much greedy possibilities in it. I think they just like that people understand that oleuropein can have many positive effects and that we dedicated to our ideas. It also didn't sound like it must be a super strict survey. They would send us free samples of what we need. They can also produce cremes out of the extract and so on. Wit emu oil or propylene glycol or ethanol or what ever.

We should just make sure to optimize the formula in the way you (are we all together) think it makes sense to have a good effect, reading as much studies as possible. Maybe even some variations of the forumlas. Of course they want some photos or so to know whats going on. I think its a fair trade and they are really helping. (They also know a lot about stuff like emu oil, that it is important where it comes from and so on. I think they tested a lot of it with there chemists...and so on). I m not too much in all the studies. Its not the easiest to translate or the studies but as soon as my exams are over I also want to read about it more. I m already happy, that somebody is endeavored to do sth like you Chemical. What I can do at the moment is too support this idea. I think you should think about the formula and probably discuss it with really experiences members here. And brainstorming all together we have at least a minimal chance to achieve sth ;)

Seuxin
12-21-2015, 02:15 PM
Seriously guys....stop talking emu oil ! Emu oil is totally shitty for hair ! If you want good vehicles, there is true vehicles, Like a mix of Polysorbate 80 / DMI / eth for liquide, and if you want a cream based, you have to look for a liposomal cream vehicle !

Stop dreaming about emu oil ! Is totaly shit, and greasy...

lukey
12-21-2015, 05:32 PM
I bought the liquid olive extract off amazon.co.uk and mixed 9ml (300mg oleuropein) into 60ml minox. I shall report back if I see any benefit - although I'm not too hopeful as minox by itself has only grown vellus hairs. I'm also currently on .25mg fin and OC.

Chemical
12-22-2015, 02:29 PM
I'm currently on no regimen...I'm up for it!

We have our first participant!

@Keeper

You've convinced me. They seem to be genuine, and they're offering their help free of charge, this'll benefit alot of users. And we'll have a consistent formula. Lets make this thing happen.

Can they create formulations with ingredients besides oleuropein? Like EGCG.


Seriously guys....stop talking emu oil ! Emu oil is totally shitty for hair ! If you want good vehicles, there is true vehicles, Like a mix of Polysorbate 80 / DMI / eth for liquide, and if you want a cream based, you have to look for a liposomal cream vehicle !

Stop dreaming about emu oil ! Is totaly shit, and greasy...

Agreed. But it helps with the irritation I get from minox. I think we should think about other potential vehicles that might make applying the formula easier. Emu oil isnt ideal as a vehicle.


I bought the liquid olive extract off amazon.co.uk and mixed 9ml (300mg oleuropein) into 60ml minox. I shall report back if I see any benefit - although I'm not too hopeful as minox by itself has only grown vellus hairs. I'm also currently on .25mg fin and OC.

Which brand did you buy? Seeing as you've already taken the plunge to go with minox, do you think you could try topical EGCG too? It should achieve near 90% suppression of AR when stacked with minox. The oleuropein would have a better chance of working too. Keep us posted.

joshuk
12-23-2015, 02:31 AM
wrong thread

SriHanuman
12-25-2015, 08:25 AM
Chemical, do you think it is ok if I mix EGCG with oleuropein; same ethanol mixture?

And it would be really great to hear your opinion on this:
http://www.ncbi.nlm.nih.gov/pubmed/24676213

Sogeking
12-25-2015, 11:51 AM
Hi Chemical I am willing to try this out.
I found a tincture in my local shop that has 65% olea europea (with water and alcohol but not sure of the exact ratio yet) and I also found 500 mg capsules of green tea which contain 15% ECGC. I intend to mix them by adding a bit more alcohol and water i n a seperate bottle.
What ratio would you use?

I'll take some pics and we'll see what happens. Have to be honest I don't expect much but I have nothing to lose so...

paleocapa89
12-25-2015, 05:24 PM
A couple of days ago I was reading up on minoxidil and it's mechanism of work. I read that minoxidil sulfate is the active metabolite that actually promotes hair growth. Minoxidil sulfate is made by the sulfotransferase enzyme. It is common knowledge that minoxidil doesn't work for everybody, possibly because we have different sulfotransferase enzyme activity. So I read up on it just out of curiosity and (if I understand it correctly) the sulfotransferase enzyme is really picky for pH changes (it is most active in 6,5pH) and temperature changes (it is most active in 30-35'C and rapidly loses its effectiveness in increasing temperature)

So I am wondering: Is it important to have a right pH balance for minoxidil and other treatments to work, or to work better? Is temperature important? I was always applying minoxidil after a hot shower to increase permeation but is it possible that at the same time I was inactivating the sulfotransferase enzyme? I don't know but from now on I will only wash my head with cold water :)

http://dmd.aspetjournals.org/content/37/5/1083.full

Keeper
12-26-2015, 03:26 AM
We have our first participant!

@Keeper

You've convinced me. They seem to be genuine, and they're offering their help free of charge, this'll benefit alot of users. And we'll have a consistent formula. Lets make this thing happen.

Can they create formulations with ingredients besides oleuropein? Like EGCG.


To be honest I don't know what ingredients they can also mix in. I could ask them but I don't want too bother them too often, so I think the best is if we collect our ideas what could be in and how to mix it with what for producing sth, and then I will ask them in one rush. (I guess sth like a cream/topiclal solution would be the best.)

They emailed me that they can produce every Oleuropein concentration we want. Would be nice if more people would think about the ideas and try to help figuring out a plan.

potato1987
12-26-2015, 04:33 AM
I am not on any routine, the only thing I do at present is castor oil and derma rolling, I would be happy to document and take part, the only thing is on swisstemples he believes it may reduce PGE2, but I think castor oil increases it, so a mix Emu, Castor and Oleuropein? I would leave in over night and apply every night.

cheers,

joshuk
12-26-2015, 05:41 AM
just thought i would post an update been using Oleuropein ethanol tincture of amazon for 2 weeks now, i stopped minox 2 months ago due to face/skin probs ( it was the minox my face is better not 100% but alot better now)

the small vellus hairs that minox made were about 1-2mm in length across the hairline since using the Oleuropein some of these have doubled in length to 3-4mm nothing groundbreaking but they are getting longer for sure so im hoping in the next few weeks they might keep growing.

this is not cosmetic regrowth as the hairs in question are not pigmented just thought i would share

Chemical
12-26-2015, 06:00 AM
Chemical, do you think it is ok if I mix EGCG with oleuropein; same ethanol mixture?

And it would be really great to hear your opinion on this:
http://www.ncbi.nlm.nih.gov/pubmed/24676213

Yes it should be fine, but before you go ahead, which brand of EGCG are you using? I'd recommend teavigo since you can get away with a lower concentration of the extract and get the raw EGCG that you actually need. I'm ot sure how the other polyphenols affect, so for now we'll stick to pure EGCG as used in the study. EGCG also has a dose dependent effect so start off with 1 capsule, then see if it leaves a residue after applying. If not, add another. Rub the skin softly to see if you get any residue, even if its just a little, dont add anymore to the solution. Also what concentration of ethanol are you using?


Hi Chemical I am willing to try this out.
I found a tincture in my local shop that has 65% olea europea (with water and alcohol but not sure of the exact ratio yet) and I also found 500 mg capsules of green tea which contain 15% ECGC. I intend to mix them by adding a bit more alcohol and water i n a seperate bottle.
What ratio would you use?

I would encourage you to try and source the extracts online because then you know what concentration to use. It's sometimes difficult to know exactly how much oleuropein a tincture has and if its got any additional unwanted ingredients. iherb is a great place to order extracts/supplements and they deliver worldwide. Theyre very cheap and alot of people including myself can vouch for them - that is if you cant find what youre looking for on amazon. 15% EGCG isnt a high enough concentration imo, so for those reasons I'd suggest acquiring the ingredients elsewhere. I'm not 100% sure on the EGCG mixing since I'm yet to try it, but use my answer to SriHanuman as a starting point.


I read that minoxidil sulfate is the active metabolite that actually promotes hair growth. Minoxidil sulfate is made by the sulfotransferase enzyme. It is common knowledge that minoxidil doesn't work for everybody, possibly because we have different sulfotransferase enzyme activity.

So I am wondering: Is it important to have a right pH balance for minoxidil and other treatments to work, or to work better? Is temperature important? I was always applying minoxidil after a hot shower to increase permeation but is it possible that at the same time I was inactivating the sulfotransferase enzyme? I don't know but from now on I will only wash my head with cold water :)

http://dmd.aspetjournals.org/content/37/5/1083.full

Absolutely correct paleocapa89. Minoxidil sulfate is the active metabolite that stimulates hair follicles. (http://www.ncbi.nlm.nih.gov/pubmed/2230218)



Dose-response studies showed that minoxidil sulfate is 14 times more potent than minoxidil in stimulating cysteine incorporation in cultured follicles. Three drugs that block production of intrafollicular minoxidil sulfate were tested for their effects on drug-induced hair growth. Diethylcarbamazine proved to be a noncompetitive inhibitor of sulfotransferase and prevented hair growth stimulation by minoxidil but not by minoxidil sulfate.



Biochemical evidence for minoxidil sulphation by two phenol sulphotransferases has been found in human scalp skin[22] and Dooley[21] reported finding mRNA expression for four sulphotransferases in human epidermal keratinocytes. There are interindividual variations in scalp sulphotransferase activity and this correlates with the level in platelets.[22] In a clinical setting, scalp sulphotransferase activity was higher in men who responded to minoxidil compared with those who did not respond [23]
http://www.medscape.com/viewarticle/470297_3

The variation in sulphotransferases enzymes impacts how people respond to minoxidil. You are also correct that PH and temperature affect the sulphotransferase enzymes. Enzymes in general have an optimal environmental state that allows them to catalyse reactions. I wouldnt worry to much about PH and temperature, your body's natural homeostasis should take care of that for you:



Normal human body temperature of 37C provides a good internal environment for enzymes to work efficiently. Enzymes in the stomach, such as pepsin ( which digests protein ), work best in very acid conditions ( pH 1 - 2 ), but most enzymes in the body work best close to pH 7.


I don't want too bother them too often, so I think the best is if we collect our ideas what could be in and how to mix it with what for producing sth, and then I will ask them in one rush. Would be nice if more people would think about the ideas and try to help figuring out a plan.

Good idea, I agree that we should wait a little till I've got some more experimental outcomes to go on before bothering them with additional requests.


The only thing I do at present is castor oil and derma rolling, I would be happy to document and take part, the only thing is on swisstemples he believes it may reduce PGE2, but I think castor oil increases it, so a mix Emu, Castor and Oleuropein? I would leave in over night and apply every night.

cheers,

Thats an interesting site you linked, I'm going to go over the stuff wen I'm free to see if theres anything of interest. As for PGE2, my next post will be an in depth analysis on how PGE2 actually works to promote hair growth. In short, Ricinoleic acid (found in castor oil) activates the EP3 receptors in women. (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3384204/) It should in theory do the same in men and exert it effects when applied topically. EP3/EP2 agonists increase Beta Catenin, and thats why they grow hair. Not sure about Castor oil inhibiting PGE2 synthesis - negative feedback? Anyways, I dont think castor oil is bad. My recent findings indicate oleuropein works faster if you use an ethanol vehicle, and using it in an oil based solution will yield sub par results. You want to aim for 1-2mg per ml and use the oils after the ethanol has dried up.

A caution for people making ethanol vehicles, you can only use ethyl alcohol/190 proof alcohol found in drinks, NOT denatured ethanol or Isopropyl/Isopropanol. This study on topical ethanol/PG formulations (http://s000.tinyupload.com/download.php?file_id=04373994853943132228&t=0437399485394313222837538) of minox shows that anything above 90% Ethanol/10 % PG results in absorption less than that of 50% ethanol/50% PG. With 50/50 to 90/10 having optimal absorption. PG seems to keep the minox from forming crystals/residue on the skin and improves absorption if my understanding is correct, whereas a 100% ethanol vehicle just doesnt work. This probably applies to oleuropein as well and possibly EGCG.

Chemical
12-26-2015, 07:10 AM
The small vellus hairs that minox made were about 1-2mm in length across the hairline since using the Oleuropein some of these have doubled in length to 3-4mm nothing groundbreaking but they are getting longer for sure so im hoping in the next few weeks they might keep growing.

This is promising! Which brand are you using?

I've been doing some more research on PGE2 and thought I'd share my findings here. We'll start off with this study that shows PGE2's effects on β-catenin:



Prostaglandin E2 promotes colon cancer cell growth through a Gs-axin-beta-catenin signaling axis. (http://www.ncbi.nlm.nih.gov/pubmed/26058972)
Abstract

We show that PGE2 stimulates colon cancer cell growth through its heterotrimeric guanine nucleotide-binding protein (G protein)-coupled receptor, EP2, by a signaling route that involves the activation of phosphoinositide 3-kinase and the protein kinase Akt by free G protein betagamma subunits and the direct association of the G protein alphas subunit with the regulator of G protein signaling (RGS) domain of axin. This leads to the inactivation and release of glycogen synthase kinase 3beta from its complex with axin, thereby relieving the inhibitory phosphorylation of beta-catenin and activating its signaling pathway. These findings may provide a molecular framework for the future evaluation of chemopreventive strategies for colorectal cancer.

PGE2 inhibits axin mediated formation of the BetaCatenin destruction complex involving GSK3Beta. It does this via the EP2 receptor and also the EP3/4 receptors:

Prostaglandin E2 promotes human cholangiocarcinoma cell proliferation, migration and invasion through the upregulation of β-catenin expression via EP3-4 receptor. (http://www.ncbi.nlm.nih.gov/pubmed/26058972)

To understand what the Axin/APC destruction complex is, heres a graphical representation of what it looks like:

http://ars.els-cdn.com/content/image/1-s2.0-S0092867412005302-fx1.jpg

Wnt Signaling through Inhibition of β-Catenin Degradation in an Intact Axin1 Complex (http://www.sciencedirect.com/science/article/pii/S0092867412005302)

The proteins surrounding β-catenin are involved in the destruction of β-catenin. First CKI prepares β-catenin for GSK3Beta. Once GSK3Beta has phosphorylated β-catenin, Axin and APC form a scaffold that that enables the β-catenin to be degraded. If any of these proteins are inactivated then β-catenin will not be destroyed and translocate to the nucleus and exert its effects with the help of TCF4. WNTs like WNT10b - which oleuropein upregulates - protect β-catenin from destruction:



The removal of β-catenin from the destruction complex is accomplished simply by direct degradation by the proteasome. This step recycles the destruction complex for another round of β-catenin degradation. We show that Wnt receptor-ligand interaction leaves the destruction complex compositionally unchanged and does not affect the activity of its kinases. The only change that we observe is the association of Axin1 with phosphorylated Lrp6 and the dissociation of β-TrCP. Indeed, phosphorylated β-catenin—still bound to the Axin1 complex—is no longer ubiquitinated and degraded. It saturates and thus effectively inactivates the Axin1 complex. We have previously reported that only β-catenin that is newly synthesized after initiation of the Wnt signal is signaling competent (Staal et al., 2002). This notion is in agreement with our current model, which predicts that newly synthesized, nonphosphorylated β-catenin will be stable in a free cytosolic form once the destruction complex is saturated. It can then translocate to the nucleus to associate with TCF and activate the Wnt transcriptional program.

Anything that blocks Axin or GSK3 or any of the proteins required to destroy β-catenin will lead to increased β-catenin. Thats why GSK3 inibitors like Valproic acid work topically. PGE2 -> ( EP2/3 ¬ Axin ) -> β-catenin. This is one possible explanation for castor oils hair growth promoting effects.

PGE2 is quite difficult to increase and analogues are very expensive. Castor oil is a viable alternative however. If there was a different molecule that could inhibit Axin then we could use that to directly increase β-catenin bypassing WNT. Thats where EGCG comes in:

The anti-adipogenic effects of (-)epigallocatechin gallate are dependent on the WNT/β-catenin pathway. (http://www.ncbi.nlm.nih.gov/pubmed/23318137)

Abstract
(-)Epigallocatechin gallate (EGCG) is the most abundant catechin in green tea and reportedly has anti-obesity and anti-adipogenic effects. In this study, we determined that the up-regulation of the WNT/β-catenin pathway is the anti-adipogenic mechanisms of EGCG in 3T3-L1 cells. EGCG treatment down-regulates the expression of major genes involved in the adipogenesis pathway including peroxisome proliferator-activated receptor (PPAR)γ, CCAAT/enhancer binding protein (C/EBP)α, fatty acid binding protein (FABP)4 and fatty acid synthase (FASN), while up-regulating the nuclear level of β-catenin. Knockdown of β-catenin using small interfering (si) RNA attenuated the inhibitory effects of EGCG on intracellular lipid accumulation. β-catenin siRNA transfection also recovered terminal adipocyte markers such as FABP4, FASN, lipoprotein lipase and adiponectin, which were down-regulated by EGCG. The DNA binding activities as well as the expression levels of PPARγ and C/EBPα, which were down-regulated by EGCG, were significantly restored by β-catenin siRNA transfection. In addition, we found that EGCG efficiently up-regulates the WNT/β-catenin pathway. Among the members of the WNT/β-catenin pathway, the expressions of low density lipoprotein receptor-related protein LRP5, LRP6, disheveled DVL2 and DVL3 were significantly up-regulated, while AXIN expression was down-regulated by EGCG, and the phosphorylation of glycogen synthase kinase 3β was increased. These results suggest that EGCG activates the WNT/β-catenin pathway, resulting in the up-regulation of β-catenin, which down-regulates the major genes of the adipogenesis pathway. Taken together, our findings clearly show that the anti-adipogenic effects of EGCG are, at least partially, dependent on the WNT/β-catenin pathway.

-------------------------------------------------

EGCG, in addition to inihibiting AR expression, downregulates Axin and reduces the amount of GSK3 available to destroy β-catenin.

So this is what the current treatment stack looks like:

(Oleuropein ¬ DDK1) -> natural WNTs can bind
Oleuropein -> WNT10b -> β-catenin

Minoxidil -> Adenosine Receptor -> β-catenin
(Minoxidil ¬ AR) -> β-catenin + TCF4 activity

(EGCG ¬ AR) -> β-catenin + TCF4 activity
(EGCG ¬ Axin) -> β-catenin

((Mico/Keto ¬ 3β-Diol) ¬ ERβ ) -> VEGF

And if you want to use castor oil:

(Ricinoleic Acid -> EP3 ¬ Axin) -> β-catenin

I think we should all try and find cost effective herbs/supplements that can downregulate AR or boost WNTs/β-catenin signalling. The more readily vailiable options we have, the greater the chance people can use what works best for them. We might even have a ridiculously powerful stack to reverse AGA or even cure it - and by cure I mean you only need to use the treatments infrequently to maintain density. I have hopes that next year we will have some interesting breakthroughs/discoveries, and we may no longer need to rely on or wait for big pharmaceutical companies for new treatments or only rely on expensive treatments to grow hair.

joshuk
12-27-2015, 09:16 AM
using this ethanol tincture http://www.amazon.co.uk/gp/product/B00B2U9MW4?psc=1&redirect=true&ref_=oh_aui_detailpage_o02_s00

do you think if i put a cap of EGCG into it, it would not mess up the Oleuropein im also using CB-03-01 (AR blocker??) would their be any point with EGCG if im using an AA or do you think it could compliment it

joshuk
12-27-2015, 09:49 AM
chemical im going to make a new topical with EGCG and Oleuropein in it

gonna use 60/40 mix of ethanol/pg so if i make a 60ml solution being 40ml ethanol 20ml PG

Oleuropein caps are = http://www.amazon.co.uk/gp/product/B0056Z7IMC?psc=1&redirect=true&ref_=oh_aui_detailpage_o03_s00
EGCG caps are = http://www.amazon.co.uk/gp/product/B0031XEF2M?psc=1&redirect=true&ref_=oh_aui_detailpage_o00_s00

how many caps of each would you add?? just 1 im thinking as a trial or would you add more

also for people wanting to try this in europe i got my ethanol from https://www.thewhiskyexchange.com/P-15105.aspx

and proplyene glycol from http://www.cremedevape.com/epages/yxve46fvrnud.sf/en_GB/?ObjectID=4164040

im also using CB-03-01 and setipirant/ neogenic and adenonise castor oil 1ml orally and nizoral 3 times a week.
so hoping this stacked with these will bring results ( cant use minox otherwise i would )

Chemical
12-27-2015, 12:48 PM
http://www.amazon.co.uk/gp/product/B00B2U9MW4?psc=1&redirect=true&ref_=oh_aui_detailpage_o02_s00

Looking at that product again it seems it may be not 100% effective as kirkland minox vehicle seeing as its got only 36% ethanol derived from cane sugar(?):



Raw Olive Leaf, Olive Leaf Extract (20% oleuropein standardised), ethanol 36% (derived from cane sugar), purified water.

And although its a prepared solution, it doesnt gaurantee it'll be as effective as a custom vehicle. The oleuropein content is around 31mg/ml which is ridiculously high. for its low ethanol percentage. If you really want to avoid minox and you're under a budget, then this will have to do. Be sure to use only 1 drop, no more.



Approx 130 servings of 20 drops. Approx. 25mg oleuropein per serving.
100/130 = 0.78ml per 20 drops.
25mg/0.78ml = 31mg/ml.



chemical im going to make a new topical with EGCG and Oleuropein in it. Gonna use 60/40 mix of ethanol/pg so if i make a 60ml solution being 40ml ethanol 20ml PG.

Oleuropein caps are = http://www.amazon.co.uk/gp/product/B0056Z7IMC?psc=1&redirect=true&ref_=oh_aui_detailpage_o03_s00
EGCG caps are = http://www.amazon.co.uk/gp/product/B0031XEF2M?psc=1&redirect=true&ref_=oh_aui_detailpage_o00_s00

how many caps of each would you add?? just 1 im thinking as a trial or would you add more?

I'm also using CB-03-01 and setipirant/ neogenic, adenonise, castor oil 1ml orally and nizoral 3 times a week. So hoping this stacked with these will bring results ( cant use minox otherwise i would )

It seems you've beaten me to it. A purer ethanol vehicle with a bit of PG will most likely yield better results even if only increases the chances/probability of regrowth by a small amount. 80% ethanol, 20% PG. Thats what I would do. 1 cap of that oluropein you linked will give around 1.5mg/ml if you're going with 100ml. 1 cap of EGCG too. The purpose of the ethanol is to break down the barrier of the skin, and the PG supposedly helps the molecules stay dissolved long enough to slowly be absorbed by the skin. Beware of irritation and itching from PG, you want to avoid that.

I realise getting ethanol in the UK is not an easy task, you cant even get everclear here. I was going to suggest spirytus but you've already beaten me to it lol. Its quite steep but it'll last you ages at least. For those of you that can use minox, it works out cheaper to use the kirkland solution as its preformulated and available cheaply in the UK.

You're already on quite a stack Josh, do you think those 2mm of growth could be attributed to CB or any of the other treatments?

I've been using ~1.8mg/ml oleuropein with minox for a little over 20 days now and I'm seeing some remarkable things on the area I normally apply. I'm convinced the oleuropein is making the biggest difference. Since I'm on two weeks break I've been using 0.5ml of the minox solution in the morning, then again at 6pm, then at 10pm I finish off with the emu oil (+ minox + oleuropein solution) which prevents the itching from just using minox + oleuropein alone. I'm going to wait for the area to completely fill in before I post pics, which is very very soon at this rate! I also cant wait to add in EGCG!

joshuk
12-27-2015, 01:00 PM
wow i have been applying about 1ml of that amazon tincture so thats way to much, im glad ive decided to make my own. not only that it stains the scalp brown so not ideal really to use during the day.

so how much Oleuropein per ml would be in 60ml of my custom solution, im guessing 1.8mg/ml as the same as a minox solution just without the minox...

i thought it might have been the Oleuropein that was getting my results becasue RU never really grew much for me so i did not think CB would either so unless CB is way better than RU or the Oleuropein tincture i was using had some effect. either way i will try using this custom mix then hopefully if a few of us start seeing some results we can work out a base formula.

Chemical
12-27-2015, 01:14 PM
I'm using the same oleuropein caps you linked. 150mg per capsule. 150mg/100ml = 1.5mg, which is ideal. For 60ml, use half a cap. Twice a day should be more than enough, less is more in the case of oleuropein. Vellus hairs can grow quite long but you need to be looking out for actual stubble. Hair that feels prickly. I'd expect that around the 30 day mark.

I hope you're not using DMSO as a vehicle for any of your treatments? because DMSO isnt too friendly to hair according to some anecdotal reports. The CB or any AA for that matter wont regrow hair that quickly but the longer your hairs are free from Androgen, the higher the chance other treatments will work faster. CB should definitely potentiate the oleurpein and EGCG, but even without those two you should notice regrowth over time.

And 1ml is way too much. I should'nt have recommended it so I apologise.

joshuk
12-27-2015, 01:36 PM
no not using dmso for anything, CB is mixed into neogenic, what im thinking is applying oleuropein/EGCG in the morning then CB/Neogenic in the evening, so if i want to only use the custom mix ole/egcg mix once a day can i just use 1 cap of each mixed in 60ml instead of half a cap used twice a day?? does this sound reasonable or would you still only use half a cap still for once a day application.

getting quite excited to see if this works to be honest, as you say if the CB is blocking my AR receptors from androgens its working as intended so my DKK1 should be lower correct? mix in EGCG/OLE on top of that.

plus the nizoral ( keto) and the castor oil (PGE2) neogenic is VEGF through hypoxia and the adenoise instead of minox ( obviously not as good) but mixed all together... this could get intresting

Keeper
12-27-2015, 02:15 PM
Keep on going Chemical and joshuk !
Proud of you for trying stuff !
Excited what you have to report later on.
Yes we should be careful. Sometimes you are so much in that regrow can be an illusion ;-)

Chemical
12-27-2015, 02:28 PM
1.5mg/ml per application - dont exceed 2mg ml of OL. EGCG can be increased at your discretion. Once a day application should be fine but my only concern is half life. OL and EGCG dont have particularly long half lives hence why I suggested twice a day, but you're better off using it only in the morning and the rest of the stuff in the evening for the sake of convenience - it shouldnt make a huge difference. For people solely using OL + minox + EGCG, twice a day is advised. I'm trying to find some info on CBs half life which would help with figuring out optimal timing. DKK1 shouldnt be concern at all with that stack, the adenosine, castor oil (topically right?) and EGCG will bypass DKK1 altogether. The main factors of concern now are TGF-Beta1 and time/timing. We need to find a way to ensure the good pathways are always active and the bad pathways are always turned off because the moment DHT/Test can bind to AR, they'll begin exerting their effects counteracting all the hard work. We want to minimise this as much as possible. Once AR stops releasing TGF-Beta1, the hairs should stop inhibiting the growth of nearby follicles so theres a very high probability of synergy between treatments if they dont end up activating detrimental pathways. Thats one of the reasons I'd encourage simple stacks instead of kitchen-sinking.

Keeper
12-27-2015, 04:03 PM
maybe this can give some information:

http://www.hairlosshelp.com/forums/messageview.cfm?catid=10&threadid=25700&STARTPAGE=4&FTVAR_FORUMVIEWTMP=Linear

jamesst11
12-27-2015, 04:13 PM
1.5mg/ml per application - dont exceed 2mg ml of OL. EGCG can be increased at your discretion. Once a day application should be fine but my only concern is half life. OL and EGCG dont have particularly long half lives hence why I suggested twice a day, but you're better off using it only in the morning and the rest of the stuff in the evening for the sake of convenience - it shouldnt make a huge difference. For people solely using OL + minox + EGCG, twice a day is advised. I'm trying to find some info on CBs half life which would help with figuring out optimal timing. DKK1 shouldnt be concern at all with that stack, the adenosine, castor oil (topically right?) and EGCG will bypass DKK1 altogether. The main factors of concern now are TGF-Beta1 and time/timing. We need to find a way to ensure the good pathways are always active and the bad pathways are always turned off because the moment DHT/Test can bind to AR, they'll begin exerting their effects counteracting all the hard work. We want to minimise this as much as possible. Once AR stops releasing TGF-Beta1, the hairs should stop inhibiting the growth of nearby follicles so theres a very high probability of synergy between treatments if they dont end up activating detrimental pathways. Thats one of the reasons I'd encourage simple stacks instead of kitchen-sinking.

do you recommend derma-rolling before application?

iaskdumbquestions
12-27-2015, 11:23 PM
Hi thank you for this. I can't say I understand much of this but I would like to try this!

How do I mix pills with Minoxidil? I currently use Kirkland's brand, so do I just open it up and drop these pills inside?

Also, on page 1 you said:"
I'd also suggest people not to take finasteride systematically because the body will naturally increase testosterone to offset the negative feedback loop, and since finasteride only inhibits ~60%, that increase in testosterone will give 5AR additional substrate to convert into DHT, defeating the whole purpose of fin. I'd like to see people try this with RU as an augmentation, since theoretically there should be less DKK1 as a result of impaired AR signalling. "

Based on that would you also suggest people not use Seti?

iaskdumbquestions
12-27-2015, 11:24 PM
edit: double post

Keeper
12-28-2015, 01:05 AM
http://www.amazon.co.uk/gp/product/B00B2U9MW4?psc=1&redirect=true&ref_=oh_aui_detailpage_o02_s00
I've been using ~1.8mg/ml oleuropein with minox for a little over 20 days now and I'm seeing some remarkable things on the area I normally apply. I'm convinced the oleuropein is making the biggest difference. Since I'm on two weeks break I've been using 0.5ml of the minox solution in the morning, then again at 6pm, then at 10pm I finish off with the emu oil (+ minox + oleuropein solution) which prevents the itching from just using minox + oleuropein alone. I'm going to wait for the area to completely fill in before I post pics, which is very very soon at this rate! I also cant wait to add in EGCG!

Hey Chemical,
- Before your break you were using minox + oleuropein how often and for how long (6 weeks?)
- How long were you using Minox before you started also using oleuropein?
- So now you use 3x 0.5 ml Minox Solution (just normal minox or is it already a combined solution with sth else?) and in the evening you also use emu oil (I like the combination for preventing itching) and oleuropein solution
- If you have been 2 weeks off Minox, you should probably get the "payback" in at least 1 month for not applying it or? I think the effect of everything you do to hair comes after around 2 months or later (like in most treatments) like people who stop minox losing the extra hair after around 2 months. What do you think about it? Do you think you can stabilize it?


Hope I didnt understand sth wrong

Chemical
12-28-2015, 06:52 AM
http://www.hairlosshelp.com/forums/messageview.cfm?catid=10&threadid=25700&STARTPAGE=4&FTVAR_FORUMVIEWTMP=Linear

The guy using minox and extra virgin olive oil seems to have had quite a bit of thickening:

July 17th (http://www.hairlosshelp.com/forums/attachments/viewattachment.cfm?attachid=38548&forumid=1)
August 2nd (http://www.hairlosshelp.com/forums/attachments/viewattachment.cfm?attachid=38549&forumid=1)
September 19th (http://www.hairlosshelp.com/forums/attachments/viewattachment.cfm?attachid=38553&forumid=1)

But you can see in the first picture he already had follicles - albeit that were miniaturising, so the minox probably rescued them and thickened them up. The OL content in oil isnt very high but it may have played a part. Its hard to tell.


do you recommend derma-rolling before application?

No need. The ethanol will reduce the skins barrier function.


How do I mix pills with Minoxidil? I currently use Kirkland's brand, so do I just open it up and drop these pills inside?
Would you also suggest people not use Seti?

Just drop the powder in and shake until you cant see anymore powder. You might want to make a small test sample of around 30ml just in case I make changes to the protocol or something comes up. Be sure to stay under 2mg/ml of oleuropein - ideally 1.5mg/ml. If you want to use EGCG start off with 1 cap, and you can increase later once I've had time to play around with doses.


If you have been 2 weeks off Minox, you should probably get the "payback" in at least 1 month for not applying it or? I think the effect of everything you do to hair comes after around 2 months or later (like in most treatments) like people who stop minox losing the extra hair after around 2 months. What do you think about it? Do you think you can stabilize it?
Hope I didnt understand sth wrong

I started using Minox, Emu oil, and Keto cream around April this year. I applied these three separately (no mixing) most days at night, but was regular with keto cream twice a day. No drastic regrowth and no effect on shedding either.

Then in late August I bought Oleuropein and saw palmetto which I mixed with emu oil and minox - we'll call this emox.

I used emox at night everyday, and the plain minox followed by keto cream in the morrning for 6 weeks straight and noticed some regrowth in peripheral regions marked green and some more vellus hairs in dotted black areas:

http://i.imgur.com/nT4agP2m.png (http://imgur.com/nT4agP2)

I apply in the region circled blue an tilt my head to the left to let it reach the other side. I saw some thickening of existing terminal hairs at the center of my hairline but most of the regrowth and significant thickening was were the emox was reaching in small amounts. This led me to believe oleuropein had a biphasic effect.

As I kept increasing the concentration of OL and Saw Palmetto. I wasnt seeing much of a difference and it might have made things worse because it was forming a very thick residue on my scalp. In late October I stopped using it during the weekdays because I was so busy with work, but I was using it heavily on the weekends. My plain minox had run out by Nov.

Unfortuneately the emox was becoming a pain to remove since I had to shampoo it out every morning so around November 20th I stopped completely. I realised I was losing alot of density in the crown area and the emox wasnt doing anything. I started using miconazole and ketoconazole twice a day everyday, thats when I noticed some hairs thickening in the blue region. This could have been due to OL gradually reaching a lower concentration over the course of its half life? Or my scalp had finally recovered from excessive shampooing? - I dont know. I saw that the left side had receded quite a bit and the follicles were miniaturising which got me kind of worried. You are right in that I did pay the price for not using the emox properly.

Around 10th December, I made a new batch of emox, using no Saw palmetto, and only two caps of OL. I also added a tiny amount of OL to plain minox - we'll call this mxol.

And I've also got some plain Emu oil thats not mixed with anything.

I use the mxol more often, twice a day and wait for it to dry up. Since I'm on break I use the plain emu oil 2-3 hrs after mxol because I noticed my scalp becomes very itchy if I dont use it. At night I use the emox 2-3 hrs after mxol. I use the mico too if I remember. The shedding is nonexistant now and frontal density is coming back, ALOT faster than my initial trial with emox + minox. My preconception that Emu Oil was suitable vehicle was incorrect, it doesnt help at all with penetration. The ethanol/PG is the more effective vehicle. I should probably make a wiki of all the updated knowledge and use this thread as more of a protocol/log discussion place, it would make things a bit more organised.

SriHanuman
12-28-2015, 07:58 AM
Yes it should be fine, but before you go ahead, which brand of EGCG are you using? I'd recommend teavigo since you can get away with a lower concentration of the extract and get the raw EGCG that you actually need. I'm ot sure how the other polyphenols affect, so for now we'll stick to pure EGCG as used in the study. EGCG also has a dose dependent effect so start off with 1 capsule, then see if it leaves a residue after applying. If not, add another. Rub the skin softly to see if you get any residue, even if its just a little, dont add anymore to the solution. Also what concentration of ethanol are you using?

I will be using:

http://www.amazon.co.uk/Ethanolic-Tincture-Concentrate-Oleuropein-Glycerine/dp/B00B2U9MW4/ref=sr_1_1?ie=UTF8&qid=1451314576&sr=8-1&keywords=olive+leaf+tincture

And yes will order teavigo. But fistly I shall try only this tincture and see what happens in one to two months.

Chemical
12-28-2015, 02:03 PM
@SriHanuman

If its within your budget you will better off with a custom vehicle using this ethyl alcohol from amazon uk:
http://www.amazon.co.uk/Spinnrad-Ethyl-Alcohol-96-5%25-100/dp/B001TJ0NJY/ref=sr_1_1?ie=UTF8&qid=1451336373&sr=8-1&keywords=ethyl+alcohol

mixed with this PG:
http://www.amazon.co.uk/1000ml-Classikool-Propylene-Glycol-Pharma/dp/B00BHGM05O/ref=sr_1_1?ie=UTF8&qid=1451336492&sr=8-1&keywords=propylene+glycol

That premade tincture wont be as effective as a custom Ethanol/PG vehicle.

Seuxin
12-28-2015, 03:01 PM
A good vehicle is REALLY important to have real result ! Using eth/pg is not a good idea. You can improve it, here is a good formula :

-> Ethanol / DMI / Polysorbate 80

potato1987
12-28-2015, 04:27 PM
Is it possible for someone to list the items required (amazon, ebay) and instruction on what to do, perhaps a youtube video to ensure we are consistent? I do apologise but I don't understand enough of the terms and so wouldn't have a clue.

Happy to document results! Can't use minox however it really messed up my face.

SriHanuman
12-29-2015, 02:31 AM
@SriHanuman

If its within your budget you will better off with a custom vehicle using this ethyl alcohol from amazon uk:
http://www.amazon.co.uk/Spinnrad-Ethyl-Alcohol-96-5%25-100/dp/B001TJ0NJY/ref=sr_1_1?ie=UTF8&qid=1451336373&sr=8-1&keywords=ethyl+alcohol

mixed with this PG:
http://www.amazon.co.uk/1000ml-Classikool-Propylene-Glycol-Pharma/dp/B00BHGM05O/ref=sr_1_1?ie=UTF8&qid=1451336492&sr=8-1&keywords=propylene+glycol

That premade tincture wont be as effective as a custom Ethanol/PG vehicle.

For sure that would be better. But I was thinking of using this tincture until I see any results or couple of months go by. If I see results, even a little bit, then will I go with a custom vehicle. Lets see if this has any effect at all, and I think this tincture will provide some, if it works.

SriHanuman
12-29-2015, 02:32 AM
double post....

InBeforeTheCure
12-29-2015, 04:05 AM
Haven't people tried topical EGCG before with no substantial results?

joshuk
12-29-2015, 08:40 AM
Haven't people tried topical EGCG before with no substantial results?

we will soon find out as in a couple of days i will be starting a custom mix of EGCG/oleuropein i dont mind guinea pigging myself as im using experimental hairloss drugs anyway what could go wrong lmao!!

iaskdumbquestions
12-29-2015, 08:52 AM
I am willing to try this and document results but let me just get this straight:

I should buy this:

http://www.amazon.com/gp/product/B00GZRIW5C/ref=s9_simh_gw_g121_i1_r?pf_rd_m=ATVPDKIKX0DER&pf_rd_s=desktop-1&pf_rd_r=1GAD1STY1SHDM19KNS0V&pf_rd_t=36701&pf_rd_p=2079475242&pf_rd_i=desktop

And then open the capsules and put them into this:

http://www.amazon.com/KIRKLAND-MINOXIDIL-Topical-Unscented-Regrowth/dp/B00L7PQLAA/ref=sr_1_18?s=hpc&ie=UTF8&qid=1451404124&sr=1-18&keywords=minoxidil+kirkland

I'm not to sure how to open the minoxidil up, but I'll have to play around with it. Also, I asked this previously but, what is your opinion on Setiprant? On page 1 you suggested that the body will compensate by creating more DHT. Would you apply the same reasoning to Seti?

joshuk
12-29-2015, 08:58 AM
I am willing to try this and document results but let me just get this straight:

I should buy this:

http://www.amazon.com/gp/product/B00GZRIW5C/ref=s9_simh_gw_g121_i1_r?pf_rd_m=ATVPDKIKX0DER&pf_rd_s=desktop-1&pf_rd_r=1GAD1STY1SHDM19KNS0V&pf_rd_t=36701&pf_rd_p=2079475242&pf_rd_i=desktop

And then open the capsules and put them into this:

http://www.amazon.com/KIRKLAND-MINOXIDIL-Topical-Unscented-Regrowth/dp/B00L7PQLAA/ref=sr_1_18?s=hpc&ie=UTF8&qid=1451404124&sr=1-18&keywords=minoxidil+kirkland

I'm not to sure how to open the minoxidil up, but I'll have to play around with it. Also, I asked this previously but, what is your opinion on Setiprant? On page 1 you suggested that the body will compensate by creating more DHT. Would you apply the same reasoning to Seti?

you cant use the foam to dissolve the oleuropein your gonna need to use the liquid unless you somehow heat it into a liquid then dissolve it or something but the foam does not have proplyene glycol in it so i dont think it will absorb.... but you can try

iaskdumbquestions
12-29-2015, 09:20 AM
you cant use the foam to dissolve the oleuropein your gonna need to use the liquid unless you somehow heat it into a liquid then dissolve it or something but the foam does not have proplyene glycol in it so i dont think it will absorb.... but you can try

I couldn't find a seller that ships the liquid to the United States. :/

Edit: Found this
http://www.amazon.com/Foods-Olive-Glycerite-Oleuropein-ounce/dp/B0019LWTWQ/ref=sr_1_2?ie=UTF8&qid=1451406073&sr=8-2&keywords=Olive+Leaf+Extract+Liquid

Ships to the United States and has 18% Oleurpein. Not as strong as the 20% you posted earlier, but it's the best I could find.

joshuk
12-29-2015, 09:33 AM
I couldn't find a seller that ships the liquid to the United States. :/

Edit: Found this
http://www.amazon.com/Foods-Olive-Glycerite-Oleuropein-ounce/dp/B0019LWTWQ/ref=sr_1_2?ie=UTF8&qid=1451406073&sr=8-2&keywords=Olive+Leaf+Extract+Liquid

Ships to the United States and has 18% Oleurpein. Not as strong as the 20% you posted earlier, but it's the best I could find.

dont think the premade stuff is going to work to be honest, cant you get kirkland liquid minoxdil from costco or walmart, im in the uk so i dont know for sure but i have heard of people getting it from these places.

failing that get everclear and propelyne glycol and make your own mix like im doing would be alot better. the reason for the premade stuff not working is the ethanol content is not high enough or stays long enough on the scalp to absorb properly.

i bought the ethanol tincture earlier in this thread and it did not absorb properly and left a brown stain on my scalp,not only that the oleuropein content is way to high chemical said you need it to be around 1.5mg/ml the one that you are using is the one i had and the oleuropein is 31mg/ml. have you applied it yet you will see what i mean by the staining of the scalp

hope this helps... but i would honestly make your own solution if you can if not use minoxil liquid as a vehicle and add the caps into that

Sogeking
12-29-2015, 10:30 AM
dont think the premade stuff is going to work to be honest, cant you get kirkland liquid minoxdil from costco or walmart, im in the uk so i dont know for sure but i have heard of people getting it from these places.

failing that get everclear and propelyne glycol and make your own mix like im doing would be alot better. the reason for the premade stuff not working is the ethanol content is not high enough or stays long enough on the scalp to absorb properly.

i bought the ethanol tincture earlier in this thread and it did not absorb properly and left a brown stain on my scalp,not only that the oleuropein content is way to high chemical said you need it to be around 1.5mg/ml the one that you are using is the one i had and the oleuropein is 31mg/ml. have you applied it yet you will see what i mean by the staining of the scalp

hope this helps... but i would honestly make your own solution if you can if not use minoxil liquid as a vehicle and add the caps into that

Let me just check if I got everything right. I found liquid form of 65% oleuropein with 270mg per mL. I though about using one ml of this oleuropein diluted in a 180-200 ml mix of ethanol and PG. m i getting this right? And afterwards dropping one teavigo capsule in that as well.
I'll probably add minox to the regime later.

joshuk
12-29-2015, 10:36 AM
Let me just check if I got everything right. I found liquid form of 65% oleuropein with 270mg per mL. I though about using one ml of this oleuropein diluted in a 180-200 ml mix of ethanol and PG. m i getting this right? And afterwards dropping one teavigo capsule in that as well.
I'll probably add minox to the regime later.

i guess you could do that yes, that should give you about 1.35mg/ml for 200ml of eth/pg and 1.5mg/ml in 180ml which would seem about right what chemical says, the only thing is 270mg/ml IS ALOT of oleuropein are you sure thats the correct dosage as i was using a very strong oleuropein tincture of amazon and that was only 31/mg per ml. yours is 8 x the strength???

Sogeking
12-29-2015, 12:46 PM
i guess you could do that yes, that should give you about 1.35mg/ml for 200ml of eth/pg and 1.5mg/ml in 180ml which would seem about right what chemical says, the only thing is 270mg/ml IS ALOT of oleuropein are you sure thats the correct dosage as i was using a very strong oleuropein tincture of amazon and that was only 31/mg per ml. yours is 8 x the strength???

Yes I know. A really strong concentration. Of course this is listed on the website of the shop in my country that sells it. It may be wrongly written down. Because on iHerbs most oleuropein liquids come at concentrations ranging from 6% to 20%. Have to check in person. But if does come at concentration of 65% at least it should last me a long time.
I'm gonna order PG from that site you linked, already ordered ECGC. Gonna buy oleuropein on Thursday. I plan to put pics here and I plan to test this out for 3-4 months. If it starts showing some results I'll add minox to the mix at some small concentrations.

Chemical
12-29-2015, 01:14 PM
A good vehicle is REALLY important to have real result ! Using eth/pg is not a good idea. You can improve it, here is a good formula :

-> Ethanol / DMI / Polysorbate 80

The DMI is a good option, it helps carry molecules quite well across the skin layer. The poly 80 not so sure, I've seen no literature on it although its commonly used in alot of creams. But we want to keep the vehicle lean, cheap, and easily made. I can do some reading but is there really a compelling advantage in using DMI + emollient?


Is it possible for someone to list the items required (amazon, ebay) and instruction on what to do, perhaps a youtube video to ensure we are consistent?

I think if you can wait, you should wait. Keeper has a manufacturer that is willing make a consistent formula which can be distributed to users free of charge for trialling, otherwise you will potentially be wasting money on an experimental protocol.

If you're in the US:

Amazon US - Oleuropein - $7.99 (http://www.amazon.com/Olive-Leaf-Extract-Super-Strength/dp/B00GZRIW5C/ref=sr_1_1?ie=UTF8&qid=1451417068&sr=8-1&keywords=oleuropein)
Amazon US - Propylene Glycol - Pick whichever is cheapest (http://www.amazon.com/s/ref=nb_sb_noss?url=search-alias%3Daps&field-keywords=propylene+glycol&rh=i%3Aaps%2Ck%3Apropylene+glycol)
Everclear 95%/190 proof - $16.99 (http://www.argonautliquor.com/r/products/everclear-grain-alcohol-190-proof) - You should try and find the best deal available instead of just using this link since I cant vouch for this site.

For those that want to use minox:

Amazon US - Kirkland Minoxidil 5% - 6 month supply - $29 (http://www.amazon.com/Kirkland-Minoxidil-Strength-Regrowth-Supply/dp/B002VLZHLI/ref=sr_1_1?ie=UTF8&qid=1451417500&sr=8-1&keywords=kirkland+minoxidil)

Simply drop the capsule contents into the solution, and shake vigorously, this isnt chemistry whatsoever.

Amazon US - Teavigo EGCG - Healthy Origins - $14 (http://www.amazon.com/Healthy-Origins-Multi-Vitamins-Count/dp/B000JLA7Y4/ref=sr_1_1?ie=UTF8&qid=1451417666&sr=8-1&keywords=teavigo)
Amazon US - Teavigo EGCG - Swanson - $14 (http://www.amazon.com/Swanson-Superior-Herbs-Teavigo-Caps/dp/B0031XEF2M/ref=sr_1_6?ie=UTF8&qid=1451417666&sr=8-6&keywords=teavigo)


Haven't people tried topical EGCG before with no substantial results?

Ironically many people have also tried olive oil with little success = oleuropein doesnt work?

People at the other hairloss forum have tried: http://www.*****************/interact/showthread.php/41102-EGCG-(topical)-stimulates-hair-growth-study

Some guy claims to have seen results:
http://www.regrowth.com/hair-loss-forums/topic/my-results-with-egcg-and-ode-to-my-methodology/

Someone has been using it on their face to reduce facial hair too:


Personal note. As many of you know, Ive been trying topical homemade green tea extract on one side of my face to see if it will reduce hair. I haven't even been doing it a month yet, but the beard on my right cheek is weaker, smaller in circumference, and lighter colored than on my left when I look close. I can also feel the difference when I run my hand down each side. I think I have found the topical anti-androgen Ive been looking for to add to my internal finasteride. Im going to call it a day on further research on a topical anti-androgen. I really think this one is sufficient

http://www.*************/hair-loss/board_entry-id-20026-page-12-category-3-order-last_answer-descasc-DESC.html

This patent by Gillette on syrian hamsters (http://www.freepatentsonline.com/EP0814754.html) that have AR dependent hair, showed that EGCG significantly reduced hair size and growth at concentrations up to 30%.

I think alot of people that try different stuff probably try them in a vaccuum, and if it works then only very small minority will post their findings on the internet whereas the vast majority will say that it didnt work. The theory is there, and on paper/animals there is convincing evidence of its efficacy. But we dont know for sure if using it in a proper vehicle or along side other treatments will yield results. Like Josh has said, this is still an experiment, I'll never know until I try.


I asked this previously but, what is your opinion on Setiprant? On page 1 you suggested that the body will compensate by creating more DHT. Would you apply the same reasoning to Seti?

I'm sorry I forgot to answer this question. Setipiprant is a PGD2 blocker, I'm under impression PGD2 isnt the main culprit but it's metabolite 15-dPGJ2 that kills hair follicles - as stated by Cotsarelis. By reducing the expression of COX-2, PGD2 should be rate limited and subsequently result in less 15-dPGJ2 being synthesized. Its a factor, but not the only or most important one, I will investigate this matter in detail later on. If you want to use Seti and can afford it - I dont see any harm, unlike fin. It's probably not going to be anything groundbreaking in my opinion.



15-dPGJ2 induces apoptosis (fig. S2A), as evidenced by plasma membrane blebbing and cell retraction/shrinkage. 15-dPGJ2 also decreased cell density, cell division, and live-cell numbers (fig. S2, B to D). Perhaps because the origin of these keratinocytes was not the hair follicle, PGD2 had no such effect on the cells. However, 15-dPGJ2 did increase sub-G1 DNA quantities and activated caspase 3 in human keratinocytes, which are features of apoptotic cell death (fig. S2, E to G). We therefore hypothesized that at least 15-dPGJ2, if not also PGD2, could directly inhibit hair growth in vivo.


Let me just check if I got everything right. I found liquid form of 65% oleuropein with 270mg per mL. I though about using one ml of this oleuropein diluted in a 180-200 ml mix of ethanol and PG.

Josh is correct. Whats the oleuropein brand you're using (link)?

Chemical
12-29-2015, 01:30 PM
@Sogeking

So long as you're getting 65% actual oleuropein and the not the leaf extract at 65% of the solution, then the dosing math should be accurate. The only concern is making sure you get less than 2mg/ml HealthMonthly deliver to europe (http://www.healthmonthly.co.uk/delivery_information) (if you're in EU?), and they stock the oleuropein that I use, maybe thats another option? http://www.healthmonthly.co.uk/swanson_sup_herb_olive_leaf_ext_1?af=gaw&gclid=CKmZncH0gcoCFasBwwodO5oO6g

iroquoispliskin
12-29-2015, 01:42 PM
Found this on amazon for US people:

http://www.amazon.com/Foods-Olive-Glycerite-Oleuropein-ounce/dp/B0019LWTWQ

Its in liquid form standardized to 18% oleuropein. Would there be any problem in using this directly as a topical? The liquid is glycerol and water. From what I've read, glycerol is a penetration enhancer when used on skin (its in a lot of soaps and cosmetic products) Only thing is based on the numbers its 22mg/ml of oleuropein, which is way more than what Chemical said. Is there a reason that exceeding 2mg/ml is detrimental? Could always dilute it further if necessary.

potato1987
12-29-2015, 01:43 PM
Chemical, when you say wait as somebody can have a batch mixed this would be totally without minox yes? (hoping so).

Happy to order and test as soon as someone can mix a batch!

Sogeking
12-29-2015, 04:50 PM
@Sogeking

So long as you're getting 65% actual oleuropein and the not the leaf extract at 65% of the solution, then the dosing math should be accurate. The only concern is making sure you get less than 2mg/ml HealthMonthly deliver to europe (http://www.healthmonthly.co.uk/delivery_information) (if you're in EU?), and they stock the oleuropein that I use, maybe thats another option? http://www.healthmonthly.co.uk/swanson_sup_herb_olive_leaf_ext_1?af=gaw&gclid=CKmZncH0gcoCFasBwwodO5oO6g

Ah yes. Thank you for that mate. It is the leaf extract at 65 % of the solution. I will most likely order from your link. In which case I just use 1 pill diluted in 50 ml of ethanol/pg mix.

TubZy
12-29-2015, 08:33 PM
just mix the OLE powder into adenogen. That is what I do..I used to use neogenic but it doesnt contain PG and adenogen does so I switched to adenogen as my vehicle

Chemical
12-30-2015, 07:58 AM
I'm sorry I forgot to answer this question. Setipiprant is a PGD2 blocker, I'm under impression PGD2 isnt the main culprit but it's metabolite 15-dPGJ2 that kills hair follicles - as stated by Cotsarelis. By reducing the expression of COX-2, PGD2 should be rate limited and subsequently result in less 15-dPGJ2 being synthesized. Its a factor, but not the only or most important one, I will investigate this matter in detail later on.

PGDTS can be induced by Estrogen (aromatased from Testosterone), but exactly which receptor mediates this effect I do not know. My guess is the ER Beta, which ketoconazole and miconazole address via 3BetaDiol suppression. Keto/Mico are like the poor mans version of Seti.


Chemical, when you say wait as somebody can have a batch mixed this would be totally without minox yes? (hoping so).
Happy to order and test as soon as someone can mix a batch!

Without minox yes, we will have to wait for Keeper and the outcome of our experiments to devise an optimal formulation with the help of Keeper's contact.


I've been doing some more research and I came across some new information on DKK-1. We know that oxidative stress (ROS) induces the expression of DKK1, but until now I didnt know how that happened. This excerpt sheds some light on this matter:



To investigate the upstream stimuli responsible for JNK pathway activation and DKK1 up-regulation by lenalidomide, we analyzed changes in gene expression that correlated with DKK1 up-regulation following lenalidomide treatment in vivo. Microarray analysis showed a clear indication of the activation of genes involved in the cellular response to oxidative stress, which is in line with previous reports indicating that thalidomide could induce oxidative injury in the rabbit model system by forming free radical-initiated reactive oxygen species. Interestingly, in the 40 most highly correlated genes, we identified genes encoding caspase 4 (CASP4, 8.7-fold increase; most up-regulated gene) and calpain 2 (CAPN2, 5.3-fold increase), which are involved in endoplasmic reticulum stress-induced apoptosis, and glutaredoxin (GLRX, 7.45-fold increase), glutathione peroxidase (GPX1, 5.7-fold increase), and glutathione S-transferase (GSTO1, 5-fold increase), which play important roles in cellular detoxification, suppressing activities of JNK and its upstream kinases through direct in,eractions.

Therefore, to determine whether oxidative stress plays a role in mediating lenalidomide-induced DKK1 up-regulation, we administered the drug along with the antioxidant agent PBN. As shown in Figure 3A, pretreating cells with PBN significantly reduced lenalidomide-induced DKK1 up-regulation (expression reduced 1.5- to 3.3-fold; mean: 2 ± 0.1; P < .01). Interestingly, preincubating cells with PBN alone could reduce the basal level DKK1 expression (data not shown). Furthermore, in line with previous reports, PBN counteracted c-Jun–binding activation (P < .01; Figure 3B) and JNK phosphorylation (data not shown). Taken together, these data demonstrate that oxidative stress is an upstream stimulus responsible for JNK pathway activation and DKK1 up-regulation induced by lenalidomide.

The antioxidant PBN could prevent the oxidative stress induced DKK-1. Just like Ascorbic Acid. Oleuropein is also a free radical scavenger. But the interesting point here is that, antioxidants could reduce DKK-1 below basal levels without a stress response stimulus. This explains why oleuropein reduced DKK-1 in the mice study. In the presence of testosterone, anti-oxidants will probably only keep DKK-1 at basal levels, but if AR is suppressed significantly, DKK-1 can be further reduced thus allowing WNT to freely bind whenever and however it wants! It seems DKK-1 is a solved case, its now time to find agents that can activate the canonical WNT pathway.

Baicalin activates the WNT pathway (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3151034/)
Baicalin inhibits AR and grows hair (https://www.baldtruthtalk.com/threads/18194-baicalin-active-ingredient-against-AGA)

The only problem is its not very water soluble. Heat can increase the solubility of baicalin in ethanol (http://pubs.acs.org/doi/abs/10.1021/je900171g). As can a surfactant like tween 80/polysorbate 80 (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3794992/).

This excellent study (http://www.sciencedirect.com/science/article/pii/S0024320511002220) goes over some of the effects of the different flavanoids on WNT/BetaCatenin. Flavanoids have differential effects depending on cell type, exerting pro-apoptotic factors in tumors and promoting survival in others. Does anyone else have any knowledge on herbs/extracts that can increase BetaCatenin and has good solubility properties?

joshuk
12-30-2015, 09:05 AM
chemical about to make my first mix of EGCG/OLE do you think a mixture of 50ml ethanol 10ml of PG is ok?? its about 80/20 split.

also i was thinking of applying this all over my scalp as i shaved my head for this experiment lmao looks wierd but im gonna give it a good go.im gonna use 1/2 cap of OLE and 1 cap of EGCG. so its about 1.35mg/ml OLE in the mix.

i have 50grams of seti that i have not started do you think it will help benifit the WNT/BetaCatenin pathways?? i just dont have any capsules to put it into and dont want to use it topically as im already using a fair amount

Chemical
12-30-2015, 02:36 PM
That should be perfect. The Seti might augment this protocol, but skip if for a few weeks since you've already got a heavy stack. If you dont see any change, then you might want to throw it in. I wish you all the best!

dunester01
12-30-2015, 06:43 PM
Hi Chemical - First, add me to the growing number of posters (and lurkers) in these forums grateful for your willingness to wade through the scientific lit related to AGA and share your insights. While the prospect of a standardized formula that incorporates oleuropein or ECGC (or both) is exciting (I'm referring to Keeper's efforts), I want to experiment on my own. I've had decent results using 5% Minoxidil so I want to continue to use it. If I understand your recent posts correctly, to replicate the formula that you'd currently recommend, I'd simply add 1/2 capsule of the Swanson's Superior Herbs Olive Leaf Extract Super Strength and 1 capsule of either the Swanson's Superior Herbs Teavigo EGCG or the Healthy Origins Teavego EGCG to a single 60 mL bottle of 5% Minox. Please correct me if I've misunderstood, and thanks again for your consideration.

InBeforeTheCure
12-30-2015, 09:08 PM
Ironically many people have also tried olive oil with little success = oleuropein doesnt work?

People at the other hairloss forum have tried: http://www.*****************/interact/showthread.php/41102-EGCG-(topical)-stimulates-hair-growth-study

Some guy claims to have seen results:
http://www.regrowth.com/hair-loss-forums/topic/my-results-with-egcg-and-ode-to-my-methodology/

Someone has been using it on their face to reduce facial hair too:



This patent by Gillette on syrian hamsters (http://www.freepatentsonline.com/EP0814754.html) that have AR dependent hair, showed that EGCG significantly reduced hair size and growth at concentrations up to 30%.

I think alot of people that try different stuff probably try them in a vaccuum, and if it works then only very small minority will post their findings on the internet whereas the vast majority will say that it didnt work. The theory is there, and on paper/animals there is convincing evidence of its efficacy. But we dont know for sure if using it in a proper vehicle or along side other treatments will yield results. Like Josh has said, this is still an experiment, I'll never know until I try.


It does say in the abstract of the mouse hair EGCG study:


Topical EGCG down-regulated the T-induced expression of androgen receptor but did not down-regulate 17β-hydroxysteroid dehydrogenase (HSD) and three β-HSD expression.

Perhaps the continued expression of β-HSD could limit results despite AR inhibition? So using EGCG alongside ketoconazole or miconazole (or maybe setipiprant?) to downregulate the ER-β pathway could have a nice synergistic effect.

By the way, the following protocol is the one I'm (tentatively) considering.

- Oleuropein
- EGCG
- Setipiprant
- PGE2
- Valproic acid

Is there anything critical missing? Something like ketoconazole or miconazole for example, or does seti take care of all the downstream effects of ER-β?

JDW
12-31-2015, 09:38 AM
Total respect to all those on this topic who are pushing the boundaries and testing out these new potential solutions. You're doing a top job

lukey
12-31-2015, 09:47 AM
How come no more than 2mg/ml? Is it unsafe or is the excess OL just not doing anything?

Chemical
12-31-2015, 09:58 AM
I want to experiment on my own. I've had decent results using 5% Minoxidil so I want to continue to use it. I'd simply add 1/2 capsule of the Swanson's Superior Herbs Olive Leaf Extract Super Strength and 1 capsule of either the Swanson's Superior Herbs Teavigo EGCG or the Healthy Origins Teavego EGCG to a single 60 mL bottle of 5% Minox.

Exactly like you've said. I hope you will keep us updated?



Perhaps the continued expression of β-HSD could limit results despite AR inhibition? So using EGCG alongside ketoconazole or miconazole (or maybe setipiprant?) to downregulate the ER-β pathway could have a nice synergistic effect.
Is there anything critical missing? Something like ketoconazole or miconazole for example, or does seti take care of all the downstream effects of ER-β?


Minoxidil increases 17 beta-hydroxysteroid dehydrogenase and 5 alpha-reductase activity of cultured human dermal papilla cells from balding scalp. (http://www.ncbi.nlm.nih.gov/pubmed/10098703)

40% increase in 17βHSD from minoxidil. This might be the reason why Keto is included in the big three. HIF-1 stabilization probably maintains sustained VEGF expression, and a decrease cuts off the blood supply, I'm unsure if it makes a big difference given that β-Catenin can induce VEGF independently, albeit for unknown amount of time. Seti would eliminate all probability of PGD2 and its metabolite killing hair cells, thats the only guarantee you get.

Keto and mico quite potently reduce 3BetaDiol (http://www.ncbi.nlm.nih.gov/pubmed/1632630), although no numbers. This study (http://www.ncbi.nlm.nih.gov/pubmed/2824931) shows bifonazole, keto and mico to be very potent at reducing only 17 alpha-hydroxylase in the testes. Bifonazole managed to bring the Ki down from 1090 to 86 +/- 3.3, and keto managed: 160 +/- 4.92. Mico wasn't as strong: 599 +/- 7.22. My assumption is that Keto and mico are additive hence my recommendation for both, but if you must choose one, get keto. They noticed a dose dependent inhibition, and thats why I use it twice a day (dont exceed 3x/week with shampoo).

Your choice of valproic is surprising, its quite harsh on skin according to anecdotal reports. Even at ~8% this study (http://www.ncbi.nlm.nih.gov/pubmed/24533507) shows there was some irritation. If you must satisfy your curiosity, use no more than 2% and with an anti-inflammatory like emu oil. I will look into dosing a little more because GSK3b inhibitors are showing more and more promise. I am tempted to suggest LiCl but not until I've done testing first.

Now for some more research findings!

It turns out activating β-Catenin pathway triggers a feedback loop increasing Axin2 (minoxidil study (http://www.ncbi.nlm.nih.gov/pubmed/21524889)) (another (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC134648/)). Axin2 can substitute axin1 and I'm not sure if the prostaglandin receptors or even EGCG can reduce Axin2 expression. Without Axin2, you'd have sustained β-Catenin level which could become cancerous in sensitive cell types. For hair this would translate to ridiculous hair regrowth rates. (More reading (http://www.ncbi.nlm.nih.gov/pubmed/18083923))

Axin1 is the rate limiting factor for β-Catenin degradation, so if its substituted with Axin2, you're back at square one - β-Catenin will be destroyed. But if you reduce GSK3b, regardless of Axin1/2, β-Catenin will stay elevated.

Indirubin from Angelica sinensis extract - Dong Quai can inhibit GSK3b (http://www.ncbi.nlm.nih.gov/pubmed/21259330). Another study (http://www.ncbi.nlm.nih.gov/pubmed/21826701).

Androgens increase GSK3b:


Androgen treatment revealed a significant decrease in the cytoplasmic/total β-catenin protein ratio and upregulation of the activity of glycogen synthase kinase-3β in DPC, indicative of canonical Wnt pathway inhibition.

http://www.ncbi.nlm.nih.gov/pubmed/22283397


I suspect this is due to AR's negative feedback loop found in the prostate cells, wherein GSK3b represses AR activity (controversial atm (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2386547/)).

By reducing AR this additional increase in GSK3b will be negated. Its becoming very complex again so I will make another diagram soon.

I also realise PGE2 is a beast:



Here, we show that PGE2 activated the E-catenin/TCFdependent transcription in colon cancer cells through the cAMP/PKA pathway. Expression of cyclin D1 and vascular endothelial growth factor (VEGF) was induced by PGE2 in LS-174T cells. Moreover, PGE2 and mutated Ecatenin stimulated the transcription of cyclin D1 and VEGF in a synergistic fashion. Mechanistically, PGE2 increased the phosphorylation of GSK-3 and consequently accumulated E-catenin.

PGE2 -> EP2/4 -> PKA ¬ GSK3b
PGE2 -> EP2/4 ¬ Axin1

Castor oil anyone?

PKA inactivates GSK3b expression. (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC17277/) Since PGE2 is so hard to effectively upregulate, other agents that increase cAMP mediated PKA can also inhibit GSK3b:

Effects of the cAMP-elevating agents cilostamide, cilostazol and forskolin on the phosphorylation of Akt and GSK-3beta in platelets. (http://www.ncbi.nlm.nih.gov/pubmed/19652884)

PTH/cAMP/PKA signaling facilitates canonical Wnt signaling via inactivation of glycogen synthase kinase-3beta in osteoblastic Saos-2 cells. (http://www.ncbi.nlm.nih.gov/pubmed/17990294)


Western blotting demonstrated that GSK-3beta was rapidly phosphorylated at Ser(9) on treatment with PTH or forskolin, leading to its inactivation. Moreover, overexpression of a constitutively active mutant of GSK-3beta abolished the TCF-dependent transactivation induced by forskolin. On the other hand, overexpression of the Wnt antagonist Dickkopf-1 (DKK1) failed to cancel the effects of forskolin on the canonical Wnt pathway

So why hasnt anyone tried forskolin yet?



Evidence that activation of protein kinase A inhibits human hair follicle growth and hair fibre production in organ culture and DNA synthesis in human and mouse hair follicle organ culture. (http://www.ncbi.nlm.nih.gov/pubmed/9217816)

Human hair follicles were isolated from facial skin by microdissection...Human hair follicle growth was inhibited by the phosphodiesterase inhibitors 3-isobutyl-1-methylxanthine and Ro 20-1724, and by the adenylate cyclase activator, forskolin.

Interpret that however you wish. Apparently PGE2 should inhibit facial hair growth too.

This study shows procyanidins (found in apple skin) paired with forskolin increases hair growth rate.



http://www.ncbi.nlm.nih.gov/pubmed/10859531

Forskolin, an adenylate cyclase activator, promotes hair epithelial cell growth and boosts the growth-promoting effect of procyanidin B-2. It is speculated that the hair-growing activity of procyanidins is related to their protein kinase C-inhibiting activity.

Furthermore: Pi3K/AKT ¬ GSK3b.

I know puerarin activates Pi3K quite strongly, so I googled, and whaddayaknow!



http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3765709/
These observations indicated that puerarin induced the phosphorylation of AKT at serine 473 and subsequently activated the phosphorylation of GSK-3β at serine 9, leading to GSK-3β inhibition and Wnt/β-catenin signaling.

http://www.healthmonthly.co.uk/swanson_kudzu_root?af=gaw&gclid=CKDe7fbDhsoCFYMIwwodQfgN3Q

Puerarin;s solubility in water can be increased with higher temperatures. Adding in a starch and using steel balls to mix the solution ridiculously enhances bioavailability lol: this (http://www.ncbi.nlm.nih.gov/pubmed/22591175).

Puerariae Flos (the flowers of Pueraria thomsonii) was found to inihibit 5ar and grow hair in mice: http://www.ncbi.nlm.nih.gov/pubmed/21822606

Not sure where to get this specfic extract since kudzu is broad and we need that flower specifically to inhibit AR, but the standard swanson kudzu I linked should inhibit GSK3b - in theory.

Theres conflicting literature on PKC regulating GSK3b, I'm looking into it. I will be experimenting with various GSK3b inhibitors over the course of next few weeks, including lithium chloride and forskolin to see if they hold any value for us.

@InBeforetheCure
Your stack is ideal, but I'm curious about the PGE2 - where are you getting it from?

@Lukey
OL appears to have a biphasic effect, meaning too much and it loses its effectiveness. In the original study OL wasnt more effective higher than 50um, and produced slightly worse results. Same was seen in OL/Androgen study. I've noticed some strange things too, most of my growth with high OL was in peripheral regions where little OL was penetrating. I've been using a reduced concentration and I'm seeing remarkable things which unfortuneately my shitty camera cant capture. As soon as the area has filled in I will post pics. Its not conclusive but for now less OL is more.

joshuk
12-31-2015, 11:25 AM
chemical you say you are seeing good results, do you think you will see a cosmetic diffrence,as in new terminal regrowth or is it just thickening of exsisting hairs.

i have just applied my first EGCG/OLE mix so i will just report back if i see any results worth mentioning. taken pictures and shaved head for this haha. hopefully have something positive to come back with.

on another note if this does bring results... im not using minox so potential for us poor souls that cant use it

Chemical
12-31-2015, 11:50 AM
It's new years eve, fvck it. You be the judge.

http://imgur.com/a/usmLd

Today I saw two terminal hairs growing right in the centre of that region, where my nw0 hairline was. You cant see it but it was more than 2 inches long. I pulled one of them and it wasnt coming out, so I pulled it until it broke halfway - thats a terminal follicle. The hair felt weird though, really really tough. I've got soft fine hair so somethings definitely going on.

JustParker
12-31-2015, 12:04 PM
Bought myself Oleuropein capsules from amazon (extra strength), and mixed it with minoxidil. I had one bottle left so I dissolved like 5 capsules into the liquid and gave it a good shake. I also added a few saw palmetto capsules which I regret because it did not dissolve at all. I let it sit for 24 hour then shook it again.

Just wanted to point out that the Oleuropein capsules are 750mg total, but only 20% Oleuropein, so each capsule is only 150mg of Oleuropein. Not sure if you accounted for that (as I don't know about uM so sorry if you already caught that). That being said, I look forward to trying this.

Also, thanks for the great initial write up, I know Lithium and Zyrtec (no joke) have both had studies showing hair growth, so I might go back and reevaluate those to see how they fit into the cycle you covered.

joshuk
12-31-2015, 12:13 PM
looks promising do you have small vellus hair throught the zone as in across the nw1 hairline and in the affected zone, but having two terminal hairs grow is awesome from nw0 hairline. if those 2 terminal hairs were from only just a month on your new regime thats positive news!! as it take awhile for hairs to grow from vellus to terminal..so intersting to see what happends in the coming months and if you get any more.

when i noticed my vellus hairs getting longer i licked my finger (i know i know) and then brushed at them and i noticed over the course of 2 weeks i had more and they were getting longer. if all these vellus hairs were to go terminal i would go from an NW4 to an NW2 thats why im excited to see if this works as that would be crazy regrowth, but im realistic as its unheard of unless your a super minox responder to get that.

it looks like your temple is not slick bald anyway as you still have pigmented hairs though out but if you were grow hairs down to the hairline then things would get really intresting. my temples are worse so i can see any changes happening, im hoping with the CB blocking my AR the EGCG/OLE can get to work as growth stimulant and turn some of these vellus terminal, if only it was that easy though lol.

still chemical were stepping into the unkown here but i would rather think outside the box then be stuck in a mindset of only using the big 3. your doing an excellent job keep it up!!! im learning all the time

joshuk
12-31-2015, 12:29 PM
Just wanted to point out that the Oleuropein capsules are 750mg total, but only 20% Oleuropein, so each capsule is only 150mg of Oleuropein. Not sure if you accounted for that (as I don't know about uM so sorry if you already caught that). That being said, I look forward to trying this.

Also, thanks for the great initial write up, I know Lithium and Zyrtec (no joke) have both had studies showing hair growth, so I might go back and reevaluate those to see how they fit into the cycle you covered.

thats fine parker tip one capsule into 60ml minox or make your own solution its up to you im going to use 1/2 of one of those caps and 1 cap of EGCG into an 80/20 ethanol/pg mix cant use minox unfortuantly

iaskdumbquestions
12-31-2015, 12:43 PM
Hi Chemical - First, add me to the growing number of posters (and lurkers) in these forums grateful for your willingness to wade through the scientific lit related to AGA and share your insights. While the prospect of a standardized formula that incorporates oleuropein or ECGC (or both) is exciting (I'm referring to Keeper's efforts), I want to experiment on my own. I've had decent results using 5% Minoxidil so I want to continue to use it. If I understand your recent posts correctly, to replicate the formula that you'd currently recommend, I'd simply add 1/2 capsule of the Swanson's Superior Herbs Olive Leaf Extract Super Strength and 1 capsule of either the Swanson's Superior Herbs Teavigo EGCG or the Healthy Origins Teavego EGCG to a single 60 mL bottle of 5% Minox. Please correct me if I've misunderstood, and thanks again for your consideration.


http://www.amazon.com/Olive-Leaf-Extract-Super-Strength/dp/B00GZRIW5C/ref=sr_1_1?ie=UTF8&qid=1451590553&sr=8-1&keywords=Swanson%27s+Superior+Herbs+Olive+Leaf+Ext ract+Super+Strength

http://www.amazon.com/Healthy-Origins-Multi-Vitamins-Count/dp/B000JLA7Y4/ref=sr_1_fkmr0_1?ie=UTF8&qid=1451590617&sr=8-1-fkmr0&keywords=Herbs+Teavigo+EGCG

http://www.amazon.com/Rogaine-Men-Extra-Strength-Minoxidil/dp/B0000ZREGI/ref=sr_1_1?ie=UTF8&qid=1451590720&sr=8-1&keywords=minoxidil+60ml

With those three items we can begin the regiment? By 'add' do you simply mean dropping the pills/capsules into the liquid minoxidil? Will it dissolve easily?

Chemical
12-31-2015, 02:31 PM
t looks like your temple is not slick bald anyway as you still have pigmented hairs though out but if you were grow hairs down to the hairline then things would get really intresting. my temples are worse so i can see any changes happening, im hoping with the CB blocking my AR the EGCG/OLE can get to work as growth stimulant and turn some of these vellus terminal, if only it was that easy though lol.

still chemical were stepping into the unkown here but i would rather think outside the box then be stuck in a mindset of only using the big 3. your doing an excellent job keep it up!!! im learning all the time

http://imgur.com/a/g6TdQ

I was slick bald in that region before the emox protocol. You can see the vellus hairs in the first picture, but thats technically bald because you cant see them under normal lighting. I'm not seeing miraculous growth in the vertex, but the surrounding hairs are getting thicker and thicker. You can see in the first picture the hair I was talking about sticking out in the middle, it was there for a while. Vellus hair seems to become terminal where the surrounding follicles are terminal - paracrine growth factors I presume. Going from vellus to terminal is difficult, its the timing and duration of treatment that increases probability of hair follicles getting a blood supply attached to DPC and then you have to sustain growth factors until the anagen cycle kicks in. Once anagen kicks in you've got a greater chance of keeping it in anagen. Its like beard growth, you start off with vellus and slowly you start to see terminal hairs. You would think that the testosterone peak at 20-22 would suddenly give people thick beards lol. My theory is; the more beard hairs you have, the quicker each individual hair will grow because every single follicle is releasing IGF-1 to nearby follicles. You can see how the IGF-1 levels start stacking up. Unfortuneately the AGA hairs sabotage nearby follicles by releasing TGF-Beta and DKK1, that's the best explanation for the gradual recession rather than patchy or complete synchronised frontal shedding.

I agree, once I get my nw0 back we can say this protocol is worth something, until then its nothing extraodinary. And not to forget, I have to be able to keep the hairs. And the real challenge lies with people that have been bald for years. With your stack, when you start to see alot of vellus hairs, it'll only be a matter of 1-2 months before they go terminal - I'm fairly confident. Since the new anagen hairs will start off as miniaturised follicles (giving the impression of vellus hairs) but will gradually get thicker at the base once the blood vessels have a chance to latch on. Otherwise they'll constantly be in limbo, trying to grow but not fully getting there.

We are indeed stepping into the unknown. Its amazing what people can achieve with enough motivation or should I say desperation, and a bit of hope.


http://www.amazon.com/Olive-Leaf-Extract-Super-Strength/dp/B00GZRIW5C/ref=sr_1_1?ie=UTF8&qid=1451590553&sr=8-1&keywords=Swanson%27s+Superior+Herbs+Olive+Leaf+Ext ract+Super+Strength
http://www.amazon.com/Healthy-Origins-Multi-Vitamins-Count/dp/B000JLA7Y4/ref=sr_1_fkmr0_1?ie=UTF8&qid=1451590617&sr=8-1-fkmr0&keywords=Herbs+Teavigo+EGCG

With those three items we can begin the regiment? By 'add' do you simply mean dropping the pills/capsules into the liquid minoxidil? Will it dissolve easily?

The Oleuropein and EGCG in your post and this minoxidil:

http://www.amazon.com/Kirkland-Minoxidil-Strength-Regrowth-Supply/dp/B002VLZHLI/ref=sr_1_1?ie=UTF8&qid=1451596397&sr=8-1&keywords=kirkland+minoxidil

Dont drop the capsule themselves, open them, and drop in the contents - the powder into the minoxidil liquid. Only half an oleuropein capsule. Then shake until you cant see any powder at the bottom. It will dissolve fine.

drgs
12-31-2015, 03:34 PM
http://www.amazon.com/Olive-Leaf-Extract-Super-Strength/dp/B00GZRIW5C/ref=sr_1_1?ie=UTF8&qid=1451590553&sr=8-1&keywords=Swanson%27s+Superior+Herbs+Olive+Leaf+Ext ract+Super+Strength

http://www.amazon.com/Healthy-Origins-Multi-Vitamins-Count/dp/B000JLA7Y4/ref=sr_1_fkmr0_1?ie=UTF8&qid=1451590617&sr=8-1-fkmr0&keywords=Herbs+Teavigo+EGCG

http://www.amazon.com/Rogaine-Men-Extra-Strength-Minoxidil/dp/B0000ZREGI/ref=sr_1_1?ie=UTF8&qid=1451590720&sr=8-1&keywords=minoxidil+60ml

With those three items we can begin the regiment? By 'add' do you simply mean dropping the pills/capsules into the liquid minoxidil? Will it dissolve easily?

http://www.skinactives.com/Oleuropein.html
http://www.skinactives.com/Green-Tea-Extract-with-EGCG.html
http://www.skinactives.com/Keratinocyte-Growth-Factor-BT-KGF.html
http://www.skinactives.com/Saw-Palmetto.html

http://www.activeformulas.com/products/oleuropein
http://www.activeformulas.com/products/green-tea-extract-with-egcg

iaskdumbquestions
12-31-2015, 03:48 PM
http://imgur.com/a/g6TdQ




The Oleuropein and EGCG in your post and this minoxidil:

http://www.amazon.com/Kirkland-Minoxidil-Strength-Regrowth-Supply/dp/B002VLZHLI/ref=sr_1_1?ie=UTF8&qid=1451596397&sr=8-1&keywords=kirkland+minoxidil

Dont drop the capsule themselves, open them, and drop in the contents - the powder into the minoxidil liquid. Only half an oleuropein capsule. Then shake until you cant see any powder at the bottom. It will dissolve fine.

Perfect. Just purchased and everything should be delivered by latest January 10th. Will 100% post progress pictures.

Seuxin
01-01-2016, 07:04 AM
Hello Chemical,

Your idea to coumpound a special formula with a labs is very good !

Somes substances to look :

-Vitamine B6
-Zinc or Zinc sulphate
-Azelaic Acid
-Saw Palmetto
-Beta Sitosterol

You should read this blog, it explain how to coumpound an enhanced formula with these : http://www.qdbd.com/hair_formulas_12.htm

--> Warning, if i'm not wrong it's bad to mix zinc with minoxidil.

In addition, you should learn about Apple Polyphenol, it appear to be very important, read this please : http://www.applepoly.com/procyanidin-b-2/

It appear to enhance a lot topical solution for hair.

Then, learn about TransReserveratrol too ;)

SriHanuman
01-01-2016, 12:19 PM
Just started using:

http://www.amazon.co.uk/Ethanolic-Tincture-Concentrate-Oleuropein-Glycerine/dp/B00B2U9MW4

A drop per area, there is absolutely no staining, absorbs quickly. Will report in a month or two with results, if any.

InBeforeTheCure
01-03-2016, 03:40 AM
Minoxidil increases 17 beta-hydroxysteroid dehydrogenase and 5 alpha-reductase activity of cultured human dermal papilla cells from balding scalp. (http://www.ncbi.nlm.nih.gov/pubmed/10098703)

40% increase in 17βHSD from minoxidil. This might be the reason why Keto is included in the big three. HIF-1 stabilization probably maintains sustained VEGF expression, and a decrease cuts off the blood supply, I'm unsure if it makes a big difference given that β-Catenin can induce VEGF independently, albeit for unknown amount of time. Seti would eliminate all probability of PGD2 and its metabolite killing hair cells, thats the only guarantee you get.

Keto and mico quite potently reduce 3BetaDiol (http://www.ncbi.nlm.nih.gov/pubmed/1632630), although no numbers. This study (http://www.ncbi.nlm.nih.gov/pubmed/2824931) shows bifonazole, keto and mico to be very potent at reducing only 17 alpha-hydroxylase in the testes. Bifonazole managed to bring the Ki down from 1090 to 86 +/- 3.3, and keto managed: 160 +/- 4.92. Mico wasn't as strong: 599 +/- 7.22. My assumption is that Keto and mico are additive hence my recommendation for both, but if you must choose one, get keto. They noticed a dose dependent inhibition, and thats why I use it twice a day (dont exceed 3x/week with shampoo).

And since ketoconazole's half-life is only a few hours, the 2x per day stuff would presumably be better for sustained HIF-1 stabilization.


Your choice of valproic is surprising, its quite harsh on skin according to anecdotal reports. Even at ~8% this study (http://www.ncbi.nlm.nih.gov/pubmed/24533507) shows there was some irritation. If you must satisfy your curiosity, use no more than 2% and with an anti-inflammatory like emu oil. I will look into dosing a little more because GSK3b inhibitors are showing more and more promise. I am tempted to suggest LiCl but not until I've done testing first.

I'm planning to use 5-7% (others have used it at 7% with no problems). If it causes irritation, I'll lower the concentration.


Now for some more research findings!

It turns out activating β-Catenin pathway triggers a feedback loop increasing Axin2 (minoxidil study (http://www.ncbi.nlm.nih.gov/pubmed/21524889)) (another (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC134648/)). Axin2 can substitute axin1 and I'm not sure if the prostaglandin receptors or even EGCG can reduce Axin2 expression. Without Axin2, you'd have sustained β-Catenin level which could become cancerous in sensitive cell types. For hair this would translate to ridiculous hair regrowth rates. (More reading (http://www.ncbi.nlm.nih.gov/pubmed/18083923))

Axin1 is the rate limiting factor for β-Catenin degradation, so if its substituted with Axin2, you're back at square one - β-Catenin will be destroyed. But if you reduce GSK3b, regardless of Axin1/2, β-Catenin will stay elevated.

Indirubin from Angelica sinensis extract - Dong Quai can inhibit GSK3b (http://www.ncbi.nlm.nih.gov/pubmed/21259330). Another study (http://www.ncbi.nlm.nih.gov/pubmed/21826701).

Androgens increase GSK3b:



I suspect this is due to AR's negative feedback loop found in the prostate cells, wherein GSK3b represses AR activity (controversial atm (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2386547/)).

By reducing AR this additional increase in GSK3b will be negated. Its becoming very complex again so I will make another diagram soon.

I also realise PGE2 is a beast:



PGE2 -> EP2/4 -> PKA ¬ GSK3b
PGE2 -> EP2/4 ¬ Axin1

Castor oil anyone?

PKA inactivates GSK3b expression. (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC17277/) Since PGE2 is so hard to effectively upregulate, other agents that increase cAMP mediated PKA can also inhibit GSK3b:

Effects of the cAMP-elevating agents cilostamide, cilostazol and forskolin on the phosphorylation of Akt and GSK-3beta in platelets. (http://www.ncbi.nlm.nih.gov/pubmed/19652884)

PTH/cAMP/PKA signaling facilitates canonical Wnt signaling via inactivation of glycogen synthase kinase-3beta in osteoblastic Saos-2 cells. (http://www.ncbi.nlm.nih.gov/pubmed/17990294)



So why hasnt anyone tried forskolin yet?



Interpret that however you wish. Apparently PGE2 should inhibit facial hair growth too.

This study shows procyanidins (found in apple skin) paired with forskolin increases hair growth rate.



Furthermore: Pi3K/AKT ¬ GSK3b.

I know puerarin activates Pi3K quite strongly, so I googled, and whaddayaknow!



http://www.healthmonthly.co.uk/swanson_kudzu_root?af=gaw&gclid=CKDe7fbDhsoCFYMIwwodQfgN3Q

Puerarin;s solubility in water can be increased with higher temperatures. Adding in a starch and using steel balls to mix the solution ridiculously enhances bioavailability lol: this (http://www.ncbi.nlm.nih.gov/pubmed/22591175).

Puerariae Flos (the flowers of Pueraria thomsonii) was found to inihibit 5ar and grow hair in mice: http://www.ncbi.nlm.nih.gov/pubmed/21822606

Not sure where to get this specfic extract since kudzu is broad and we need that flower specifically to inhibit AR, but the standard swanson kudzu I linked should inhibit GSK3b - in theory.

Theres conflicting literature on PKC regulating GSK3b, I'm looking into it. I will be experimenting with various GSK3b inhibitors over the course of next few weeks, including lithium chloride and forskolin to see if they hold any value for us.

Interestingly enough, PGD2 activation of CRTH2 supposedly activates GSK3, but also results in phosphorylation of AKT.

http://s2.postimg.org/qo35u38w9/text1.png

http://s2.postimg.org/tjg90ycw9/text2.png

Link: New Drugs and Targets for Asthma and COPD (https://books.google.com/books?id=-Zg7AQAAQBAJ&pg=PT207)


@InBeforetheCure
Your stack is ideal, but I'm curious about the PGE2 - where are you getting it from?

Thanks for the opinion. I'm getting PGE2 through a group buy.


It's new years eve, fvck it. You be the judge.

http://imgur.com/a/usmLd



Today I saw two terminal hairs growing right in the centre of that region, where my nw0 hairline was. You cant see it but it was more than 2 inches long. I pulled one of them and it wasnt coming out, so I pulled it until it broke halfway - thats a terminal follicle. The hair felt weird though, really really tough. I've got soft fine hair so somethings definitely going on.

Encouraging so far. Hopefully it keeps progressing. :)

SriHanuman
01-03-2016, 04:05 PM
Chemical, what is your opinion on this publication:

http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0092984

BRIANBOY
01-03-2016, 09:35 PM
Chemical, I think you are on the right path here. Initially I was a norwood 3+. Then had 2 transplants. The results were very moderate after a year. Hair growth was very sparse and thin. The doctor did a biopsy on my scalp and the results came back as a variant of alopecia areata. So, I have both mpb and a form of alopecia areata (jackpot!!). When I started using a 4%-5% solution of (green tea w/50% egcg) in a water / alcohol vehicle, the hair growth really took off. Within a year, I had grown a lot of hair. I kept upping the percentage of green tea, thinking it would further increase the hair growth. (I was up to a 13% solution.) The hair started to get quite thick. Almost too thick in front to even style properly. It was as if the transplants grew in and the hair that was there before started growing back strong as well. I thought, there's no such thing as too much hair. People told me I was lucky to have all my natural hair at my age. At that time, I was a norwood 0 - 1. (And, I was 58 at the time. I also workout / bicycle a lot. So, most thought I was in my mid - late 30s) Then, I developed an allergic reaction (probably because the concentration of green tea was too high). I had to stop all treatments. I didn't use anything for about 6+ months. All the hair that had grown started falling out. After 2 years, I was back where I was before, with very thin hair even though I was using minoxidil. Whenever I challenged using green tea solution again, the allergic response would kick in immediately. I backed off again for another 2 years.

I am now back using a 4% solution of green tea w/50% egcg (in a 74 mil - 75/25 - water / alcohol solution) with rosemary officinalis extract - 1 mil, and 10 drops tea tree oil, 1 mil jojoba oil. Currently using 2x daily. My hair is starting to grow back again. I am also using minoxidil foam and ketoconazole cream daily. I find I cannot go higher than about 4-5% green tea/egcg 2x daily, otherwise it causes folliculitis / allergic reaction as it did before. Folliculitis is something to be careful of, as it can spread rapidly. My theory is that the keratinocytes that have been stimulated to multiply are not moving up the follicle canal properly and thus trigger an infection which then leads to an immune / allergic response. But, green tea/egcg seems to be a potent stimulator of hair growth at higher concentrations. Most users have used very low concentrations. There is some solid science behind green tea / egcg (as you have pointed out) and rosemary extract (strong androgen inhibition and immune modulating factors). Both are also water / alcohol soluble, and penetrate the skin easily. I am also adding oleuropein as per your research. I would caution users to be careful about adding too many ingredients. Too many substances can trigger an immune / allergic response on the scalp. Once you trigger an immune allergic response, you will have to stop using everything for a rather long period of time (months or longer) to let the immune system back off / reset. I wouldn't underestimate this possibility.

I realize my testimony has to be taken with a grain of salt, considering multiple factors ... i.e. my age, alopecia areata + mpb, transplant, no pics, etc. So, I'm just throwing it out there. I will keep an update on my progress from time to time. I am encouraged by the regrowth that is restarting again, and by the potential of oleuropein being added to the mix. Here is a link to the rosemary extract research.

http://www.ncbi.nlm.nih.gov/pubmed/22517595

Chemical
01-04-2016, 01:07 PM
And since ketoconazole's half-life is only a few hours, the 2x per day stuff would presumably be better for sustained HIF-1 stabilization.

I'm planning to use 5-7% (others have used it at 7% with no problems). If it causes irritation, I'll lower the concentration.

Interestingly enough, PGD2 activation of CRTH2 supposedly activates GSK3, but also results in phosphorylation of AKT.
Link: New Drugs and Targets for Asthma and COPD (https://books.google.com/books?id=-Zg7AQAAQBAJ&pg=PT207)
Thanks for the opinion. I'm getting PGE2 through a group buy.
Encouraging so far. Hopefully it keeps progressing. :)

If you look at figure 2E, you can see PGD2 being elevated 2.5 fold compared to normal haired scalp.



PGD2 levels were then measured using ultra–high-performance liquid chromatography–mass spectrometry (UHPLC-MS) because of its reported superior accuracy in measuring prostaglandins compared to immunoassay (17). In a larger series of paired bald and haired samples from 17 men with AGA, we noted an increase in PGD2 in bald scalp compared to haired scalp (Fig. 2E).

PGD2 activating GSK3b is a very plausibly mechanism for its DPC growth inhibitory effects, so far there hasnt been any evidence of how PGD2 might inhibit hair - just that it does so via GPR44. Cotsarelis also says that PGD2 rises with anagen cycle progression, and peaks during catagen, perhaps there is a feedback loop? There is also the issue of reduced PGE2 increasing the amount of substrate abailable for PTGDS - and androgens apparently reduce PGE2 synthesis (not conclusive).

Regarding HIF-1 destabilisation, I'm still trying to find some more info on whether destabilizing HIF-1 can reduce VEGF expression induced via other mechanisms like BetaCatenin. But blocking ERBeta activation with keto 2x/day should cover all bases and reduce any chance of the HSD family causing any damage. The HSD family can increase locally synthesized androgens possibly adding to the already detrimental testes produced T/DHT.

I came across this study on topical Valproic Acid and LiCl vs minox on mice hair growth: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3323655/

Looks like LiCl isnt too suitable due to its aberrant epidermis thickening effects which wasnt seen in VA. It turns out, anything that activates AKT/(PKB) will inactivate (phosphorylate) GSK3b, which includes minox and IGF-1. OL significantly increased IGF-1 more than minox, so stacked with minox theres serious potential of synergy. For people that cant use minox then Valproic Acid seems like a better alternative with equal efficacy.


Chemical, what is your opinion on this publication:

http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0092984

The study was focusing on FAS-l mediated signalling cascades which is not really indicative of general hair growth promoting effects, but it increase KGF moderately. It can also activate the Pi3K pathway and promote angiogenesis so its definitely caught my attention. I will look into this a bit more when I'm free.

@BRIANBOY

You are a very interesting case study. Its unfortuneate that you've got both MPB and AA, so I can only sympathise, but holy frickin sh*t, you grew back all your hair with EGCG. When did you find out you had AA? And when did you start receding?

My theory is that the transplanted hairs started secreting growth factors to nearby follicles since they're probably less AGA prone, so as soon as the EGCG reduced AR the AGA follicles had a chance to grow. I am curious about the allergic reaction, I dont understand why EGCG might elicit that kind of reaction - then again you noticed it happen out of the blue. Its something to keep in mind for my own experiments. Rosemary oil could also provide additional 5AR inhibition just to add to EGCG's effect, excellent find Brian. Thank you for sharing your experience with us, and I am more than delighted that you understand you might be an outlier/special case given your circumstances, but your anecdote is helpful none the less.

Update

I received by ketoconazole 2% cream last wednesday which I've been using 2x a day. And I also got my EGCG today, which I've mixed with my mxol solution.

~1.5mg OL + 5mg EGCG / 1ml Minox. Now things will start to get interesting.

joshuk
01-04-2016, 01:26 PM
chemical i put 1 cap of EGCG into 60ml of my eth/pg mix which equals 2.5mg/ml i see your using 5mg/ml is it worth putting an extra cap in or just carry on for 1 for a month then add to it.

Seuxin
01-04-2016, 01:48 PM
WARNING : Using too more Keto is not bad for the body (especially your liver) ?

ppxrare
01-05-2016, 05:26 AM
Can anyone post a TL:DR for those of us who don't understand the scientific conversation being held here?

TubZy
01-05-2016, 07:26 AM
WARNING : Using too more Keto is not bad for the body (especially your liver) ?

Oral only buddy u should know this lol

BRIANBOY
01-05-2016, 11:48 AM
Chemical - I found out I had AA after the transplant, when the hairs would not grow in certain spots. That's when a biopsy was done to confirm. Regarding the mpb, I started receding around 17-18 yrs old. Regarding the allergic reaction with EGCG, I think I was simply using too high of a concentration. Regarding the Rosemary Extract (not the oil), the literature seems to indicate it is not so much a 5AR inhibitor, more of an AR receptor blocker / interference.

<"~1.5mg OL + 5mg EGCG / 1ml Minox. Now things will start to get interesting." -- Chemical >

Please confirm, that you are using 5mg "pure" EGCG per ml = .5% solution? And, the 1.5 mg "pure" OL(oleuropein) per ml = .15% solution? Initially, you were using commercial products which contained a percentage of the active extracts (750 mg Olive Leaf = 150 mg OL), so the active extracts may actually be a lower percentage in solution. I just want to be clear what the actual percentage of active ingredient you are currently using. Your percentages seem low (.5% EGCG & .15% OL per ml), but, maybe you theorize that the lower percent solutions are closer to the clinical tests done on the mice? .. i.e. - less is better?

I am currently adding OL to the mix and applying keto as well. Hoping for the best. Thanks for your input.

SriHanuman
01-05-2016, 11:55 AM
Study also said that at least 0.4% solution of oleuropein was required...

Chemical
01-05-2016, 02:08 PM
chemical i put 1 cap of EGCG into 60ml of my eth/pg mix which equals 2.5mg/ml i see your using 5mg/ml is it worth putting an extra cap in or just carry on for 1 for a month then add to it.

Looks like we might want to keep EGCC concentration low until we have further confirmation of its topical use in a high ethanol solution, there's potential for irritation as Brian ha pointed out. I will test the current EGCG dose for two weeks before recommending a higher EGCG concentration, just to be on the safe side because I know everyone reacts differently. The last thing we want is irritation induced hair loss. Although perhaps PGE2 might be increased? Wishful thinking...


WARNING : Using too more Keto is not bad for the body (especially your liver) ?

Oral keto at 200mg+ has liver toxicity. We are using it topically, and at reduced concentrations.


Can anyone post a TL:DR for those of us who don't understand the scientific conversation being held here?

I'll be creating a blog/wiki soon explaining stuff in layman terms - also there is too much info to cover.

@Brian

Turns out you were right, EGCG is irritating: http://www.teavigoinfo.com/pdf/study-7.pdf

I did notice slight irritation in the morning (then again I havent used emu oil for 3 days). Good thing I only added 150mg - I will dilute to 2.5mg if I notice excessive irritation. The OL extract I'm using is 750mg of OL standardized to 20% = 150mg OL per capsule. I'm using the actual OL content figure of 150mg and not the 750mg. Same for EGCG standardized from teavigo @90% yielding 150mg pure EGCG per capsule. The reason for the low OL dose is because I suspect there is a biphasic effect, with higher doses being less effective.

And apparently rosemary oil can be irritating, which is why the extract is much better suited - like you said. It is indeed an AR suppressor too.


Study also said that at least 0.4% solution of oleuropein was required...

0.4mg was the minimum OL dose found to be effective.

SriHanuman
01-05-2016, 02:14 PM
Chemical,

Yes, it was mg and not %, sorry man, my bad.

potato1987
01-05-2016, 03:59 PM
Hi Guys,

I am really hoping someone can break down what to buy and use, my hair seems to be thinning at the front and temples at such a rate. I am currently just using castor oil and Oleuropein with some emu oil and derma rolling once a week.

Have done so for about 6 weeks with little to no results.

I tried minox but it gave me such bad eye bags.

I need a minox free solution and I'm getting pretty desperate.

joshuk
01-06-2016, 12:23 PM
Hi Guys,

I am really hoping someone can break down what to buy and use, my hair seems to be thinning at the front and temples at such a rate. I am currently just using castor oil and Oleuropein with some emu oil and derma rolling once a week.

Have done so for about 6 weeks with little to no results.

I tried minox but it gave me such bad eye bags.

I need a minox free solution and I'm getting pretty desperate.

you are not using anything to stop MPB. castor oil and Oleuropein wont stop hairloss they are added to help an exsiting protocol, you need FIN/DUT or an AA like RU/CB otherwise you will go bald.you not tried any of these??

i cant use minox either so im using Oleuropein/EGCG mix as a alternative been on it 5 days to early for results.

potato1987
01-06-2016, 12:30 PM
Hi Josh, I tried Minox but the bags under my eyes where black and sunken to the bone. I aged so, so quickly and people even commented on it regularly. my eyes are now normal tone but sadly the collagen seems gone, it was belgravia 10% minox. I can't start Fin as my wife and I would like children soon so this throws a spanner in the works. Your on just Oleuropein/EGCG? Could I do the same? I wanted to private message you Josh but couldn't find how.

Sogeking
01-07-2016, 05:08 AM
you are not using anything to stop MPB. castor oil and Oleuropein wont stop hairloss they are added to help an exsiting protocol, you need FIN/DUT or an AA like RU/CB otherwise you will go bald.you not tried any of these??

i cant use minox either so im using Oleuropein/EGCG mix as a alternative been on it 5 days to early for results.

I disagree what is the point of adding something to fin and/or minox if that something doesn't work. I'll test oleuropein +ecgc combo on its own to see if it does something. If it doesn'nt then there is no point in adding it to any kind of regime.

BaldingEagle
01-07-2016, 07:07 AM
I disagree what is the point of adding something to fin and/or minox if that something doesn't work. I'll test oleuropein +ecgc combo on its own to see if it does something. If it doesn'nt then there is no point in adding it to any kind of regime.

Agreed, how can you possibly gauge results when fin and min are already disrupting the balding process if you're taking them. You have to test one thing at a time. That is how every clinical trial is done for a reason.

joshuk
01-07-2016, 09:54 AM
its up to you what you do i was only giving some advice its your choice im gonna stick to my regime. hope it does something for you

pilipili
01-07-2016, 09:54 AM
Chemical stated he added EGCG to maintain regrowth right? Or at least to try to... I'm wondering if this Oleuropein/EGCG combo could make existing hair thicker ,stronger

Sogeking
01-07-2016, 10:48 AM
its up to you what you do i was only giving some advice its your choice im gonna stick to my regime. hope it does something for you

Yeah sure man. Whatever works. I mean if this works on its own then I'm sure it would work even better with fin.

Chemical
01-07-2016, 11:59 AM
you are not using anything to stop MPB. castor oil and Oleuropein wont stop hairloss they are added to help an exsiting protocol, you need FIN/DUT or an AA like RU/CB otherwise you will go bald.you not tried any of these??


I agree with josh.


Your on just Oleuropein/EGCG? Could I do the same?

You can try the OL + EGCG but do not expect results, this is still in experimental stages.


I disagree what is the point of adding something to fin and/or minox if that something doesn't work. I'll test oleuropein +ecgc combo on its own to see if it does something. If it doesn'nt then there is no point in adding it to any kind of regime.


Agreed, how can you possibly gauge results when fin and min are already disrupting the balding process if you're taking them. You have to test one thing at a time. That is how every clinical trial is done for a reason.

You both raise a valid point. If we wanted to see if each treatment worked by itself, then I'd urge you just try OL for a few weeks, and you definitely wont see any results. The way OL works is by increasing BetaCatenin, and Androgens block this pathway significantly. So by itself, even after 3 months, you wont see anything revolutionary - therefore we can conclude it doesnt work and it probably wont work when stacked with anything else. You could also try EGCG by itself, which has a higher probability of yielding cosmetic improvement, but if you test it for 2 months and dont see anything - can we conclude it doesnt work in humans at all? I see alot of people doing this kind of experimentation all over the internet on the basis of "its more scientific and controlled". Unfortuneately our scalps are not petri dishes where you can control the locally produced cytokines. If you wanted to see if something works on you, you would have to use it only on a certain area, and compare the difference between control regions. These are topical treatments after all.

Moreover, the scalp is like a black box, you only see the output (hair) but you dont see whats going on inside. So this logic of trying one thing at a time to see if works is not scientific at all. Mice are a different story, their hairs are not androgen dependent and respond to all hair growth promoting treatments. But give them testosterone shots, and then treatments take ages to show any change. Since you cant dice up your scalp and analyze the protein expressions, you have to use probability and biochemical pathway models to figure out what is going on inside the black box. Only then do you have a greater chance of influencing whats going on inside. Its not scientific but its a whole lot better than blind trial error. In the likelihood that a treatment does impact hair growth both on paper and mice (without T injection), and its effectiveness is negated in human scalp due to AR or some other detrimental pathway, does that mean it doesnt work? Or does it mean AR was preventing it from working? This is a schrodingers cat analogy. You just wont know. You never will. However, if you remove AR from the equation, and the treatment works, then you will say it would work regardless of AR being present - which you cant prove.

Oleuropein and other growth agonists are additive, meaning you'll see results quicker and a quantifiable difference. I've tried minoxidil by itself, and I've tried minox + OL. I can say for a fact that the minox + OL had much better efficacy with results being apparent in a shorter time frame. This reasoning isnt something I can easily convey, but if we must make this really scientific, then it is up to the participants to run local control experiments. One side OL, the other OL + EGCG, or nothing at all.


Chemical stated he added EGCG to maintain regrowth right? Or at least to try to... I'm wondering if this Oleuropein/EGCG combo could make existing hair thicker ,stronger

EGCG to block AR and allow minox + OL to work faster. Taking the brakes off the car so it can reach full speed. I've noticed thickening of existing haired areas using Minox + OL. And 60% of those new hairs on my left temple have gone terminal. I will post pics soon.

potato1987
01-07-2016, 02:30 PM
you are not using anything to stop MPB. castor oil and Oleuropein wont stop hairloss they are added to help an exsiting protocol, you need FIN/DUT or an AA like RU/CB otherwise you will go bald.you not tried any of these??

i cant use minox either so im using Oleuropein/EGCG mix as a alternative been on it 5 days to early for results.


Really Saddened to hear, Minox didn't agree with me and Fin isn't advisable before trying for children, Which out of FIN/DUT or an AA like RU/CB are you using?

InBeforeTheCure
01-07-2016, 02:57 PM
If you look at figure 2E, you can see PGD2 being elevated 2.5 fold compared to normal haired scalp.

You forgot the link: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3319975/

Not only that, but PGD2 production is 12 times higher in bald vs. haired scalp in men with AGA:

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3319975/figure/F2/


PGD2 activating GSK3b is a very plausibly mechanism for its DPC growth inhibitory effects, so far there hasnt been any evidence of how PGD2 might inhibit hair - just that it does so via GPR44.

Possibly. Interestingly enough, not everyone with hair loss is sensitive to PGD2's effects. A poster from the World Congress for Hair Research last month, courtesy of hellouser (right click and select "view image" or "open image in new tab" for a larger version):

http://i.imgur.com/0D8aeAK.jpg

As you can see, they identified a few SNPs (which appear to be in perfect linkage disequilibrium) in the CRTH2 (GPR44) gene associated with PGD2 sensitivity as well. I would guess that PGD2 is one problem (in those people who are sensitive to it), but not the only problem. Maybe PGD2 sensitivity accelerates things?

Sort of a side note, but I'd love to see more studies done into the genetics of AGA. In particular, differences in age, pattern, rate of loss, effectiveness of certain treatments, etc. associated with different genes. There's been some work done on which genes are associated with AGA, but nothing really on the details AFAIK.


Cotsarelis also says that PGD2 rises with anagen cycle progression, and peaks during catagen, perhaps there is a feedback loop? There is also the issue of reduced PGE2 increasing the amount of substrate abailable for PTGDS - and androgens apparently reduce PGE2 synthesis (not conclusive).

Yeah, here's the graph that Cotsarelis presented:

http://i49.tinypic.com/ic2wlz.jpg

So it steadily rises during anagen then spikes in very late anagen, soon followed by catagen.


Regarding HIF-1 destabilisation, I'm still trying to find some more info on whether destabilizing HIF-1 can reduce VEGF expression induced via other mechanisms like BetaCatenin. But blocking ERBeta activation with keto 2x/day should cover all bases and reduce any chance of the HSD family causing any damage. The HSD family can increase locally synthesized androgens possibly adding to the already detrimental testes produced T/DHT.

I came across this study on topical Valproic Acid and LiCl vs minox on mice hair growth: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3323655/

Looks like LiCl isnt too suitable due to its aberrant epidermis thickening effects which wasnt seen in VA. It turns out, anything that activates AKT/(PKB) will inactivate (phosphorylate) GSK3b, which includes minox and IGF-1. OL significantly increased IGF-1 more than minox, so stacked with minox theres serious potential of synergy. For people that cant use minox then Valproic Acid seems like a better alternative with equal efficacy.

The downside is that VPA is harder to get than minox.

BTW, your ideas about paracrine effects are interesting. I wonder if full regrowth would stop the nasty paracrine positive feedback loop, effectively returning the state of the follicles to what it was before hair loss started (you would still of course need maintenance drugs then), or whether certain genes/negative growth signals would remain upregulated?


EGCG to block AR and allow minox + OL to work faster. Taking the brakes off the car so it can reach full speed. I've noticed thickening of existing haired areas using Minox + OL. And 60% of those new hairs on my left temple have gone terminal. I will post pics soon.

In one week???

Keeper
01-08-2016, 06:54 AM
I m really interessed in your pictures Chemical. I would not judge sth before at least 2 months. Sounds really good. But is it not also possible that with your consequent usage of minox it can be its effect alone? Do you preclude that completely? Looking forward too your pictures soon then if you see its effects already go ahead :)

Chemical
01-08-2016, 12:58 PM
Not only that, but PGD2 production is 12 times higher in bald vs. haired scalp in men with AGA:

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3319975/figure/F2/


Sorry about that, only realised after I couldnt edit my post anymore.


We discovered a significant increase in PGD2 in the balding scalp compared to haired scalp by immunoassay (Fig. 2D). The absolute level of PGD2 was 16.3 ng/g tissue in balding scalp and 1.5 ng/g tissue in haired scalp. PGD2 levels were then measured using ultra–high-performance liquid chromatography–mass spectrometry (UHPLC-MS) because of its reported superior accuracy in measuring prostaglandins compared to immunoassay (17). In a larger series of paired bald and haired samples from 17 men with AGA, we noted an increase in PGD2 in bald scalp compared to haired scalp (Fig. 2E).

Figure 2E is the averaged level of PGD2 from a greater sample, using a more accurate measurement method. Not as high as 12x but still high enough to retard hair growth. Paired with AR it will definitely cause balding.



As you can see, they identified a few SNPs (which appear to be in perfect linkage disequilibrium) in the CRTH2 (GPR44) gene associated with PGD2 sensitivity as well. I would guess that PGD2 is one problem (in those people who are sensitive to it), but not the only problem. Maybe PGD2 sensitivity accelerates things?


"Approx half of Alopecia patients" - random sample and half were immune? My stats knowledge isnt the best but this is a clear indication that PGD2 isnt the holy grail after all. I would also like to see more research on genetic influence. It could be that we've all got different variations of AGA and respond only when the main individual-specific antagonists are suppressed.

PTGDS is being upregulated as anagen progresses, I cant figure out how. One theory is that its TCF/LEF dependent like Axin2 is, but is it an extracellular process? If so, then human hair should enter telogen in groups. Which isnt the case because they cycle independently. Furthermore:



Firstly, the first two cycles of the mouse hair follicle are synchronized whereas in humans at a time when biopsies could be taken, neighbouring follicles cycle independently of each other. Secondly, the mouse hair cycle is short, taking about 3 weeks; in contrast, human scalp hairs have a cycle time of several years, and even vellus hairs take months. The short synchronized hair cycle thus allows hair follicles to be harvested and examined at specific time points in the cycle very easily.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1571051/

The mouse model isnt entirely reliable for analysis. My guess is PTGDS is being increased in human scalp by AR or ERb.

Regarding VPA, sodium valproate is what you want. Not valproic acid because that'll burn (according to an anecdote). I use this pharmacy alot and they stock it. (http://www.4nrx-uk.md/neurological-health/valparin-sodium-valproate.html) I'm tempted to buy some but I'll hold off for now.

DPC can release cytokines to the neighboring epidermis as a result of canonical WNT signalling. Including IGF-1 and KGF/VEGF which can bind to the originating cell surface receptors and possibly even nearby follicles. But the distance between the follicles might be too great for the factors to reach them. I dont understand fully how autocrine/paracrine signalling works with DPC but I do know that balding DPC produce DKK-1 and TGF-Beta1 that are released into the extracellular environment. The studies done with AGA DPC co-culture may not be an accurate representation of the scalp so its only speculation - but the theory of paracrine signalling is there. By removing the antagonist you return to baseline which is perfect for growth maintenance. But for regrowth you'll need to be more aggressive in increasing BetaCatenin. Increasing BetaCatenin in the skin/epidermis to high levels will automatically induce hair canal formation (post (https://www.baldtruthtalk.com/threads/22104-Updated-Research-and-Knowledge-Cutting-Edge?p=225455&viewfull=1#post225455)). The more positive growth factors you have floating around in the epidermis, the greater the chance it'll bind to DPC and not the thousands of other keratinocytes in between the hairs. It all boils down to a game of probability.

Another thing that I've been thinking about lately is angiogenesis. Hair follicles that have an a blood vessel attached grow larger in diameter and grow much faster:

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC199257/

However, if the blood vessel is directly serving the DPC with "nutrients"/glucose then wont that also mean androgens can easily enter the follicles? Its sort of a lose-lose. You'd need an AR suppressor with a very long half life to mitigate the constantly elevated T in the blood stream. Food for thought.

As for the growth I've seen, the follicles I saw last week were most likely anagen already, they were thin at the tips giving the impression of vellus hairs. They haven't fallen out, and they feel quite strong when pulled quite hard.


But is it not also possible that with your consequent usage of minox it can be its effect alone? Do you preclude that completely?

I know for a fact it was all minox. I was using 3x a day during christmas break. The OL probably had an additive effect. I think having sustained application of a treatment will overcome the body's constant growth retarding effects on hair, seeing as most topicals dont have a long half life. If for a few hours you increase BetaCatenin, and then its completely inhibited by AR for 6 hours, you'll never see growth. If I could use minox + OL 3x a day for a year I would be a nw0 gauranteed.

http://imgur.com/a/K4dcQ

http://imgur.com/a/g6TdQ

Chemical
01-09-2016, 11:56 AM
I've been doing some more reading on PKC and understood a little better how it works with regards to hair growth. PKC caught my attention when I read this study (http://www.ncbi.nlm.nih.gov/pubmed/10859531) on procyanidins (found in apple skin) increasing hair growth.

The confusing thing was that PKC can actually inactivate (phopsphorylate) gsk3b and we know gsk3b inhibition increases β-catenin. So procyanidins mediated PKC inhibition had to be working through a different mechanism.

Then I found this study:


Protein-kinase-C-mediated β-catenin phosphorylation negatively regulates the Wnt/β-catenin pathway (http://jcs.biologists.org/content/119/22/4702.long)



A23187 = PKC activator

A23187-mediated β-catenin degradation requires the β-catenin N-terminus but not GSK-3β activity

Since the phosphorylation of β-catenin by GSK-3β and its subsequent association with β-TrCP leads to β-catenin degradation, we examined whether A23187-mediated inhibition of CRT requires GSK-3β activity. To this end, HEK293 reporter cells were incubated with A23187 and LiCl, an inhibitor of GSK-3β. As shown in Fig. 2A, A23187 suppressed LiCl-induced CRT. Furthermore, Western blot analysis using anti-β-catenin antibody consistently showed that A23187 reduced the level of β-catenin that accumulated with LiCl treatment (Fig. 2B), indicating that A23187-mediated inhibition of the Wnt/β-catenin pathway is independent of GSK-3β.

This is quite surprising. β-catenin can be degraded regardless of GSK-3β. This is not good news at all. So even PGE2 and minox's effectiveness will be greatly diminished if PKC is elevated.

And get this, PGD2 can activate PKC.


These results strongly suggest that PGD2 stimulates IL-6 synthesis through intracellular Ca2+ mobilization in osteoblasts, and that the PKC activation by PGD2 itself regulates the over-synthesis of IL-6.

http://www.ncbi.nlm.nih.gov/pubmed/10582659


We previously showed that PGD2 stimulates the induction of heat shock protein 27 (HSP27) via protein kinase C (PKC)-dependent p38 mitogen-activated protein (MAP) kinase and p44/p42 MAP kinase in osteoblast-like MC3T3-E1 cells.

http://www.ncbi.nlm.nih.gov/pubmed/15743775

And PKC can in turn increase PTGDS expression:

Protein kinase C activates human lipocalin-type prostaglandin D synthase gene expression through de-repression of notch-HES signaling and enhancement of AP-2 beta function in brain-derived TE671 cells. (http://www.ncbi.nlm.nih.gov/pubmed/15743775)

Bear in mind these are in different cell types so its not 100% accurate.

If PGD2 increases PKC then it could mean that in some people the increase in PKC mediated β-catenin degradation may offset its GSK3b inhibiting effects (net yield of no change in β-catenin). PGD2 also inactivates AKT (InBeforeTheCure (https://www.baldtruthtalk.com/threads/22104-Updated-Research-and-Knowledge-Cutting-Edge?p=227078&viewfull=1#post227078)) so GSK3b is further increased doubling up on the PKC ¬ β-catenin.

Another related protein kinase is PKA that has the ability to prevent β-catenin degradation by occupying the SER675 position that the proteosomes require to carry out the ubiquitinition (study (http://www.ncbi.nlm.nih.gov/pubmed/16199882)).

This is why forskolin can boost the effect of procyanidins on hair growth:



Nonselective protein kinase inhibitors, such as staurosporine and K252a, inhibit the growth of hair epithelial cells. 1,2-Dioctanoyl-sn-glycerol, a protein kinase C activator, dose-dependently decreases the growth of hair epithelial cells. Forskolin, an adenylate cyclase activator, promotes hair epithelial cell growth and boosts the growth-promoting effect of procyanidin B-2. It is speculated that the hair-growing activity of procyanidins is related to their protein kinase C-inhibiting activity.

Apples are known to contain the highest concentration of procyanidin b-2, and the polyphenol extract is quite cheap from amazon uk (http://www.amazon.co.uk/Swanson-Maximum-Strength-Polyphenols-Capsules/dp/B0017OAZPS/ref=sr_1_1?ie=UTF8&qid=1452364008&sr=8-1&keywords=apple+polyphenol). (Apple polyphenols contain procyanidin (http://pubs.acs.org/doi/abs/10.1021/jf070569k)). Or alternatively grape seed extract.

I'm going to order some forskolin and apple/grape polyphenol to try on my right temple, versus the minox + Ol + EGCG on my left.

Update:

I've got significantly more new terminal follicles that are prickly to touch growing in the vertex area, behind the hairline.

I added more minox to my solution. I had 20ml left and added around 20ml more. The total original EGCG content in the 20ml is ~100mg. I also added another EGCG capsule since I wasnt seeing any irritation - if I keep my skin hydrated I dont get any redness at all or flaking. The total EGCG content is now around 350mg/40ml = 8.75%. The OL percent is less than 1mg now. I might not increase OL further. The mice study used 10% EGCG and they still saw slight Testosterone induced apoptosis. This leads me to believe 5% may not be enough, and like @BRIANBOY has stated, he's been able to use 10%+, hence my decision to use more. Everyone using EGCG can increase the EGCG dose at your own discretion or wait till I've gone 2 more weeks using this new dose without any sign of irritation. I've started using this new solution since today.

Also the left temple area is gradually taking on the hallmark scalp appearance (white skin tone) and texture - starting from the back. Its only been 3 weeks since using the mxol and 1 week using the EGCG. I wonder what will happen at the 3 month mark...

Seuxin
01-09-2016, 12:37 PM
For informations, i use VPA ( the acid solution) without any problems ! PH is near the skin PH, i don't burn at all :)

PS : Anyone know why i cannot publish directly my messages there ? I'm not new member here.Thanks

joshuk
01-09-2016, 01:41 PM
chemical so you think taking setipirant would be a good idea then if it reduces PKC with reduction of PGD2

burtandernie
01-09-2016, 06:51 PM
What percentage of people have PGD2 sensitivity? Things like propecia and dut work in such a huge percentage of men it makes you think almost all balding men are sensitive to androgens to some degree. I wonder if PGD2 is similar or if its more a smaller group of men that it affects.
So right now someone losing hair should take or do what? It seems like we know a lot more than just DHT is an issue, but there are no practical physical treatments beyond just propecia. Its years and years to wait for something better.

InBeforeTheCure
01-09-2016, 11:38 PM
Figure 2E is the averaged level of PGD2 from a greater sample, using a more accurate measurement method. Not as high as 12x but still high enough to retard hair growth. Paired with AR it will definitely cause balding.

Ah yes, I misread it. My bad.


"Approx half of Alopecia patients" - random sample and half were immune? My stats knowledge isnt the best but this is a clear indication that PGD2 isnt the holy grail after all. I would also like to see more research on genetic influence. It could be that we've all got different variations of AGA and respond only when the main individual-specific antagonists are suppressed.

Here's a recent study on risk alleles associated with AGA: http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0127852

No association between the CRTH2 gene and AGA has yet been found AFAIK, and the allele frequencies of that gene were similar in the poster subset as they are in the population as a whole, so it seems as if variation in CRTH2 is not a risk factor for AGA. But PGD2 has been shown to lead to hair loss and miniaturization, so if you have AGA and are PGD2-sensitive, you may do better if you deal with PGD2 as part of your protocol, especially with what you've posted about PGD2 and PKC. Maybe.

Some interesting discussion from that paper:


The polygenic nature of MPB was discovered in early studies [40,41] and confirmed in GWAS analyses that followed [9,12,14,16]. The role of androgens had also been established as an important part of the predisposition to MPB and its age-related onset. Therefore, the androgenetic pathway is a process certain to contribute to MPB variation [27,42]. The Xq12 region that includes androgen receptor (AR, OMIM: 313700) continues to show the best-documented and strongest association with MPB. This region also contains ectodysplasin A2 receptor (EDA2R, OMIM: 300276), but it is still not fully understood whether one or both genes play a role in the progression of AGA. Our study confirmed that the AR/EDA2R region forms the major risk factor for MPB with the highest significance shown by rs5919324 located upstream of AR. The same SNP was previously shown to have the most significant association with MPB in the study of Cobb et al, 2010 [11]. Cobb found the second strongest association with MPB from the 20p11 region between PAX1 encoding paired box protein 1 and FOXA2 encoding forkhead box protein A2 [9,14]. From seven SNPs located in this region and included in our study, the highest significance was recorded for rs1998076, which was previously shown to be associated with MPB in a German population sample [14]. Richards et al. reported that the risk of AGA increases substantially (OR = 7.12) in individuals having at least one risk allele at both the Xq12 and 20p11 loci. They further estimated that these two loci have very high sensitivity of MPB prediction (98.2%) but very low specificity (6.6%) [9]. Interestingly, different SNPs on Xq12 have been shown to be most significantly associated in various European populations, indicating a complex genetic architecture for the region [4,8,10,11]. Moreover, the AGA-associated region on 20p11 contains no recognized genes to date, so it can only be speculated whether variation in this area has a regulatory function for PAX1 and/or FOXA2 located at each of the region’s ends [43]. It is also worth emphasizing that in our study six SNPs from Xq12 and five SNPs from 20p11 were found to have positive influence on prediction accuracy and thus all were included in the extended 20-SNPs prediction model. Further studies are necessary to analyze in more detail whether multiple DNA variants may contribute to MPB development in these two major AGA loci. If this is the case, it will have a strong impact on prediction modeling. Allelic heterogeneity is already recognized as an important factor affecting trait prediction analyses [21,25,37,44].

Beyond Xq12 and 20p11, ten additional loci have been shown to contribute to the overall risk of developing MPB [12,15,16]. From these, the most significant associations with AGA in our study were found for SNPs located on chromosomes 1, 5 and 7. Beyond rs5919324 (Xq12) and rs1998076 (chr20), three additional SNPs indicated independent effects when assessed with multivariate regression analysis. First, we found strong association for rs929626 located in an intron of EBF1 (early B-cell factor 1), with this SNP originally identified in large meta-analysis of European males [16]. Transcription factor EBF-1 encoded by EBF1 is an important regulator of cell differentiation of adipocytes [45]; known to be involved in the regulation of hair follicle cycling [46]. SNP rs929626 was observed to have a positive impact on prediction in this study as well as interacting with rs1998076 (chr20). This interaction is novel and further studies on larger sample sets are necessary to confirm the effect and its biological mechanism. Implementation of the epistatic effect into the prediction model was found to have an ambiguous effect on accuracy and therefore was not included in the final 20-SNP prediction model. Second, rs12565727 close to TARDBP (TAR DNA binding protein) on chr1 gave the next highest association. This AGA determinant gene was recently identified by a meta-analysis performed by Li et al, in 2012. TARDBP codes for the 43 kDa transactive response DNA binding protein (TDP-43) and is involved in regulating gene expression and RNA splicing [47]. Third, the last SNP selected in our multivariate regression model was rs756853 located in an intron of HDAC9 (histone deacetylase 9) on chr7. This association was first discovered in a GWAS of German and Australian subjects [15]. The histone deacetylase 9 protein encoded by HDAC9 belongs to the extensive HDAC superfamily, which plays a critical role in the regulation of gene expression. HDAC proteins are responsible for deacetylation of histones leading to chromatin condensation and consequently to transcriptional repression [48]. Brockschmidt, et al. suggested that HDAC9 might interact with AR through MEF2C transcription factor modulating AR transcriptional activity [15]. Of six SNPs previously associated with hair morphology [30], none revealed independent association with MPB in our study. Only DNA variant rs7349332 in WNT10A showed a positive effect on prediction accuracy (a marginal AUC increase from 0.862 to 0.864) and was among markers included in the final 20-SNPs prediction model. This SNP was initially associated with hair morphology [30] and then also associated with MPB in a study of Heilmann et al. who suggested a possible link between hair curliness and hair loss [16].

Our results are in agreement with the genetic data obtained for AGA so far, indicating the involvement of multiple genetic loci with average or small individual effects. The study data indicates individuals carrying seven or more AGA risk alleles, in the five most associated loci, are significantly more susceptible to MPB.

From another paper:


EDA2R is capable of activating the NF-κB pathway and also through TRAF3,6, JNK (c-Jun N-terminal kinase) (Sinha et al., 2002), which activates c-Jun.


EDA2R could influence the onset of AGA through the activation of the NF-κB pathway or by c-Jun, which has been shown to be critical for AR transactivation (Bubulya et al., 1996). Moreover, in adult mice, EDA2R is also expressed in the hair bulb and in differentiating hair matrix (Botchkarev and Fessing, 2005). Looking at the human expression data from the UniGene database (http://www.ncbi.nlm.nih.gov/sites/entrez), we noticed that it is expressed during embryonic life and, especially, in the first weeks after birth. Expression then seems to be absent until the 17th year of age, when it recurs in different tissues, including skin. This expression pattern fits very well with the course of AGA, with its onset around puberty.

http://www.nature.com/jid/journal/v128/n9/full/jid200860a.html

EBF1 interacts with ERbeta: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3738513/


Because the EBF1 binding motif was enriched at ERβ binding sites, the interaction between EBF1 protein and a few ERβ binding sites was investigated. When EBF1 was transiently expressed in C4–12/Flag.ERβ cells, it was recruited to several ERβ binding sites in an E2 dependent manner (Figures 6A). Moreover, the recruitment of ERβ at these sites was enhanced in the presence of EBF1 and E2 (figure 6B).

We then used co-immunoprecipitation to test for an interaction between these two proteins. As shown in figure 6C, V5-tagged EBF1 was detected in the ERβ immunoprecipitate, indicating an interaction between the two proteins. However, when V5-EBF1 was immunoprecipitated with V5 antibody, no ERβ was detected (data not shown). These results suggest a stoichiometry in which most of the ERβ interacts with EBF1, while only a small portion of EBF1 interacts with ERβ, indicating that ERβ levels are limiting. Notably, cells used in these assays were treated with MG132 because ERβ levels were very low (figure 6C).

Because the presence of EBF1 correlated with low ERβ protein levels, we wished to test the influence of EBF1 on ERβ protein levels and function. Due to the low ERβ expression in stably transfected C4–12/Flag.ERβ cells, transiently over-expressed ERβ was assayed in the presence and absence of EBF1. As shown in figure 7A, EBF1 significantly reduced ERβ protein stability while ERβ transcript levels remained unchanged (Figure 7B), indicating that EBF1 regulates ERβ stability at the protein level. ERβ transcriptional activity was also suppressed, as measured by an ERE-luciferase reporter assay (figure 7C). This suppressive effect was also observed for endogenous target genes. Thus, when C4–12/Flag.ERβ cells were transfected with EBF1, ERβ target gene expression in response to E2 was significantly reduced (figure 7D).


PTGDS is being upregulated as anagen progresses, I cant figure out how. One theory is that its TCF/LEF dependent like Axin2 is, but is it an extracellular process? If so, then human hair should enter telogen in groups. Which isnt the case because they cycle independently. Furthermore:



The mouse model isnt entirely reliable for analysis. My guess is PTGDS is being increased in human scalp by AR or ERb.

The working hypothesis at Kythera was through AR:

http://i.imgur.com/ujqSDHS.png

Either way, certainly downstream of androgens.


Regarding VPA, sodium valproate is what you want. Not valproic acid because that'll burn (according to an anecdote). I use this pharmacy alot and they stock it. (http://www.4nrx-uk.md/neurological-health/valparin-sodium-valproate.html) I'm tempted to buy some but I'll hold off for now.

I don't think most people have much of a problem with VPA, but we'll see...


DPC can release cytokines to the neighboring epidermis as a result of canonical WNT signalling. Including IGF-1 and KGF/VEGF which can bind to the originating cell surface receptors and possibly even nearby follicles. But the distance between the follicles might be too great for the factors to reach them. I dont understand fully how autocrine/paracrine signalling works with DPC but I do know that balding DPC produce DKK-1 and TGF-Beta1 that are released into the extracellular environment. The studies done with AGA DPC co-culture may not be an accurate representation of the scalp so its only speculation - but the theory of paracrine signalling is there. By removing the antagonist you return to baseline which is perfect for growth maintenance. But for regrowth you'll need to be more aggressive in increasing BetaCatenin. Increasing BetaCatenin in the skin/epidermis to high levels will automatically induce hair canal formation (post (https://www.baldtruthtalk.com/threads/22104-Updated-Research-and-Knowledge-Cutting-Edge?p=225455&viewfull=1#post225455)). The more positive growth factors you have floating around in the epidermis, the greater the chance it'll bind to DPC and not the thousands of other keratinocytes in between the hairs. It all boils down to a game of probability.

Well, let's hope. Maintenance is much less inconvenient than regrowth lol.


Another thing that I've been thinking about lately is angiogenesis. Hair follicles that have an a blood vessel attached grow larger in diameter and grow much faster:

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC199257/

However, if the blood vessel is directly serving the DPC with "nutrients"/glucose then wont that also mean androgens can easily enter the follicles? Its sort of a lose-lose. You'd need an AR suppressor with a very long half life to mitigate the constantly elevated T in the blood stream. Food for thought.

Maybe we need some sort of DPC border control. Let in the nutrients, keep out the androgens. I assume that's many years away, sadly. ;)


What percentage of people have PGD2 sensitivity?

60 percent in that sample.

BRIANBOY
01-10-2016, 12:23 AM
Chemical - I believe an 8% solution of EGCG in 40ml would be 3.2 grams (3200 mg). So, 320 mg in 40ml is not 8.75%.

InBeforeTheCure
01-10-2016, 12:38 AM
Speaking of NFkB (which EDA2R activates), NFkB is implicated in AR overexpression in androgen-independent prostate cancer...


Prostate cancers that progress during androgen-deprivation therapy often overexpress the androgen receptor (AR) and depend on AR signaling for growth. In most cases, increased AR expression occurs without gene amplification and may be due to altered transcriptional regulation. The transcription factor nuclear factor (NF)-κB, which is implicated in tumorigenesis, functions as an important downstream substrate of mitogen-activated protein kinase, phosphatidylinositol 3-kinase, AKT, and protein kinase C and plays a role in other cancer-associated signaling pathways. NF-κB is an important determinant of prostate cancer clinical biology, and therefore we investigated its role in the regulation of AR expression. We found that NF-κB expression in prostate cancer cells significantly increased AR mRNA and protein levels, AR transactivation activity, serum prostate-specific antigen levels, and cell proliferation. NF-κB inhibitors decrease AR expression levels, prostate-specific antigen secretion, and proliferation of prostate cancer cells in vitro. Furthermore, inhibitors of NF-κB demonstrated anti-tumor activity in androgen deprivation-resistant prostate cancer xenografts. In addition, levels of both NF-κB and AR were strongly correlated in human prostate cancer. Our data suggest that NF-κB can regulate AR expression in prostate cancer and that NF-κB inhibitors may have therapeutic potential.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2716950/

HairlossAt15
01-10-2016, 01:33 AM
Chemical, you say PGD2 does not play the major role, but what about the fact that genetically altered mice which overexpress Ptgs2 phenocopy AGA?


Transgenic mice overexpressing Ptgs2 in the epidermis phenocopy AGA

Given the correlation of increased levels of PGD2 with balding scalp in humans and the presumptive inhibitory role of PGD2 on the mouse follicle, we hypothesized that mice with high levels of PGD2 in the skin might develop features of AGA. Because Ptgs2 (cyclooxygenase 2, prostaglandin G/H synthase) is the enzyme upstream to Ptgds, we further hypothesized that mice overexpressing Ptgs2 would have elevated PGD2 levels. Transgenic mice that overexpress Ptgs2 in the epidermis had been developed previously for carcinogenesis studies. The hair follicles in these K14-Ptgs2 transgenic mice were noted to enter catagen prematurely, and these mice reportedly developed alopecia and sebaceous gland enlargement (14, 23).

We further analyzed the skin and hair follicles of the K14-Ptgs2 mouse. These mice developed alopecia, which was evident as a decrease in the normal murine pelage coat compared to control (Fig. 5, A and B). By histology, we also detected sebaceous gland hyperplasia as indicated by enlarged sebocytes clustered around the hair follicle (Fig. 5, C and D). The hair follicles in the K14-Ptgs2 mice were miniaturized compared to controls (Fig. 5, C and D), and these follicles bore a marked resemblance to the miniaturized follicles in human bald scalp.

To determine the prostaglandin content in the alopecic skin of the K14-Ptgs2 mice, we measured prostaglandin levels by HPLC-MS during the anagen phase of the hair follicle cycle. PGE2 was elevated in the K14-Ptgs2 mice compared to age-matched wild-type controls, as was previously shown using immunoassays measuring PGE2 and PGF2α content in biopsied mouse skin (14, 24). PGD2 was also elevated and was more abundant than PGE2 in both wild-type and K14-Ptgs2 mice. 15-dPGJ2 was elevated in K14-Ptgs2 mice compared to controls and demonstrated the largest fold increase (~14-fold), although baseline values were low (5.7 ng/g tissue) (Fig. 5E). We found low levels (18.4 ng/g tissue) of PGF2α, and an absence of prostacyclin (6k-PGF1α) and thromboxane (TxB2) (Fig. 5E), which are not known to be present in normal skin. Together, the balding phenotype in these mice is likely a result of the overwhelming PGD2 and 15-dPGJ2 inhibitory effects on the hair follicle, despite the presence of PGE2, a known promoter of hair growth (20).

Chemical
01-10-2016, 05:08 AM
For informations, i use VPA ( the acid solution) without any problems ! PH is near the skin PH, i don't burn at all :)
PS : Anyone know why i cannot publish directly my messages there ? I'm not new member here.Thanks

How long have you been using VPA, and have you seen any change? Also where did you get the acid form?


chemical so you think taking setipirant would be a good idea then if it reduces PKC with reduction of PGD2

PGD2 is quite important for REM sleep and I dont like the idea of messing with neurotransmitters. Thats why I dont like fin either (messes with pregnenolone). If seti can be used effectively topically then that might be ideal. You might also want to increase your EGCG dose too seeing as we're both using very low doses. I'm going to add another cap bumping up the total to 500mg/40ml = 1.25% EGCG.


Things like propecia and dut work in such a huge percentage of men it makes you think almost all balding men are sensitive to androgens to some degree.

Indeed, AGA is definitely an androgen mediated disease.


Chemical - I believe an 8% solution of EGCG in 40ml would be 3.2 grams (3200 mg). So, 320 mg in 40ml is not 8.75%.



DOSAGE EQUIVALENCE PERCENT
1mg/mL 0.1%
0.1mg/mL 0.01%
0.01mg/mL 0.001%
0.005mg/mL 0.0005%

Sorry you're right. I'm using a 0.875% solution. How much EGCG are you using?

@InBeforeTheCure

From those excerpts it seems they are saying having a combination of AR related alleles can predispose individuals to AGA, with EDAR/EDA2R being the most significant predictor. I dont particularly like lookng at nf-kb because its functions are so broad and it plays a hand in alot of signalling cascades which makes it difficult to see the bigger picture. But looking this picture from wikipedia (https://en.wikipedia.org/wiki/File:Signal_transduction_v1.png) I see PKC activating nf-kb.



The transcription factor nuclear factor (NF)-kappaB, which is implicated in tumorigenesis, functions as an important downstream substrate of mitogen-activated protein kinase, phosphatidylinositol 3-kinase, AKT, and protein kinase C and plays a role in other cancer-associated signaling pathways.
http://www.ncbi.nlm.nih.gov/pubmed/19628766


I read previously that Andrpgens have the ability to upregulate or maintain AR transcriptional activity. There are feedback loops including GSK3b that try to inhibit AR, but we know PKC can phosphorylate GSK3b possibly preventing the feedback loop. AR also inhibits the PI3K/AKT pathway (http://www.ncbi.nlm.nih.gov/pubmed/21575859) which prevents the additional degradation of GSK3b. However, inhibiting AR causes an increase in Pi3K/AKT signalling which is good. Without PI3K/AKT, PKA will not be as elevated (?) and PKA is known to upregulate AR (http://www.ncbi.nlm.nih.gov/pubmed/23410945). These feedback loops are ridiculously complex and we're only scratching the surface. I just wish it was simpler.

About EBF1, I remember making a post about the relationship between adipocytes and hair. EBF1 is expressed during anagen and also from the study you posted, inhibits ERb. In mice ERb is known to be hair growth suppressive so thats probably a good thing? Or perhaps EBF1 is doing something else behind the scenes.



Analysis of Ebf1 mRNA expression using in situ hybridization revealed that Ebf1 is expressed in the DP in mature, growing hair follicles at P4 (Rendl et al., 2005); however, bulge, hair germ, and DP cells lack Ebf1 expression during the initiation of a new anagen during the hair cycle (Figure S3B), when adipogenesis is active. This expression pattern was confirmed by real time PCR on isolated DP cells and epithelial cells (Figure S3C).

Theres a disparity between mice ERb receptor distribution and male ERb receptor distribution in the scalp. (females have different ER distribution too) (post (https://www.baldtruthtalk.com/threads/22104-Updated-Research-and-Knowledge-Cutting-Edge?p=224562&viewfull=1#post224562)).

I was going over the research on 3b-Diol again and found something I'd missed:



In addition, 3β-adiol is considered a powerful DHT metabolite since its intraprostatic protein level is 100-fold higher than that of estradiol (E2) (29). Notably, 3β-adiol has antiproliferative actions which are not reproduced by 17β-estradiol (30). http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4212017/



We found that 3beta-Adiol not only inhibits PC3-Luc cell migratory properties, but also induces a broader anti-tumor phenotype by decreasing the proliferation rate, increasing cell adhesion, and reducing invasive capabilities in vitro. All these 3beta-Adiol activities are mediated by ERbeta and cannot be reproduced by the physiological estrogen, 17beta-estradiol, suggesting the existence of different pathways activated by the two ERbeta ligands in PC3-Luc cells.

http://www.ncbi.nlm.nih.gov/pubmed/20562232


So Estrogen when applied topically in males doesnt inihibit hair unlike 3B Diol which has antiproliferative actions despite acting via ERb. Regardless of how AR is being increased, preventing the ability of AR to bind to the cell surface and also prevent the intracelluar nuclear trranslocation might be the answer we're looking for. I think given the variation in genetic components, theres a chance these treatments could be hit and miss.





To determine the prostaglandin content in the alopecic skin of the K14-Ptgs2 mice, we measured prostaglandin levels by HPLC-MS during the anagen phase of the hair follicle cycle. PGE2 was elevated in the K14-Ptgs2 mice compared to age-matched wild-type controls, as was previously shown using immunoassays measuring PGE2 and PGF2α content in biopsied mouse skin (14, 24). PGD2 was also elevated and was more abundant than PGE2 in both wild-type and K14-Ptgs2 mice. 15-dPGJ2 was elevated in K14-Ptgs2 mice compared to controls and demonstrated the largest fold increase (~14-fold), although baseline values were low (5.7 ng/g tissue) (Fig. 5E).



InBeforeTheCure has shown that PGD2 can increase GSK3b, and so it would be incorrect of me to say PGD2 doesnt have a role. I think it has a role but not as significant as the parent mediator of PTGDS, Androgens. I believe we should be focusing more on Androgen as that way we can eliminate multiple bad pathways with one big swoop.

Furthermore, I'd encourage you to read the previous page where I mention cotsarelises findings on actual real world PGD2 expression levels in bald scalp, which shows a modest 2.5-4 fold increase. InBeforeTheCure has also brought to light that 50% if AGA individuals are not sensitive to PGD2 further reinforcing my statement that PGD2 is not the only or most significant factor implicating AGA.

Although the analysis done on mice showed hair phenotype resembling AGA, you can see I've boded the bit that says "15-dPGJ2 was increased 14 fold" in the Ptgs2 overpressed mice. if you look at figure 2F: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3319975/figure/F2/

You can see that 15-dPGJ2 is only a small fraction of PGD2, so a 14 fold increase in the metabolite would mean a ridiculously high concentration of PGD2 in the mice. Its not at all surprising that suraphysical levels of PGD2 can retard hair growth. But we have to be realistic here, in AGA humans its not that high anyway. If you inject mice with testosterone or DHT, they also show follicle miniturisation exactly like humans. In fact, anything that reduces BetaCatenin (antibody or what have you) will result in AGA phenotypes. I hope this has clarified my opinion on PGD2's effects on human hair.

* * *

On the topic of AR, I found a study talking about synergistic effects of 5ar inibitors and AR antagonists:



Progesterone (P), a 5 alpha RI, and spironolactone (SL), an ARI, produced a dose responsive decrease in SGS at topical concentrations of 0.01% to 5.0%. At concentrations of 1, 3, and 5%, P and SL combinations produced neither an additive nor synergistic inhibition of SGS. At very low concentrations of up to 0.10%, neither P nor SL alone produced any effect on SGS. When combinations of these two steroids were applied at low concentrations, SGS decreased unilaterally to approximately 50%. This synergy occurred best at a P:SL ratio of 1:2. The lower effective concentrations of P may be explained by its greater percutaneous absorption. Synergy was also demonstrated at low concentrations with other antiandrogens: cyproterone acetate, canrenone, hydroxyflutamide, and N-N-diethyl-4-methyl-3-oxo-4-aza-5 alpha-androstane- 17 beta-carboxamide.

So if I use a 5ar antagonist alongside EGCG theoretically there should be even greater AR suppression. EGCG can inhibit AR to an extent, but when DHT binds to AR its effects are order of magnitudes greater than T. I'm not taking anything strong enough to inhibit 5ar. I found out that Gamma Linoleic acid can inhibit 5ar quite well (study (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1132824/)).

I've bought some Evening Primrose Oil gel capsules which I'll be adding to my Emu oil for use at night and in the morning before work after the MXOLCG has dried. Emu oil also has potential to reduce 5ar due its Beta-Sitosterol contents.

Eire1980
01-10-2016, 07:15 AM
Hi chemical

1st thank you for your commitment to the thread.
All very technical and my knowledge of this stuff is next to nothing.
http://www.amazon.co.uk/gp/product/B00B2U9MW4?psc=1&redirect=true&ref_=oh_aui_detailp%20age_o00_s00[/url][/B]

Im in Ireland and cannot get the product above shipped from the U.K.

I have been taking the below as a supplement http://www.comvita.com/products/olive-leaf-extract---natural/H5488

Would this do mixed with Emu oil?
Appreciate some feedback from all on the thread

Thank you and good luck.

jackhammer199
01-10-2016, 09:53 AM
Chemical,

I often find myself coming on this website hoping for some sort of miracle cure/new breakthrough treatment/some semblance of hope that I can hold on to. Your knowledge, willingness to explain things in detail and sheer pro-activeness with this awful affliction is great to read, and great to be aware of. Really hoping your hard work and dedication pays off and that you've answered some, if not all of the questions that this sort of hairloss poses.

Have ordered my first lot of EGCG and OL because of this thread. Fingers crossed it works!

Thanks again for your efforts; please post your pictures when you have any updates/progress! I'm not in a situation to post pictures for another 2 months but absolutely will when I can mix my new ingredients with minox.

Jackhammer.

BRIANBOY
01-10-2016, 10:28 AM
Chemical - I am currently using a 4% (2960 mg EGCG / 50% Green Tea blend, so about 1480 EGCG proper) in 74ml .......5% OL (it's a blend w/20% OL - so about 300mg of Oleuropein proper) ..... 1% Rosemary Ext ... 1% Jojoba Oil .... (.2%) Tea Tree Oil. This is in a distilled water solution. I add maybe 4 ml of 70% ethyl alcohol as well. Apply that, then wait for that to absorb and apply Minox foam, then finish with Ketoconazole 2% cream. I do this 3 times a day if possible. Scalp seems ok with this regimen so far (2 weeks). I would like to use even a higher dose of EGCG blend, but, the hair growth stimulation seems to occur just under the threshold of when the folliculitis starts. So, have to be careful. I don't want to be forced to stop treatments. Scalp feels in harmony and in a positive direction again.

SriHanuman
01-10-2016, 04:34 PM
http://www.ncbi.nlm.nih.gov/pubmed/24116284

Kokles
01-11-2016, 02:03 AM
http://www.ncbi.nlm.nih.gov/pubmed/24116284

Saitama? LOL! Seriously I wonder why the guy is not the poster boy for young balding men.

Anyway the numbers in the study are mighty mighty fine.

kuba197
01-11-2016, 02:50 AM
Chemical,

Can you give me your e-mail or something that I could contact you.

Seuxin
01-11-2016, 03:35 AM
http://www.ncbi.nlm.nih.gov/pubmed/24116284

Yeah, chemical should read this study...

Chemical
01-11-2016, 01:06 PM
Im in Ireland and cannot get the product above shipped from the U.K.
I have been taking the below as a supplement http://www.comvita.com/products/olive-leaf-extract---natural/H5488
Would this do mixed with Emu oil?

If you can use minox then I'd recommend you get your hands on some minox from here: http://www.kirklandminoxidiluk.co.uk/

Then you can just use this oleuropein from amazon uk (http://www.amazon.co.uk/Swanson-Superior-Extract-Strength-Capsules/dp/B0056Z7IMC/ref=sr_1_1?ie=UTF8&qid=1452540546&sr=8-1&keywords=oleuropein) and this EGCG from amazon uk (http://www.amazon.co.uk/Swanson-Superior-Caffeine-Vegetarian-Capsules/dp/B0031XEF2M/ref=sr_1_1?ie=UTF8&qid=1452540598&sr=8-1&keywords=teavigo) too. The OL you linked doesnt have a high enough ethanol concentration and likely wont work as effectively as a minox vehicle or a custom Ethanol/PG solution. If you cant use minox then you can use this post from josh (https://www.baldtruthtalk.com/threads/22104-Updated-Research-and-Knowledge-Cutting-Edge?p=226633&viewfull=1#post226633) as a starting point. Alternatively you can wait for Keeper to organise a OL/EGCG trial with his contact.



Have ordered my first lot of EGCG and OL because of this thread. Fingers crossed it works!
Thanks again for your efforts; please post your pictures when you have any updates/progress! I'm not in a situation to post pictures for another 2 months but absolutely will when I can mix my new ingredients with minox.

Thank you for your kind words, it really makes me happy to know people value the research we are doing here. The biggest motivation is that I think with the combined knowledge and effort of people in this forum we can actually find something that genuinely woks to regrow hair - and keep it. I will indeed be posting more pictures as I see progress. I hope this really works for you and everyone else who's decided go ahead and try this experiment, especially given that its still just experimental research with little real world evidence.


Chemical - I am currently using a 4% (2960 mg EGCG / 50% Green Tea blend, so about 1480 EGCG proper) in 74ml .......5% OL (it's a blend w/20% OL - so about 300mg of Oleuropein proper) ..... 1% Rosemary Ext ... 1% Jojoba Oil .... (.2%) Tea Tree Oil.

Thats an awfully high amount of OL you're using and EGCG too. I would definitely lower the OL if you can but i not, then I'm interested to see how the higher dose works. I have a few questions. Does the EGCG dissolve well in just water and do you notice any crystal-like residue left after it dries up? I think I will get in contact wit hthe Oleuropein study researchers to find out what happened when they used 3mg OL.


http://www.ncbi.nlm.nih.gov/pubmed/24116284

That is an amazing find SriHanuman. According to the study, PGE2 was increased but I couldnt see where they mentioned how it that. They also mentioned minox increasing COX-1 as a mechanism for increasing PGE2, so if G. elliptica increases cox-1 then it wont be anymore useful than using other ways of increasing COX-1/2 production. However it does have strong 5ar inihibitory properties that are dose dependent. The only problem is its quite to find (I didnt look hard enough?).

Rosmarinus officinalis (http://www.swansonvitamins.com/swanson-premium-rosemary-400-mg-90-caps). Its available from amazon uk too (http://www.amazon.co.uk/Swanson-Rosemary-400mg-90-capsules/dp/B004QIWHAS/ref=sr_1_1?ie=UTF8&qid=1452541908&sr=8-1&keywords=rosemary+swanson). As Brian has shown, rosemary has AR and 5ar suppressive properties making it a potential treatment to stack with EGCG.

Herse the complete list of treatments we have available so far:

Oleuropein: ¬DKK1, ->WNT10b, ->IGF-1, ->BetaCatenin
Emu oil: ¬5ar, ¬DKK1 (via antioxidant activity)
EGCG: ¬Axin, ¬AR, ->BetaCatenin
Rosmarinus Officinalis: ¬AR, ¬5ar (Only rosemary extract not oil or rosmarinic acid)
Gamma Linoleic: ¬5ar (Evening primrose extract)
Procyanidins: ¬PKC, ->BetaCatenin (Apple polyphenols/Grape seed extract)
Forskolin?: ->PKA
Valproic Acid: ¬GSK3b, ->BetaCatenin
Miconazole/Ketoconazole: ¬17bHSD ¬3bHSD

@Kuba197

I would encourage you to ask any questions you may have on the forums so that it may help anyone else who might have the same question. If you truly must contact me in private then: chemxrs at gmail dot com (I hope I dont get in trouble for doing this)

Seuxin
01-11-2016, 02:48 PM
You really have to forget about emu oil ! There is really no REAL SCIENTIST STUDY about emu oil. Emu oil is just a scam for hairloss, it don't decrease 5AR or DHT ;)

What about Zinc/Zinc Sulphate, Vitamin B6, BetaSitosterol ? It can be a good addition.
In addition, you're attacki AR/5AR/DHT/DKK1 but you should find a way to increase grow factor...because if you want regrowth, you need grow factor (VEGF-> Increased with stemoxydine, but there is FGF ; KGF ; Follistatin).

Look at thistogen : They just play on grow factors...not on DHT and look at the regrowth ! Awesome !

Conclusion : Your idea is good, but now, you should find treatements to add which can increase grow factors ( FGF, KGF, VEGF, FOLLISTATIN, PGE2)

BRIANBOY
01-11-2016, 03:38 PM
Chemical - I am using higher EGCG because I have used at least that strength before, and had no problems. Yes, it dissolves completely in distilled water. It will be a brown color, and stains anything it touches. As for the OL .5%, that's the percentage recommended by SkinActives.com for oleuropein in topical formulations. We'll see how it goes.

BRIANBOY
01-11-2016, 11:49 PM
I have also added 50 mcg of KGF (from Skinactives.com) to 74ml of solution. Don't want to add anything else, as my scalp seems to be ok with the ingredients and percentages currently.

SriHanuman
01-12-2016, 01:39 AM
That is an amazing find SriHanuman. According to the study, PGE2 was increased but I couldnt see where they mentioned how it that. They also mentioned minox increasing COX-1 as a mechanism for increasing PGE2, so if G. elliptica increases cox-1 then it wont be anymore useful than using other ways of increasing COX-1/2 production. However it does have strong 5ar inihibitory properties that are dose dependent. The only problem is its quite to find (I didnt look hard enough?).



I can't find it either, sadly, but will go on searching... One question about EGCG, does it stain much, as in, does it show on scalp or not?

SriHanuman
01-12-2016, 02:00 AM
I found this, similiar, can get the extract on amazon:

http://www.mdpi.com/1422-0067/13/5/6407/htm
https://www.amazon.co.uk/s/ref=nb_sb_ss_c_0_8?url=search-alias%3Daps&field-keywords=ecklonia+cava&sprefix=ecklonia+cava%2Caps%2C180

Sogeking
01-12-2016, 01:06 PM
At what concentrations should one use primrose oil, grape seed extract and rosemary extract?

Also it would be cool if we could find a source for Grateloupia elliptica.

SriHanuman
01-13-2016, 01:51 AM
wnt agonist:

http://www.sciencedirect.com/science/article/pii/S0024320512005073

fo-ti, upregulating Shh and β-catenin expression:

http://www.sciencedirect.com/science/article/pii/S0378874111001644

ryan82
01-13-2016, 03:48 AM
Very interesting this!

ryan82
01-13-2016, 05:30 AM
its boost testosterone levels ? That is bad for hair?

http://www.ergo-log.com/oleuropein-boosts-testosterone-lowers-cortisol-stimulates-anabolism.html

FeelsBad
01-13-2016, 06:39 PM
It's not going to raise T levels when applied topically

ryan82
01-14-2016, 01:29 AM
It's not going to raise T levels when applied topically

I understand. So if i buy olive extract pills and put it in minox for example, i can reduces DKK-1 ?

lukey
01-14-2016, 05:38 AM
just thought i would post an update been using Oleuropein ethanol tincture of amazon for 2 weeks now, i stopped minox 2 months ago due to face/skin probs ( it was the minox my face is better not 100% but alot better now)

the small vellus hairs that minox made were about 1-2mm in length across the hairline since using the Oleuropein some of these have doubled in length to 3-4mm nothing groundbreaking but they are getting longer for sure so im hoping in the next few weeks they might keep growing.

this is not cosmetic regrowth as the hairs in question are not pigmented just thought i would share

Josh, have you got anything to update us with? I've decided to come off minox for a while - i'm sure it's what's causing the problems with my sinuses - and hoping the OL + EGCG mixture will at least help prevent further loss.

Chemical, what's your thoughts on OC?

hammerhead
01-14-2016, 12:46 PM
I take a liquid Olive Oil leaf extract (contains Oleuropein) for general health and well being - works great especially if you are sick with a cold or flu. Do you think taking any of these items orally instead of or in addition to topically will help with hair loss? Amazing information on this thread - very educational - thanks.

burtandernie
01-14-2016, 06:28 PM
If something dissolves completely does that mean its optimally absorbed into the correct layers of the scalp or dermal layer where it needs to be for the amount of time it needs to be to get used properly? Im not a chemist/biology person so I dont know if just mixing stuff together would ever even work topically. Everyone knows the skin is a very strong barrier to keep things out

jamesst11
01-14-2016, 06:52 PM
If something dissolves completely does that mean its optimally absorbed into the correct layers of the scalp or dermal layer where it needs to be for the amount of time it needs to be to get used properly? Im not a chemist/biology person so I dont know if just mixing stuff together would ever even work topically. Everyone knows the skin is a very strong barrier to keep things out

If something dissolves completely in solution, it does not mean it will be delivered transdermally.

InBeforeTheCure
01-14-2016, 09:36 PM
PGD2 is quite important for REM sleep and I dont like the idea of messing with neurotransmitters.

I think the PGD2 receptor involved in sleep is DP1, not the GPR44 receptor that affects hair growth and which seti blocks.



From those excerpts it seems they are saying having a combination of AR related alleles can predispose individuals to AGA, with EDAR/EDA2R being the most significant predictor.

EDA2R, but not EDAR, is associated. No other study has been able to replicate the result of EDA2R being the most significant predictor -- maybe it's the case in Sardinians, somewhat of a genetic isolate, but not other populations? Still, EDA2R is one of the most linked genes, along with AR itself, a region on Chr20 near PAX1 and FOXA2, EBF1, TARDBP, and HDAC9.


I dont particularly like lookng at nf-kb because its functions are so broad and it plays a hand in alot of signalling cascades which makes it difficult to see the bigger picture. But looking this picture from wikipedia (https://en.wikipedia.org/wiki/File:Signal_transduction_v1.png) I see PKC activating nf-kb.

I read previously that Andrpgens have the ability to upregulate or maintain AR transcriptional activity. There are feedback loops including GSK3b that try to inhibit AR, but we know PKC can phosphorylate GSK3b possibly preventing the feedback loop. AR also inhibits the PI3K/AKT pathway (http://www.ncbi.nlm.nih.gov/pubmed/21575859) which prevents the additional degradation of GSK3b. However, inhibiting AR causes an increase in Pi3K/AKT signalling which is good. Without PI3K/AKT, PKA will not be as elevated (?) and PKA is known to upregulate AR (http://www.ncbi.nlm.nih.gov/pubmed/23410945). These feedback loops are ridiculously complex and we're only scratching the surface. I just wish it was simpler.

According to this (http://www.wikipathways.org/index.php/Pathway:WP138), AR -> PTEN normally (?), which inhibits the Pi3K -> Akt step. But supposedly PTEN is widely expressed throughout the body as a tumor suppressor. I'm not sure how that would affect the efficacy of increasing Pi3K if AR's inhibitory effect on the Akt pathway is one step downstream of Pi3K. Any ideas?

http://www.frontiersin.org/files/Articles/67693/fonc-03-00326-HTML/image_m/fonc-03-00326-g002.jpg


About EBF1, I remember making a post about the relationship between adipocytes and hair. EBF1 is expressed during anagen and also from the study you posted, inhibits ERb. In mice ERb is known to be hair growth suppressive so thats probably a good thing? Or perhaps EBF1 is doing something else behind the scenes.

Theres a disparity between mice ERb receptor distribution and male ERb receptor distribution in the scalp. (females have different ER distribution too) (post (https://www.baldtruthtalk.com/threads/22104-Updated-Research-and-Knowledge-Cutting-Edge?p=224562&viewfull=1#post224562)).

I was going over the research on 3b-Diol again and found something I'd missed:





So Estrogen when applied topically in males doesnt inihibit hair unlike 3B Diol which has antiproliferative actions despite acting via ERb. Regardless of how AR is being increased, preventing the ability of AR to bind to the cell surface and also prevent the intracelluar nuclear trranslocation might be the answer we're looking for. I think given the variation in genetic components, theres a chance these treatments could be hit and miss.

Interesting. I'll have to read more about EBF1, ERbeta, adipogenesis, and so on.

Chemical
01-15-2016, 12:20 PM
You really have to forget about emu oil ! There is really no REAL SCIENTIST STUDY about emu oil. Emu oil is just a scam for hairloss, it don't decrease 5AR or DHT.

What about Zinc/Zinc Sulphate, Vitamin B6, BetaSitosterol ?
You should find a way to increase grow factor...because if you want regrowth, you need grow factor (VEGF-> Increased with stemoxydine, but there is FGF ; KGF ; Follistatin).

I have to disagree with you on Emu oil. Its not really being marketed by big companies for anything spectacular. In fact, I am. I've used it when I first started receding at 17 by itself and I saw modest regrowth after 2 months. Its got BetaSitosterol which you've just listed lol. Its not a scam, its a weak treatment for hair, however it does posses potent anti inflammatory effects which are proven.

The growth factors you've listed all inevitably end up increasing β-catenin to mediate their hair growth promoting effects.

IGF-1 inhibits GSKb3 which increases β-catenin
PGE2 inibits Axin which increases β-catenin
VEGF is increased by β-catenin
β-catenin also upregulates PDGF-A which is required for hair canal formation and anagen induction.

Regardless of how you activate β-catenin, you will see hair growth.



Oleuropein: ¬DKK1, ->WNT10b, ->IGF-1, ->β-catenin
Emu oil: ¬5ar, ¬DKK1 (via antioxidant activity)
EGCG: ¬Axin, ¬AR, ->β-catenin
Rosmarinus Officinalis: ¬AR, ¬5ar (Only rosemary extract not oil or rosmarinic acid)
Gamma Linoleic: ¬5ar (Evening primrose extract)
Procyanidins: ¬PKC, ->β-catenin (Apple polyphenols/Grape seed extract)
Forskolin?: ->PKA
Valproic Acid: ¬GSK3b, ->β-catenin
Miconazole/Ketoconazole: ¬17bHSD ¬3bHSD


I have also added 50 mcg of KGF (from Skinactives.com) to 74ml of solution. Don't want to add anything else, as my scalp seems to be ok with the ingredients and percentages currently.

I'm intrigued by your usage of KGF. I will dig up some research on this soon.


I found this, similiar, can get the extract on amazon:

Effect of Dieckol, a Component of Ecklonia cava, on the Promotion of Hair Growth (http://www.mdpi.com/1422-0067/13/5/6407/htm)

Ecklonia Cava amazon uk (https://www.amazon.co.uk/s/ref=nb_sb_ss_c_0_8?url=search-alias%3Daps&field-keywords=ecklonia+cava&sprefix=ecklonia+cava%2Caps%2C180)

wnt agonist:

Hair growth-promoting effect of Aconiti Ciliare Tuber extract mediated by the activation of Wnt/β-catenin signaling (http://www.sciencedirect.com/science/article/pii/S0024320512005073)

fo-ti, upregulating Shh and β-catenin expression:

Topical application of Polygonum multiflorum extract induces hair growth of resting hair follicles through upregulating Shh and β-catenin expression in C57BL/6 mice (http://www.sciencedirect.com/science/article/pii/S0378874111001644)


Ecklonia cava is 40% fat soluble and water soluble (?) too which means it can be used in an oil based vehicle I take?

Unfortuneately:



When DPC were treated with E. cava enzymatic extract in the concentrations of 0.001, 0.01, 0.1, 1, 10 and 100 μg/mL, E. cava enzymatic extract significantly promoted the proliferation of DPC compared with the vehicle-treated control at all the concentrations, except the 100 μg/mL (Figure 3).

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3382810/

Figure 3 shows 100 μg/mL did worse. Not promising.

Couldnt find any solubility info on ACT, nor Fo-Ti which actually has alot of potential to work seeing as it uses the shh pathway.

Baicalin (http://www.amazon.co.uk/gp/product/B001RTVU9S?keywords=baicalin&qid=1452884086&ref_=sr_1_1&sr=8-1) (study (http://www.ncbi.nlm.nih.gov/pubmed/25434532)) however, directly activates WNT and is quite solvent in ethanol with increasing temperature (http://pubs.acs.org/doi/abs/10.1021/je900171g).


At what concentrations should one use primrose oil, grape seed extract and rosemary extract?
Also it would be cool if we could find a source for Grateloupia elliptica.

Gamma Linoleic Acid is very soluble in ethanol and can be mixed with oil:

https://pubchem.ncbi.nlm.nih.gov/compound/linoleic_acid#section=Solubility

So perhaps straight ethanol + GLA or ethanol + oil + GLA. I've got my hands on GLA (primrose extract) and I'm thinking of how to go about this.

Rosemarinus Officinalis isnt soluble in water but is soluble in solvents (ethanol?):

http://www.jmloveridge.com/cosh/Rosemary%20Oil.pdf

Also the main constituents of Rosemary are carnosol and carnosic acid:



Soluble in DMSO (250 mg/ml), ethanol (8 mg/ml), methanol (5 mg/ml), DMF (35 mg/ml), and PBS(pH7.2) (<0.03 mg/ml).

http://www.scbt.com/datasheet-204672-carnosol.html

Water soluble too apparently @1,425 mg/L at 25 deg C (est) (https://pubchem.ncbi.nlm.nih.gov/compound/carnosol#section=Solubility).


its boost testosterone levels ? That is bad for hair?
http://www.ergo-log.com/oleuropein-boosts-testosterone-lowers-cortisol-stimulates-anabolism.html


It's not going to raise T levels when applied topically

So if i buy olive extract pills and put it in minox for example, i can reduces DKK-1 ?

FeelsBad is correct. Someone pointed this out earlier and I made a post here (https://www.baldtruthtalk.com/threads/22104-Updated-Research-and-Knowledge-Cutting-Edge?p=225455&viewfull=1#post225455).

Yes the Oleuropein will reduce DKK1. In fact, anything that has anti-inflamatory properties has the potential to reduce DKK1.

Will reply to other posts tomorrow and with some updates.

SriHanuman
01-15-2016, 03:07 PM
Fo-Ti seems to be solubale in distilled water:

http://www.scielo.br/pdf/bjmbr/v39n9/6134

LongWayHome
01-15-2016, 04:04 PM
Chemical, thank you very much for this.
I'm sure that I'm speaking on behalf of everyone that is not registered to this forum and follows this.
I Hope it will lead to something this time.

Chemical
01-16-2016, 03:14 AM
Chemical, what's your thoughts on OC?

I'm not too familiar with the efficacy OC versus seti. I cant really comment on its topical vs oral intake effectiveness either. I dont see it being a huge problem taking it orally given that it doesnt interact with PGD2 itself, but I'm not a fan of systemic usage.


Do you think taking any of these items orally instead of or in addition to topically will help with hair loss?

It could work but if does increase hair then you'd notice hair everywhere. OL and EGCG work differently when taken orally and I cant vouch for their oral effectiveness on hair growth. Theres not alot of research on oral supplements increasing scalp hair growth in AGA unfortuneately. You're much better off using them topically since they are quite soluble and have low-ish molecular weights.


If something dissolves completely does that mean its optimally absorbed into the correct layers of the scalp or dermal layer where it needs to be for the amount of time it needs to be to get used properly? Everyone knows the skin is a very strong barrier to keep things out

Good question. Simply dissolving in a solution does not mean it will permeate the skin. The molecular weight in addition to solubility properties are a much predictor of topical absorption. This is a probabilistic model where complete absorption and equal tissue distribution is not guaranteed. Ethanol has the ability to strip the skin of lipids and enhance the absorption of molecules. Heres a post I made on minox/OL molecular weight and absorption. (https://www.baldtruthtalk.com/threads/22104-Updated-Research-and-Knowledge-Cutting-Edge?p=225875&viewfull=1#post225875)


I think the PGD2 receptor involved in sleep is DP1, not the GPR44 receptor that affects hair growth and which seti blocks.


http://www.ncbi.nlm.nih.gov/pubmed/22024172

I apologise, you are correct. It is indeed the DP1, so CRTH2 anatagonists shouldnt be a problem. I think I need you to correct mistakes in my analysis lol.



EDA2R, but not EDAR, is associated. No other study has been able to replicate the result of EDA2R being the most significant predictor -- maybe it's the case in Sardinians, somewhat of a genetic isolate, but not other populations? Still, EDA2R is one of the most linked genes, along with AR itself, a region on Chr20 near PAX1 and FOXA2, EBF1, TARDBP, and HDAC9.


Two receptors for EDA were found that are specific for the two isoforms EDA-A1 and EDA-A2: EDAR and EDA2R, respectively. EDA-A1 and its receptor EDAR are capable of activating the NF-κB pathway and are implicated in hair growth. EDA2R is capable of activating the NF-κB pathway and also through TRAF3,6, JNK (c-Jun N-terminal kinase), which activates c-Jun. Mutations in EDA and EDAR give rise to ectodermal dysplasia, a clinical syndrome characterized by loss of hair, sweat glands, and teeth, whereas mutations in EDA2R do not. Recently, a preliminary report suggested that EDAR may influence hair thickness in Asians, A scan for genetic determinants of human hair morphology: EDAR is associated with Asian hair thickness.

EDA2R could influence the onset of AGA through the activation of the NF-κB pathway or by c-Jun, which has been shown to be critical for AR transactivation. Moreover, in adult mice, EDA2R is also expressed in the hair bulb and in differentiating hair matrix (Botchkarev and Fessing, 2005).



Our previous studies suggest that the proto-oncoprotein c-Jun is an AR coactivator that stimulates AR transactivation by mediating receptor dimerization and subsequent DNA binding. (study (http://www.ncbi.nlm.nih.gov/pubmed/16732317))

Indeed, its the EDA2R that is involved in AR transactivation. But the EDAR variant also activates nf-kb without negative effect on hair. It seems theres alot genes that can influence the AR and transactivation of AR via different mechanisms leading to increased nuclear translocation. A combination of these alleles that enhance AR be it subtly or directly, definitely have the ability to predispose individuals to AGA. The nf-kb pathway seems to have differential effects depending on its mechanism of activation? I think I'm missing something that doesnt explain why EDAR can increase hair thickness.




According to this (http://www.wikipathways.org/index.php/Pathway:WP138), AR -> PTEN normally (?), which inhibits the Pi3K -> Akt step. But supposedly PTEN is widely expressed throughout the body as a tumor suppressor. I'm not sure how that would affect the efficacy of increasing Pi3K if AR's inhibitory effect on the Akt pathway is one step downstream of Pi3K. Any ideas?

So this means in the presence of AR, anything that wants to activate AKT via PI3K will be unsuccessful. This includes IGF-1, shh, EGF (wiki (https://en.wikipedia.org/wiki/PI3K/AKT/mTOR_pathway)). Beautiful diagram here: https://en.wikipedia.org/wiki/File:MTOR-pathway-v1.7.svg

But does this mean beard DPC do not inhibit PI3K via PTEN in response to AR activation? Apparently PTEN deficiency results in accelerated hair follicle morphogenesis and enhanced AKT(PKB) activation (study (http://cancerres.aacrjournals.org/content/63/3/674.long)). Very interesting.

Heres some more research on ERb and hair.


Recent in vitro studies have shown that 17β-estradiol inhibits female scalp hair shaft elongation (Nelson 2006), although stimulation occurs in hair follicles derived from frontotemporal male scalp (Conrad et al 2004). In addition, in female hair follicles the phytoestrogen, genistein inhibits hair shaft elongation to a similar extent as 17β-estradiol. Since genistein preferentially binds to ERβ, this opens the possibility that the inhibition of hair growth in response to 17β-estradiol may be mediated via ERβ rather than ERα (Nelson 2006). Therefore the development of selective estrogen receptor ligands may provide important clinical applications for the prevention and treatment of disorders of hair growth.

So in females, ERb increases frontotemporal hair growth but inhibits in other areas?



ERbeta was the major steroid receptor expressed in human skin. It was highly expressed in epidermis, blood vessels and dermal fibroblasts, in contrast to ERalpha and AR. In the hair follicle, ERbeta expression was localized to nuclei of outer root sheath, epithelial matrix and dermal papilla cells, in contrast to ERalpha, and the AR, which was only expressed in dermal papilla cells.

Studies say that estrogen prolongs anagen but inhibits hair shaft elongation (in females). Perhaps ERb in the ORS is inhibiting proliferation, but ERa in the DPC is maintaining BetaCatenin. But Estrogen acts differently in frontotemporal regions? Females have a differential scalp response phenotype. Males start off as females in the womb, so what if Androgens exploit this localised response in a detrimental manner? This sets off the chain reaction whereby follicles release DKK-1 and TGF-Beta into the ECM affecting nearby follicles that arent fully susceptible to AR's effects.

Anyways, I want to know what role ERa has in male DPC. ERb can increase proliferation of existing hair, but does it secrete growth factors in a paracrine manner? Or does ERa promote WNT activation by itself in DPC to prolong anagen?


Fo-Ti seems to be solubale in distilled water:

http://www.scielo.br/pdf/bjmbr/v39n9/6134

It can! This is excellent research SriHanuman. Unfortuneately I cant use this because I'm trying a different stack, so I wont be able to gauge its effectiveness. People who cant use minox might find fo-ti useful.


Chemical, thank you very much for this.
I'm sure that I'm speaking on behalf of everyone that is not registered to this forum and follows this. I Hope it will lead to something this time.

Thank you! We're uncovering so much research that I think it is already leading to something.

Update

Last week I increased the EGCG concentration totalling 12.5mg/ml. The hairs that I grew using minox + OL are 100% terminal. Really wasnt expecting results this fast. I'm seeing more tiny vellus hairs along nw1 hairline and the skin turning grey/green. My nw1/0 hairs grow sideways, as in they come out of the skin at very low degree angles. My nw0 is hairline is completely bald atm so it might be harder to regrow. I'm not sure if my aggressive micro-needling (3mm derma pen) last year has caused scarring. I hope not because I'd be devastated.

Bear in mind I'm using the MXOLCG once a day at night because of work and laziness, and Ketoconazole in the morning. During the weekends I use MXOLCG 3x day. If only I could use minox 3x a day everyday... I try to use Emu oil every two days, and I'll be adding the Gamma Linoleic Acid to the Emu oil (which has minox in it already). I'll be posting pics soon. I am tempted to use Rosemary but I'll wait.

I'm also going to ask the moderators to let me edit my first post so I can reorganise the research for people to find easily.

UNBEAT
01-16-2016, 05:54 AM
HEY Chemical thank you for what are you doing.

Can you do a summarise of your invention, like what exactly to use( what products it contains) , the concentration ,and how often to use like instructions on drughs???

scooterboy
01-16-2016, 07:03 AM
Chemical , Can you please tell me how much EGCG and OL pills you are now using in a 60 MG bottle of minox ? I was dumping in one EGCG pill and a half pill of OL . Can you update the mix ?

pilipili
01-16-2016, 07:38 AM
There are a lot of new pages, sadly I did not find the courage to read everything ! ^^ So the idea to edit the first posts would be excellent.
Anyway I remember you said you don't take any anti DHT. According to you new hairs get thicker and potentially hold on thanks to EGCG but what about existing hair ? Do you apply the solution all over the scalp or only at temples ? Thanks for keeping us updated!

bluesuedeshoes
01-16-2016, 01:47 PM
Thanks for the all the work Chemical and Brianboy. Ive purchased the supplies and keen to start soon.

Im already using seti in an etch/pg solution so keen to not add too much more ethanol to my scalp each day. That said, I want to ensure proper delivery to the follicles.

I have DMSO as well. Would a water/eth/pg/dmso be a good idea? What ratios are you both using?

I don't have any Keto to hand but I have some Dexamethasone, which apparently raises PGE2 and is an AA. Would adding that to the mix be too much? I see that you put your Keto on in the morning. Important to use it hours before the EGCG/OL mix?

lukey
01-16-2016, 05:59 PM
Thanks for the all the work Chemical and Brianboy. Ive purchased the supplies and keen to start soon.

Im already using seti in an etch/pg solution so keen to not add too much more ethanol to my scalp each day. That said, I want to ensure proper delivery to the follicles.

I have DMSO as well. Would a water/eth/pg/dmso be a good idea? What ratios are you both using?

I don't have any Keto to hand but I have some Dexamethasone, which apparently raises PGE2 and is an AA. Would adding that to the mix be too much? I see that you put your Keto on in the morning. Important to use it hours before the EGCG/OL mix?

How are you getting on with seti?

inbrugge
01-17-2016, 03:28 PM
I'm not too familiar with the efficacy OC versus seti. I cant really comment on its topical vs oral intake effectiveness either. I dont see it being a huge problem taking it orally given that it doesnt interact with PGD2 itself, but I'm not a fan of systemic usage.



It could work but if does increase hair then you'd notice hair everywhere. OL and EGCG work differently when taken orally and I cant vouch for their oral effectiveness on hair growth. Theres not alot of research on oral supplements increasing scalp hair growth in AGA unfortuneately. You're much better off using them topically since they are quite soluble and have low-ish molecular weights.



Good question. Simply dissolving in a solution does not mean it will permeate the skin. The molecular weight in addition to solubility properties are a much predictor of topical absorption. This is a probabilistic model where complete absorption and equal tissue distribution is not guaranteed. Ethanol has the ability to strip the skin of lipids and enhance the absorption of molecules. Heres a post I made on minox/OL molecular weight and absorption. (https://www.baldtruthtalk.com/threads/22104-Updated-Research-and-Knowledge-Cutting-Edge?p=225875&viewfull=1#post225875)



http://www.ncbi.nlm.nih.gov/pubmed/22024172

I apologise, you are correct. It is indeed the DP1, so CRTH2 anatagonists shouldnt be a problem. I think I need you to correct mistakes in my analysis lol.



Two receptors for EDA were found that are specific for the two isoforms EDA-A1 and EDA-A2: EDAR and EDA2R, respectively. EDA-A1 and its receptor EDAR are capable of activating the NF-κB pathway and are implicated in hair growth. EDA2R is capable of activating the NF-κB pathway and also through TRAF3,6, JNK (c-Jun N-terminal kinase), which activates c-Jun. Mutations in EDA and EDAR give rise to ectodermal dysplasia, a clinical syndrome characterized by loss of hair, sweat glands, and teeth, whereas mutations in EDA2R do not. Recently, a preliminary report suggested that EDAR may influence hair thickness in Asians, A scan for genetic determinants of human hair morphology: EDAR is associated with Asian hair thickness.

EDA2R could influence the onset of AGA through the activation of the NF-κB pathway or by c-Jun, which has been shown to be critical for AR transactivation. Moreover, in adult mice, EDA2R is also expressed in the hair bulb and in differentiating hair matrix (Botchkarev and Fessing, 2005).



Indeed, its the EDA2R that is involved in AR transactivation. But the EDAR variant also activates nf-kb without negative effect on hair. It seems theres alot genes that can influence the AR and transactivation of AR via different mechanisms leading to increased nuclear translocation. A combination of these alleles that enhance AR be it subtly or directly, definitely have the ability to predispose individuals to AGA. The nf-kb pathway seems to have differential effects depending on its mechanism of activation? I think I'm missing something that doesnt explain why EDAR can increase hair thickness.




So this means in the presence of AR, anything that wants to activate AKT via PI3K will be unsuccessful. This includes IGF-1, shh, EGF (wiki (https://en.wikipedia.org/wiki/PI3K/AKT/mTOR_pathway)). Beautiful diagram here: https://en.wikipedia.org/wiki/File:MTOR-pathway-v1.7.svg

But does this mean beard DPC do not inhibit PI3K via PTEN in response to AR activation? Apparently PTEN deficiency results in accelerated hair follicle morphogenesis and enhanced AKT(PKB) activation (study (http://cancerres.aacrjournals.org/content/63/3/674.long)). Very interesting.

Heres some more research on ERb and hair.



So in females, ERb increases frontotemporal hair growth but inhibits in other areas?



Studies say that estrogen prolongs anagen but inhibits hair shaft elongation (in females). Perhaps ERb in the ORS is inhibiting proliferation, but ERa in the DPC is maintaining BetaCatenin. But Estrogen acts differently in frontotemporal regions? Females have a differential scalp response phenotype. Males start off as females in the womb, so what if Androgens exploit this localised response in a detrimental manner? This sets off the chain reaction whereby follicles release DKK-1 and TGF-Beta into the ECM affecting nearby follicles that arent fully susceptible to AR's effects.

Anyways, I want to know what role ERa has in male DPC. ERb can increase proliferation of existing hair, but does it secrete growth factors in a paracrine manner? Or does ERa promote WNT activation by itself in DPC to prolong anagen?



It can! This is excellent research SriHanuman. Unfortuneately I cant use this because I'm trying a different stack, so I wont be able to gauge its effectiveness. People who cant use minox might find fo-ti useful.



Thank you! We're uncovering so much research that I think it is already leading to something.

Update

Last week I increased the EGCG concentration totalling 12.5mg/ml. The hairs that I grew using minox + OL are 100% terminal. Really wasnt expecting results this fast. I'm seeing more tiny vellus hairs along nw1 hairline and the skin turning grey/green. My nw1/0 hairs grow sideways, as in they come out of the skin at very low degree angles. My nw0 is hairline is completely bald atm so it might be harder to regrow. I'm not sure if my aggressive micro-needling (3mm derma pen) last year has caused scarring. I hope not because I'd be devastated.

Bear in mind I'm using the MXOLCG once a day at night because of work and laziness, and Ketoconazole in the morning. During the weekends I use MXOLCG 3x day. If only I could use minox 3x a day everyday... I try to use Emu oil every two days, and I'll be adding the Gamma Linoleic Acid to the Emu oil (which has minox in it already). I'll be posting pics soon. I am tempted to use Rosemary but I'll wait.

I'm also going to ask the moderators to let me edit my first post so I can reorganise the research for people to find easily.

Any pictures Chemical?

ryan82
01-18-2016, 05:30 AM
Chemical , Can you please tell me how much EGCG and OL pills you are now using in a 60 MG bottle of minox ? I was dumping in one EGCG pill and a half pill of OL . Can you update the mix ?

I want to know also! What must i buy for same regime. ??

InBeforeTheCure
01-18-2016, 08:39 PM
I apologise, you are correct. It is indeed the DP1, so CRTH2 anatagonists shouldnt be a problem. I think I need you to correct mistakes in my analysis lol.

A rare occurrence, I'm sure, since your knowledge of these things far exceeds mine, as I'm a noob to this material. ;)



Indeed, its the EDA2R that is involved in AR transactivation. But the EDAR variant also activates nf-kb without negative effect on hair. It seems theres alot genes that can influence the AR and transactivation of AR via different mechanisms leading to increased nuclear translocation. A combination of these alleles that enhance AR be it subtly or directly, definitely have the ability to predispose individuals to AGA. The nf-kb pathway seems to have differential effects depending on its mechanism of activation? I think I'm missing something that doesnt explain why EDAR can increase hair thickness.

The EDAR variant associated with greater hair thickness in Asians is the one that reduces Nf-kB, not increases it. (http://hmg.oxfordjournals.org/content/17/6/835.long)


Interestingly, the C allele that was associated with thicker hair showed lower relative luciferase activities than the T allele in both the cell lines. These results indicated that the amino acid replacement in the death domain causes a functional change and results in the lower activity of NF-κB. Although the relation between NF-κB activation level and hair thickness has not been clear, it has been reported that steroid induces NF-κB suppression as well as hair regrowth (21,22), which supports that the lower NF-κB level may be associated with higher activity of hair formation.


So this means in the presence of AR, anything that wants to activate AKT via PI3K will be unsuccessful. This includes IGF-1, shh, EGF (wiki (https://en.wikipedia.org/wiki/PI3K/AKT/mTOR_pathway)). Beautiful diagram here: https://en.wikipedia.org/wiki/File:MTOR-pathway-v1.7.svg

But does this mean beard DPC do not inhibit PI3K via PTEN in response to AR activation? Apparently PTEN deficiency results in accelerated hair follicle morphogenesis and enhanced AKT(PKB) activation (study (http://cancerres.aacrjournals.org/content/63/3/674.long)). Very interesting.

Who knows? Is anyone familiar with any research about differences in the way AR works within the cycling of head hair vs. the cycling of facial hair?


Heres some more research on ERb and hair.



So in females, ERb increases frontotemporal hair growth but inhibits in other areas?



Studies say that estrogen prolongs anagen but inhibits hair shaft elongation (in females). Perhaps ERb in the ORS is inhibiting proliferation, but ERa in the DPC is maintaining BetaCatenin. But Estrogen acts differently in frontotemporal regions? Females have a differential scalp response phenotype. Males start off as females in the womb, so what if Androgens exploit this localised response in a detrimental manner? This sets off the chain reaction whereby follicles release DKK-1 and TGF-Beta into the ECM affecting nearby follicles that arent fully susceptible to AR's effects.

Anyways, I want to know what role ERa has in male DPC. ERb can increase proliferation of existing hair, but does it secrete growth factors in a paracrine manner? Or does ERa promote WNT activation by itself in DPC to prolong anagen?

Frontotemporal = temples? But balding can start at the vertex as well in some cases. Paracrine signals may still play a role though and contribute to feedback loops in nearby follicles though, I assume.

By the way, this was posted in another thread: Mapping out cell conversion -
Algorithm takes the field of cell reprogramming forward (http://www.sciencedaily.com/releases/2016/01/160118134444.htm).

Link to the software: http://www.mogrify.net/

Dermal papilla cell to hair follicle cell (do they mean hair follicle epithelial cells?):

http://s29.postimg.org/9st7qxds7/DPCto_HF.png

Hair follicle cell to dermal papilla cell:

http://s29.postimg.org/5iejvc8p3/HFto_DPC.png

Interesting how EBF1 is involved in mesenchymal -> epithelial proliferation, while VDR and NFKB1 are involved in epithelial -> mesenchymal transition. (this all assuming "hair follicle cell" = epithelial cell; maybe it means undifferentiated cells -> hair follicle cells or something, as opposed to feathers, scales, normal skin cells, etc.)

And another systems biology paper I came across recently, which may or may not be helpful, but is certainly interesting: Mouse Hair Cycle Expression Dynamics Modeled as Coupled Mesenchymal and Epithelial Oscillators (http://journals.plos.org/ploscompbiol/article?id=10.1371/journal.pcbi.1003914)

Abstract:


The hair cycle is a dynamic process where follicles repeatedly move through phases of growth, retraction, and relative quiescence. This process is an example of temporal and spatial biological complexity. Understanding of the hair cycle and its regulation would shed light on many other complex systems relevant to biological and medical research. Currently, a systematic characterization of gene expression and summarization within the context of a mathematical model is not yet available. Given the cyclic nature of the hair cycle, we felt it was important to consider a subset of genes with periodic expression. To this end, we combined several mathematical approaches with high-throughput, whole mouse skin, mRNA expression data to characterize aspects of the dynamics and the possible cell populations corresponding to potentially periodic patterns. In particular two gene clusters, demonstrating properties of out-of-phase synchronized expression, were identified. A mean field, phase coupled oscillator model was shown to quantitatively recapitulate the synchronization observed in the data. Furthermore, we found only one configuration of positive-negative coupling to be dynamically stable, which provided insight on general features of the regulation. Subsequent bifurcation analysis was able to identify and describe alternate states based on perturbation of system parameters. A 2-population mixture model and cell type enrichment was used to associate the two gene clusters to features of background mesenchymal populations and rapidly expanding follicular epithelial cells. Distinct timing and localization of expression was also shown by RNA and protein imaging for representative genes. Taken together, the evidence suggests that synchronization between expanding epithelial and background mesenchymal cells may be maintained, in part, by inhibitory regulation, and potential mediators of this regulation were identified. Furthermore, the model suggests that impairing this negative regulation will drive a bifurcation which may represent transition into a pathological state such as hair miniaturization.

They use a modified version of the Kuramoto model (https://en.wikipedia.org/wiki/Kuramoto_model) to model the hair cycle. Such models of coupled oscillators have been used to model other biological systems before.

Mesenchymal (dermal papilla) cells are positively coupled and epithelial cells are negatively coupled.

http://s24.postimg.org/fllmj4lph/tasseff.png

http://s16.postimg.org/ax6vh4qwl/tasseff2.png

A high proportion of positively coupled oscillators (as opposed to negative ones) leads to a synchronized and stable state. As this proportion gets lower, the system is kicked into a different state of rapidly cycling, miniaturized hair. As p gets even lower, the system becomes totally decoherent - physically, this would correspond to continuous quiescence, I think.

Seuxin
01-19-2016, 04:34 AM
Hello guys,

What about this Oleuropein 40% source ? : http://www.skinactives.com/Oleuropein.html
0.6g -> 1.76€ !

Chemical
01-19-2016, 01:21 PM
HEY Chemical thank you for what are you doing.

Can you do a summarise of your invention, like what exactly to use( what products it contains) , the concentration ,and how often to use like instructions on drughs???

I will update the first post with all this information, for now you can go through my recent posts here (https://www.baldtruthtalk.com/search.php?searchid=231347&pp=).


Chemical , Can you please tell me how much EGCG and OL pills you are now using in a 60 MG bottle of minox ? I was dumping in one EGCG pill and a half pill of OL . Can you update the mix ?

Right now I'm using ~12mg/ml EGCG and around 0.5-1mg/ml of OL.
I found out EGCG's max solubility in EtOh is 20mg/ml. I think I read somewhere kirkland minox is 70% ethanol, so if thats true then the minox is saturating the ethanol a bit. And the OL is too, reducing the maximum saturation of EGCG. I noticed the EGCG leaving residue, and I can literally peel it off after a day or so. Not sure if that could be increased keratinocyte turnover? So for my next mix I'm going to use only 2 x EGCG caps = 300mg EGCG (actual) in 30ml. If it still leaves a residue I'll dilute further. I'm probably going to use 1/4 cap of OL in 30ml.



Anyway I remember you said you don't take any anti DHT. According to you new hairs get thicker and potentially hold on thanks to EGCG but what about existing hair ? Do you apply the solution all over the scalp or only at temples ? Thanks for keeping us updated!

Yes taking an oral DHT blocker will only increase endogenous testosterone to compensate the feedback loop. You'll have a marginal decrease in DHT but a moderate elevation in T. Not worth it imo. You're better off using non systemic 5ar inhibitors with an AR antagonist of some sort.

My existing occipital hairs and regions beside the hairline are getting alot thicker and longer. Shedding is like 10 hairs per day. Minox is known to do this and I fully suspect its minox. Regrowth is what we're looking out for.



I'm already using seti in an etch/pg solution so keen to not add too much more ethanol to my scalp each day. That said, I want to ensure proper delivery to the follicles.

I have DMSO as well. Would a water/eth/pg/dmso be a good idea? What ratios are you both using?

I don't have any Keto to hand but I have some Dexamethasone, which apparently raises PGE2 and is an AA. Would adding that to the mix be too much? I see that you put your Keto on in the morning. Important to use it hours before the EGCG/OL mix?

I think alot of people are curious to know - Any progress with Seti?
I'm on the fence about DMSO. There are reports it increases shedding when used as a vehicle so just to be on the safe side, skip it.

Heres what BRIAN is using (https://www.baldtruthtalk.com/threads/22104-Updated-Research-and-Knowledge-Cutting-Edge?p=227768&viewfull=1#post227768).

I wouldnt advocate dexamethasone. Its quite a strong corticosteroid and from my understanding it shouldnt be used off-label for anything other than reducing severe inflamation or skin conditions.


I want to know also! What must i buy for same regime. ??

Just because I've seen results does not mean you will too. This is still experimental and for all we know my results could very well be just minox. You should make this decision after careful consideration because you'll only set yourself up for disappointment if you start thinking this is a one size fits all protocol. I'll edit first post with info.




The EDAR variant associated with greater hair thickness in Asians is the one that reduces Nf-kB, not increases it. (http://hmg.oxfordjournals.org/content/17/6/835.long)

The 1540T/C polymorphism is located in the death domain, that is, the intracellular domain necessary to interact with EDAR-binding death domain adapter protein, EDARADD. It is known that EDAR/EDARADD interaction results in the activation of the downstream transcription factor NF-κB, and this molecular pathway plays a key role in formation of hair placode. Therefore, a possibility is that 1540T/C affects the NF-κB activity through an altered efficiency of interaction between EDAR and EDARADD. To compare the 1540T and C alleles in the ability of NF-κB activation, we performed luciferase assays using HeLa and 293A cells. These cells were transfected with EDAR expression vectors carrying each allele (pEF1-EDAR-1540T and pEF1-EDAR-1540C), reporter plasmids with the luciferase gene under control of the five NF-κB promoter elements, and internal control vectors. The NF-κB/luciferase activities were compared among 1540T, 1540C and 1540T+C (artificial heterozygote). We observed significant differences in relative luciferase activities between 1540T and 1540C (t-test: HeLa cell P = 5.7 × 10−3, 293A cell P = 1.9 × 10−5) and between 1540T and 1540T+C (293A cell P = 5.8 × 10−5) (Fig. 5). Interestingly, the C allele that was associated with thicker hair showed lower relative luciferase activities than the T allele in both the cell lines. These results indicated that the amino acid replacement in the death domain causes a functional change and results in the lower activity of NF-κB.

Inhibition of nf-kb or reduced nf-kb activation?

This study (http://www.nature.com/jid/journal/v134/n7/pdf/jid201482a.pdf?WT.ec_id=JID-201407) says that nf-kb activity is necessary for anagen...



Frontotemporal = temples? But balding can start at the vertex as well in some cases. Paracrine signals may still play a role though and contribute to feedback loops in nearby follicles though, I assume.

The figure (http://synapse.koreamed.org/ViewImage.php?Type=F&aid=452449&id=F1&afn=140_AD_25_3_387&fn=ad-25-387-g001_0140AD) in this study (http://synapse.koreamed.org/search.php?where=aview&id=10.5021/ad.2013.25.3.387&code=0140AD&vmode=FULL) shows pictures of "frontotemporal" hairloss exactly like the signature norwood pattern, so the AGA pattern is indeed in females too but actually enhances hair growth. I cant explain the vertex thinning though.



Interesting how EBF1 is involved in mesenchymal -> epithelial proliferation, while VDR and NFKB1 are involved in epithelial -> mesenchymal transition. (this all assuming "hair follicle cell" = epithelial cell; maybe it means undifferentiated cells -> hair follicle cells or something, as opposed to feathers, scales, normal skin cells, etc.)

I'm going to read that study you linked.

I realise I was being stupid. The original study that mentioned EBF1 (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3298746/) shows that EBF1 regulates the Adipocyte precursor lineage, and also controls PDGF-A:



PDGFR is activated in the DP and the lower part of the hair germ (Figure 6E). To determine if intradermal adipose regeneration is required for activation of the PDGFR, we analyzed hair follicles from BADGE-treated and Ebf1 null mice for activation of the PDGFR at P21. As seen in Figure 6E, PDGFR activation was diminished in the DP of both BADGE-treated and Ebf1 null mice.

In an earlier post I went over how PDGF signalling induces hair canal formation and subsequent anagen induction: here (https://www.baldtruthtalk.com/threads/22104-Updated-Research-and-Knowledge-Cutting-Edge?p=225455&viewfull=1#post225455).

On a separate discussion, I found this study:


Induction of transforming growth factor-beta 1 by androgen is mediated by reactive oxygen species in hair follicle dermal papilla cells. (http://www.ncbi.nlm.nih.gov/pubmed/24064061)

This supports the notion that anti-oxidants/ROS scavengers can reduce TGF-Beta.

More importantly though!

http://imgur.com/a/rdWnB

TheKingofFighters
01-19-2016, 02:23 PM
hey Chemical do u have an email address i can contact u with?

tiktok
01-19-2016, 03:11 PM
Those results are very interesting. Looking forward to seeing the future progress!

burtandernie
01-19-2016, 05:17 PM
So your of the opinion that RU is better than using fin? The big issue is there arent any good AR antagonists or no one would be using fin still. I mean we have known androgens cause MPB for like 20 or 30 years yet still have no real way to actually do anything about that. There is no practical way to stop androgens non systemically even still

"Yes taking an oral DHT blocker will only increase endogenous testosterone to compensate the feedback loop. You'll have a marginal decrease in DHT but a moderate elevation in T. Not worth it imo. You're better off using non systemic 5ar inhibitors with an AR antagonist of some sort. "

scooterboy
01-19-2016, 05:58 PM
So your using 4 x EGCG caps and 1 half OL cap in 60MLS of minox .

Swooping
01-20-2016, 03:32 AM
What is your background Chemical? Doing any work/study related to biology? Or just pure interest.

Seuxin
01-20-2016, 08:45 AM
Hello Guys'

I'm planning to coumpound a custom cream for my temples. ( Cream is better to use with a lot of shit).

I'm thinking about :

-Adenosine (high amount like 5%)
-Baicailin
-Vitamin B6
-Zinc Sulphate
-Oleuropein high dosed (0.6gr in a 4oz cream jar)
-ECGC (-> Don't really know if usefull since oleuropein is antioxydant)
-Saw Palmetto
-Vitamin E Succinate ( cause an increase of PGE2)
-KGF (Keratinocyte Grow Factor) ( 50mcg)

--> What do you think ? Any advice ?

Thanks.

bluesuedeshoes
01-20-2016, 12:09 PM
To those that have asked about a seti update...only been using for a few weeks so too early to make any sort of decent appraisal. My vehicle isnt ideal - etc/pg. I have noticed a slight reduction of the itch but that's really it. The people who have had some sort of success on other forums with seti have been using a custom vehicle.

potato1987
01-20-2016, 03:16 PM
I m really interessed in your pictures Chemical. I would not judge sth before at least 2 months. Sounds really good. But is it not also possible that with your consequent usage of minox it can be its effect alone? Do you preclude that completely? Looking forward too your pictures soon then if you see its effects already go ahead :)

Any joy with the custom stuff mate? I can't touch fin or minox so would be great to have a pre mix of natural components.

ryan82
01-21-2016, 02:35 AM
To those that have asked about a seti update...only been using for a few weeks so too early to make any sort of decent appraisal. My vehicle isnt ideal - etc/pg. I have noticed a slight reduction of the itch but that's really it. The people who have had some sort of success on other forums with seti have been using a custom vehicle.

What is that custom vehicle?

JustParker
01-21-2016, 12:32 PM
Does anyone know much about IGF-1's involvement with the PGE pathways? I've found a few studies related to increasing IGF-1 and hair growth, but wasn't sure if this thread would be the place for them

pilipili
01-22-2016, 09:20 AM
Chemical what do you think about apple polyphenols /Procyanidin b2? It potentially looks like good additions.
http://www.applepoly.com/procyanidin-b-2
http://www.ncbi.nlm.nih.gov/pubmed/11841365

bluesuedeshoes
01-22-2016, 03:14 PM
Chemical - I am currently using a 4% (2960 mg EGCG / 50% Green Tea blend, so about 1480 EGCG proper) in 74ml .......5% OL (it's a blend w/20% OL - so about 300mg of Oleuropein proper) ..... 1% Rosemary Ext ... 1% Jojoba Oil .... (.2%) Tea Tree Oil. This is in a distilled water solution. I add maybe 4 ml of 70% ethyl alcohol as well. Apply that, then wait for that to absorb and apply Minox foam, then finish with Ketoconazole 2% cream. I do this 3 times a day if possible. Scalp seems ok with this regimen so far (2 weeks). I would like to use even a higher dose of EGCG blend, but, the hair growth stimulation seems to occur just under the threshold of when the folliculitis starts. So, have to be careful. I don't want to be forced to stop treatments. Scalp feels in harmony and in a positive direction again.

Going to follow your instructions here. However, thinking about adding some DMSO. If I'm trying to increase absorption, should I add more eth and DMSO?

BRIANBOY
01-23-2016, 12:12 AM
Going to follow your instructions here. However, thinking about adding some DMSO. If I'm trying to increase absorption, should I add more eth and DMSO?

I wouldn't add dmso. You are adding an additional factor that's not really needed, and might even have its own problems. EGCG is very soluble in water and crosses the skin barrier easily. The Jojoba oil will also act as a carrier. Just be aware that high dose topical EGCG can trigger / cause folliculitis. If that begins, you have reached your threshold and have to back the % down. I have also added 25 mcg of KGF, 1 ml of Polygonum Multiforum. As of now, my scalp seems comfortable with the percentage solution of 4% Green Tea/EGCG blend. I'm about 3+ weeks in now. I am applying it 3 - 6 times per day. So far, just an occasional single folliculitis which I can control with temporary ketocanozole / hydrocortisone. Not really a problem, so I will continue to use the high dose. Scalp feels very much like it did when a lot of hairgrowth increased 5 years ago. Losing very little hair daily. I am backing off on the Minox and Keto. Minox is giving me water retention and Keto is causing a slight bit of rash if I use it daily, so I am only going to use occasionally. 5 years ago, I only used the high dose Green Tea/EGCG blend in distilled water, so that is my mainstay and core. I remember it took about 2 months before I noticed dramatic changes.

BRIANBOY
01-23-2016, 12:13 AM
deleted double post.

joshuk
01-23-2016, 02:12 AM
chemical i have been using OLE/EGCG mix now for almost a month and im seeing improvement, but i think if i was to use minox with this i would get some serious regrowth. and i mean like 2+NW back

as i cant use 5% minox due to side effects puffy eyes dark circles etc, do you think 2% minox would have less sides or the same as it has a higher ethanol % than the 5% bottle.

anyone else can help here?? i really think i can get some serious regrowth if i add in minox but also dont want to have a loads more hair but a bloated and dark circles on face again...sucks

Chemical
01-23-2016, 06:44 AM
hey Chemical do u have an email address i can contact u with?

I'd prefer not to give out my email, but if you truly must speak to me in private you can find it here (https://imgur.com/user/Chemicalxr).


So your of the opinion that RU is better than using fin? The big issue is there arent any good AR antagonists or no one would be using fin still. I mean we have known androgens cause MPB for like 20 or 30 years yet still have no real way to actually do anything about that. There is no practical way to stop androgens non systemically even still

RU is definitely preferable to Fin, alot of people have seen huge improvements using RU so its definitely effective at suppressing the Androgen Receptor and not just partially reducing DHT conversion.

This is where EGCG also comes in. Its a non systemic AR suppressor and increases BetaCatenin - I've covered the science in previous posts. Feel free to look back. I'm also experimenting with Evening Primrose oil which contains Gamma Linoleic acid - a 5ar inhibitor that also works topically. I realise it's quite difficult to go through all my posts to find what you're looking for and the moderators havent responded to my request so I might just make a new thread with all the research.


So your using 4 x EGCG caps and 1 half OL cap in 60MLS of minox .

roughly 4 caps of EGCG in 40ml. Its not dissolved completely so I'm going to use less for my next run. Also I found out EGCG degrades over time, especially in warm and humid conditions. (study (http://arizona.openrepository.com/arizona/handle/10150/280241)) (study (http://www.ncbi.nlm.nih.gov/pubmed/21495730/)) So it might be better to make smaller batches - 30ml at a time?


What is your background Chemical? Doing any work/study related to biology? Or just pure interest.

I work for a Hedge Fund as a software engineer, and I've got a strong background in Big Data sciences, specifically application of machine learning to artificial intelligence. I developed an interest in biology when I was 15 while researching cognitive enhancement, and realised just how much you can manipulate the human body to get what you want. Its just a big system with rules and models, if you spend enough time understanding how it works you can find ways to fix it (or improve it). It's interesting for me because its just another puzzle that needs solving.


I'm planning to coumpound a custom cream for my temples.

-Adenosine (high amount like 5%)
-Baicailin
-Vitamin B6
-Zinc Sulphate
-Oleuropein high dosed (0.6gr in a 4oz cream jar)
-ECGC (-> Don't really know if usefull since oleuropein is antioxydant)
-Saw Palmetto
-Vitamin E Succinate ( cause an increase of PGE2)
-KGF (Keratinocyte Grow Factor) ( 50mcg)


I'm a little bit skeptical about zinc (It can potentiate binding of DHT to nuclear AR (http://www.ncbi.nlm.nih.gov/pubmed/6466648)?). What makes you want to use zinc? B6 too.

I personally wouldnt use anymore than 1.5mg/ml of OL because its been shown to have biphasic properties, but it you're willing to try it at a high dose anyway then please report back if you notice any change.

The EGCG isnt for ROS scavenging, its an AR suppressor and inhibits Axin thus preventing the degradation of BetaCatenin. Other than that, your stack is fine.


Does anyone know much about IGF-1's involvement with the PGE pathways? I've found a few studies related to increasing IGF-1 and hair growth, but wasn't sure if this thread would be the place for them

Yes this is the perfect place to post studies!


Chemical what do you think about apple polyphenols /Procyanidin b2? It potentially looks like good additions.
http://www.applepoly.com/procyanidin-b-2
http://www.ncbi.nlm.nih.gov/pubmed/11841365

I made a post about PKC and apple polyphenols here (https://www.baldtruthtalk.com/threads/22104-Updated-Research-and-Knowledge-Cutting-Edge?p=227696&viewfull=1#post227696). I'm yet to try it but it has promise.




Going to follow your instructions here. However, thinking about adding some DMSO. If I'm trying to increase absorption, should I add more eth and DMSO?

I wouldn't add dmso. You are adding an additional factor that's not really needed, and might even have its own problems. EGCG is very soluble in water and crosses the skin barrier easily. Just be aware that high dose topical EGCG can trigger / cause folliculitis. 5 years ago, I only used the high dose Green Tea/EGCG blend in distilled water, so that is my mainstay and core. I remember it took about 2 months before I noticed dramatic changes.

@Bluesuedeshoes,
I second what Brian has said about adding DMSO.

@Brian
the solubility of EGCG in water is <5mg/ml (http://www.scbt.com/datasheet-200802.html). Are you sure its such a good idea to use water instead of Ethanol (which has max 20mg/ml solubility) especially at such high concentrations? I'm a little concerned with your vehicle choice.


chemical i have been using OLE/EGCG mix now for almost a month and im seeing improvement, but i think if i was to use minox with this i would get some serious regrowth. and i mean like 2+NW back. As I cant use 5% minox due to side effects puffy eyes dark circles etc, do you think 2% minox would have less sides or the same as it has a higher ethanol % than the 5% bottle.

Improvement as in thickening or vellus hairs?
I doubt reducing the frequency or dose will help with those side effects seeing as you're prone to them. I'm going to be trying sodium valproate because I'm not seeing regrowth fast enough. If I see any improvement you might want to consider using it instead of minox?

I'm considering adding Rosemary extract and apple polyphenols to my stack.



Topical administration of Rosmarinus officinalis leaf extract (RO-ext, 2 mg/day/mouse) improved hair regrowth in C57BL/6NCrSlc mice that experienced hair regrowth interruption induced by testosterone treatment. In addition, RO-ext promoted hair growth in C3H/He mice that had their dorsal areas shaved. To investigate the antiandrogenic activity mechanism of RO-ext, we focused on inhibition of testosterone 5α-reductase, which is well recognized as one of the most effective strategies for the treatment of androgenic alopecia. RO-ext showed inhibitory activity of 82.4% and 94.6% at 200 and 500 µg/mL, respectively. As an active constituent of 5α-reductase inhibition, 12-methoxycarnosic acid was identified with activity-guided fractionation. In addition, the extract of R. officinalis and 12-methoxycarnosic acid inhibited androgen-dependent proliferation of LNCaP cells as 64.5% and 66.7% at 5 µg/mL and 5 μM, respectively. These results suggest that they inhibit the binding of dihydrotestosterone to androgen receptors. Consequently, RO-ext is a promising crude drug for hair growth.

http://www.ncbi.nlm.nih.gov/pubmed/22517595

I've stupidly mixed some evening Primrose oil with the remainder of my minox and then found out GLA enhances the skins barrier function. So I might not see any more regrowth for the next two weeks. My mid scalp is shedding and I've been skipping applications the last few days. Luckily the hairs that I regrew arent thinning and are getting longer so its not too bad. Ultimately I want to find a set of treatments that I can put in a cream and just use that for the rest of my life. This liquid vehicle formulation is very difficult to be consistent with and I have to keep my head tilted back until it dries, which sucks because I dont always have time/feel bothered to do.
I know about polysorbate 80 and DMI that can be used to create creams (courtesy of Seuxin), but I wonder if gels might be better suited for drugs that dissolve better in ethanol vehicles.

Swooping
01-23-2016, 07:00 AM
What is your view overall on the pathology of AGA?

Do you find it likely that it is prostaglandin mediated?

Are you more in the camp of senescence/cell cycle arrest?

Perhaps something else?

Also, why do you think 17b-estradiol is so good at regrowing hair in men? Any particular targets you find interesting?

Chemical
01-23-2016, 08:32 AM
I think the overall pathology is androgen dependent, which isnt anything new. But just because we've known about it for a long time doesnt mean its wrong and that there's something more special or a pathway that we havent yet discovered is implicated in the pathogenesis of AGA. Recent findings (https://www.baldtruthtalk.com/threads/22104-Updated-Research-and-Knowledge-Cutting-Edge?p=228304&viewfull=1#post228304) have revealed that the AGA pattern originates from females, and since all males start off as females in the womb, this explanation is very plausible. In females, the AGA pattern manifests itself as a positive modulator of hair growth, increasing the hair growth in response to Estrogens. Alot of womem have very rounded hairlines with thick temples(examples (https://www.google.co.uk/search?q=female+hairline&espv=2&biw=1366&bih=623&source=lnms&tbm=isch&sa=X&ved=0ahUKEwiP4qmHkMDKAhVJthQKHXmtBJoQ_AUIBigB#tbm= isch&q=female+ponytail+hairstyles)) - completely opposite to men who will typically have recessed temples. Evolution is responsible for a lot of polar opposite differences we see in genders and its quite common to see differential hormonal responses between the two sexes. I suspect this ability of estrogen to increase hair growth in frontal regions is still intact even in AGA males. I've talked about possible explanations of how Estrogen might increase hair growth here (https://www.baldtruthtalk.com/threads/22104-Updated-Research-and-Knowledge-Cutting-Edge?p=224562&viewfull=1#post224562) and briefly here (https://www.baldtruthtalk.com/threads/22104-Updated-Research-and-Knowledge-Cutting-Edge?p=227744&highlight=estrogen#post227744).

My initial assumption that ERb was bad is incorrect. 3bDiol activates this receptor with different effects that cannot be reproduced by physiological doses of 17b Estradiol which indicate ERb is actually a positive modulator of hair. ERb is also the predominant receptor expressed in the hair follicle regions, except for the DPC where only ERalpha is expressed. Furthermore, Estrogen receptors are present in adipocyte precursor cells (they can induce hair canal formation via PDGF) so it could be that estrogens act on the stem cells directly. This area of research is still a work in progress but its clear that Estrogens can and do increase hair growth/regrowth in men.

I've talked alot about how Androgens suppress BetaCatenin expression at multiple levels, and given that the AR is significantly upregulated in frontal regions in comparison to occipital regions, its not at all surprising that hair growth is diminished.

I've had this discussion about PGD2 with InBeforeTheCure which I'd definitely recommend reading: here (https://www.baldtruthtalk.com/threads/22104-Updated-Research-and-Knowledge-Cutting-Edge?p=227531&highlight=pgd2#post227531) and here (https://www.baldtruthtalk.com/threads/22104-Updated-Research-and-Knowledge-Cutting-Edge?p=227738&highlight=pgd2#post227738)

In short, some people arent sensitive to PGD2. Also, the PGD2 levels seen in balding scalp isnt ridiculously high, but I dont know how one should interpret 2.5-4 fold differences. The consensus is that PGD Synthase activity is an Androgen dependent process. I've yet to find any other possible link explaining the rise in PTGDS.

The increased conversion of arachidonic acid to PGD2 reduces the production of PGE2 since they both use arachidonic acid as their substrate. This reduction in PGE2 paired with PGD2's PKC activating effects directly enhance the proteosomal degradation of BetaCatenin, so this works additively with other BetaCatenin inhibitors. Heres a post (https://www.baldtruthtalk.com/threads/22104-Updated-Research-and-Knowledge-Cutting-Edge?p=226530&viewfull=1#post226530) where I talk about PGE2 and how it works to grow hair.

Without BetaCatenin the hair follicles will stop prolifereating and end up in telogen permanently or senescent as you might say. The telogen - anagen cycle is blocked and the local paracrine feedback loop controlling the cycle is disrupted subsequently resulting in the hairs failing to recruit blood vessels necessary to keep growing. I believe that the DPC in AGA do not completely die - as in they dont disappear. Rather, like you say, the DPC become senescent (study (http://www.ncbi.nlm.nih.gov/pubmed/25647436)).

This is good because the DPC can still be modulated to respond to PDGF-A originating from the Adipocyte lineage precursor cells, and reconstruct the hair follicle canal (post (https://www.baldtruthtalk.com/threads/22104-Updated-Research-and-Knowledge-Cutting-Edge?p=225455&viewfull=1#post225455)). One study showed that androgens can interfere with this signalling loop further antagonising hair growth (post (https://www.baldtruthtalk.com/threads/22104-Updated-Research-and-Knowledge-Cutting-Edge?p=225455&viewfull=1#post225455)).

In the case that DPC are actually dead and there is no physical intact DPC, then it's still not impossible to regrow hair. This study shows that transiently elevated BetaCatenin induces the formation of new hair follicle:



The formation of hair follicles during embryogenesis depends on a series of signals that are exchanged between the epidermis and the underlying dermis. In the embryo the initiating signal comes from the dermis and involves activation of Wnt signalling; the response in the overlying epithelium also involves activation of β-catenin. In K14ΔNβ-cateninER skin the dermal signal is not required and activation of β-catenin signalling in the epidermis leads to organisation of a dermal papilla (Fig. 3G-J). In each location where new follicles formed in K14ΔNβ-cateninER epidermis there was induction of Shh, Ptc and Lef1. Just as Shh drives anagen, Shh is downstream of Wnt signalling in hair follicle development: in mice lacking Shh hair follicle formation is initiated and the dermal condensate is formed but mature hair follicles fail to develop. Lef1 is a known transcriptional target of β-catenin, required for normal hair follicle formation. Although during normal hair placode formation expression of Lef1 is regulated by Noggin, produced by dermal cells, in our system Lef1 upregulation is independent of a pre-existing dermal signal.

http://dev.biologists.org/content/131/8/1787.long

This methodology of suppressing AR and increasing BetaCatenin may seem too simple to be effective at regrowing hair, but sometimes the simplest approaches are the best. And even though the goal is simple, inhibiting AR and increasing BetaCatenin are very challenging.

Other pathways that are heavily involved in hair follicle formation and growth (anagen induction) include Noggin (inhibits BMP's that negatively regulate growth) and Shh which regulates Noggin. Both are downstream targets of WNT which I havent covered yet.

wwesley
01-23-2016, 09:17 AM
seriously need the article with all info contained in a single post :-)

For EU residents, which products do you recommend we buy? It'd be nice to have an easy table from which US/EU residents can easily buy the ingredients. Same for the new ones you seem to have added (apple polyphenols, rosemary extract, etc) - dosage, etc..

thanks for this thread!