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    May 2014

    Default Updated Research and Knowledge - Cutting Edge

    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

    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.)

    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
    An endocrine pathway in the prostate, ERβ, AR, 5α-androstane-3β,17β-diol, and CYP7B1, regulates prostate growth

    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.
    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].
    Androgens actually enhances the expression of HIF-1 via Androgen Receptor mediated signalling which explains the procarcinogenic effect of androgens in prostate cancer:
    Androgens stimulate hypoxia-inducible factor 1 activation via autocrine loop of tyrosine kinase receptor/phosphatidylinositol 3'-kinase/protein kinase B in prostate cancer cells.
    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.
    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.
    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.
    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
    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.
    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 [B]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 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.


    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.
    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.

    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.


    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:

    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.

    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:

    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?

  2. #2
    Join Date
    Feb 2012


    Very interesting, I found some wiki pages that confirm your theory...


    DKK-1 - How do we kill it?

  3. #3
    Join Date
    May 2014


    Quote Originally Posted by bananana View Post
    Very interesting, I found some wiki pages that confirm your theory...


    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).

  4. #4
    Senior Member
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    Oct 2015


    Quality post.

    Thanks for taking the time. Very interesting theory.

  5. #5
    Join Date
    Feb 2012


    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?


  6. #6
    Junior Member
    Join Date
    Jun 2014


    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.or.../3672.abstract).

  7. #7
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    Join Date
    Nov 2012


    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

  8. #8
    Senior Member
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    Jun 2014


    Quote Originally Posted by burtandernie View Post
    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.

  9. #9
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    Jun 2015


    Looking forward to your experiments with topical oleuropein, Chemical. I am interested in doing similar.

  10. #10
    Join Date
    May 2014


    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

    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.

    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.

    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).

    Oleuropein somehow manages to increase IGF1 (by a lot) and VEGF too. This study 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.

    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:

    Click image for larger version

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    ( 6 weeks into the regimen):

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

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    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.

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