Updated Research and Knowledge - Cutting Edge

[InBeforeTheCure]

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/

[BRIANBOY]

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]

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/art...l.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:



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. 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). 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.

[burtandernie]

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.

[joshuk]

chemical so you think taking setipirant would be a good idea then if it reduces PKC with reduction of PGD2

[Seuxin]

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

[Chemical]

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 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

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.

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) 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).

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. (Apple polyphenols contain procyanidin). 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...

[Chemical]

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. 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). 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

[Keeper]

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

[InBeforeTheCure]

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):



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:



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???

[potato1987]

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?

[Chemical]

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.

[Sogeking]

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.

[pilipili]

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

[joshuk]

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