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Ectodysplasin-a2 Induces Dickkopf 1 Expression In Human Balding Dermal Papilla Cells Overexpressing

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Dimitri001

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The study is way above my paygrade, to be honest, but it sounds like it might be of interest to some of the more knowledgeable members

https://www.sciencedirect.com/science/article/abs/pii/S0006291X20313164

Collectively, our data strongly suggest that EDA-A2 induces DKK-1 secretion and causes apoptosis in HFs by binding EDA2R, which is overexpressed in the bald scalp. EDA-A2/EDA2R signaling could inhibit hair growth through DKK-1 induction, and an inhibitor of EDA-A2/EDA2R signaling may be a promising agent for the treatment and prevention of Androgenetic Alopecia.
 
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Xander94

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BaldAsshole said:
Metabolites of vitamin C and vitamin D inhibit dickkopf1.

L-ascorbic acid 2-phosphate represses the dihydrotestosterone-induced dickkopf-1 expression in human balding dermal papilla cells
https://pubmed.ncbi.nlm.nih.gov/20701628/

Changes in Dickkopf-1 (DKK1) and Sclerostin following a Loading Dose of Vitamin D2 (300,000 IU)
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4274669/
Click to expand...
https://pubmed.ncbi.nlm.nih.gov/28849028/

We've been through this sh*t over and over, none of this crap grows hair
 
inmyhead

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whatevr said:
DKK-1 can be effectively inhibited with ascorbate & metabolites (incl. L-Threonate), but in itself is not enough to stop hair loss or regrow significant amounts of hair. It will slightly free up WNT though.
Click to expand...
Has anyone tried topical vitamin C ?
 
whatevr

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Xander94 said:
Man people tried all kinds of sh*t, nothing grows hair like dutasteride and minoxidil
Click to expand...

Yes, sad but true, but that's understandable when you're aware of the insanely skewed Testosterone/Epitestosterone ratio in balding follicles and how overactive the androgen cascade is in those hairs. You can't really expect to fully mitigate that without addressing the root cause. But it goes to show the problem is even further above 5-AR though. Since Epi-T is also an androgen receptor antagonist and a 5-AR blocker basically a natural antiandrogen is missing in our follicles. Too much pregnenolone goes down the DHEA pathway into testosterone and not enough into 5-androstene-3b,17a-diol / 7a-Hydroxytestosterone like in follicles of non-balding people. The cascade then branches of into dozens of negative growth signals downstream of AR so the problem has to be fixed as high up as possible for the best results.

In other words we need truly topical androgen receptor antagonists, high affinity with the best vehicle possible.
 
Xander94

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whatevr said:
Yes, sad but true, but that's understandable when you're aware of the insanely skewed Testosterone/Epitestosterone ratio in balding follicles and how overactive the androgen cascade is in those hairs. You can't really expect to fully mitigate that without addressing the root cause. But it does go even beyond 5-AR though. Since Epi-T is also an androgen receptor antagonist and a 5-AR blocker basically a natural antiandrogen is missing in our follicles.
Click to expand...

Its also about restoring a natural homeostasis in the area thats getting disrupted by androgens/pollutants stress etc

Not blindly inhibiting some random pathway that inhibits hair in a lab setting and hope that it results in nw0 hair IRL thats just stupid.

Minoxidil isnt even well understood and acts on alot of pathways that are theorized to help hair growth.
 
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whatevr said:
Yes, sad but true, but that's understandable when you're aware of the insanely skewed Testosterone/Epitestosterone ratio in balding follicles and how overactive the androgen cascade is in those hairs. You can't really expect to fully mitigate that without addressing the root cause. But it goes to show the problem is even further above 5-AR though. Since Epi-T is also an androgen receptor antagonist and a 5-AR blocker basically a natural antiandrogen is missing in our follicles. Too much pregnenolone goes down the DHEA pathway into testosterone and not enough into 5-androstene-3b,17a-diol / 7a-Hydroxytestosterone like in follicles of non-balding people. The cascade then branches of into dozens of negative growth signals downstream of AR so the problem has to be fixed as high up as possible for the best results.

In other words we need truly topical androgen receptor antagonists, high affinity with the best vehicle possible.
Click to expand...

Speaking of DHT synthesis at the follicle, I once heard someone say the idea of a locally acting topical 5AR inhibitor is dubious, because DHT that gets made at the liver (or prostate?) would get to the hair through the blood. I doubt that there is, but are you aware of any science that settles the question of whether this would negate any effects of a locally acting 5AR inhibitor?
 
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dgadgdea

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^^^ this is worth discussing and I really haven't seen it covered enough.

This is best reading I've found on this topic:
https://pubmed.ncbi.nlm.nih.gov/1551803/

I think this is the full text link and definitely worth the read:
https://onlinelibrary.wiley.com/doi/pdf/10.1002/j.1939-4640.1992.tb01621.x

I'm a bit out of my depth here so please point out where I'm wrong, but my understanding from what I have pieced together is that DHT is not some hormone that is created in a gland or the liver and then starts circulating through the body, eventually ending up at your scalp to wreak havoc on your hair follicles. Hormones created this way I believe are called endocrine hormones.

DHT on the other hand is a paracrine hormone. This means that the DHT that acts on your hair follicles was actually created IN THE SCALP through 5 alpha reduction from testosterone. This also means that DHT in serum measured through bloodwork is not actually a super useful biomarker. This DHT reading just represents the amount of DHT leakage from the tissues where it was actually created (places like the scalp, prostate). So when I see my serum DHT is 50 ng/dL that's fine and great but it doesn't say much about how much DHT is actually on my scalp and is there causing miniaturization. That said it's not completely useless, but more like a distant proxy indication of what's going on with DHT in the body. Side note: if anyone knows how to get scalp biopsies to measure for DHT let me know. I think that is a much more useful piece of info.

What may actually be a better blood test reading if you're trying to get a sense for overall DHT body in the blood is referenced in the article above as 3a androstanediol (3a diol). This is the main metabolite that DHT breaks down into. So in a case where your blood DHT might be quite low, but you could still have a zillion ng/dL of DHT on your scalp, you would be better able to recognize this by tracing 3a diol or whatever it's called

I have not been able to find an independent lab test for it so may require a doctor, but Quest and Labcorp can both do it:

https://testdirectory.questdiagnostics.com/test/test-detail/92208/3a-androstanediol-glucuronide-elisa?p=r&q=3a-Androstanediol Glucuronide, ELISA&cc=MASTER

https://www.labcorp.com/tests/500881/androstanediol-glucuronide-endocrine-sciences

Long/Short, if this is all true then I think your hunch above is incorrect and that it is precisely at the scalp/hair follicle we want to stop 5AR from turning testosterone into DHT therefore topical 5ARs make sense.

Last comment just to undermine any remaining credibility -- I actually thought the comments in this video at 5:53 summed up this point pretty well:

(you'll have to skip to 5:53, it won't let me time link for some reason)

 
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Dimitri001

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I mean, I assume the claim that a locally acting 5AR inhibitor wouldn't work for that reason is wrong, because to begin with finasteride is said to cut DHT by about 60-70%, so you still got some DHT circulating around, yet people get results from finasteride, but...
 
whatevr

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Dimitri001 said:
Speaking of DHT synthesis at the follicle, I once heard someone say the idea of a locally acting topical 5AR inhibitor is dubious, because DHT that gets made at the liver (or prostate?) would get to the hair through the blood. I doubt that there is, but are you aware of any science that settles the question of whether this would negate any effects of a locally acting 5AR inhibitor?
Click to expand...

This is a bit of a murky area. Apparently, hair follicles can even create their own testosterone:

"Human pilosebaceous units possess enough enzymes to form the active androgens testosterone and dihydrotestosterone."[3]

However, I am not sure how relevant this is because we know that castration stops baldness. My guess is that the majority of testosterone coming to the hair follicle is from serum. It is then converted via 5-AR into DHT right in the follicle, where it acts. There is one problem with this though.

We know that the testosterone/epitestosterone ratio in balding follicles is greatly increased (too much testosterone and its downstream metabolites). However that same ratio seems to be normal in the serum of balding people. Epitestosterone is synthesized somewhere in the testicles and increases in response to HCG, but it is not made from testosterone (it is presumably made from pregnenolone just the same but branches off somewhere before DHEA); see this
upload_2020-8-27_19-33-0.png


"The difference between the fathers of the two groups was more clear - the T/E ratio of the balding fathers (mean 46.41, range 32.99±68.34, p < 0.001) was about five times that of the nonbalding fathers (9.17, 6.34±11.41)."
https://www.researchgate.net/public...uctase_as_Indicators_of_Male-Pattern_Baldness


So if the ratio is normal in serum (there is no direct study, but this ratio is used for doping control tests, and if balding people had 5 times as much T / Epi-T they would be constantly failing and testing positive for doping) but is five times higher in balding follicles, why is that? Couple of possibilities:

1. The follicle is for some reason taking up way too much testosterone from serum (but not epitestosterone)?
2. Epitestosterone is not taken up from serum but synthesized in the follicle (in far too small amounts)?
3. Something else that I can't think of right now

Epitestosterone is important because it is basically a natural anti-androgen that balances out testosterone and its metabolites.

"Epitestosterone is believed to form in a similar way to testosterone; a 1993 study found that around 50% of epitestosterone production in human males can be ascribed to the testis,[3] although the exact pathway of its formation is still the subject of research."

"Epitestosterone, or isotestosterone, also known as 17α-testosterone or as androst-4-en-17α-ol-3-one, is an endogenous steroid and an epimer of the androgen sex hormone testosterone. It is a weak competitive antagonist of the androgen receptor (AR) and a potent 5α-reductase inhibitor.[1][2]"

It's both a natural 5-AR inhibitor and androgen receptor antagonist, and we have on average 5 times too little of it - no wonder our hair is dying.

Given that this has been known about for 20 years now, it seems that an epitestosterone topical would be the logical treatment course for Androgenetic Alopecia then, wouldn't it, since it would tackle the root of the problem? Only one issue with that though - as a natural molecule it cannot be patented, and that's just not where the money is.

I think this is a subject matter deserving of its own thread though, so I might get on making one sometime later.
 
Xander94

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whatevr said:
Given that this has been known about for 20 years now, it seems that an epitestosterone topical would be the logical treatment course for Androgenetic Alopecia then, wouldn't it, since it would tackle the root of the problem? Only one issue with that though - as a natural molecule it cannot be patented, and that's just not where the money is.
Click to expand...
why not ask one of those custom compound pharmacies to make a topical epistestosterone
 
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Dimitri001

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whatevr said:
This is a bit of a murky area. Apparently, hair follicles can even create their own testosterone:

"Human pilosebaceous units possess enough enzymes to form the active androgens testosterone and dihydrotestosterone."[3]

However, I am not sure how relevant this is because we know that castration stops baldness. My guess is that the majority of testosterone coming to the hair follicle is from serum. It is then converted via 5-AR into DHT right in the follicle, where it acts. There is one problem with this though.

We know that the testosterone/epitestosterone ratio in balding follicles is greatly increased (too much testosterone and its downstream metabolites). However that same ratio seems to be normal in the serum of balding people. Epitestosterone is synthesized somewhere in the testicles and increases in response to HCG, but it is not made from testosterone (it is presumably made from pregnenolone just the same but branches off somewhere before DHEA); see thisView attachment 145703

"The difference between the fathers of the two groups was more clear - the T/E ratio of the balding fathers (mean 46.41, range 32.99±68.34, p < 0.001) was about five times that of the nonbalding fathers (9.17, 6.34±11.41)."
https://www.researchgate.net/public...uctase_as_Indicators_of_Male-Pattern_Baldness


So if the ratio is normal in serum (there is no direct study, but this ratio is used for doping control tests, and if balding people had 5 times as much T / Epi-T they would be constantly failing and testing positive for doping) but is five times higher in balding follicles, why is that? Couple of possibilities:

1. The follicle is for some reason taking up way too much testosterone from serum (but not epitestosterone)?
2. Epitestosterone is not taken up from serum but synthesized in the follicle (in far too small amounts)?
3. Something else that I can't think of right now

Epitestosterone is important because it is basically a natural anti-androgen that balances out testosterone and its metabolites.

"Epitestosterone is believed to form in a similar way to testosterone; a 1993 study found that around 50% of epitestosterone production in human males can be ascribed to the testis,[3] although the exact pathway of its formation is still the subject of research."

"Epitestosterone, or isotestosterone, also known as 17α-testosterone or as androst-4-en-17α-ol-3-one, is an endogenous steroid and an epimer of the androgen sex hormone testosterone. It is a weak competitive antagonist of the androgen receptor (AR) and a potent 5α-reductase inhibitor.[1][2]"

It's both a natural 5-AR inhibitor and androgen receptor antagonist, and we have on average 5 times too little of it - no wonder our hair is dying.

Given that this has been known about for 20 years now, it seems that an epitestosterone topical would be the logical treatment course for Androgenetic Alopecia then, wouldn't it, since it would tackle the root of the problem? Only one issue with that though - as a natural molecule it cannot be patented, and that's just not where the money is.

I think this is a subject matter deserving of its own thread though, so I might get on making one sometime later.
Click to expand...

This is interesting, but, and pardon the aggressively noobish question, but isn't the difference between balding and non balding men that the non balding men's hair follicles aren't sensitive to DHT?

If that is so, then T/E ratio should be irrelevant (although it's hard to believe it is, given the disparity in baldies vs non-bald).
 
Armando Jose

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whatevr said:
I think this is a subject matter deserving of its own thread though, so I might get on making one sometime later.
Click to expand...

Very good idea because this is a very important key, including the mantra that castration stops baldness
 
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whatevr

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Dimitri001 said:
This is interesting, but, and pardon the aggressively noobish question, but isn't the difference between balding and non balding men that the non balding men's hair follicles aren't sensitive to DHT?

If that is so, then T/E ratio should be irrelevant (although it's hard to believe it is, given the disparity in baldies vs non-bald).
Click to expand...

Both testosterone and epitestosterone compete for downstream metabolism by 5-alpha reductase.
Testosterone → 5AR → 5a-Dihydrotestosterone ( very potent androgen DHT)
Epitestosterone → 5AR → 5a-Dihydroepitestosterone (mostly inactive metabolite)

Since they both compete for the same enzyme (with epitestosterone having perhaps even more affinity for 5-AR than testosterone), we can say that Epitestosterone would be a 5-AR "inhibitor" since it would bind 5-AR and keep it busy with metabolizing itself, rather than testosterone.

Epi-T's metabolites are largely inactive as androgens, and do not cause androgenic effects.

The more Epi-T you have, the more your 5-AR will be metabolizing it instead of testosterone, so you have more inactive androgen metabolites, and less active ones such as DHT.

In other words there is really no such "sensitivity to DHT". The sensitivity comes from the fact that there is 1. too much testosterone relative to Epi-T and 2. consequently too much active androgen metabolites (DHT) - this causes both a further upregulation of 5-AR (DHT upregulates its own production [1]) and the constant activation of the androgen receptor by DHT further upregulates it [2]. Overexpressed 5-AR and AR have been found in balding follicles.

You can actually kill safe, donor area hair (the one on the sides and back of your head which is supposedly resistant to androgens) by giving it sufficiently high amounts of T & DHT (essentially mimicking what is happening in balding follicles):

Effect of 5α-Dihydrotestosterone and Testosterone on Apoptosis in Human Dermal Papilla Cells
Thus, we investigated the influence of T and 5α-DHT on proliferation, cell death and bcl-2/bax expression in cultured dermal papilla cells (DPC) from nonbalding scalp regions of healthy volunteers. ... T and 5α-DHT induced apoptosis in DPC in a dose-dependent and time-related manner; in addition a necrotic effect due to T at 10–5M was found. ... These data suggest that DPC from nonbalding scalp regions do have the capacity to undergo apoptosis, but need a high androgen stimulus.

In other words, there is nothing particularly fancy or sensitive about the hairs on the top of your head, other than that they synthesize and are exposed to way too high amounts of androgens on a constant basis - the genetic aspect probably explains why some of these key enzymes and proteins regulating androgen synthesis are so imbalanced in these follicles.

Finally, I will leave you with this paragraph from 1987, just so you get an idea of how long this has been known, and how little has been done about it:

upload_2020-9-16_7-47-38.png
[3]


[1] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC52442/
[2] https://pubmed.ncbi.nlm.nih.gov/14556282/
[3] https://pubmed.ncbi.nlm.nih.gov/3598212/
 

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