If DHT IS the cause of YOUR hairloss...

[Bryan]

Well, you have a point there, of course. It would be interesting to know what approximate percentage of testosterone gets converted to estrogen in a typical, healthy young male.

An amount too tiny (<1%) to have any significant impact in T levels. The only impact it has is through HPTA upregulation.

That information is probably available somewhere...

Yes!

http://www.endotext.com/male/male2/male2.htm

That's an excellent article! Thanks for the link!

By the way, when you block estrogen (by means of arimidex for instance), there seems to be a pretty strong T elevation (look at the figure).

Yes, demonstrating how strong an anti-gonadotropin estrogen is!

I wonder to what extent those people who are blocking aromatase in an attempt to prevent/treat gynecomastia are rendering their 5AR blocker useless through the ~50% ("Both doses were associated with comparable suppression of E2 (50%), with parallel increases in testosterone and free testosterone") increase in T levels.

I doubt that's a problem at all. The high potency and irreversible inhibition of both finasteride and dutasteride would almost certainly overwhelm the presence of a little extra testosterone, IMHO.

Bryan

 

[Bryan]

I think that, when using 5AR blockers, the ratio of E/T elevation is probably higher than 1, because another reason (more important than T elevation from my point of view) that accounts for the raise in estrogen levels is the fact that DHT antagonizes aromatase enzyme, so if you block DHT, there is more free aromatase and ergo, for a given level of T, E levels will tend to be higher.

Do you have a reference or citation for the claim that DHT antagonizes the aromatase enzyme?

Bryan

 

[Bryan]

Let's put it this way:

1) Blocking DHT 'frees' aromatase enzyme, which implies an elevation in E/T ratio.

See my previous post. I'd like to see a reference for the claim that DHT blocks or inhibits the aromatase enzyme.

2) DHT antagonizes the ER, so, for a given level of E, their physiologic effect is going to be bigger.

I hate to sound like I'm questioning every little thing you say, but can you cite a reference for the claim that DHT antagonizes the ER?

3) ER agonism downregulates the HPTA through the ER present at the hypothalamus. The more estrogens, the more supression there will be (ever wondered why aromatase blockers tend to produce sharp raises in E levels? )

You mean sharp rises in T (not E)??

Bryan

 

[Armando Jose]

It's amazing the quality of the posters here!
Thank you.
But I wonder, what happen in the hair follicle? You are talking about general pathways but, it could be that pilosebaceous unit orchestrate its own melody?.
Germand researchers think about a autonomous H-P-A axis in hair.
Have a nice day
Armando

 

[Radio]

It's amazing the quality of the posters here!

Thanks!

 

[socks]

Bryan & Triton2,

Awesome info gentlemen. Thank you both for sharing

 

[Dave001]

The incidence of Propecia failing to work is reported by Merck to be only 17%. I beleive the reason Propecia fails in this small percentage is due to the pharmadynamics of the drug as opposed to the pharmakinetics. For those of you who are unsure about the difference between the two, pharmadynamics refers to the absorption, metabolism and distribution of the drug throughout the body. Some people (very few - estimates vary between 7%-19%) simply cannot absorb and have benefits from ANY medication taken orally. This is because either the drug is not being absorbed or broken down or distributed correctly by the body. Because the incidence of Propecia not working is only 17% (as reported by Merck) I believe that the failure of Propecia in these patients is due to pharmadynamics and not the action of the drug itself (pharmakinetics).

A tutorial on pharmacodynamics and pharmacokinetics from someone who cannot spell them correctly.

 

[socks]

The incidence of Propecia failing to work is reported by Merck to be only 17%. I beleive the reason Propecia fails in this small percentage is due to the pharmadynamics of the drug as opposed to the pharmakinetics. For those of you who are unsure about the difference between the two, pharmadynamics refers to the absorption, metabolism and distribution of the drug throughout the body. Some people (very few - estimates vary between 7%-19%) simply cannot absorb and have benefits from ANY medication taken orally. This is because either the drug is not being absorbed or broken down or distributed correctly by the body. Because the incidence of Propecia not working is only 17% (as reported by Merck) I believe that the failure of Propecia in these patients is due to pharmadynamics and not the action of the drug itself (pharmakinetics).

A tutorial on pharmacodynamics and pharmacokinetics from someone who cannot spell them correctly.

Ouch Dave!

 

[triton2]

3) ER agonism downregulates the HPTA through the ER present at the hypothalamus. The more estrogens, the more supression there will be (ever wondered why aromatase blockers tend to produce sharp raises in E levels? )

You mean sharp rises in T (not E)??

Bryan

Yes! you are right, I meant T, not E. Sorry.

I hate to sound like I'm questioning every little thing you say, but can you cite a reference for the claim that DHT antagonizes the ER?

http://jcem.endojournals.org/cgi/content/full/85/7/2370

J Clin Invest. 1984 Dec;74(6):2272-8.


Antiestrogenic action of dihydrotestosterone in mouse breast. Competition with estradiol for binding to the estrogen receptor.

Casey RW, Wilson JD.

Feminization in men occurs when the effective ratio of androgen to estrogen is lowered. Since sufficient estrogen is produced in normal men to induce breast enlargement in the absence of adequate amounts of circulating androgens, it has been generally assumed that androgens exert an antiestrogenic action to prevent feminization in normal men. We examined the mechanisms of this effect of androgens in the mouse breast. Administration of estradiol via silastic implants to castrated virgin CBA/J female mice results in a doubling in dry weight and DNA content of the breast. The effect of estradiol can be inhibited by implantation of 17 beta-hydroxy-5 alpha-androstan-3-one (dihydrotestosterone), whereas dihydrotestosterone alone had no effect on breast growth. Estradiol administration also enhances the level of progesterone receptor in mouse breast. Within 4 d of castration, the progesterone receptor virtually disappears and estradiol treatment causes a twofold increase above the level in intact animals. Dihydrotestosterone does not compete for binding to the progesterone receptor, but it does inhibit estrogen-mediated increases of progesterone receptor content of breast tissue cytosol from both control mice and mice with X-linked testicular feminization (tfm)/Y. Since tfm/Y mice lack a functional androgen receptor, we conclude that this antiestrogenic action of androgen is not mediated by the androgen receptor. Dihydrotestosterone competes with estradiol for binding to the cytosolic estrogen receptor of mouse breast, whereas 17 beta-hydroxy-5 beta-androstan-3-one (5 beta-dihydrotestosterone) neither competes for binding nor inhibits estradiol-mediated induction of the progesterone receptor. Dihydrotestosterone also promotes the translocation of estrogen receptor from cytoplasm to nucleus; the ratio of cytoplasmic-to-nuclear receptor changes from 3:1 in the castrate to 1:2 in dihydrotestosterone-treated mice. Thus, the antiestrogenic effect of androgen in mouse breast may be the result of effects of dihydrotestosterone on the estrogen receptor. If so, dihydrotestosterone performs one of its major actions independent of the androgen receptor.

I will quote from this study some other sentences which support the thesis that DHT antagonizes the ER:

"Evidence has been developed in the MCF7 cell
line that 17,3-hydroxy-5a-androstan-3-one (dihydrotestosterone)'
functions as an antiestrogen by binding to the estrogen
receptor itself""

"Dihydrotestosterone binds weakly to the estrogen receptor in mouse breast and like some other antiestrogens appears to anchor the estrogen-receptor in the nucleus of the cell. These effects have only been studied with pharmacological amounts of hormone, but the fact that the relative binding affinities of dihydrotestosterone, 313-androstanediol, testosterone, and Sfdihydrotestosterone correlate with their capacities to inhibit induction of the progesterone receptor is in keeping with the finding in MCF7 tumor cells (10) that androgens bind to the estrogen receptor."


These quotes seem to corroborate an idea which I often advocate: the physiological actions of X levels of E with Y levels of (T+DHT) is going to be less 'agressive' than those of X levels of E with Y/2 levels of (T+DHT):

"Lewin (8) originally proposed that the determinant of feminization in
men is not so much the absolute level of estrogen but rather the ratio of androgen to estrogen, a concept that has received support from detailed studies of androgen and estrogen metabolism in men with feminization in diverse clinical states"

"Third, it has been generally assumed, certainly by us, that feminization of the breasts in human subjects with defective androgen receptor (testicular feminization [complete and incomplete] and the Reifenstein
syndrome) is in large part due to androgen resistance (25). However, estrogen production is also increased in these states, and it may be that estrogen itself is the primary determinant of breast enlargement in these disorders (1)."

Some other studies:

Attenuation of Estrogenic Effects by Dihydrotestosterone in the Pig Uterus Is Associated with Downregulation of the Estrogen Receptors1
Horacio Cárdenas2 and William F. Pope

Department of Animal Sciences, The Ohio State University, Columbus, Ohio 43210

Androgens are known to attenuate some effects of estradiol-17ß (E) in the uterus. The objectives of the present experiment were to determine effects of 5-dihydrotestosterone (DHT) on estrogenic actions in the pig uterus and its associations with changes in expression of the estrogen receptor (ER) and ERß. Postpubertal gilts (120–130 kg of body weight; n = 16) were ovariectomized, and 3–4 weeks later received once-a-day injections (i.m.) of one of the following treatments during four consecutive days: 1) vehicle (corn oil), 2) E (250 µg), 3) E (250 µg) plus 1 mg DHT, or 4) E (250 µg) plus 10 mg DHT. Uterine tissues were collected 24 h after the last treatment. Gilts receiving E or E plus 1 mg DHT had greater uterine wet weight, uterine horn diameter, luminal epithelium thickness, and endometrial gland diameter compared with gilts treated with vehicle or E plus 10 mg DHT. Gilts receiving E or E plus 1 mg DHT were not different in these characteristics. Relative amounts of mRNAs in the endometrium for the cell proliferation marker histone H2a and the E-inducible protein complement component C3 increased in gilts treated with E compared with gilts treated with vehicle. E-induced increases in histone H2a and C3 mRNAs were not altered by cotreatment with E plus 1 mg DHT but were inhibited by E plus 10 mg DHT. Androgen receptor (AR) mRNA in the endometrium increased by treatment with E. Cotreatment of gilts with E and DHT did not alter the E-induced AR mRNA increase. Gilts treated with E plus 10 mg DHT had lesser amounts of immunoreactive ER in cell nuclei of the myometrium and endometrial stroma and a tendency for a decrease in luminal epithelium compared with gilts treated with E. Amounts of immunoreactive ER in glandular epithelium were not influenced by the treatments. Relative amounts of ER and ERß mRNAs decreased in the endometrium of gilts treated with E plus 10 mg DHT compared with gilts treated with E. Downregulation of the ERs, particularly ER in the myometrium and endometrial stroma, might be a relevant mechanism in the antagonism of estrogenic effects by DHT in the pig uterus.


Testosterone inhibits estrogen-induced mammary epithelial proliferation and suppresses estrogen receptor expression
JIAN ZHOU, SIU NG, O. ADESANYA-FAMUIYA, KRISTIN ANDERSON and CAROLYN A. BONDY1

http://www.fasebj.org/cgi/content/full/14/12/1725#B24

"Labrie et al. have shown that dihydrotestosterone suppresses ER expression and estrogen-induced proliferation in ZR-75–1 breast cancer cells and blocks the development of estrogen-dependent mammary tumors in rats"

It also looks like DHT has been shown to be quite an effective treatment against gynecomastia:

Presse Med. 1983 Jan 8;12(1):21-5.

Gynecomastia: effect of prolonged treatment with dihydrotestosterone by the percutaneous route

[Article in French]

Kuhn JM, Laudat MH, Roca R, Dugue MA, Luton JP, Bricaire H.

Gynaecomastia is a frequent disorder, sometimes painful or psychologically disturbing. Percutaneous dihydrotestosterone (DHT) was used to treat 30 patients with idiopathic gynaecomastia (IG) and 17 patients in whom the condition was associated with hypogonadism. All patients complaining of pain were relieved. Breast enlargement regressed or was substantially reduced in 22 of the IG patients and in all cases with hypogonadism, except those with gonadal dysgenesis. Plasma levels of testosterone and 17 beta-estradiol were significantly lowered in patients with IG as compared with controls. There was a significant increase in plasma DHT levels and in plasma androgen/estradiol ratio in all cases. The beneficial effects of the drug were manifest within 1 to 2 months in responsive patients. These effects may be due to a local and/or systemic activity. It is suggested that this medium-term treatment without side-effects should be tried in all cases of hypogonadism with gynaecomastia and in IG before considering more drastic therapeutic measures.

I'd like to see a reference for the claim that DHT blocks or inhibits the aromatase enzyme.

Unfortunately, this is a thing that, as I read it somewhere, I automatically assumed it had to be true and sent it up into my brain, without any previous validation. So I cannot cite any reference which proves that DHT blocks aromatase. However, I don't think this is so important, as the main idea I wanted to express was that, if you supress DHT, estrogen is somewhat 'freed' and is likely to promote disorders such as gyno (hence the need for an aromatase blocker and/or a SERM).

 

[triton2]

I wonder to what extent those people who are blocking aromatase in an attempt to prevent/treat gynecomastia are rendering their 5AR blocker useless through the ~50% ("Both doses were associated with comparable suppression of E2 (50%), with parallel increases in testosterone and free testosterone"[/u]) increase in T levels.

I doubt that's a problem at all. The high potency and irreversible inhibition of both finasteride and dutasteride would almost certainly overwhelm the presence of a little extra testosterone, IMHO.

Bryan

I am sure that a 50% increase in T levels is not enough to override dutasteride/finasteride effects, rendering it ineffective. What I don't know is to what extent it could reduce its effectiveness.
Let's suppose that finasteride blocks 70% of scalp DHT, which would you leave with a 30% of what you'd have hadn't you taken any medication. If we then add the aromatase blocker and promote a 50% increase in T levels, do you think it would be logical to expect a 50% increase in DHT levels (a 50% increase over the 30% levels you previously had of course). If that were the case, DHT levels would be a 45% of what they'd be if we hadn't taken anything; in other words: finasteride would turn into a 55%-scalp-DHT-inhibitor as opposed to a 70%-scalp-inhibitor. Not bad, I guess it'd still be pretty effective at stopping male pattern baldness.
What really concern me are those claims that postulated that finasteride inhibited less than 40% scalp DHT (do you remember that famous (or infamous ) graph comparing dutasteride and finasteride?); if that graph turned out to be realiable and, at the same time, the premise "x% T increase promotes x% DHT increase" were valid it would mean that the 50% raise in T levels would render finasteride almost completely useless, for scalp DHT levels would probably return to baseline (what one would have before taking any medication).

Another thing that 'concerns' me: taking into account that 17-alpha-estradiol (or was it 17-beta?) seems to be a hair growth promoter, to what extent finasteride/dutasteride effectiveness might be a product of their estrogenic side effects? If E played an important role in finasteride/dutasteride anti-hairloss properties, we'd be really screwing our favourite 5AR blocker if we combined it with an anti-E, wouldn't we?

I just hope that blocking E is not that 'harmful' (as far as hair is concerned), because the idea of developing a nice pair of bitchy tits is not something I would be precisely proud of.

P.S.: Bryan, I really need your help here in this post:

http://www.hairlosstalk.com/discussions ... hp?t=21765

 

[chewbaca]

There is also something known as DHT senstivity...if u are genetically programmed to be sensitive to even a small amount, the blocking 80% DHT whic propecia will not work..U need to block 100% ...this is the reaon why propecia does not work for some people....

There is yet another possible factor, too, which people always overlook: a fundamentally different response to DHT and other androgens. Didn't you ever consider that maybe some people who just never ever experience male pattern baldness have scalp hair follicles that have more of the characteristics of BODY hair follicles?? Think about this simple question: why does DHT make beard hair (for example) grow nice and big and strong? It's because of a different RESPONSE to androgens that beard follicles have. And maybe people who are highly resistant to balding have scalp hair follicles with characteristics that are more along those same lines.

Bryan

how dou compare the characteristics

 

[Bryan]

I've previously cited a study in which human scalp hair follicles were removed, and their growth tested in vitro by adding testosterone to them. It was found that some individual follicles were unaffected by the androgen, whereas others (as expected) had their growth inhibited, and I'm talking about from the very same scalp!

Bryan

 

[misterium]

Oh sh*t, I got myself into a lot of trouble asking this question

I was looking for a simple answer.. how silly of me.

 

[Bryan]

Here's my favorite Albert Einstein quote:

"Physics should be made as simple as possible, but not simpler."

Bryan

 

[jack2]

What kind of T upregulation would you expect from taking propecia and avodart together? much more than avodart by itself?

 

[chewbaca]

I've previously cited a study in which human scalp hair follicles were removed, and their growth tested in vitro by adding testosterone to them. It was found that some individual follicles were unaffected by the androgen, whereas others (as expected) had their growth inhibited, and I'm talking about from the very same scalp!

Bryan

So saying T could cause male pattern baldness too and some tpye f male pattern baldness suferrers hve T driven male pattern baldness?

 

[triton2]

Bryan, what do you think about this? I'd really like to know your opinion.

I wonder to what extent those people who are blocking aromatase in an attempt to prevent/treat gynecomastia are rendering their 5AR blocker useless through the ~50% ("Both doses were associated with comparable suppression of E2 (50%), with parallel increases in testosterone and free testosterone"[/u]) increase in T levels.

I doubt that's a problem at all. The high potency and irreversible inhibition of both finasteride and dutasteride would almost certainly overwhelm the presence of a little extra testosterone, IMHO.

Bryan

I am sure that a 50% increase in T levels is not enough to override dutasteride/finasteride effects, rendering it ineffective. What I don't know is to what extent it could reduce its effectiveness.
Let's suppose that finasteride blocks 70% of scalp DHT, which would you leave with a 30% of what you'd have hadn't you taken any medication. If we then add the aromatase blocker and promote a 50% increase in T levels, do you think it would be logical to expect a 50% increase in DHT levels (a 50% increase over the 30% levels you previously had of course). If that were the case, DHT levels would be a 45% of what they'd be if we hadn't taken anything; in other words: finasteride would turn into a 55%-scalp-DHT-inhibitor as opposed to a 70%-scalp-inhibitor. Not bad, I guess it'd still be pretty effective at stopping male pattern baldness.
What really concern me are those claims that postulated that finasteride inhibited less than 40% scalp DHT (do you remember that famous (or infamous ) graph comparing dutasteride and finasteride?); if that graph turned out to be realiable and, at the same time, the premise "x% T increase promotes x% DHT increase" were valid it would mean that the 50% raise in T levels would render finasteride almost completely useless, for scalp DHT levels would probably return to baseline (what one would have before taking any medication).

Another thing that 'concerns' me: taking into account that 17-alpha-estradiol (or was it 17-beta?) seems to be a hair growth promoter, to what extent finasteride/dutasteride effectiveness might be a product of their estrogenic side effects? If E played an important role in finasteride/dutasteride anti-hairloss properties, we'd be really screwing our favourite 5AR blocker if we combined it with an anti-E, wouldn't we?

I just hope that blocking E is not that 'harmful' (as far as hair is concerned), because the idea of developing a nice pair of bitchy tits is not something I would be precisely proud of.

P.S.: Bryan, I really need your help here in this post:

http://www.hairlosstalk.com/discussions ... hp?t=21765

 

[Bryan]

Bryan, what do you think about this? I'd really like to know your opinion.

I am sure that a 50% increase in T levels is not enough to override dutasteride/finasteride effects, rendering it ineffective. What I don't know is to what extent it could reduce its effectiveness.
Let's suppose that finasteride blocks 70% of scalp DHT, which would you leave with a 30% of what you'd have hadn't you taken any medication. If we then add the aromatase blocker and promote a 50% increase in T levels, do you think it would be logical to expect a 50% increase in DHT levels (a 50% increase over the 30% levels you previously had of course). If that were the case, DHT levels would be a 45% of what they'd be if we hadn't taken anything; in other words: finasteride would turn into a 55%-scalp-DHT-inhibitor as opposed to a 70%-scalp-inhibitor. Not bad, I guess it'd still be pretty effective at stopping male pattern baldness.

Well, from my own point of view, you've started off on the wrong foot for at least a couple of different reasons.

First of all, I don't like references to "scalp DHT", because I think that's a very ambiguous term. A lot of DHT in a chunk of scalp tissue comes from the sebaceous glands, but that DHT is probably only slightly relevant to male pattern baldness, if at all.

Second of all, the DHT that primarily concerns us is the DHT inside hair follicles, and the 5a-reductase within hair follicles seems to be almost exclusively the type 2 form. Propecia probably inhibits the type 2 form of that enzyme by around 85% to 90% (that's my "guesstimate"). Therefore, my notion is that even if you increase testosterone levels by 50%, the increase in the local production of DHT (within the dermal papilla of the hair follicle) is _still_ only going to be rather modest. I wouldn't worry about it, if I were you.

What really concern me are those claims that postulated that finasteride inhibited less than 40% scalp DHT (do you remember that famous (or infamous ) graph comparing dutasteride and finasteride?); if that graph turned out to be realiable and, at the same time, the premise "x% T increase promotes x% DHT increase" were valid it would mean that the 50% raise in T levels would render finasteride almost completely useless, for scalp DHT levels would probably return to baseline (what one would have before taking any medication).

Let me make this point again: FORGET SCALP DHT LEVELS, which are only indirectly related to hairloss. If the levels of DHT within the dermal papilla are already being reduced very significantly (nearly 90% or so), then a modest increase in the testosterone substrate is not going to be that much of a problem, IMHO.

Another thing that 'concerns' me: taking into account that 17-alpha-estradiol (or was it 17-beta?) seems to be a hair growth promoter, to what extent finasteride/dutasteride effectiveness might be a product of their estrogenic side effects? If E played an important role in finasteride/dutasteride anti-hairloss properties, we'd be really screwing our favourite 5AR blocker if we combined it with an anti-E, wouldn't we?

I think the proportion of finasteride/dutasteride effectiveness relating to their estrogenic side-effects is quite small! Don't worry about it!

Bryan

 

[triton2]

Hello Bryan.
First of all I'd like to thank you very much for answering my questions, because an opinion from a knowledgeable man like you is very valuable to me.
Given the fact that these 5AR blockers reduce dermal papilla DHT by up to 90% then your argument would be very valid because, even if there was a 100% increase in T levels, DHT within the dermal papilla would barely change. What I really don't understand now is why, if 5AR-type1 is so irrelevant as far as derma papilla are concerned, dutasteride would be a better choice than finasteride; perhaps JUST because it blocks more 5AR-type2? By the way, to what extent do you think serum DHT would make a difference as far as hairloss is concerned? Does AR activation within these dermal papilla depend exclusively on local produced DHT or does serum DHT play an important role as well?

At last, all those issues about estrogen being benefitial concern me more since I have had to answer this post today:

http://www.hairlosstalk.com/discussions ... hp?t=22223

Anyway, I hope you are right and that we don't have to choose between hair and gyno!

 

[Bryan]

Given the fact that these 5AR blockers reduce dermal papilla DHT by up to 90% then your argument would be very valid because, even if there was a 100% increase in T levels, DHT within the dermal papilla would barely change. What I really don't understand now is why, if 5AR-type1 is so irrelevant as far as derma papilla are concerned, dutasteride would be a better choice than finasteride; perhaps JUST because it blocks more 5AR-type2?

Part of it is that, PLUS the inhibition of type 1 (and the resulting serum DHT reduction). I've never said that 5AR-type1 is completely irrelevant, just that androgenetic alopecia is more strongly associated with the type 2 enzyme than the type 1 enzyme.

By the way, to what extent do you think serum DHT would make a difference as far as hairloss is concerned? Does AR activation within these dermal papilla depend exclusively on local produced DHT or does serum DHT play an important role as well?

Serum DHT clearly plays _some_ role, because they did an interesting little experiment with a couple of those "pseudohermaphrodites" from the Dominican Republic: they injected DHT into them twice a week for a period of time, and their prostates started to enlarge. That clearly shows that DHT can have a true function as an endocrine hormone; however, it should be noted that the dose of DHT that was used was quite large.

My opinion is that serum DHT (which obviously includes the contribution from the 5a-reductase type 1 enzyme) has a relatively minor role in male pattern baldness, while the DHT produced within the follicle itself by the type 2 enzyme gets the lion's share of the blame!

Bryan