Non-aromatase related estrogenic effects from androgen use

quote:

---

[i]- no proof that gynecomastia could occur without T/E2 ratio disturbance, aromatase dys-regulation, 5-a reductase deficiency etc or other endocrine parameters that involved an estrogenic effect mediated by estrogens and their own receptors.

---

This is entirely true.

However, ishikawa et al (2005) demonstrate that estrogenic effects do take place in aromatase negative mice, and they are blocked by a 5a-reductase blocker. Steckelbroeck determined that 3b-androstanediol is an estrogen, and formation from DHT is irreversible. For years users have complained of gyno issues with non estrogenic drugs, and we know that AKR1C is expressed highly in mammary tissue.

what i was trying to put forth is that the POSSIBILITY exists to explain the appearance of gyno in low or no estrogen conditions. I do however agree with you 100% that this is not a likely option and remain of the opinion that most if not all of those cases are simply a misdiagnose by panicked fear-stricken kids.

quote:

---

- the rare cases of gyno with non estrogenic drugs you referred are not documented. And it does not mean that the traditional reasons advanced in breast enlargment in normal healthy men are not valid.

---

I agree 100%. I wanted to put forth that such cases, if true, could be explained. I did not mean to insinuate that they are in fact true.

Even if what I presented was the case, 90% would still be fake since it is unlikely that many drugs activate the ERE via the AR, or form a plausible estrogenic metabolite.

quote:

---

- no proof that non-aromatisable steroids or nandrolone are able to promote gyno by an estrogenic AR-mediated effect.

---

true, but for nandrolone gyno is actually more frequent than with drugs like Testosterone and methandrostenolone, making it a more than likely thing. I do not pretend this is the case for any other drug.

quote:

---

- the local origin is often advanced in studies because the absence of disturbance in the biological parameters and the absence of other female signs.

Good point, but to immediately name local aromatase the culprit is overboard. Increased estrogen sensitivity was named, and possibly aromatase upregulation by other mediators, like cox-2. In which case the insignificant amount of adipose tissue in the area would contain an uncharacteristically high aromatase level, which is simply not the case for 99.9% of the population.

Posted by: Big Cat

Uhm, were you paying attention to this discussion ?

I never said anything like that, on the contrary, I even stated the very fact. That aromatisation occurs in peripheral tissues and liver, and then systemically distributes itself, to among other places the mammary tissue (which expresses no aromatase). What BB and the others seem to want to propose is that the aromatisation is local from adipose tissue near the mammary gland. However in males the mammary gland is barely developed and there is no adipose tissue deposition to speak of in the area, ruling out any significant degree of local aromatisation.

As opposed to 3beta-androstanediol formation, which is formed directly in mammary tissue, as well as most other tissues.

Or to reiterate from the original post :

Yeah, but I always wanted to say that. Initial aromatization is probably systemic but after glands are formed it could also be local. I don't really have an opinion about the original subject, of androgens causing gyno, except it's interesting.

Posted by: Seabiscuit Hogg

Yeah, but I always wanted to say that. Initial aromatization is probably systemic but after glands are formed it could also be local. I don't really have an opinion about the original subject, of androgens causing gyno, except it's interesting.

In that case we are completely in agreement. Of course after initial development local adipose deposition as the result of glandular development will sustain aromatase action to drive breast development. I'm assuming the deposition of fat by breast development is mechanism of self-sustenance.

Makes sense. Obese ppl who develope gyno often find it persists after they lose weight. From what I've seen, guys who get it from gear usually have to either use non-aromatizing drugs exclusively, use anti-E's every cycle or have it surgically removed.

i just wanted to say excellent post and a very informative read....thanks BC, BB, and others

Originally posted by Black Baccara

Normal healthy men have both glandular tissue and adipose tissue surroundig it.

Re: Non-aromatase related estrogenic effects from androgen use

Posted by: Big Cat

Not only can effects of this nature not be blocked by aromatase inhibitors, they are likely worsened by aromatase inhibitors, which would increase the substrate for 5AR.

I guess that when you say "substrate" you are referring to Testosterone, aren't you? Given the fact that only a tiny 0.1-1% of T interacts with aromatase enzyme, I would be surprised if blocking aromatase even completely would lead to any degree of T elevation; that would surely happen in someone who is OFF steroids (in which case, as we saw in the past, taking adex supressing 50% estrogen leads to ~40-50% increase in T levels), but it would be a consequence of HPTA upregulation, not a consequence of "freeing" T from aromatase. Someone who is ON steroids and whose HPTA is almost completely supressed shouldn't expect any significant increase in T levels; even if he got to supress 100% of aromatase all the T elevation he should get would be in the tiny 0.1-1% range moreless.

Posted by: Big Cat

However, ishikawa et al (2005) demonstrate that estrogenic effects do take place in aromatase negative mice, and they are blocked by a 5a-reductase blocker.

Indeed if we follow the study conclusions we might believe that by blocking 5AR we would become less prone to estrogenic side effects, while upregulating 5AR (and DHT) would increase the chance of estrogen related side effects. I was really surprised when, weeks ago, I read that study's conclusion: "This finding raises the possibility that the combination of a 5 alpha-reductase inhibitor and an aromatase inhibitor may reduce estrogenic steroids in vivo more completely than an aromatase inhibitor alone."

However, I believe that the authors of the study are overlooking the fact that DHT is also a potent antiestrogen (being an ER antagonist). I firmly believe that even though DHT converts to these sort of estrogenic steroids and that results in ER agonism, the degree of ER antagonism that DHT promotes through other mecanism is stronger and overall blocking DHT tends to promote estrogen side effects and vice-versa. We have always read that the higher the E/(T+DHT) ratio is the more likely you become to estrogen-like side effects. All those people getting gyno as a result of using a 5AR blocker (I myself have experienced it to some degree while using Dutasteride to fight hairloss) are somewhat demonstrating that supressing DHT leads to increased estrogen effects and not the opposite.

Re: Re: Non-aromatase related estrogenic effects from androgen use

Posted by: neurotic

I guess that when you say "substrate" you are referring to Testosterone, aren't you? Given the fact that only a tiny 0.1-1% of T interacts with aromatase enzyme, I would be surprised if blocking aromatase even completely would lead to any degree of T elevation; that would surely happen in someone who is OFF steroids (in which case, as we saw in the past, taking adex supressing 50% estrogen leads to ~40-50% increase in T levels), but it would be a consequence of HPTA upregulation, not a consequence of "freeing" T from aromatase. Someone who is ON steroids and whose HPTA is almost completely supressed shouldn't expect any significant increase in T levels; even if he got to supress 100% of aromatase all the T elevation he should get would be in the tiny 0.1-1% range moreless.

It would depend on what they are "ON". If they were on test, the exogenous test wouldn't convert so levels would be higher.

Re: Re: Non-aromatase related estrogenic effects from androgen use

Posted by: neurotic

I guess that when you say "substrate" you are referring to Testosterone, aren't you? Given the fact that only a tiny 0.1-1% of T interacts with aromatase enzyme, I would be surprised if blocking aromatase even completely would lead to any degree of T elevation; that would surely happen in someone who is OFF steroids (in which case, as we saw in the past, taking Adex supressing 50% estrogen leads to ~40-50% increase in T levels), but it would be a consequence of HPTA upregulation, not a consequence of "freeing" T from aromatase. Someone who is ON steroids and whose HPTA is almost completely supressed shouldn't expect any significant increase in T levels; even if he got to supress 100% of aromatase all the T elevation he should get would be in the tiny 0.1-1% range moreless.

5alpha reduction is quantitatively in the same order as aromatisation, and blocking either enzyme has shown to elevate output of the other. men taking 5AR blockers experience higher estrogen, and estrogenic problems, same holds true for aromatase blockers.

Posted by: neurotic

Indeed if we follow the study conclusions we might believe that by blocking 5AR we would become less prone to estrogenic side effects, while upregulating 5AR (and DHT) would increase the chance of estrogen related side effects. I was really surprised when, weeks ago, I read that study's conclusion: "This finding raises the possibility that the combination of a 5 alpha-reductase inhibitor and an aromatase inhibitor may reduce estrogenic steroids in vivo more completely than an aromatase inhibitor alone."

However, I believe that the authors of the study are overlooking the fact that DHT is also a potent antiestrogen (being an ER antagonist). I firmly believe that even though DHT converts to these sort of estrogenic steroids and that results in ER agonism, the degree of ER antagonism that DHT promotes through other mecanism is stronger and overall blocking DHT tends to promote estrogen side effects and vice-versa. We have always read that the higher the E/(T+DHT) ratio is the more likely you become to estrogen-like side effects. All those people getting gyno as a result of using a 5AR blocker (I myself have experienced it to some degree while using dutasteride to fight hairloss) are somewhat demonstrating that supressing DHT leads to increased estrogen effects and not the opposite.

That is all very much open for debate. But keep in mind that I presented these cases here to offer an explanation for the rare cases where inexplicable gyno occurs in cases where technically it cannot occur.

Don't presume that any of this applies to the majority or even a sizeable minority. These are exceptions to the rule, and everything presented here is in defence of the POSSIBILITY of estrogenic effects in the absence of known estrogens.

My stance on the matter however hasn't changed, I deem gyno a rather infrequent side-effect even with more estrogenic drugs, and a largely exaggerated condition. Most cases reported are people who cannot distinguish between an itchy nipple and gyno, and just freak out because message boards are just so full of gyno talk.

Re: Re: Re: Non-aromatase related estrogenic effects from androgen use

Posted by: Big Cat

5alpha reduction is quantitatively in the same order as aromatisation, and blocking either enzyme has shown to elevate output of the other. men taking 5AR blockers experience higher estrogen, and estrogenic problems, same holds true for aromatase blockers.

extreme generalization-extreme truth= fanatical-dogmatical truth,

I have used any of the two blockers, alone or simultaneously (dutasteride and nolva or femara) and my estradiol levels are the same,ever low (i take weekly estradiol blood tests over 14 weeks) under 2 gr of e test and 500 mg of boldelone weekly,post cycle estrogen ever low too (estradiol blood tests also).

anyway you can reduce 5alpha reduced androgens via 13-cis-retinoic acid

Evidence for decreased androgen 5 alpha-reduction in skin and liver of men with severe acne after 13-cis-retinoic acid treatment.

Boudou P, Chivot M, Vexiau P, Soliman H, Villette JM, Julien R, Belanger A, Fiet J.

Department of Hormonal Biology, Saint-Louis University Hospital, Paris, France.

To investigate the effect of 13-cis-retinoic acid (13-cis-RA) treatment on androgen metabolism in men with severe nodulocystic acne, eight men with severe acne received an oral daily dose of 0.7 mg/kg 13-cis-RA over 3 months. Exploration of androgen metabolism in serum samples, 24-h urine collections, and skin biopsies obtained before and at the end of the treatment revealed no significant alterations in serum levels of either adrenal or gonadal androgens. However, the treatment did induce significant decreases in serum levels of the 5 alpha-reduced androgens: 5 alpha-dihydroTestosterone(P < 0.02), androsterone glucosiduronate (P < 0.04), and 5 alpha-androstan-3 alpha, 17 beta-diol glucosiduronate (P < 0.004). Unlike serum, the urinary 5 alpha-reduced metabolites 5 alpha-androstan-3 alpha, 17 beta-diol and androsterone did not vary significantly despite a decrease in the excretion of the latter. Moreover, a marginally significant increase in urinary excretion of etiocholanolone, very similar to the decrease in androsterone excretion, was observed. The ratio of androsterone to etiocholanolone decreased significantly (P < 0.004) after 13-cis-RA therapy and suggested a metabolic deviation from the androgen 5 alpha- to 5 beta-reduction pathway in the liver. The most pronounced effect was observed in skin biopsies, which lost 80% of their ability to form 5 alpha-dihydrotestosterone (P < 0.001). It is concluded that 13-cis-RA therapy in men with severe nodulocystic acne did not alter gonadal or adrenal functions, but it did induce 1) a highly significant decrease in 5 alpha-dihydrotestosterone formation by skin biopsies; 2) significant decreases in serum 5 alpha-dihydrotestosterone, androsterone glucosiduronate, and 5 alpha-androstan-3 alpha, 17 beta-diol glucosiduronate; and, finally, 3) deviation of the liver androgen 5 alpha- to 5 beta-reduction pathway. The effect of 13-cis-RA treatment on severe acne is consistent with the dramatic decrease in androgen 5 alpha-reduction observed mainly in the skin.

Re: Re: Re: Non-aromatase related estrogenic effects from androgen use

Posted by: Big Cat

5alpha reduction is quantitatively in the same order as aromatisation, and blocking either enzyme has shown to elevate output of the other.

---

Do you have any references that measure these enzyme levels and how they change when the other enzyme is blocked?

quote:

---

men taking 5AR blockers experience higher estrogen, and estrogenic problems,

---

Yes, but not necessarily because blocking 5AR leads to increased aromatase. I think that the rationale behind estrogen related problems due to 5AR inhibitors is a matter of estrogen/androgen ratio. DHT has shown to be an ER antagonist and, when you block it, even if estrogen levels remain the same, that quantity of estrogen is more likely to promote side effects than it would be in a higher androgenic hormonal environment.
Anyway, even if blocking 5AR resulted in increased aromatase levels that would prove that DHT is a kind of aromatase inhibitor. You couldn't extrapolate and say "if you block estrogen the same is likely to happen with 5AR enzyme", that would imply that E is a 5ar inhibitor, which would be too odd from my point of view, any reference?

quote:

---

same holds true for aromatase blockers. [/B]

---

Yes. In some one who is OFF (i.e. someone who is not taking steroid or anything that promotes HPTA supression) blocking estrogen clearly leads to increased testosterone (and hence, increased DHT) as has been shown in studies with Arimidex for instance (1).

However, this happens as a result of HPTA upregulation. Someone who is taking steroids has a supressed HPTA, so this fenomenum is unlikely to take place. Bearing in mind that only 0.1-1% of T converts to estrogen (2) (as shown in the figure below), even if we supressed aromatase completely, the amount of T that would be "freed" would be TINY (0.1-1%). So why would someone who is ON (taking steroids), whose HPTA is supressed, experience any increase in T & DHT levels as a result of aromatase inhibition?

1: J Clin Endocrinol Metab. 2000 Jul;85(7):2370-7.
J Clin Endocrinol Metab. 2001 Apr;86(4):1836-8.
Estrogen suppression in males: metabolic effects.
Mauras N, O'Brien KO, Klein KO, Hayes V.

2: Endotext.
ANDROGENS
Chapter 2 - David J Handelsman MB BS, FRACP, PhD
August 17, 2004

Re: Re: Re: Re: Non-aromatase related estrogenic effects from androgen use

Posted by: oswaldosalcedo

[B]extreme generalization-extreme truth= fanatical-dogmatical truth,

---

You have some real drama issues ...

quote:

---

I have used any of the two blockers, alone or simultaneously (dutasteride and nolva or femara) and my estradiol levels are the same,ever low (i take weekly estradiol blood tests over 14 weeks) under 2 gr of e test and 500 mg of boldelone weekly,post cycle estrogen ever low too (estradiol blood tests also).

---

I question the outcome of that if you get the same results on estradiol levels using femara or nolvadex, since femara should drastically reduce estrogen, whereas nolvadex should slightly elevate estradiol (since it doesn't change production of estrogen, but it does displace it from the receptor resulting in more serum-borne estradiol). which in turn questions the validity of any other results you present as being from blood tests.

quote:

---

anyway you can reduce 5alpha reduced androgens via 13-cis-retinoic acid

There are many ways to reduce 5-alpha-reduction. However, I fail to see why you mention it, if it is your contention that aromatase blocking does not raise systemic DHT ?

Re: Re: Re: Re: Non-aromatase related estrogenic effects from androgen use

Posted by: neurotic

[B]Do you have any references that measure these enzyme levels and how they change when the other enzyme is blocked?

I wasn't proposing any change in enzyme levels, only change in enzyme output due to change in substrate level ...

quote:

---

Yes, but not necessarily because blocking 5AR leads to increased aromatase.

---

I didn't say that either ...

quote:

---

I think that the rationale behind estrogen related problems due to 5AR inhibitors is a matter of estrogen/androgen ratio. DHT has shown to be an ER antagonist and, when you block it, even if estrogen levels remain the same, that quantity of estrogen is more likely to promote side effects than it would be in a higher androgenic hormonal environment.[/quote$

A highly debatable issue, but nonetheless plausible. I'm also not arguing against it. In fact I would add that the higher substrate is a prime cause as well.

We know that HCG leads to increased estradiol because there is a fast and high concentration increase of testosterone, yet no increase in aromatase. Only an increase in substrate. We also know that anti-estrogens increase testosterone to a (scientifically, obviously not practically) significant degree. 5-alpha reduction occurs in function of substrate, as does aromatization.

Anyway, even if blocking 5AR resulted in increased aromatase levels that would prove that DHT is a kind of aromatase inhibitor. You couldn't extrapolate and say "if you block estrogen the same is likely to happen with 5AR enzyme", that would imply that E is a 5ar inhibitor, which would be too odd from my point of view, any reference?

---

i didn't say it increased aromatase, for the third time, and we already know for sure that actual DHT is kind of an aromatase inhibitor.

Whether or not E and DHT block each others conversion enzymes is further irrelevant in the case, since we are talking about situations where a lack of DHT or E is already caused by something else, so that the influence of either is insignificant.

quote:

---

However, this happens as a result of HPTA upregulation. Someone who is taking steroids has a supressed HPTA, so this fenomenum is unlikely to take place. Bearing in mind that only 0.1-1% of T converts to estrogen (2) (as shown in the figure below), even if we supressed aromatase completely, the amount of T that would be "freed" would be TINY (0.1-1%). So why would someone who is ON (taking steroids), whose HPTA is supressed, experience any increase in T & DHT levels as a result of aromatase inhibition?

---

As was stated before, only the increase from reduced aromatization, which is admittedly slighter. But 5alpha-reduction is of the same order as aromatization, you can easily check that on your own blood results if you have some lying around.