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Non-aromatase related estrogenic effects from androgen use

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Big Cat
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In the past we've been pretty uniform about estrogen. Despite theories flying around about progestins, prolactin and what have you not, none showed evidence of having an effect on the development of gyno in the absence of estrogen. Therefor, the use of an anti-estrogen was sufficient to treat problems of this kind.

Gyno is a fairly infrequent problem on proper cycles, and of the number that did have problems a very few people reported it when non estrogenic drugs were used. Of those we need to take into account a lot of them probably couldn't recognize gyno and were overreacting.

Nonetheless, reports of this nature have been around for a long time and continue to persist, begging us to ask the question over and over if there is a factor we are overlooking. Here I would like to present two.

Case number 1 : The appearance of estrogenic effects with Testosterone in aromatase negative mice (Ishikawa et al, 2005). This study reported the presence of estrogenic effects in the absence of aromatization, and this effect was blocked by a 5-alpha-reductase inhibitor. Meaning a metabolite of DHT is acting as an androgen. Since we already know that saturated A-ring steroids with a 3-hydroxyl group act as estrogens since 5AD is a every potent estrogen, the likely culprits include the neuroactive steroids 3alpha and 3beta androstanediol. Steckelbroeck et al (2004) demonstrated that 5beta-androstanediol is indeed and ER ligand. Now your question will likely be what the relevance of this is to gyno. Its likely less active than estrogens themselves. This is true, but estrogens are produced by aromatase and dumped into circulation and have to make their way to mammary tissue. Mammary tissue itself contains no aromatase. 3beta-androstanediol is produced by AKR1C, and this gene is expressed directly in mammary tissue, leading to direct local conversion if DHT is present in the tissue. 5AR is also present in mammary tissue. This means despite weaker activity, the presence of the product in the tissue is likely higher.

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. This also opens the door for ER binding of 3beta derivatives of other A-ring saturated androgens. They can be treated with SERMS.

Another important issue pointed out in that study is that unlike the 3-alpha isomer, 3-beta hydroxyl are NOT converted back to DHT.

CASE 2 : the binding of Androgen receptor to estrogen response elements induced by certain ligands. I won't go into detail on this too much as I know I adressed this before. For nandrolone it has been demonstrated that it can bind the AR and cause the AR to activate estrogen-responsive genes. Nandrolone is 60% as estrogenic as estradiol itself and Aromatase inhibitors and ER-blockers and RU486 did not significantly change that number, showing that nandrolone's strong estrogenic effects are caused entirely by the androgen receptor.

Natural nandrolone is a by-product of aromatisation. Likely other 19-Nor-3-oxo steroids are capable of inducing a similar change, to a different extent.

This effect, which is androgen receptor mediated, cannot be blocked by either aromatase or SERMS.

Good things come to those who weight.

The Big Cat is a researcher and theoreticist. His advice must never be taken in the stead of proper advice from a medical professional, it is entirely intended for research purposes.


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D-Termined
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Thank You BC,

Whenever I have to read a post a minimum of 5 times to understand it, I consider it a NANDI worthy post,

Thanks Bro, good info


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liftsiron
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Very interesting and very well written.

liftsiron is a fictional character and should be taken as such.


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D-Termined
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Posted by: liftsiron
very well written.

Yes it was well written... I'm just no where near the intelligence of you guys about this kind of thing, thought I was, but upon returning to the boards, I feel like a dumb ass again, so.. therefore it takes me 5 times to understand a sentence like,

"A-ring steroids with a 3-hydroxyl group act as estrogens since 5AD is a every potent estrogen, the likely culprits include the neuroactive steroids 3alpha and 3beta androstanediol"

Sorry to insinuate that it was tough to read, just tough, for me, lol


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Big Cat
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Posted by: D-Termined
Yes it was well written... I'm just no where near the intelligence of you guys about this kind of thing, thought I was, but upon returning to the boards, I feel like a dumb ass again, so.. therefore it takes me 5 times to understand a sentence like,

"A-ring steroids with a 3-hydroxyl group act as estrogens since 5AD is a every potent estrogen, the likely culprits include the neuroactive steroids 3alpha and 3beta androstanediol"

Sorry to insinuate that it was tough to read, just tough, for me, lol

That's just the only way to put it down accurately and concisely. If you don't understand something you should always feel free to ask, the idea is that you come away with as much as you can from the board.

Good things come to those who weight.

The Big Cat is a researcher and theoreticist. His advice must never be taken in the stead of proper advice from a medical professional, it is entirely intended for research purposes.


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

Posted by: Big Cat
Nandrolone is 60% as estrogenic as estradiol itself and Aromatase inhibitors and ER-blockers and RU486 did not significantly change that number, showing that nandrolone's strong estrogenic effects are caused entirely by the androgen receptor.

Natural nandrolone is a by-product of aromatisation. Likely other 19-Nor-3-oxo steroids are capable of inducing a similar change, to a different extent.

This effect, which is androgen receptor mediated, cannot be blocked by either aromatase or SERMS.

Very interesting indeed.

Would tren be similar to nandrolone in this way? Since there are reports of gyno from use of tren?


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

Posted by: Dizzy
Very interesting indeed.

Would tren be similar to nandrolone in this way? Since there are reports of gyno from use of tren?

No evidence to support that, and estrogenic problems with Tren Are far more rare than with nandrolone, but it remains a possibility that this is a characteristic of 19-Nor steroids. Methyltrienolone for example has been shown to cause segmentation of the 12th helix of the AR ligand binding domain, responsible for Class I co-activator recruitment. That could explain such differential effects, in which case it does seem plausible for trenbolone as well.

Good things come to those who weight.

The Big Cat is a researcher and theoreticist. His advice must never be taken in the stead of proper advice from a medical professional, it is entirely intended for research purposes.


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

Posted by: Big Cat
Case number 1 : The appearance of estrogenic effects with testosterone in aromatase negative mice (Ishikawa et al, 2005). This study reported the presence of estrogenic effects in the absence of aromatization, and this effect was blocked by a 5-alpha-reductase inhibitor. Meaning a metabolite of DHT is acting as an androgen. Since we already know that saturated A-ring steroids with a 3-hydroxyl group act as estrogens since 5AD is a every potent estrogen, the likely culprits include the neuroactive steroids 3alpha and 3beta androstanediol. Steckelbroeck et al (2004) demonstrated that 5beta-androstanediol is indeed and ER ligand. Now your question will likely be what the relevance of this is to gyno. Its likely less active than estrogens themselves. This is true, but estrogens are produced by aromatase and dumped into circulation and have to make their way to mammary tissue. Mammary tissue itself contains no aromatase. 3beta-androstanediol is produced by AKR1C, and this gene is expressed directly in mammary tissue, leading to direct local conversion if DHT is present in the tissue. 5AR is also present in mammary tissue. This means despite weaker activity, the presence of the product in the tissue is likely higher.

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. This also opens the door for ER binding of 3beta derivatives of other A-ring saturated androgens. They can be treated with SERMS.

Another important issue pointed out in that study is that unlike the 3-alpha isomer, 3-beta hydroxyl are NOT converted back to DHT.

CASE 2 : the binding of Androgen receptor to estrogen response elements induced by certain ligands. I won't go into detail on this too much as I know I adressed this before. For nandrolone it has been demonstrated that it can bind the AR and cause the AR to activate estrogen-responsive genes. Nandrolone is 60% as estrogenic as estradiol itself and Aromatase inhibitors and ER-blockers and RU486 did not significantly change that number, showing that nandrolone's strong estrogenic effects are caused entirely by the androgen receptor.

Natural nandrolone is a by-product of aromatisation. Likely other 19-Nor-3-oxo steroids are capable of inducing a similar change, to a different extent.

This effect, which is androgen receptor mediated, cannot be blocked by either aromatase or SERMS.

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.

Please excuse my ignorance but you said to ask.

Does this mean that using a 5-alpha-reductase inhibitor like finasteride would make estrogenics effects worse when on a cycle???

W.


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

Posted by: Wheelies
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.

Please excuse my ignorance but you said to ask.

Does this mean that using a 5-alpha-reductase inhibitor like finasteride would make estrogenics effects worse when on a cycle???

W.

That wasn't implied in the piece you quoted, but yes, use of finasteride tends to increase estrogenic problems, since it increases the substrate for the aromatase enzyme.

What was implied is that the reverse is true too, that blocking aromatase increases substrate for 5AR and ARKC1 in breast tissue and can cause the very same thing.

Good things come to those who weight.

The Big Cat is a researcher and theoreticist. His advice must never be taken in the stead of proper advice from a medical professional, it is entirely intended for research purposes.


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w_llewellyn
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One thing to point out though. I've had a great deal of experience with both the 3-alpha and 3-beta isomers of androstanediol. Patented them both. Have seen both used in high doses with never any hint of estrogenic effect. If anything, both are strongly anti-estrogenic. This may be one of those situations where an in-vitro study just doesn't relate perfectly to the real world.


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Big Cat
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The aromatase knock-out mice study was not in vitro though. A lot could depend on dose and rate of conversion. As I aptly pointed out for molecules that start from a 5-alpha-3-oxo structure, you'd have a high conversion rate in vivo locally in breast tissue, as opposed to aromatase. One might not see the same concentration increase with direct systemic adminstration of 3-beta-androstanediol (same reason why test is more androgenic in target tissues than just administering DHT).

Why did you use 3-beta anyway ? From what I've seen so far it doesn't convert to DHT at all and has little intrinsic activity, except possibly estrogenic.

Good things come to those who weight.

The Big Cat is a researcher and theoreticist. His advice must never be taken in the stead of proper advice from a medical professional, it is entirely intended for research purposes.


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w_llewellyn
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Posted by: Big Cat
The aromatase knock-out mice study was not in vitro though. A lot could depend on dose and rate of conversion. As I aptly pointed out for molecules that start from a 5-alpha-3-oxo structure, you'd have a high conversion rate in vivo locally in breast tissue, as opposed to aromatase. One might not see the same concentration increase with direct systemic adminstration of 3-beta-androstanediol (same reason why test is more androgenic in target tissues than just administering DHT).

Why did you use 3-beta anyway ? From what I've seen so far it doesn't convert to DHT at all and has little intrinsic activity, except possibly estrogenic.

The 3-beta was the first one, mainly due to availability. I soon after was able to have the alpha isomer synthesized, and it was indeed much more potent. That is the only thing I sold through Molecular. There definitely was something to that 3-beta though. A ton of people used it with decent effect; usually providing a harder/dryer look. I can tell you for certain that if it may be estrogenic on paper, it definitely was not in practice; many people were taking 1 gram or more per day, and if anything it was proving to be anti-estrogenic.


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guijr
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Just wondering if one of your clients had done any blood work confirming lower E2 levels while on the aforementioned supplements?

"The medals don't mean anything and the glory doesn't last. It's all about your happiness. The rewards are going to come, but my happiness is just loving the sport and having fun performing" ~ Jackie Joyner Kersee.


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Big Cat
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Posted by: w_llewellyn
The 3-beta was the first one, mainly due to availability. I soon after was able to have the alpha isomer synthesized, and it was indeed much more potent. That is the only thing I sold through Molecular. There definitely was something to that 3-beta though. A ton of people used it with decent effect; usually providing a harder/dryer look. I can tell you for certain that if it may be estrogenic on paper, it definitely was not in practice; many people were taking 1 gram or more per day, and if anything it was proving to be anti-estrogenic.

Of course use of double hydroxylated substances in an oral fashion would lead to quick glucuronidation and secretion, poor uptake in the cells, and the eventual bloodborne concentration, let alone in estrogenic target tissues would be relatively low, even with consumption of 1 gram.

If an effect was obtained it would imply intrinsic anabolic activity, as it seems most tissues cannot convert the 3beta back to 3-oxo. Perhaps the liver can though, which could explain possible effect of oral consumption. intrinsic activity, as well as DHT mediated anabolic activity seem less likely. To refer to the ojasoo and raynaud study again, they have low affinity for the AR, and the DHT would be reduced to 3-alpha in muscle.

Good things come to those who weight.

The Big Cat is a researcher and theoreticist. His advice must never be taken in the stead of proper advice from a medical professional, it is entirely intended for research purposes.


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

quote:


Mammary tissue itself contains no aromatase


Aromatase is present at least in breast adipose tissues, and is a source of local estrogen production in breast tissues.
It's well documented in studies about the treatment of breast cancer.


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