From where do Anadrol's apparent "gynecomastic" effects originate?

[Type-IIx]

Interesting question, from where do oxymetholone's ostensible "gynecomastic" sides arise?
1. Tendency to increase 17-OHP, a "weak" progestin
2. Potential ER-α activation potency of 17α-methyl-5α-androstane-3α,17β-diol (also a methyltestosterone metabolite)
3. Potential for MR agonism?
4. Potential activation of RAAS?

On 1: Debatable. Progestins may induce gynecomastia (or more likely, perhaps lactation) by several mechanisms (by increasing sensitivity to estrogens, directly contributing to HPG axis suppression/secondary hypogonadism, estrogens up-regulate PR synthesis, some evidence of PR in some male breast cells, etc.) Conversely, Camerino cites Junkmann and Suchowsky, 1962 that "showed no gestagenic effect" at therapeutic doses. Oxymetholone possesses no direct PR binding: moderately to AR, weakly to ER-α (weaker than oxandrolone and stanozolol) & ER-β in mammalian reporter gene bioassay (Houtman). Likely irrelevance of model (H295R cells; adrenocortical carcinoma cells). This would seem to be a weak or disputable hypothesis...

On 2: A similar testosterone metabolite, 5α-androstane-3β,17β-diol, is a known potent activator of ER-β, and it lacks the 17α-methyl group present in this oxymetholone metabolite (which serves to prolong any anabolic effects via hepatic metabolism, and hinders aromatization of the A-ring; its 17β-OH group would serve to form a strong bond with the C-terminus/carboxy- group of the AR; saturated A-ring & 5α-androstane [hydrophobic backbone; flatness] structure confers considerable anabolic potency; α-oriented 3-OH provides electrochemical properties conducive to eventually binding to the AR's ligand-binding domain [though perhaps not as readily as a 3-keto])). Cursorily, 17α-methyl-5α-androstane-3α,17β-diol would appear to be a good candidate for AR activity.

On 3: Speculatively, oxymetholone may act as an agonist to the MR: increasing aldosterone, thereby increasing sodium retention in the renal tubules. In this sense, Anadrol may act oppositely of Tren in this regard (as methyltrienolone has been demonstrated to act as an antagonist at the MR).

On 4: Speculatively, there is some data that androgens interact with/activate the renin-aldosterone angiotensin system (RAAS). The RAAS regulates water and electrolyte balance, connective tissue cell growth, and the metabolism of loose and dense connective tissue or tissue repair, as well as bone metabolism. Pathologically, it increases vascoconstriction, cardiac hypertrophy, fibrosis (i.e., chronic activation may cause myocardial infarction, fibrosis of the liver).

... Let's explore possibility number 2 more deeply:

Oxymetholone itself is a very weak AR ligand
Fragkaki found Anadrol's AR Κᵢ (dissociation constant) to be so high/RBA too low for measurement! It is proposed that there must be an indirect mechanism of action (e.g., via biotransformation to active compound). This is also consistent with Saartok, demonstrating immeasurably low binding affinity in rat & rabbit muscle, human SHBG; but higher binding affinities for some DHT metabolites bearing some structural similarity to oxymetholone's principal active metabolite...

Metabolism
Schanzer hypothesizes that oxymetholone likely acts as a prohormone to its more active metabolites that cursorily seem to possess AR activity.

17α-methyl-5α-androstane-3α,17β-diol (Oxymetholone's active metabolite)
- Decent bioavailability (0.55)
- Druglikeness profound
- GI absorption high
- BBB permeant
- Moderately soluble
- Lipophilicity: Consensus Log Po/w 3.55


(Truncated, Summary)

The data is interesting: it does appear that oxymetholone likely acts as a prohormone to this active compound. If anyone has any data quantifying 17α-methyl-5α-androstane-3α,17β-diol's potency to activate AR, ER, GR, MR in, for example, a luciferase assay, I would be most interested!

 

[hometeam]

From a personal observation, when I take it together with tren it worsens gyno issues more than either alone. And we don't know a lot about how it creates anabolism other than not so much with the androgen receptor, which allows it to complement tren because tren is a strong AR ligand, but I think it's probably working on that progesterone receptor more than we'd like. And that might be why it's so potent.

But if its metabolite is working on the AR receptor that would make sense. But if that were the case you'd probably see enlarged prostates in the rat studies and virulizing side effects when used for anemia and osteoporosis.

It's interesting that aldosterone causes gyno though. Apparently gyno is occasionally caused by blood pressure meds like diltiazem and diuretics like spironolactone which increase aldosterone. But if that was going on with anadrol to a degree it would cause gyno, wouldn't we see lower blood pressure instead of higher blood pressure? And wouldn't we see dehydration instead of water retention?

 

[Type-IIx]

From a personal observation, when I take it together with tren it worsens gyno issues more than either alone. And we don't know a lot about how it creates anabolism other than not so much with the androgen receptor, which allows it to complement tren because tren is a strong AR ligand, but I think it's probably working on that progesterone receptor more than we'd like. And that might be why it's so potent.

But if its metabolite is working on the AR receptor that would make sense. But if that were the case you'd probably see enlarged prostates in the rat studies and virulizing side effects when used for anemia and osteoporosis.

It's interesting that aldosterone causes gyno though. Apparently gyno is occasionally caused by blood pressure meds like diltiazem and diuretics like spironolactone which increase aldosterone. But if that was going on with anadrol to a degree it would cause gyno, wouldn't we see lower blood pressure instead of higher blood pressure? And wouldn't we see dehydration instead of water retention?

Oh, RAAS activation would be more associated with fluid retention rather than gynecomastia. Not clear as presented (this was originally under a heading of Fluid retention).

Also, it's quite possible a fair amount of the 5α-androstanes' anabolism derives from ER-β activation (involved in tissue remodeling).

Still, this active metabolite seems to principally be an AR ligand with some affinity for the other nuclear receptors. This is an abbreviated table, some of the lower probability interactions include other nuclear receptors.

 

[Alphalfa]

Great article, like always,a pleasure to read your conclusions and how you detailedly explain everything.

Based on the following table @PeterBond posted on the thread:

Do Nandrolone metabolites have a large impact on natural recovery?

While its commonly known that deca is a very long estered compound and takes forever to clear out of your system. I've read and heard about how the metabolites of the nandrolone can be detectable in your system for up to 18 months after your last dosage. While I know the politically correct...

thinksteroids.com

On 2: A similar testosterone metabolite, 5α-androstane-3β,17β-diol, is a known potent activator of ER-β, and it lacks the 17α-methyl group present in this oxymetholone metabolite (which serves to prolong any anabolic effects via hepatic metabolism

Also, it's quite possible a fair amount of the 5α-androstanes' anabolism derives from ER-β activation (involved in tissue remodeling).

Indeed, the 3β, it is 10 times more potent to the ERb receptor than the 3α, but to that point to cause anabolism via this pathway? Obviously it is a relative comparison potency to activation of E2=1 to the ER.
The 3α version without the 17α-methyl is 47%more potent than the 3β on the AR, so since you said the 17α-methyl version of the oxy metabolite is responsible of the prolonged anabolic effect, it will probably increase heavily the potency on the AR compared to the non 17α-methyl metabolite which is already way more potent than the 3β metabolite.

17α-methyl-5α-androstane-3α,17β-diol (Oxymetholone's active metabolite)

Still, this active metabolite seems to principally be an AR ligand with some affinity for the other nuclear receptors.

(Truncated, Summary)

Where does this table come from if I could know? What paper/study?
The 17α-methyl group deffo hugely increased their biding to AR and ER-α/β, comparing to the non-17α-methyl, although I guess both tables cannot compare since one indicates relative potency vs binding affinity.

 

[Type-IIx]

Great article, like always,a pleasure to read your conclusions and how you detailedly explain everything.

Based on the following table @PeterBond posted on the thread:

Do Nandrolone metabolites have a large impact on natural recovery?

While its commonly known that deca is a very long estered compound and takes forever to clear out of your system. I've read and heard about how the metabolites of the nandrolone can be detectable in your system for up to 18 months after your last dosage. While I know the politically correct...

thinksteroids.com

Indeed, the 3β, it is 10 times more potent to the ERb receptor than the 3α, but to that point to cause anabolism via this pathway? Obviously it is a relative comparison potency to activation of E2=1 to the ER.
The 3α version without the 17α-methyl is 47%more potent than the 3β on the AR, so since you said the 17α-methyl version of the oxy metabolite is responsible of the prolonged anabolic effect, it will probably increase heavily the potency on the AR compared to the non 17α-methyl metabolite which is already way more potent than the 3β metabolite.

Interestingly, I suspect that yes - this level of potency likely is sufficient to be anabolic via ER-β. Note that E2 is particulary potent at activating ER-β. We know that ecdysterone is anabolic, likely via its action at ER-β.

It's difficult to compare such heterogeneous data, but we might be able to say that 5α-androstane-3β,17β-diol has sufficient relative potency (0.0054) vs E2 to induce some muscle anabolism via ER-β.

Here is some data from my notes:
E₂ (estradiol) is a potent ligand for ER-β. Its rate of dissociation (κd) for this receptor is 2.08 nM in humans. Its rate of dissociation (κd) for ER-α, by comparison, is 0.24 nM in humans.

EC₅₀ (EC50) of E₂ (estradiol) at ER-β (-beta) is 8.66 x 10⁻¹¹ M. At ER-α this value is 5.66 x 10⁻¹¹ M.

EC₅₀ (EC50) of Ecdy (ecdysterone; 20E; 20-HE) at ER-β is 1.30 x 10⁻⁸ M and at ER-α this value is 2.57 x 10⁻⁸ M

(HEK293 cells)

So even with differences in EC50's to orders of magnitude, Ecdy is a known potent activator of ER-β, and at least most of its muscle anabolism (bear in mind, its lack of efficacy in humans is due to short biological half life and poor bioavailability) indicates that, perhaps, active metabolites like those of T, DHT & the 5α-androstan-3-ones, derive some human skeletal muscle anabolism via ER-β (though this is certainly secondary to AR-mediated effects).

Where does this table come from if I could know? What paper/study?
The 17α-methyl group deffo hugely increased their biding to AR and ER-α/β, comparing to the non-17α-methyl, although I guess both tables cannot compare since one indicates relative potency vs binding affinity.

So this isn't from a study actually, this is from the data produced by modeling in Swiss Target Prediction.

 

[All Nats McGee]

If I’d had to guess it makes you more estrogen sensitive. I’ve always though it’s though progesterone. I know SERMs and mast stop gyno from adrol. Plus the other symptoms of high estrogen are associated with adrol.

 

[jJjburton]

If I’d had to guess it makes you more estrogen sensitive. I’ve always though it’s though progesterone. I know SERMs and mast stop gyno from adrol. Plus the other symptoms of high estrogen are associated with adrol.

Serms are like nolva?

 

[TheRingloVale]

Serms are like nolva?

Yes, SERMS are nolva or raloxifene or clomid

 

[Type-IIx]

If I’d had to guess it makes you more estrogen sensitive. I’ve always though it’s though progesterone. I know SERMs and mast stop gyno from adrol. Plus the other symptoms of high estrogen are associated with adrol.

It's possible that Anadrol increases estrogen sensitivity. The only thing I would add: increased estrogen sensitivity is a sort of black-box concept for something particular, mechanistically, that might explain the increased "sensitivity" to estrogens.

One possibility I've been chatting with Dr. Scott Stevenson about is an oxymetholone effect on phase II metabolism (glucoronidation, conjugation) that might decrease clearance/excretion of estrogens.

My assumption, before delving in: it's likely a very minor mechanism, as I doubt oxymetholone-only increases estrogen concentrations.

But I'll post more about this if people are interested.

It makes sense that SERMs and Masteron (reduces estrogen uptake into breast tissue) reduce gynecomastic symptoms of Anadrol, as: SERMs would attenuate the progestin-induced increase in estrogen sensitivity (via several mechanisms) if the trend increase in 17-OHP is a factor; and, since this principal active metabolite of Anadrol has estrogenic activity, these also would function to decrease 17α-methyl-5α-androstane-3α,17β-diol's potency to activate ER-α in breast tissue.

 

[Type-IIx]

Dr. Stevenson also believes mERs are a likely mechanism for gynecomastic effects of Anadrol. Another thing I'm going to delve into.

 

[Theworm]

So….. nolva should present anadrol related gyno right? So if I was going to add anadrol to end of blast, I should switch from my ai to nolva or add nolva with the ai?

 

[asaly]

@Type-IIx what do you think about anadrols acid metabolites? I read a study whose authors specaulted that these acids may be toxic and potentially teratogenic

I wonder if they can cause gastric problems related to hyperacidity

 

[Type-IIx]

@Type-IIx what do you think about anadrols acid metabolites? I read a study whose authors specaulted that these acids may be toxic and potentially teratogenic

I wonder if they can cause gastric problems related to hyperacidity

You'll have to link me to the study, I haven't read it.

 

[asaly]

You'll have to link me to the study, I haven't read it.

End of that study

Bi H, Du P, Masse R. Studies on anabolic
steroids-8. GC/MS characterization of
unusual seco acidic metabolites of oxy￾metholone in human urine. J Steroid
Biochem Mol Biol. 1992;

 

[Type-IIx]

End of that study

Bi H, Du P, Masse R. Studies on anabolic
steroids-8. GC/MS characterization of
unusual seco acidic metabolites of oxy￾metholone in human urine. J Steroid
Biochem Mol Biol. 1992;

Well, hopefully the teratogenic implications are avoided by oxymetholone's androgenic effects in women, making them unlikely to conceive. Of course, a pregnant woman should never initiate oxymetholone or any androgen.

The formation of seco acidic metabolites is interesting, and may plausibly confer some degree, however minimal, of particular hepatotoxicity to oxymetholone, but as the author's conclude: "[the ]possibility as to whether the seco acidic steroids described herein are associated to the molecular events leading to the hepatic toxicity that may result from oxymetholone administration...since several lipophilic acids have been shown to be teratogenic in human.... However, such a hypothesis is highly speculative, not only because anabolic 17a-methyl steroids in general are hepatotoxic, which is also true for steroids with an unsaturated A-ring, but also because the latter steroids do not form seco-acidic metabolites. This indicates that the formation of seco-acidic steroids from oxymetholone is likely not related to its hepatotoxicity in human."

I'm more curious about what motivated you to peruse the literature for boring oxymetholone metabolism studies like this?

 

[asaly]

I'm more curious about what motivated you to peruse the literature for boring oxymetholone metabolism studies like this?

I like reading advanced studies on the chemistry and mechanisms of steroids, I became interested in the topic of anadrol metabolism by reading Schanzer's work "Metabolism of anabolic androgenic steroids",

I had the idea that acidic metabolites of Anadrol may cause digestive system diseases, but I didnt find any data on this subject.

 

[Type-IIx]

I like reading advanced studies on the chemistry and mechanisms of steroids, I became interested in the topic of anadrol metabolism by reading Schanzer's work "Metabolism of anabolic androgenic steroids",

I had the idea that acidic metabolites of Anadrol may cause digestive system diseases, but I didnt find any data on this subject.

Ah, yes, Schänzer 1996, a seriously important work. Welcome.

 

[Type-IIx]

@asaly - you may find something pertinent here: Androgens and acid reflux, peptic ulcer

 

[asaly]

@asaly - you may find something pertinent here: Androgens and acid reflux, peptic ulcer

I read this like many of your articles before registering here, this text made me associate the acidic metabolites of anadrol with digestive problems

 

[asaly]

@asaly - you may find something pertinent here: Androgens and acid reflux, peptic ulcer

I confused the texts, I meant your other one "Androgens and GERD, gastric reflux and peptic ulcer"