5a-dehydroprogesterone And 3a- Hydroxysteroid Dehydrogenase

[Drareg]

Does anybody know more on this enzyme 3a-HSD?
One of its many functions is To convert 5a-DHP into allopregnenolone. If supplementing 5a-DHP will this not increase this enzyme? Or does it use it up possibly?
SSRI's have been shown to activate it hence the allopregnenolone increase with some SSRI's.

What concerns me is its reversible effects on DHT,does this enzyme not convert DHT to a less potent form in muscle in particular?
The internet is ripe with brah science on it along with the hair loss forums wanting to rub 3a-HSD into the scalp to lower DHT,thyroxine is rumoured to increase it also.

 

[Dante]

Does anybody know more on this enzyme 3a-HSD?


What concerns me is its reversible effects on DHT,does this enzyme not convert DHT to a less potent form in muscle in particular?
The internet is ripe with brah science on it along with the hair loss forums wanting to rub 3a-HSD into the scalp to lower DHT,thyroxine is rumoured to increase it also.

From what i think , you are talking about this metabolite - https://en.wikipedia.org/wiki/3α-Androstanediol
Quoting from the wikipedia - " As a neurosteroid, it acts as a potent positive allosteric modulator of the GABAA receptor,[4] and has been found to haverewarding,[5][6] anxiolytic,[7] pro-sexual,[8] and anticonvulsanteffects.[9][10] As androgens such as testosterone and DHT are known to have many of the same effects as 3α-diol and are converted into it in vivo, it is thought that this compound may in part be responsible for said effects.[5][6][7][10] "
I don't think you need to be concerned about this reversible weaker metabolite. Not all benefits of DHT come from DHT itself binding to the AR. Further downstream metabolites bind to ER's and produce very androgenic-like(anti-anxiety, high cognition, mood boosting etc) effects

Now there is 3-beta HSD (makes proges. from preg. ) and a DHT metabolite 3-beta-diol ( slightly from Hair loss perspective)
The Anticancer Testosterone Metabolite 3β-Adiol - Meridian Valley Lab
3β-Androstanediol - Wikipedia
Now what's is interesting is that 3-beta -diol produces very much DHT like benefits but it has very high binding affinity for the
ER-beta (much more than E2) .Often people write on this forum about - "DHT kicking estrogen out of the cells" - Now i don't know if it really happens but since DHT has no affinity for ER-a or ER-b , i would take a take a guess and say these two metabolites are what displaces E2 and other xenoestrogens,etc. Cocunut oil, zinc, T3, retinoic acid also upregulate 3-beta-HSD.
Also, 3-beta-diol is anti-carcinogenic and pro-differentiating and it's believed that fin/dut inhibition of DHT also decreases this metabolite and hence , increases your chance of getting high gleason score cancer.
Just a guess but either of these or both is impaired at hair follicle level ,hence the buildup of DHT there.

 

[LeeLemonoil]

I agree with Dante`s argument.

Also, it's hard to predict the action of a supplement steroid on your enzyme system. It's partly determined by genetics and undergoes epigenetic changes throughout your lifetime. Differnet individuals will experience very different effects and the enzyme-system is not easily influenced by supplements.
I tend to agree with the thesis of the meridian article, 3ß-diol is a "more important" metabolite than 3alpha. I'd also speculate that 3ß-diol would be more important to hairloss prevention than 3alpha.

 

[Drareg]

Thanks.

 

[haidut]

Does anybody know more on this enzyme 3a-HSD?
One of its many functions is To convert 5a-DHP into allopregnenolone. If supplementing 5a-DHP will this not increase this enzyme? Or does it use it up possibly?
SSRI's have been shown to activate it hence the allopregnenolone increase with some SSRI's.

What concerns me is its reversible effects on DHT,does this enzyme not convert DHT to a less potent form in muscle in particular?
The internet is ripe with brah science on it along with the hair loss forums wanting to rub 3a-HSD into the scalp to lower DHT,thyroxine is rumoured to increase it also.

The 3a-HSD is what converts the 5a-DHP into allopregnanolone, as you said, and it is also responsible for the reversible conversion of DHT into androstanediol as well as androsterone into androstanedione. It is a bi-directional enzyme, it has a reductive and oxidative function. It has been shown that in aging the reductive side of 3a-HSD increases while the oxidative one decreases. This is not surprising since the oxidative side needs NAD as cofactor while the reductive one needs NADH, and the NAD/NADH raio declines with age. Supplementing niacinamide or MB can reverse that pattern.
I would not call 3a-HSD a deactivating enzyme. Reality is much richer than what the simplistic modern endocrinology would have you believe. Some of these "inactive" metabolites of DHT like androstanediol are actually what drives much of the protective effects of DHT observed clinically.
3alpha-androstanediol, but not testosterone, attenuates age-related decrements in cognitive, anxiety, and depressive behavior of male rats. - PubMed - NCBI

Same with androsterone - it may very well be the most pro-thyroid of all androgens and it is considered "inactive" by most endocrinologists. There are no inactive metabolites, if something is truly inactive it gets excreted or stored. If it gets metabolized into something else then it is not inactive and has some kind of role in the health of the organism. If thyroid promotes 3a-HSD activity it should be in indication enough that the steroids it produces are probably very important. In contrast, thyroid inhibits aromatase. Aging and and boredom inhibit while environmental stimulation promotes both 5-AR and 3a-HSD.
Environmental enrichment attenuates the age-related decline in the mRNA expression of steroidogenic enzymes and reduces the methylation state of th... - PubMed - NCBI

 

[Drareg]

The 3a-HSD is what converts the 5a-DHP into allopregnanolone, as you said, and it is also responsible for the reversible conversion of DHT into androstanediol as well as androsterone into androstanedione. It is a bi-directional enzyme, it has a reductive and oxidative function. It has been shown that in aging the reductive side of 3a-HSD increases while the oxidative one decreases. This is not surprising since the oxidative side needs NAD as cofactor while the reductive one needs NADH, and the NAD/NADH raio declines with age. Supplementing niacinamide or MB can reverse that pattern.
I would not call 3a-HSD a deactivating enzyme. Reality is much richer than what the simplistic modern endocrinology would have you believe. Some of these "inactive" metabolites of DHT like androstanediol are actually what drives much of the protective effects of DHT observed clinically.
3alpha-androstanediol, but not testosterone, attenuates age-related decrements in cognitive, anxiety, and depressive behavior of male rats. - PubMed - NCBI

Same with androsterone - it may very well be the most pro-thyroid of all androgens and it is considered "inactive" by most endocrinologists. There are no inactive metabolites, if something is truly inactive it gets excreted or stored. If it gets metabolized into something else then it is not inactive and has some kind of role in the health of the organism. If thyroid promotes 3a-HSD activity it should be in indication enough that the steroids it produces are probably very important. In contrast, thyroid inhibits aromatase. Aging and and boredom inhibit while environmental stimulation promotes both 5-AR and 3a-HSD.
Environmental enrichment attenuates the age-related decline in the mRNA expression of steroidogenic enzymes and reduces the methylation state of th... - PubMed - NCBI

Thanks.
I'm starting to get disillusioned with any research I'm doing when it comes to complex substances such as enzymes,you can't trust anything their saying,it all comes down to perceptions and what they leave out.
The Peat quote recently about SHBG is another example, it's a waste of time to spend time researching said substance if the initial seed of understanding is incorrect or partial.

I'm guessing even 10-20mg niacinamide with androsterone would be enough for positive effect.

 

[haidut]

Thanks.
I'm starting to get disillusioned with any research I'm doing when it comes to complex substances such as enzymes,you can't trust anything their saying,it all comes down to perceptions and what they leave out.
The Peat quote recently about SHBG is another example, it's a waste of time to spend time researching said substance if the initial seed of understanding is incorrect or partial.

I'm guessing even 10-20mg niacinamide with androsterone would be enough for positive effect.

May I ask what Peat said about SHBG?
Yes, any amount of niacinamide would be good but beyond 1g - 1.5g there is probably no further benefit in terms of increased steriodogenesis. See study below. Beyond ~300uM there was no further increase in steroidogenesis.
The activity of 3 beta-hydroxysteroid dehydrogenase and delta 4-5 isomerase in human follicular tissue. - PubMed - NCBI

 

[Drareg]

May I ask what Peat said about SHBG?
Yes, any amount of niacinamide would be good but beyond 1g - 1.5g there is probably no further benefit in terms of increased steriodogenesis. See study below. Beyond ~300uM there was no further increase in steroidogenesis.
The activity of 3 beta-hydroxysteroid dehydrogenase and delta 4-5 isomerase in human follicular tissue. - PubMed - NCBI

I'm mistaken ,It's a quote from @suchsaturation,I don't think anybody asked Peat. Still very interesting.

"Where he bolded the last part of the citation. So it seems he thinks SHBG should be as high as possible to keep estrogen out of cells, and that it actually enters cells when it is unloaded, unlike albumin. He doesn't say anything about androgens on SHBG but if he claims it's less lipophilic when loaded with estrogen, I don't see why he wouldn't say it becomes more lipophilic when it's loaded with androgens."

From this thread-
Maximise Your Free Testosterone Levels

 

[haidut]

I'm mistaken ,It's a quote from @suchsaturation,I don't think anybody asked Peat. Still very interesting.

"Where he bolded the last part of the citation. So it seems he thinks SHBG should be as high as possible to keep estrogen out of cells, and that it actually enters cells when it is unloaded, unlike albumin. He doesn't say anything about androgens on SHBG but if he claims it's less lipophilic when loaded with estrogen, I don't see why he wouldn't say it becomes more lipophilic when it's loaded with androgens."

From this thread-
Maximise Your Free Testosterone Levels

Thanks. Matches my understanding as well. I never understood the idea of free vs. bound steroid. For example, progesterone can knock cortisol out of the carrier protein transcortin and that makes cortisol LESS bioavailable to the cell and accelerates its excretion. Why the same idea is not extended to the other steroids like androgens and estrogens - i.e. protein-bound steroids are the ones that matter and not the free ones - is beyond me. I have asked endocrinologist and have gotten blank stares and answers along the likes of "well, that's how we learned it works in medical school". But then again, hypothyroidism is diagnosed by measuring TSH and total T4 and T3 and not by free T3/T4. So, the total steroid levels do matter. However, for which steroids it matters and for which it does not is beyond the knowledge of most encrocrinologists and they blindly follow dogma instead.

 

[Dante]

The 3a-HSD is what converts the 5a-DHP into allopregnanolone, as you said, and it is also responsible for the reversible conversion of DHT into androstanediol as well as androsterone into androstanedione. It is a bi-directional enzyme, it has a reductive and oxidative function. It has been shown that in aging the reductive side of 3a-HSD increases while the oxidative one decreases. This is not surprising since the oxidative side needs NAD as cofactor while the reductive one needs NADH, and the NAD/NADH raio declines with age. Supplementing niacinamide or MB can reverse that pattern.

As always, respect. Now The bolded lines become very important from MPB point of view. I would not be surprised if the enzyme 3a-HSD(at the follicle level) is somehow towards its reductive side while 3b-HSD is also impaired (due to lack of thyroid,NAD+,other factors etc) ,hence the buildup of DHT there simply because it is not getting properly broken down into further metabolites.
I have read some odd reports on MB regrowing hair back. There was a user BenjaminButton who literally changed from near Norwood 4 to somewhere near Norwood 3 after adding thyroid and sugar. Does topical niacinamide also help ? However , he also got a massive shed while taking androsterone. So, does taking androsterone could exert a negative feedback loop on the 3a-HSD or deplete NAD+ or something like that? (BTW small amounts of estradiol is also needed for hair growth especially in the anagen phase if i remember but i guess you already know this)

 

[Koveras]

I'm mistaken ,It's a quote from @suchsaturation,I don't think anybody asked Peat. Still very interesting.

"Where he bolded the last part of the citation. So it seems he thinks SHBG should be as high as possible to keep estrogen out of cells, and that it actually enters cells when it is unloaded, unlike albumin. He doesn't say anything about androgens on SHBG but if he claims it's less lipophilic when loaded with estrogen, I don't see why he wouldn't say it becomes more lipophilic when it's loaded with androgens."

From this thread-
Maximise Your Free Testosterone Levels

Thanks. Matches my understanding as well. I never understood the idea of free vs. bound steroid. For example, progesterone can knock cortisol out of the carrier protein transcortin and that makes cortisol LESS bioavailable to the cell and accelerates its excretion. Why the same idea is not extended to the other steroids like androgens and estrogens - i.e. protein-bound steroids are the ones that matter and not the free ones - is beyond me. I have asked endocrinologist and have gotten blank stares and answers along the likes of "well, that's how we learned it works in medical school". But then again, hypothyroidism is diagnosed by measuring TSH and total T4 and T3 and not by free T3/T4. So, the total steroid levels do matter. However, for which steroids it matters and for which it does not is beyond the knowledge of most encrocrinologists and they blindly follow dogma instead.

Sex Hormone Binding Globulin Modifies Testosterone Action and Metabolism in Prostate Cancer Cells

"Sex Hormone Binding Globulin (SHBG) is the major serum carrier of sex hormones. However, growing evidence suggests that SHBG is internalised and plays a role in regulating intracellular hormone action. This study was to determine whether SHBG plays a role in testosterone uptake, metabolism, and action in the androgen sensitive LNCaP prostate cancer cell line. Internalisation of SHBG and testosterone, the effects of SHBG on testosterone uptake, metabolism, regulation of androgen responsive genes, and cell growth were assessed. LNCaP cells internalised SHBG by a testosterone independent process. Testosterone was rapidly taken up and effluxed as testosterone-glucuronide; however this effect was reduced by the presence of SHBG. Addition of SHBG, rather than reducing testosterone bioavailability, further increased testosterone-induced expression of prostate specific antigen and enhanced testosterone-induced reduction of androgen receptor mRNA expression. Following 38 hours of testosterone treatment cell morphology changed and growth declined; however, cotreatment with SHBG abrogated these inhibitory effects. These findings clearly demonstrate that internalised SHBG plays an important regulatory and intracellular role in modifying testosterone action and this has important implications for the role of SHBG in health and disease."

 

[Dante]

Sex Hormone Binding Globulin Modifies Testosterone Action and Metabolism in Prostate Cancer Cells

"Sex Hormone Binding Globulin (SHBG) is the major serum carrier of sex hormones. However, growing evidence suggests that SHBG is internalised and plays a role in regulating intracellular hormone action. This study was to determine whether SHBG plays a role in testosterone uptake, metabolism, and action in the androgen sensitive LNCaP prostate cancer cell line. Internalisation of SHBG and testosterone, the effects of SHBG on testosterone uptake, metabolism, regulation of androgen responsive genes, and cell growth were assessed. LNCaP cells internalised SHBG by a testosterone independent process. Testosterone was rapidly taken up and effluxed as testosterone-glucuronide; however this effect was reduced by the presence of SHBG. Addition of SHBG, rather than reducing testosterone bioavailability, further increased testosterone-induced expression of prostate specific antigen and enhanced testosterone-induced reduction of androgen receptor mRNA expression. Following 38 hours of testosterone treatment cell morphology changed and growth declined; however, cotreatment with SHBG abrogated these inhibitory effects. These findings clearly demonstrate that internalised SHBG plays an important regulatory and intracellular role in modifying testosterone action and this has important implications for the role of SHBG in health and disease."

haidut once posted a study that estradiol.SHBG complex can activate the AR and hence cause worsening of PCa. Neither estradiol nor SHBG activated AR but their combo did

 

[LeeLemonoil]

My huch is that SHGB or parts of it transport sulfated steroids into the cells wich are otherwise not very lipophillic. Please look up the recently discussed study here about http://www.biomed.cas.cz/physiolres/pdf/64 Suppl 2/64_S275.pdf steroid leve measurements in men with affectiv diorders vs control.

though SHGB levels were not different when corrected by ANOVA-factors, the tendency is clear that healthy control has much lower SHGB levels while deprssive men have the highest. Th study also gives a strong indictaion that sulfated steroids play a major role in neurological health, maybe even "more" so than unconjugated ...
It's an interesting aspect, and one where "we" are probably on a very important trail much different than conventional medical knwoledge.

3ß-diol can be coverted too into DHT, but in very smal quantities only. there was a very new Nature review about it, I'll dig it up next wekk ... 3ß-diol is something pivotal in a healthy male endo-situation, mch more so than 3a - a certain ratio that is.

 

[Drareg]

This is why it's essential to not neglect "experience" as the true method of knowledge,studies help but should not stop people from acting,there is obvious risk as with anything.
Most of the positive reports from substances lowering SHBG could be from other effects they have on estrogen,nettle root for example.

 

[Dante]

Turns out i am completely wrong, MPB keeps confusing me. I thought 3b-HSD activity must be downregulated in balding areas but i am quite wrong i guess.
delta 5-3 beta-hydroxysteroid dehydrogenase activity in sebaceous glands of scalp in male-pattern baldness. - PubMed - NCBI
Quoting from the text - " Sebaceous glands were isolated by manual dissection using a stereomicroscope from skin specimens of bald scalp of men with male-pattern baldness undergoing hair transplant or scalp reduction surgery and also from specimens taken from hairy and bald areas of scalp at autopsy of adult male victims of accidental death within 3 h post mortem
Since substantial 3 beta HSD activity was present in the cytosol, and cytosol of Balding glands showed increased 3 beta HSD activity, the increased conversion of DHA to AD may be a critical step for androgenic action and may be responsible for excessive androgenicity in male-pattern baldness"
Regional scalp differences of the androgenic metabolic pattern in subjects affected by male pattern baldness. - PubMed - NCBI
This study showed that while DHT activity was higher in balding areas but 3-beta diol was the predominant metabolite in balding areas.
The greater formation of beta DIOL in the sebaceous glands-enriched alopecic skin supports the hypothesis for a specific role of this metabolite in the control of the sebaceous activity

 

[Drareg]

Turns out i am completely wrong, MPB keeps confusing me. I thought 3b-HSD activity must be downregulated in balding areas but i am quite wrong i guess.
delta 5-3 beta-hydroxysteroid dehydrogenase activity in sebaceous glands of scalp in male-pattern baldness. - PubMed - NCBI
Quoting from the text - " Sebaceous glands were isolated by manual dissection using a stereomicroscope from skin specimens of bald scalp of men with male-pattern baldness undergoing hair transplant or scalp reduction surgery and also from specimens taken from hairy and bald areas of scalp at autopsy of adult male victims of accidental death within 3 h post mortem
Since substantial 3 beta HSD activity was present in the cytosol, and cytosol of Balding glands showed increased 3 beta HSD activity, the increased conversion of DHA to AD may be a critical step for androgenic action and may be responsible for excessive androgenicity in male-pattern baldness"
Regional scalp differences of the androgenic metabolic pattern in subjects affected by male pattern baldness. - PubMed - NCBI
This study showed that while DHT activity was higher in balding areas but 3-beta diol was the predominant metabolite in balding areas.
The greater formation of beta DIOL in the sebaceous glands-enriched alopecic skin supports the hypothesis for a specific role of this metabolite in the control of the sebaceous activity

Is it possible its displacing DHT hence the reason for DHT build up,not all DHT gets converted to lesser forms immedietaly?

 

[PUTFOT]

"Where he bolded the last part of the citation. So it seems he thinks SHBG should be as high as possible to keep estrogen out of cells, and that it actually enters cells when it is unloaded, unlike albumin. He doesn't say anything about androgens on SHBG but if he claims it's less lipophilic when loaded with estrogen, I don't see why he wouldn't say it becomes more lipophilic when it's loaded with androgens."

If Ray thinks SHBG should be kept high, why does he recommend sugar? Sugar strongly lowers SHBG. Monosaccharide-induced lipogenesis regulates the human hepatic sex hormone-binding globulin gene. - PubMed - NCBI

 

[haidut]

Addition of SHBG, rather than reducing testosterone bioavailability, further increased testosterone-induced expression of prostate specific antigen and enhanced testosterone-induced reduction of androgen receptor mRNA expression. Following 38 hours of testosterone treatment cell morphology changed and growth declined; however, cotreatment with SHBG abrogated these inhibitory effects. These findings clearly demonstrate that internalised SHBG plays an important regulatory and intracellular role in modifying testosterone action and this has important implications for the role of SHBG in health and disease

Thanks for this! I think the part above should be bolded in your quote as it is quite important. Most people will just skip the post without even blinking unless there is some emphasis to draw their attention to it.

 

[Drareg]

If Ray thinks SHBG should be kept high, why does he recommend sugar? Sugar strongly lowers SHBG. Monosaccharide-induced lipogenesis regulates the human hepatic sex hormone-binding globulin gene. - PubMed - NCBI

I'm guessing he understands SHBG is far more dynamic than what the main stream currently think,this is what we are discussing here and in the other thread I linked.

 

[Dante]

Is it possible its displacing DHT hence the reason for DHT build up,not all DHT gets converted to lesser forms immedietaly?

Sorry i did not understand but what exactly does displacing DHT mean here(displacing from what)?