TRT Effect on 5 Alpha Reductase and Upstream Hormones- Cause of Low Mood and Anxiety?

[SSHSSA74]

I can attest to hCG seemingly having a critical threshold that needs to be achieved for full benefit. Although I did feel better taking 100-140iu’s daily than not taking it, and my new protocol’s still just a week in, taking 350-500iu’s close to EOD is a different ball game so far. Did 350 Monday and Wednesday and 500 on Friday since I’d be picking up again on Monday. Still injecting test daily.

Started Pregnenolone cream last night at 50mg as well. That had me feeling very calm and drowsy in a pleasant way, and I’m still very calm now the day after.

For full disclosure, I’m also usually on 250-333iu’s of BPC-157 once or twice a day, 2iu’s of HGH 4x a week, and 1 grain of NDT in the morning and 50mcg T4 daily at night. I have gut issues and BPC knocks those out within a week.

A different ball game in what regard?

 

[Nelson Vergel]

Hey guys....this thread is 5 pages long. Unless you are sharing info on pregnenolone, please start a new thread. Thanks

 

[Charliebizz]

Hey guys....this thread is 5 pages long. Unless you are sharing info on pregnenolone, please start a new thread. Thanks

Great thread!! Anyone have anymore to share since last post in August??

 

[Anonymon]

Great thread!! Anyone have anymore to share since last post in August??

I’ve been playing around with different protocols and mixes outside of test, as for me that stays constant. Had some good results with 200-300mg of pregnenolone pills in the morning alongside my 50mg preg cream and 25mg progesterone cream, alongside my 750iu-ish HCG 3x a week.

 

[Gianluca]

I’ve been playing around with different protocols and mixes outside of test, as for me that stays constant. Had some good results with 200-300mg of pregnenolone pills in the morning alongside my 50mg preg cream and 25mg progesterone cream, alongside my 750iu-ish HCG 3x a week.

wow, that's a good dose of Pregnenolone. I'm experimenting now with Progesterone cream at night 12.5mg and Pregnenolone cream in the am 25mg, building up dose first with Progesterone to achieve normal serum levels, then Pregnenolone symptomatically.

Why are you using cream and capsules of Pregnenolone? i did the same in the past, my rationale to use caps along with the cream was to raise Progesterone levels

 

[Anonymon]

wow, that's a good dose of Pregnenolone. I'm experimenting now with Progesterone cream at night 12.5mg and Pregnenolone cream in the am 25mg, building up dose first with Progesterone to achieve normal serum levels, then Pregnenolone symptomatically.

Why are you using cream and capsules of Pregnenolone? i did the same in the past, my rationale to use caps along with the cream was to raise Progesterone levels

I originally came into all this after Finasteride, and the cream likely helps with mood because of the higher AR content of the skin. I also have issues with lower cortisol, however, so I figured it had less of a chance to help with that. So far the capsules actually has seemed to help with that, and without the downsides of taking Hydrocortisone or Cortisone Acetate.

I’d tried 100mg of it for a while and it was okay, but 200mg was a lot better, so I jumped into 300mg since a lot of the studies on guys were at 500mg and 300mg’s worth is something I’m comfortable affording at the price I get it at.

I used to do progesterone cream at night and it was calming. I use them all in the morning now with the hope it’ll all help more with cortisol. Tried progesterone on the scrotum at 50mg and that mostly made me angry.

At 50mg of the preg cream and 25-50mg of the progesterone cream, my progesterone level was a little bit high on the lab scale I went with, and my pregnenolone levels were still near the bottom of the range. Also on 750iu’s of HCG 3 x a week.

 

[Gman86]

I originally came into all this after Finasteride, and the cream likely helps with mood because of the higher AR content of the skin. I also have issues with lower cortisol, however, so I figured it had less of a chance to help with that. So far the capsules actually has seemed to help with that, and without the downsides of taking Hydrocortisone or Cortisone Acetate.

I’d tried 100mg of it for a while and it was okay, but 200mg was a lot better, so I jumped into 300mg since a lot of the studies on guys were at 500mg and 300mg’s worth is something I’m comfortable affording at the price I get it at.

I used to do progesterone cream at night and it was calming. I use them all in the morning now with the hope it’ll all help more with cortisol. Tried progesterone on the scrotum at 50mg and that mostly made me angry.

At 50mg of the preg cream and 25-50mg of the progesterone cream, my progesterone level was a little bit high on the lab scale I went with, and my pregnenolone levels were still near the bottom of the range. Also on 750iu’s of HCG 3 x a week.

So what are u currently doing in regards to progesterone, just one capsule in the morning? How many mgs are u currently taking in capsule form?

Have u had ur cortisol levels checked while on the prog capsules?

Have u heard or read that oral prog increases cortisol more than other forms? I’m currently using injectable prog at night, but also have low cortisol, so I’m jc if oral is the preferred form to raise cortisol levels

Have u researched sorghum? It increases 5ar activity, and seems to be pretty popular with guys suffering from post finasteride syndrome

 

[Gianluca]

I originally came into all this after Finasteride, and the cream likely helps with mood because of the higher AR content of the skin. I also have issues with lower cortisol, however, so I figured it had less of a chance to help with that. So far the capsules actually has seemed to help with that, and without the downsides of taking Hydrocortisone or Cortisone Acetate.

I’d tried 100mg of it for a while and it was okay, but 200mg was a lot better, so I jumped into 300mg since a lot of the studies on guys were at 500mg and 300mg’s worth is something I’m comfortable affording at the price I get it at.

I used to do progesterone cream at night and it was calming. I use them all in the morning now with the hope it’ll all help more with cortisol. Tried progesterone on the scrotum at 50mg and that mostly made me angry.

At 50mg of the preg cream and 25-50mg of the progesterone cream, my progesterone level was a little bit high on the lab scale I went with, and my pregnenolone levels were still near the bottom of the range. Also on 750iu’s of HCG 3 x a week.

Historically, I had lower Pm cortisol and I used Hydrocortisone before, between Pregnenolone capsule or cream, the latter seemed to have a similar effect to taking straight hydrocortisone.

According to some studies attached to a wiki link, Pregnenolone cream preferably converts into Cortisol and DHEA, whereas the capsule converts mainly into Progesterone/Allopregnenolone, but less into Cortisol/DHEA. But we are all different, as in your case capsule did a better job for Cortisol. I can attest it is more difficult to increase Pregnenolone levels with a cream, capsule did a better job for that in my case as well.

Pregnenolone (medication) - Wikipedia

en.wikipedia.org

 

[Anonymon]

Historically, I had lower Pm cortisol and I used Hydrocortisone before, between Pregnenolone capsule or cream, the latter seemed to have a similar effect to taking straight hydrocortisone.

According to some studies attached to a wiki link, Pregnenolone cream preferably converts into Cortisol and DHEA, whereas the capsule converts mainly into Progesterone/Allopregnenolone, but less into Cortisol/DHEA. But we are all different, as in your case capsule did a better job for Cortisol. I can attest it is more difficult to increase Pregnenolone levels with a cream, capsule did a better job for that in my case as well.

Pregnenolone (medication) - Wikipedia

en.wikipedia.org

I recently did a trial of 5mg of Hydrocortisone again, and although it helped as it always does, I actually preferred the results in general of upping pregnenolone in pill form, so I came off it after a week. Based on past tests and general feeling, my cortisol’s low all throughout the day and higher than that in the evening despite still being low. On higher oral pregnenolone in the morning, my output in the evening feels higher and I feel generally better as if I’m on HC, but without some of the unwanted side effects. It helps me tolerate higher doses of thyroid meds as well.

 

[Anonymon]

So what are u currently doing in regards to progesterone, just one capsule in the morning? How many mgs are u currently taking in capsule form?

Have u had ur cortisol levels checked while on the prog capsules?

Have u heard or read that oral prog increases cortisol more than other forms? I’m currently using injectable prog at night, but also have low cortisol, so I’m jc if oral is the preferred form to raise cortisol levels

Have u researched sorghum? It increases 5ar activity, and seems to be pretty popular with guys suffering from post finasteride syndrome

25-50mg of cream in the morning, no capsules as I don’t have prescription access to that. My cortisol test while on this though was the bottom number of the range in the morning. I have never tried oral prog.

I have Sorghum but haven’t gotten around to trying it. I have had minor aid with using glycine in powdered form in drinks though, mostly in the evening, with taurine in the morning. Table spoon or so.

 

[MIP1950]

I’d say the enzyme 5ar would not be down regulated. Dht further reinforces its own creation by upregulating 5ar to some extent. Also Does aromatase get burned? I’d say not. To me it seems that high levels of circulating androgens can and alter estrogens activity at the receptor or depending on the androgen actually lower aromatase. and in turn lower thyroid hormone output through several vectors. Thyroid hormone is responsible for stimulating the pregnenolone and subsequent steroid cascade. High or imbalanced levels of androgens can strongly oppose estrogens action and therefore cortisol to the point that thyroid hormone may not be cellularly viable. Cortisol is important for active thyroid to be a metabolically viable chemical. Try to recreate what nature intended. Not just speed our way to feeling better by taking large infrequent injections. If you need more testosterone than what you naturally created when you felt your best when you were in your prime, then there are other parts of your metabolism/hormonal cascade that need to be examined. Not adding more test.

Where does one find a doctor like Dr. Gordon who will do the in-depth analysis of labs and symptoms/issues AND takes insurance? @Cataceous and I had a discussion about how does one restore the hormonal/neuroendocrine environment that we had when we were young. We're talking about looking for he proverbial needle in a haystack. Simpy said; It's complicated.

 

[MIP1950]

I recently did a trial of 5mg of Hydrocortisone again, and although it helped as it always does, I actually preferred the results in general of upping pregnenolone in pill form, so I came off it after a week. Based on past tests and general feeling, my cortisol’s low all throughout the day and higher than that in the evening despite still being low. On higher oral pregnenolone in the morning, my output in the evening feels higher and I feel generally better as if I’m on HC, but without some of the unwanted side effects. It helps me tolerate higher doses of thyroid meds as well.

Your pregnenolone dose? Thanks.

 

[Anonymon]

Your pregnenolone dose? Thanks.

400mg daily in the morning.

 

[Gianluca]

400mg daily in the morning.

what is your level of Pregnenolone with that dose?

 

[Anonymon]

what is your level of Pregnenolone with that dose?

Not sure but I’m ordering a test the next time I go in. Was going to be tomorrow but I’m changing my thyroid meds again so I’m waiting for that to even out more first. Hoping for the best with it. High does preg has been a great boon to me despite some side effects like minor water retention.

 

[Mastodont]

Not sure but I’m ordering a test the next time I go in. Was going to be tomorrow but I’m changing my thyroid meds again so I’m waiting for that to even out more first. Hoping for the best with it. High does preg has been a great boon to me despite some side effects like minor water retention.

Have you stayed on preg and on that dose?

 

[Anonymon]

Have you stayed on preg and on that dose?

Yep! Hoping to be able to get off it but it’s been a constant for me.

 

[Nelson Vergel]

alpha reductase enzyme, that beside being responsible for converting Test into DHT, it is also responsible for converting Progesterone into Allopregnanolone in the brain.

I don't think TRT "burns 5 alpha reductase", but it shuts down LH, which is needed for pregnenolone and its downstream hormones like allopregnanolone.

Allopregnanolone: An overview on its synthesis and effects

Abstract Allopregnanolone, a 3α,5α-progesterone metabolite, acts as a potent allosteric modulator of the γ-aminobutyric acid type A receptor. In the present review, the synthesis of this neuroactive steroid occurring in the nervous system is discussed with respect to physiological and...

www.excelmale.com

Allopregnanolone is a super important neurosteroid.

**************

5α-reductase plays a crucial role in the biosynthesis of allopregnanolone in the brain and nervous system. Here is a summary of its role:

Biosynthesis of Allopregnanolone​

Allopregnanolone is synthesized from progesterone in the following two-step process:

1. Progesterone is converted to 5α-dihydroprogesterone (5α-DHP) by the enzyme 5α-reductase .
2. 5α-DHP is then converted to allopregnanolone by the enzyme 3α-hydroxysteroid dehydrogenase (3α-HSD) .

So 5α-reductase catalyzes the rate-limiting first step in the biosynthesis of allopregnanolone from progesterone . The two main isoforms involved are:

• 5α-reductase type 1 - Expressed in many brain regions like cortex, hippocampus, amygdala
• 5α-reductase type 2 - Expressed in some specific brain regions like thalamus, striatum

Importance​

Allopregnanolone is a potent positive allosteric modulator of GABAA receptors and has anxiolytic, antidepressant, neuroprotective and other effects . Downregulation of 5α-reductase and allopregnanolone levels in the brain has been linked to psychiatric conditions like depression, anxiety, premenstrual dysphoric disorder, and neurodegenerative diseases .Inhibitors of 5α-reductase like finasteride can decrease allopregnanolone synthesis in the brain, potentially contributing to side effects like depression and anxiety .In summary, 5α-reductase catalyzes the critical rate-limiting step in allopregnanolone biosynthesis in the brain and nervous system, making it an important enzyme regulating this neurosteroid's levels and effects .

************

Luteinizing hormone (LH) plays a significant role in the production of allopregnanolone, a neurosteroid derived from progesterone. The relationship between LH and allopregnanolone production can be understood through several mechanisms:

1. Stimulation of Steroidogenesis: LH is crucial for stimulating the synthesis and secretion of ovarian steroid hormones, including progesterone, which is a precursor for allopregnanolone. LH facilitates the conversion of cholesterol to progesterone in ovarian and testicular cells, which is then metabolized to allopregnanolone by the action of specific enzymes such as 5α-reductase and 3α-hydroxysteroid dehydrogenase (3α-HSD) .
2. Regulation of Enzymatic Activity: LH influences the activity of enzymes involved in the biosynthesis of allopregnanolone. For instance, LH can increase the expression and activity of 3β-hydroxysteroid dehydrogenase (3β-HSD), which is involved in the conversion of pregnenolone to progesterone, thereby providing more substrate for allopregnanolone synthesis .
3. Neuroendocrine Feedback: The production of allopregnanolone is also regulated by the hypothalamic-pituitary-gonadal (HPG) axis, where LH plays a pivotal role. The secretion of LH is stimulated by gonadotropin-releasing hormone (GnRH) from the hypothalamus, which in turn is influenced by neurosteroids like allopregnanolone. This creates a feedback loop where allopregnanolone can modulate the release of GnRH and subsequently LH, affecting its own production indirectly .
4. Impact on Ovarian Function: Allopregnanolone has been shown to affect ovarian functions such as folliculogenesis, luteolysis, and steroidogenesis. By modulating these processes, allopregnanolone can influence the levels of LH and other hormones, creating a complex interplay between LH and allopregnanolone production .

In summary, LH is integral to the production of allopregnanolone by stimulating the synthesis of its precursor, progesterone, and regulating the activity of key enzymes involved in its biosynthesis. Additionally, the feedback mechanisms within the HPG axis further modulate this relationship, highlighting the intricate balance between LH and allopregnanolone production.

******************

TRT shuts down LH and decreases pregnenolone, progesterone, and related hormones.

Anabolic steroids and TRT decrease SHBG, DHEA, pregnenolone and progesterone in men.

Response of serum testosterone and its precursor steroids, SHBG and CBG to anabolic steroid and testosterone self-administration in man. Ruokonen A, et al. J Steroid Biochem. 1985. Abstract The influence of high doses of testosterone and anabolic steroids on testicular endocrine function...

www.excelmale.com

hCG at high enough doses may help restore pregnenolone, progesterone, and allopregnanolone in men on TRT. But it may be expensive and cause side effects like water retention and increased blood pressure.

Pregnenolone supplementation may also help increase progesterone and allopregnanolone, at least in men not on TRT (no data yet of PREG+TRT). It would be interesting to perform a study in men on TRT taking hCG or pregnenolone.

"Allopregnanolone, a pregnenolone metabolite with analgesic properties, exhibited a pattern similar to pregnenolone. Allopregnanolone levels did not differ between groups at baseline (mean [SE], 62.22 [5.10] pg/mL for placebo and 67.96 [9.83] pg/mL for pregnenolone; P = .95); however, participants receiving pregnenolone had significantly increased allopregnanolone levels after 1 week of 100 mg of pregnenolone (6.5-fold increase; mean [SE], 59.73 [5.64] pg/mL vs 508.98 [55.31] pg/mL; P < .001). Allopregnanolone levels markedly increased again after participants received 1 week of 300 mg of pregnenolone (14.3-fold increase; mean [SE], 71.22 [11.07] pg/mL vs 1036.50 [108.04] pg/mL; P < .001) and continued to increase after 2 weeks of 500 mg (17.6-fold increase; mean [SE], 61.32 [6.00] pg/mL vs 1263.10 [136.90] pg/mL; P < .001)."

Source: Pregnenolone vs Placebo for Chronic Low Back Pain Among US Military Veterans (men not on TRT)

 

[Mastodont]

Allopregnanolone has been shown to affect ovarian functions such as folliculogenesis, luteolysis, and steroidogenesis. By modulating these processes, allopregnanolone can influence the levels of LH and other hormones, creating a complex interplay between LH and allopregnanolone production .

In summary, LH is integral to the production of allopregnanolone by stimulating the synthesis of its precursor, progesterone, and regulating the activity of key enzymes involved in its biosynthesis. Additionally, the feedback mechanisms within the HPG axis further modulate this relationship, highlighting the intricate balance between LH and allopregnanolone production.

Pregnenolone supplementation may also help increase progesterone and allopregnanolone, at least in men not on TRT (no data yet of PREG+TRT). It would be interesting to perform a study in men on TRT taking hCG or pregnenolone.

Could there be some feedback loop that would cause LH to drop when a natural male is supplementing with high doses of pregnenolone? So just wondering if you could actually end up worse testosterone wise when not on trt, it seems the claim that preg supplementation increases or may increase testosterone is found all over but no actual studies measured this?

 

[Gianluca]

I don't think TRT "burns 5 alpha reductase", but it shuts down LH, which is needed for pregnenolone and its downstream hormones like allopregnanolone.

I agree. In fact if injecting more Testosterone would "burn 5 alpha reductase" we would see a drop in DHT as well, but not quite I believe.

I don't think TRT "burns 5 alpha reductase", but it shuts down LH, which is needed for pregnenolone and its downstream hormones like allopregnanolone.

Allopregnanolone: An overview on its synthesis and effects

Abstract Allopregnanolone, a 3α,5α-progesterone metabolite, acts as a potent allosteric modulator of the γ-aminobutyric acid type A receptor. In the present review, the synthesis of this neuroactive steroid occurring in the nervous system is discussed with respect to physiological and...

www.excelmale.com

Allopregnanolone is a super important neurosteroid.

View attachment 44837

View attachment 44838


**************

5α-reductase plays a crucial role in the biosynthesis of allopregnanolone in the brain and nervous system. Here is a summary of its role:

Biosynthesis of Allopregnanolone​

Allopregnanolone is synthesized from progesterone in the following two-step process:

1. Progesterone is converted to 5α-dihydroprogesterone (5α-DHP) by the enzyme 5α-reductase .
2. 5α-DHP is then converted to allopregnanolone by the enzyme 3α-hydroxysteroid dehydrogenase (3α-HSD) .

So 5α-reductase catalyzes the rate-limiting first step in the biosynthesis of allopregnanolone from progesterone . The two main isoforms involved are:

• 5α-reductase type 1 - Expressed in many brain regions like cortex, hippocampus, amygdala
• 5α-reductase type 2 - Expressed in some specific brain regions like thalamus, striatum

Importance​

Allopregnanolone is a potent positive allosteric modulator of GABAA receptors and has anxiolytic, antidepressant, neuroprotective and other effects . Downregulation of 5α-reductase and allopregnanolone levels in the brain has been linked to psychiatric conditions like depression, anxiety, premenstrual dysphoric disorder, and neurodegenerative diseases .Inhibitors of 5α-reductase like finasteride can decrease allopregnanolone synthesis in the brain, potentially contributing to side effects like depression and anxiety .In summary, 5α-reductase catalyzes the critical rate-limiting step in allopregnanolone biosynthesis in the brain and nervous system, making it an important enzyme regulating this neurosteroid's levels and effects .

************

Luteinizing hormone (LH) plays a significant role in the production of allopregnanolone, a neurosteroid derived from progesterone. The relationship between LH and allopregnanolone production can be understood through several mechanisms:

1. Stimulation of Steroidogenesis: LH is crucial for stimulating the synthesis and secretion of ovarian steroid hormones, including progesterone, which is a precursor for allopregnanolone. LH facilitates the conversion of cholesterol to progesterone in ovarian and testicular cells, which is then metabolized to allopregnanolone by the action of specific enzymes such as 5α-reductase and 3α-hydroxysteroid dehydrogenase (3α-HSD) .
2. Regulation of Enzymatic Activity: LH influences the activity of enzymes involved in the biosynthesis of allopregnanolone. For instance, LH can increase the expression and activity of 3β-hydroxysteroid dehydrogenase (3β-HSD), which is involved in the conversion of pregnenolone to progesterone, thereby providing more substrate for allopregnanolone synthesis .
3. Neuroendocrine Feedback: The production of allopregnanolone is also regulated by the hypothalamic-pituitary-gonadal (HPG) axis, where LH plays a pivotal role. The secretion of LH is stimulated by gonadotropin-releasing hormone (GnRH) from the hypothalamus, which in turn is influenced by neurosteroids like allopregnanolone. This creates a feedback loop where allopregnanolone can modulate the release of GnRH and subsequently LH, affecting its own production indirectly .
4. Impact on Ovarian Function: Allopregnanolone has been shown to affect ovarian functions such as folliculogenesis, luteolysis, and steroidogenesis. By modulating these processes, allopregnanolone can influence the levels of LH and other hormones, creating a complex interplay between LH and allopregnanolone production .

In summary, LH is integral to the production of allopregnanolone by stimulating the synthesis of its precursor, progesterone, and regulating the activity of key enzymes involved in its biosynthesis. Additionally, the feedback mechanisms within the HPG axis further modulate this relationship, highlighting the intricate balance between LH and allopregnanolone production.

******************

TRT shuts down LH and decreases pregnenolone, progesterone, and related hormones.

Anabolic steroids and TRT decrease SHBG, DHEA, pregnenolone and progesterone in men.

Response of serum testosterone and its precursor steroids, SHBG and CBG to anabolic steroid and testosterone self-administration in man. Ruokonen A, et al. J Steroid Biochem. 1985. Abstract The influence of high doses of testosterone and anabolic steroids on testicular endocrine function...

www.excelmale.com

hCG at high enough doses may help restore pregnenolone, progesterone, and allopregnanolone in men on TRT. But it may be expensive and cause side effects like water retention and increased blood pressure.

Pregnenolone supplementation may also help increase progesterone and allopregnanolone, at least in men not on TRT (no data yet of PREG+TRT). It would be interesting to perform a study in men on TRT taking hCG or pregnenolone.

"Allopregnanolone, a pregnenolone metabolite with analgesic properties, exhibited a pattern similar to pregnenolone. Allopregnanolone levels did not differ between groups at baseline (mean [SE], 62.22 [5.10] pg/mL for placebo and 67.96 [9.83] pg/mL for pregnenolone; P = .95); however, participants receiving pregnenolone had significantly increased allopregnanolone levels after 1 week of 100 mg of pregnenolone (6.5-fold increase; mean [SE], 59.73 [5.64] pg/mL vs 508.98 [55.31] pg/mL; P < .001). Allopregnanolone levels markedly increased again after participants received 1 week of 300 mg of pregnenolone (14.3-fold increase; mean [SE], 71.22 [11.07] pg/mL vs 1036.50 [108.04] pg/mL; P < .001) and continued to increase after 2 weeks of 500 mg (17.6-fold increase; mean [SE], 61.32 [6.00] pg/mL vs 1263.10 [136.90] pg/mL; P < .001)."

Source: Pregnenolone vs Placebo for Chronic Low Back Pain Among US Military Ve

I don't think TRT "burns 5 alpha reductase", but it shuts down LH, which is needed for pregnenolone and its downstream hormones like allopregnanolone.

Allopregnanolone: An overview on its synthesis and effects

Abstract Allopregnanolone, a 3α,5α-progesterone metabolite, acts as a potent allosteric modulator of the γ-aminobutyric acid type A receptor. In the present review, the synthesis of this neuroactive steroid occurring in the nervous system is discussed with respect to physiological and...

www.excelmale.com

Allopregnanolone is a super important neurosteroid.

View attachment 44837

View attachment 44838


**************

5α-reductase plays a crucial role in the biosynthesis of allopregnanolone in the brain and nervous system. Here is a summary of its role:

Biosynthesis of Allopregnanolone​

Allopregnanolone is synthesized from progesterone in the following two-step process:

1. Progesterone is converted to 5α-dihydroprogesterone (5α-DHP) by the enzyme 5α-reductase .
2. 5α-DHP is then converted to allopregnanolone by the enzyme 3α-hydroxysteroid dehydrogenase (3α-HSD) .

So 5α-reductase catalyzes the rate-limiting first step in the biosynthesis of allopregnanolone from progesterone . The two main isoforms involved are:

• 5α-reductase type 1 - Expressed in many brain regions like cortex, hippocampus, amygdala
• 5α-reductase type 2 - Expressed in some specific brain regions like thalamus, striatum

Importance​

Allopregnanolone is a potent positive allosteric modulator of GABAA receptors and has anxiolytic, antidepressant, neuroprotective and other effects . Downregulation of 5α-reductase and allopregnanolone levels in the brain has been linked to psychiatric conditions like depression, anxiety, premenstrual dysphoric disorder, and neurodegenerative diseases .Inhibitors of 5α-reductase like finasteride can decrease allopregnanolone synthesis in the brain, potentially contributing to side effects like depression and anxiety .In summary, 5α-reductase catalyzes the critical rate-limiting step in allopregnanolone biosynthesis in the brain and nervous system, making it an important enzyme regulating this neurosteroid's levels and effects .

************

Luteinizing hormone (LH) plays a significant role in the production of allopregnanolone, a neurosteroid derived from progesterone. The relationship between LH and allopregnanolone production can be understood through several mechanisms:

1. Stimulation of Steroidogenesis: LH is crucial for stimulating the synthesis and secretion of ovarian steroid hormones, including progesterone, which is a precursor for allopregnanolone. LH facilitates the conversion of cholesterol to progesterone in ovarian and testicular cells, which is then metabolized to allopregnanolone by the action of specific enzymes such as 5α-reductase and 3α-hydroxysteroid dehydrogenase (3α-HSD) .
2. Regulation of Enzymatic Activity: LH influences the activity of enzymes involved in the biosynthesis of allopregnanolone. For instance, LH can increase the expression and activity of 3β-hydroxysteroid dehydrogenase (3β-HSD), which is involved in the conversion of pregnenolone to progesterone, thereby providing more substrate for allopregnanolone synthesis .
3. Neuroendocrine Feedback: The production of allopregnanolone is also regulated by the hypothalamic-pituitary-gonadal (HPG) axis, where LH plays a pivotal role. The secretion of LH is stimulated by gonadotropin-releasing hormone (GnRH) from the hypothalamus, which in turn is influenced by neurosteroids like allopregnanolone. This creates a feedback loop where allopregnanolone can modulate the release of GnRH and subsequently LH, affecting its own production indirectly .
4. Impact on Ovarian Function: Allopregnanolone has been shown to affect ovarian functions such as folliculogenesis, luteolysis, and steroidogenesis. By modulating these processes, allopregnanolone can influence the levels of LH and other hormones, creating a complex interplay between LH and allopregnanolone production .

In summary, LH is integral to the production of allopregnanolone by stimulating the synthesis of its precursor, progesterone, and regulating the activity of key enzymes involved in its biosynthesis. Additionally, the feedback mechanisms within the HPG axis further modulate this relationship, highlighting the intricate balance between LH and allopregnanolone production.

******************

TRT shuts down LH and decreases pregnenolone, progesterone, and related hormones.

Anabolic steroids and TRT decrease SHBG, DHEA, pregnenolone and progesterone in men.

Response of serum testosterone and its precursor steroids, SHBG and CBG to anabolic steroid and testosterone self-administration in man. Ruokonen A, et al. J Steroid Biochem. 1985. Abstract The influence of high doses of testosterone and anabolic steroids on testicular endocrine function...

www.excelmale.com

hCG at high enough doses may help restore pregnenolone, progesterone, and allopregnanolone in men on TRT. But it may be expensive and cause side effects like water retention and increased blood pressure.

Pregnenolone supplementation may also help increase progesterone and allopregnanolone, at least in men not on TRT (no data yet of PREG+TRT). It would be interesting to perform a study in men on TRT taking hCG or pregnenolone.

"Allopregnanolone, a pregnenolone metabolite with analgesic properties, exhibited a pattern similar to pregnenolone. Allopregnanolone levels did not differ between groups at baseline (mean [SE], 62.22 [5.10] pg/mL for placebo and 67.96 [9.83] pg/mL for pregnenolone; P = .95); however, participants receiving pregnenolone had significantly increased allopregnanolone levels after 1 week of 100 mg of pregnenolone (6.5-fold increase; mean [SE], 59.73 [5.64] pg/mL vs 508.98 [55.31] pg/mL; P < .001). Allopregnanolone levels markedly increased again after participants received 1 week of 300 mg of pregnenolone (14.3-fold increase; mean [SE], 71.22 [11.07] pg/mL vs 1036.50 [108.04] pg/mL; P < .001) and continued to increase after 2 weeks of 500 mg (17.6-fold increase; mean [SE], 61.32 [6.00] pg/mL vs 1263.10 [136.90] pg/mL; P < .001)."

Source: Pregnenolone vs Placebo for Chronic Low Back Pain Among US Military Veterans (men not on TRT)

On TRT, Progesterone needs to be monitored, and supplemented to raise levels. I don't know why this is not common practice for practitioners out there. In fact many call Progesterone a "feminizing" hormone and don't give it to men, when in some cases it is desperately needed it, especially for people who worsen their anxiety/mental health, sleep and adrenal function while on TRT.

I believe allot are not successful with Progesterone supplementation due to the wrong delivery method used.