I have to switch from TRT to HCG monotherapy every 6 to 9 months to get my libido back. Does anyone know what is happening and how I can avoid this?

[Stoak]

Also I will say my libido was in the gutter 2 weeks ago and had been for some time which is why I began my current reset. I am 2 weeks and a day from my last test cyp shot and have had 6 1000iu HCG shots and my libido is absolutely raging again. Thats why I want to see where I am bloodwork wise.

 

[Systemlord]

I can't get any of my doctors to prescribe TRT with hCG (I've been on both over the years, but not at the same time). I keep telling them that I don't feel the same just being on TRT. How do you guys convince your doctors to prescribe both? And how do you get insurance to pay for both?

The majority of insurance companies will not cover hCG.

 

[billsman]

The majority of insurance companies will not cover hCG.

Mine covered it for 10 years when I was having kids. That was 10 years ago. Is there still a shortage?

 

[billsman]

I never have. I don't know where my e2 has been during those HCG intervals. When I use 500iu twice per week it does nothing to my e2 levels. I got a blood test today testing my e2, pregnenolone, DHEA and SHBG... let's see if I can get to the bottom of this.

I'd def check. I was taking 2,500 three times per week for 10 years and developed gyno. Only then did my endo put me on an AI.

 

[Stoak]

I'd def check. I was taking 2,500 three times per week for 10 years and developed gyno. Only then did my endo put me on an AI.

It took 10 years to develop gyno?

 

[billsman]

It took 10 years to develop gyno?

Probably had it for a few years. It was a mild case I suppose but I still had to have surgery.

 

[Stoak]

Probably had it for a few years. It was a mild case I suppose but I still had to have surgery.

Was it cosmetic or painful that made surgery necessary?

 

[Systemlord]

I'd def check. I was taking 2,500 three times per week for 10 years and developed gyno. Only then did my endo put me on an AI.

HCG can stimulate the LH receptors in the breast tissue and trigger gyno.

 

[Fernando Almaguer]

Was it cosmetic or painful that made surgery necessary?

its possible that HCG as a peptide is just a natural(er) way to bring test and function up. Test being synthetic it does have side effects of lowering libido in some.

 

[WhatSayYou89]

Interesting in trying this method.

However for this I would def have to utilize an AI or I will be tits McGee from the hcg.

Getting bloodwork next week then I’m gonna give this a shot.

 

[billsman]

Was it cosmetic or painful that made surgery necessary?

No pain, cosmetic. It's strange, I just didn't really notice it over the years. Although, to be fair, back then my body fat % was higher (now I'm about 18%).

I recently just began hCG mono again in an effort to get my ferritin levels up and improve my libido. One thing I recall from when I was on it 12 years ago is that someone mentioned that AIs cannot penetrate the testes, where hCG converts T to e2. I think I am recalling that correctly, but it's been so many years.

 

[billsman]

The majority of insurance companies will not cover hCG.

Mine just did, and I was surprised. But for mono. I think they were eager to stop paying for Xyosted, which cost them $3.5k per month!

 

[Stoak]

So my labs are in. This is 15 days from my last test cyp shot of 50mg and 6 shots in of 1000iu HCG MWF. My libido was RAGING after being in the dumps.

Total T 352
Free T 127
E2 24

DHEA 318
Pregnenolone ZERO... did not even register on the lab test

SHBG 10

So obviously the libido restoration has NOTHING TO DO with my Pregnenolone levels based on these bloods. My DHEA is thst level no matter what and never really varies.

It seems the most important number in the entire chart is E2 24 which is roughly where I am during TRT anyways. Unless the labs can't measure something like ITT intratesticular testosterone and intratesticular estrogen if that is even a thing.

I have finished my HCG monotherapy and resumed TRT. One thing thst happened this time is I was getting some night sweats in week 3 and my small pre existing gyno seemed to be flaring. I also lost my morning wood in week 3. Zero. I am wondering if week 3 pushed me over the edge e2 wise while my twst was basically zero as the ester finally cleared. Going fwd I may try to just stay on test and run HCG 1000iu MWF and never come off the test. Or add the clomid alongside like Lipschultz suggests in the literature.

Also for reference on 50mg of test cyp and 500iu HCG e3.5d my total t is 700, free t 290, e2 25-30, SHBG low teens. I am really confused now.




Is it long term unhealthy to have Pregnenolone of zero? Or can we view it like LH and FSH being zero due to therapy?

 

[FunkOdyssey]

Is it long term unhealthy to have Pregnenolone of zero? Or can we view it like LH and FSH being zero due to therapy?

I don't think it matters. Opus 4.6 says:

Pregnenolone is lipophilic and readily crosses the blood-brain barrier after parenteral administration PubMed Central. So serum pregnenolone does contribute to brain levels. Marx et al. (2006) demonstrated that serum pregnenolone levels are closely correlated with hippocampal pregnenolone levels in rats, and CSF pregnenolone levels in humans correlate with temporal cortex pregnenolone levels within the same subject cohort PubMed Central. Based on this, serum pregnenolone may serve as a proxy or surrogate marker for brain pregnenolone levels PubMed Central.

However, here's the critical nuance: pregnenolone is present in human brain tissue at physiologically relevant concentrations in the nanomolar range that are greater than 10-fold higher than those frequently observed in serum or plasma PubMed Central. The brain isn't passively dependent on peripheral supply—it's actively concentrating and producing its own.

The brain has an entirely independent synthesis pathway

This is where the recent literature gets really interesting. Although pregnenolone is one of the most abundant neurosteroids in the brain, expression of CYP11A1 is difficult to detect PubMed Central. The peripheral enzyme that makes pregnenolone in the adrenals and Leydig cells is essentially absent in human brain tissue. Instead, glial cells use mitochondrial CYP1B1 to synthesize pregnenolone PubMed Central—a completely different enzyme than CYP11A1. This was confirmed in a 2022 JBC paper and extended in 2023 follow-up work.

This is a key point: pregnenolone production in the brain is independent of CYP11A1 PubMed Central, and pregnenolone production in glial cells was not inhibited by CYP11A1 inhibitors PubMed Central. The brain's pregnenolone factory runs on completely different machinery than your testes or adrenals. A 2024 comparative study found that CYP1B1 is likely the dominant pregnenolone synthesis enzyme in the human brain ScienceDirect, with CYP1B1 mRNA higher than CYP11A1 across nearly all brain regions examined.

What this means for TRT-induced suppression

When TRT suppresses LH, you lose Leydig cell pregnenolone production. That's real—serum levels can drop dramatically. But the brain's CYP1B1-mediated pathway is not regulated by LH or ACTH. It's locally controlled by TSPO-mediated cholesterol transport into glial mitochondria, and cholesterol availability in the brain is maintained independently (the brain makes its own cholesterol via astrocytes, since peripheral cholesterol doesn't cross the BBB).

So the mechanism of TRT-induced serum pregnenolone suppression doesn't directly touch the brain's production line. What you lose is the peripheral "top-up" from serum crossing the BBB—but given brain concentrations are already an order of magnitude higher than serum, that contribution is likely a relatively small fraction of total brain pregnenolone under normal conditions.

Why you're probably right that it doesn't matter much in practice

Your observation that low serum pregnenolone on TRT doesn't seem to produce obvious effects is consistent with this biology. The men in the TRT space who attribute brain fog or emotional flattening to pregnenolone depletion are likely conflating serum levels with brain levels, not realizing the brain has its own independent synthesis system using a different enzyme entirely. Individual variation in CYP1B1 activity could theoretically make some men more dependent on peripheral supply, but there's no clinical data to support this as a common scenario.

The one caveat worth noting: pregnenolone sulfate, the form that acts as an NMDA receptor modulator and memory enhancer, can access the brain parenchyma from blood by transport across the BBB via organic anion transporters PubMed Central. Sulfation/desulfation dynamics are compartmentalized, so there's a theoretical question about whether serum pregnenolone sulfate levels (which would also drop on TRT) contribute meaningfully to the brain's PregS pool. But again, no clinical evidence that this produces detectable cognitive effects in TRT populations.

Bottom line: serum pregnenolone is a rough correlate of brain levels but not a determinant of them. The brain runs its own pregnenolone production via CYP1B1, independent of the HPG axis suppression caused by TRT. hCG use restores some Leydig cell steroidogenesis, but even without it, the brain appears well-insulated from TRT-related pregnenolone depletion.

 

[Stoak]

I don't think it matters. Opus 4.6 says:

Pregnenolone is lipophilic and readily crosses the blood-brain barrier after parenteral administration PubMed Central. So serum pregnenolone does contribute to brain levels. Marx et al. (2006) demonstrated that serum pregnenolone levels are closely correlated with hippocampal pregnenolone levels in rats, and CSF pregnenolone levels in humans correlate with temporal cortex pregnenolone levels within the same subject cohort PubMed Central. Based on this, serum pregnenolone may serve as a proxy or surrogate marker for brain pregnenolone levels PubMed Central.

However, here's the critical nuance: pregnenolone is present in human brain tissue at physiologically relevant concentrations in the nanomolar range that are greater than 10-fold higher than those frequently observed in serum or plasma PubMed Central. The brain isn't passively dependent on peripheral supply—it's actively concentrating and producing its own.

The brain has an entirely independent synthesis pathway

This is where the recent literature gets really interesting. Although pregnenolone is one of the most abundant neurosteroids in the brain, expression of CYP11A1 is difficult to detect PubMed Central. The peripheral enzyme that makes pregnenolone in the adrenals and Leydig cells is essentially absent in human brain tissue. Instead, glial cells use mitochondrial CYP1B1 to synthesize pregnenolone PubMed Central—a completely different enzyme than CYP11A1. This was confirmed in a 2022 JBC paper and extended in 2023 follow-up work.

This is a key point: pregnenolone production in the brain is independent of CYP11A1 PubMed Central, and pregnenolone production in glial cells was not inhibited by CYP11A1 inhibitors PubMed Central. The brain's pregnenolone factory runs on completely different machinery than your testes or adrenals. A 2024 comparative study found that CYP1B1 is likely the dominant pregnenolone synthesis enzyme in the human brain ScienceDirect, with CYP1B1 mRNA higher than CYP11A1 across nearly all brain regions examined.

What this means for TRT-induced suppression

When TRT suppresses LH, you lose Leydig cell pregnenolone production. That's real—serum levels can drop dramatically. But the brain's CYP1B1-mediated pathway is not regulated by LH or ACTH. It's locally controlled by TSPO-mediated cholesterol transport into glial mitochondria, and cholesterol availability in the brain is maintained independently (the brain makes its own cholesterol via astrocytes, since peripheral cholesterol doesn't cross the BBB).

So the mechanism of TRT-induced serum pregnenolone suppression doesn't directly touch the brain's production line. What you lose is the peripheral "top-up" from serum crossing the BBB—but given brain concentrations are already an order of magnitude higher than serum, that contribution is likely a relatively small fraction of total brain pregnenolone under normal conditions.

Why you're probably right that it doesn't matter much in practice

Your observation that low serum pregnenolone on TRT doesn't seem to produce obvious effects is consistent with this biology. The men in the TRT space who attribute brain fog or emotional flattening to pregnenolone depletion are likely conflating serum levels with brain levels, not realizing the brain has its own independent synthesis system using a different enzyme entirely. Individual variation in CYP1B1 activity could theoretically make some men more dependent on peripheral supply, but there's no clinical data to support this as a common scenario.

The one caveat worth noting: pregnenolone sulfate, the form that acts as an NMDA receptor modulator and memory enhancer, can access the brain parenchyma from blood by transport across the BBB via organic anion transporters PubMed Central. Sulfation/desulfation dynamics are compartmentalized, so there's a theoretical question about whether serum pregnenolone sulfate levels (which would also drop on TRT) contribute meaningfully to the brain's PregS pool. But again, no clinical evidence that this produces detectable cognitive effects in TRT populations.

Bottom line: serum pregnenolone is a rough correlate of brain levels but not a determinant of them. The brain runs its own pregnenolone production via CYP1B1, independent of the HPG axis suppression caused by TRT. hCG use restores some Leydig cell steroidogenesis, but even without it, the brain appears well-insulated from TRT-related pregnenolone depletion.

Additionally I would imagine that my adrenals are indeed working if I have 318 DHEA-S