T Nation

Studies: Down Regulation of Leydig Cells and HCG

first study
Here’s a different extract
And yet another

So, I don’t remember who asked for these, but it took me less than a second to encounter these and several other studies. You didn’t look very hard if you couldn’t find them.

A better one


That was me, and it looks like these are all studies on rats and mice. I’ve seen studies like these in rodents and one on pigs I think but I still haven’t found one showing this happens to humans even on high doses.

Not a lot of men volunteering to have their testicles removed and dissected in the name of science.


Yes but a lot of studies out there where men are on 3000iu eod for extended periods of time for fertility, often going over a year, or even 5000iu 2-3x a week with no signs of hCG losing effect, still good serum T levels and ITT levels, only thing if I remember correctly the 5000iu per shot guys had mean E levels in the low 100s. Btw I don’t recommend anyone to use that much hCG unless absolutely necessary,

I’ve heard from drs that it’s theoretically possible, like catching CJD prions from urinary hCG, also theoretically possible but hasn’t happened so far. Btw you can avoid the theoretical risk of catching prions by using recombinant hCG. I used it for a longish time, like around 10 months when I was on trt then into pct, never noticed it really lose effect for extended periods of time except when I was on Tren A.

1 Like

By long term, we’re not talking about a year. Guys are going on TRT and HCG with the intention of using both forever. If it’s for life, it would be unrealistic to expect that in say 5 years of continuous use everything is the same, or 10 years. Most things work better if you cycle off of them periodically and let things reset, and HCG is no different. If guys are actually concerned about fertility, then continuous use just to maintain size is a big risk.

Well sure if you take a break from anything periodically than you may get a better effect when going back on, but actual desensitization in the sense of damaged balls in humans is basically a myth at this point, I’m sure if you use some absurd amount like >10,000iu eod you might run the risk, but with the low dose men use on trt probably not or there would have been cases. Like clomid has a rare paradoxical effect in some men of lowering sperm count and testosterone, likely because of the Zuclomifene, I would think if something similar happened with hCG in humans it would have been documented, but I can’t find anything on pubmed.

I’m going to check out the articles.

As said several times on this board, I have been on HCG for nearly five years, with the first time being for HCG monotherapy with 3,000 IU three times per week, then going onto TRT with HCG for 1,000 IU three times per week, and recently to 500 IU twice per week. I’m expecting my second kid this summer and besides these two pregnancies, there were miscarriages. Yes, I’m only one guy, but there are many others using HCG for years on end, even some using 10,000 IU for years.

My doc told me several years ago that there has not been one documented case published showing testicular dysfunction from long-term HCG use.

So, desensitization is not damage. Down regulation is something normal that happens all the time.You androgen receptors desensitize on TRT over time, but it has been demonstrated that the body increases the quantity of the receptors for androgen over time. So hen guys run cycles part of the reason to cycle is to allow regeneration of receptors. Thus far, no one has shown that the same prediliction exists for Leydig cells. It’s not damage, it’s a normal biochemical reaction that we experience with receptors. Fertility does not require 10000 iu’s in most men. The real question is, what is the life cycle of a Leydig cell? Under normal life circumstances you replace these things on a regular basis so down-regulation is not an issue - you simply have a new cell by the time down-regulation looms it’s head. Anyone on TRT is not in that situation. Synthetic exogynous is just that, and your body is not going to react the same way to it as your actual endogynous production of LH. If everythinf functioned normally down there, you wouldn’t need TRT.
Secondly, HCG is extremely new in regards to use in men. I wouldn’t expect any data past lab rats for at least another ten years. And as a sidenote, Pubmed is only one of 5 databases used by academia for publishing studies and new information. The fact that something is not there does not in fact mean much regarding it’s possible existence.

1 Like

No evidence that there is any significant reduction in the efficacy of hCG in humans, I’ve also searched google, where you can find shady articles with no sources claiming there’s significant risk etc. A normal person is exposed to various levels of testosterone 24 hours a day, it never really loses effect, sure it will for building excess muscle but for it’s main purposes, maintaining spermatogenisis, secondary sexual characteristics it stay. Yes men don’t have much hCG naturally, only trace amounts but I think it’s still more natural the exogenous T, the human fetus is exposed to hCG so it’s not entirely foreign. hCG for male infertility has been in use for awhile, but treatment for hypo may not have been so common although you can find reports if it’s use from awhile back, and certainly not low dose adjunct to trt. I’m always researching it but from everything I’ve come across I’m comfortable using it continuously, although hopefully my need for it will be coming to an end pretty soon.

Oh the >10,000iu eod dose was just an example of a very high dose that could potentially cause harm, I wouldn’t want to test out using 20,000iu eod. But no I don’t actually think any male needs that much

1 Like

Agree with what @BrickHead just said Im going to be 31 next month. I started out on HCH mono therapy which was 500I.U EOD then E2 became uncontrollable so I switched to Testosterone. On top of that I have grade 3 varicocele bilaterally. So now I am taking 50I.U of HCG and 14mg of Testosterone ED and I seriously thought I was infertile and it turns out to be I’m not because my girlfriend just got pregnant

1 Like

It on;y takes one good swimmer and a little luck to get someone pregnant, so the odds are that most guys would be fine on low does HCG. There is evidence from rat studies that down-regulation occurs in Leydig Cells, which is as direct as anyone is going to have for a long time, possibly ever. We still don’t have any good studies of the effects of exogynous T in men and how long have steroids been around? The HCG studies are all going to be in women or rats. Receptors down-regulate, that’s what happens. The more of something you take, the more that happens.
If fertility is really important to someone, for whatever reason, it’s risk mitigation to not run HCG without a break. It won’t hurt anything to cycle and it improves his chances of success form a statistical point of view. Comparing our response to endogynous T to our expected response to any endogynous substance is unrealistic. The HCG is synthetic, it’s not being extracted from pregnant women. Our response to low dose natural production has no bearing on our response to synthetics. What is your normal LH production versus HCG doses? Down regulation of androgen receptors occurs in normal men in the presence of normal production, just not fast enough or severe enough to make much difference to the average man. It’s dangerous advice to tell a guy that has issues with these things (He’s on TRT after all) that there is no risk because you and your two buddies were fine, just ignore what the science points to.

Yea most of studies on HCG desensitization are not clinical studies. This is because HCG desensitization does not happen clinically in FDA approved dosages. There is a single study on men that showed a very small leveling on T production, but again this was in dosages above 5,000 IU for a single dose.

In 10 years, we have never seen anyone desensitize their leydig cells. What I mean is no matter what every single male we have ever seen, HCG will make the testes stimulate T at the right dosage. That doesn’t mean the testes will continue to produce T upon cessation, but during HCG mono-therapy there is always a boost in TT production. Hope this makes sense.

Edit: To add I think some may confuse down regulation with desensitization. Since HCG has a biphasic pattern there is some down regulation after a shot, but this was shown to last only up to 72 hours and is temporary. This is why we think HCG should not be injected more than 2-3 per week.

Just my 2 cents

It makes sense. It’s a tough subject because how do you actually show down regulation (or to an extent desensitization) without sampling the cells? And nobody is volunteering to take shots for a year or 5 years and then sacrifice one of the boys to see what happened. Although I guess you’d have to sacrifice one up front and then the second one down the road for an accurate comparison. But if you are not currently trying to conceive, it’s just an expensive extra thing to dial in to your mix as far as full-time use goes. A run of a month or so here and there will preserve size.

1 Like

We have seen men on TRT crank the HCG up to 1500 IU 3x a week (not crazy high like studies) and get pregnant in just a couple to 6 weeks. Multiple times, some are my close friends.

So our advice for those on testosterone, or have been on testosterone just drop the T for a month and up the HCG dosage and see what happens. You would be surprised how good you still feel on the HCG. A lot of people worry about really high estradiol but we have not seen it. Chances are this will work.

If not then drop the HCG and do Climid for 6 weeks and that almost always works. I know guys that have been on TRT 10 years and that worked, with both of their kids.

Also I know size seems important but the truth is the leydig cells only make up 10% of the teste so unfortunately it is a poor indicator of function. The truth is we have not seen a guy not be able to get prego yet under any scenario, and have had a handful realize it was actually the wife after going getting sperm tested after the HCG mono.

If you are not trying to conceive there are other benefits to HCG, like progesterone production which is responsible for endothelial function and it we see the adrenals shut down eventually if you do not stimulate the HPTA. Not to mention men tend to lose sensitivity down there if they don’t keep the motor turning, but then again some men feel no ill affects without concomitant HCG and TRT. So it is in the eye of the beholder as far as value goes, but I would definitely at least run HCG a couple times a year, maybe at a higher dosage, just to make sure they are capable of functioning.

Sorry for the rant, hope this helps.

Perfectly reasonable, size is just about vanity. I think that’s kind of the argument, why just be on it if you don’t have to? There are risks involved, and nobody seems to think cycling hurts anything.

1 Like

What do you mean that men start to lose sensitivity down there? Because that is something I have been struggling with for sometime now and I’m wondering sense you brought it up if you could help me connect the dots by explaining to me what you mean and if there is anything I could do to help increase my sensitivity?

Decreased blood flow, for starters. If they’re just hanging out and not doing anything…do the math. Cycling HCG is a positive as long as you don’t get negative sides.

1 Like

A lot of men report not having as much feeling down there during intercourse and when you finish when they are really shut down.

HCG seems to stimulate that sensitivity. There are other things involved in the HPTA feedback loop besides just testosterone production. So when the HPTA is completely shut-down a lot of other hormones are not being produced, even though you are replacing testosterone.

So taking HCG can bring this sensitivity per se back. Hope this helps.

So do you think the solution is to increase the HCG?
What other hormones are shut down maybe i should do blood work on them.

What are your numbers? HCG dose? E2 level? Test? Frre Test?