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Human Chorionic Gonadotropin (hCG) - Usage and mechanism of action

GetXXL

GetXXL

Member
Oct 3, 2012
27
1
#1
I wrote this quite a while ago, thought I might share it here as well. There are some things in it I'm not particularly fund of, but ok.

Unfortunately, a lot of bodybuilders to date still do not seem to appreciate the value of hCG usage during a cycle in regards of post cycle HPG axis recovery. For some it feels weird to use something, which serves the same goal as PCT, during a cycle instead of after. For others it is odd to use 'low dosages' of something they are used to inject after their cycle, instead of during. Allegedly they assume these 'low dosages' do not do anything at all, seemingly because their HPG axis is suppressed anyhow. Moreover, some claim it to be 'purely cosmetic', without any functional purpose.

If anything, and I would like to make this loud and clear, correct hCG usage is the absolute pinnacle of HPG axis recovery.

What is Human Chorionic Gonadotropin (hCG)?
As most do know, hCG is an endogeneous hormone. Normally hCG is solely produced by pregnant women and men do not usually produce it in signifcant amounts. The hormone has quite a lot in common with something both sexes produce, namely LH. LH is, as most of you reading this will know, secreted by the anterior pituitary in response to GnRH and binds to the LH Receptor (LHR) on Leydig cells to stimulate the steroidogenesis.

Structurally, both LH and hCG belong to a group of glycoproteins and exist out of two subunits, the alpha- and beta-subunit. LH and hCG share the same alpha-subunit, as do TSH and FSH. However, they differ in their beta-subunits. Nevertheless, LH and hCG are 80% homologous in their beta-subunit. Furthermore, they are ligands to exactly the same receptor, the LHR (also commonly dubbed the LHCGR). Since the LHR is a membrane bound receptor (more specific a G-protein coupled receptor),activating the LHR works much like an on/off switch, contrary to nuclear receptors which form a complex with their ligands and translocate to the nucleus to initiate gen transcription, and thus the response can be directly influenced by their ligands (be it by binding to a different hormone response element, recruiting different transcriptional cofactors, etc.). So unless hCG (or LH for that matter) also bind to other receptors with significant affinity, the two are biologically very much alike. Any difference would evolve from their pharmacokinetic differences. Notably, the big difference between the two is their half-lifes. Whereas hCG has a half-life of about 36 hours (depending on the literature source, I've also seen about 24 hours, but you'll get the point),the half-life of LH is less than half an hour.

So what would this imply? Well, for one instance, under physiological normal conditions, LH is secreted in pulses (as is GnRH). Most likely because this is efficient, as their receptors get temporarily desensitized. Mention the word 'temporarily'. Of most users concern is that, for some reason, the receptors get permanently desensitized, however this is not the case. The occuring desensitization is actually quite normal and is common among a lot of G-protein coupled receptors. As mentioned before, the LHR is a G-protein coupled receptor. G-protein coupled receptors exert their effects through G-proteins, activating a signaling cascade through several protein kinases fosforylating their downstream effectors. Now, this fosforylation can lead to (de)activation of the fosforylated molecule. The 'problem' is that the LHR also gets -temporarily- fosforylated due to its own cellular response, deactivating it, as it can not bind to a G-protein. Now, and I would lik to repeat this, this is a completely normal and commonly occuring biological process. It happens ALL the time.

Furthermore, if we were to look to a clinical study evaluating a rather high bolus of hCG through injection (Trinchard-Lugan et al. [2002]),we can see that, even on multiple injections, a strong steroidogenic response is retained. Implying this autofosforylation process probably is not of practical concern to us. For the ones wondering, we also see that SQ injection hardly differs from IM injection; SQ injection really is fine. Do not bother yourself with IM injections and suit yourself with SQ injections by means of a painless insulin needle.

Practical implications?
Now we get to the good part. As known, without a doubt, primary hypogonadism is the major obstacle in post-cycle recovery. Not secondary hypogonadism, as it usually resolves spontaneously and can be fastened by usage of SERMs (even leading to supraphysiological levels of the gonadotrophins). Now this is exactly where hCG is interesting, prevention of primary hypogonadism. Resolve this, and your only concern is secondary hypogonadism which is quickly recovered. As most readers know, when you apply AAS, you suppress your own endogeneous testosterone production due to suppression on level of the anterior pituitary as well as the hypothalamus, both of which is the result of the androgens and estrogens from AAS usage. Now, when the hypothalamus is suppressed concerning the secretion of GnRH, the anterior pituitary is strongly inhibited in its secretion of the gonadotropins: LH & FSH.

LH binds to the LHR on the Leydig cells and FSH binds to the FSHR on the Sertoli cells. The Leydig cells is where steroidogenesis take place, as they have all the machinery (steroidogenic enzymes) in place to do so. Binding of LH and LHR is a very potent signal to stimulate the steroidogenesis. In addition, some other factors also enhance this, this includes Sertoli derived factors working in paracrine manner (which are secreted on binding of FSH on the FSHR),as well as IGF-I, etc. But of primary concern is the activation of the LHR itself on the Leydig cell. If it not gets activated, testosterone production stalls and you'll be hypogonadal. As a result, intratesticulair testosterone levels drop immensly (normally they are roughly a 100 times higher than circulating androgens, hence why your exogeneous androgens do not matter concerning this),which is a prime paracrine regulator in the testes. As known, the testes experience, sometimes extremely severe, atrophy.

Now post-cycle, when your testes have shrunk, and you stimulate your gonadotrophins by means of a SERM, the hypothalamus and anterior pituitary part of the axis is OK. They'll even be heightened. But your testes fail to provide an adequate testosterone response! The steroidogenesis is impaired. This can take weeks or even months to recover, despite heightened gonadotropin levels. In some cases I have read this to be permanent.

Now, this is not what you want. So what you want is to maintain the internal milieu of the testes as much as possible, so recovery is quick after a cycle. By injecting hCG during a cycle (and I know this probably already made sense to a lot of you),you keep activating the LHR and the steroidogenesis will continue. You WILL continue producing testosterone during your cycle and you WILL maintain your intratesticulair testosterone (ITT) levels.

When we delve into the literature, a study by Coviello et al. (2005) provides us with some straight on directly useful results. In this study, they recruited healthy men and suppressed their HPG axis by means of testosterone injection (this is as close as to 'practical' for bodybuilders it will get). In addition, they seperated these men into groups, only varying in the amount of hCG they applied. They had a control group injecting no hCG, and three groups injecting 125 IU, 250 IU and 500 IU of hCG EOD. They measured, among other variables, LH, FSH and ITT. As expected, the gonadotropins were heavily suppressed. Now interestingly, the group applying 250 IU hCG EOD expressed ITT levels very similar to baseline. This implies that this amount of hCG was stimulating the steroidogenesis in the Leydig cells as LH would under physiological normal conditions!

Now, one drawback of this study is that it could have been that the injected testosterone, due to some unkown and mysterious mechanism, influenced the ITT (it is again, highly unlikely that it would, as ITT levels are roughly 100~ higher than circulating). So ok, in 2010, Roth et al. evaluated if the testosterone might have influenced the results by suppressing the HPG axis by means of an GnRH antagonist acyline. This was, as expected, not the case. Unfortunately, the highest dose evaluated in this particular study was 125 IU EOD, as the goal was not to provide juiceheads with valuable information, but rather from a fertility perspective (roughly about 20% of normal ITT is required to maintain normal spermatogenesis).

However, another drawback of this study, is that it evaluated the effects over 3 weeks. We do not know how this could evolve over a longer period of time. So unfortunately, this is the best we got and have to go with. Of course, other factors, besides activation of the LHR and its resulting signaling cascade, could play a part then. It is logically to assume that, if something like that was the case, addition of FSH could solve this. But data is lacking. Nevertheless, I'm convinced hCG on is perfectly adequate, derived from empirical evidence.

So it seems 250 IU hCG EOD is an adequate and valuable protocol, some might to dose it even higher due to interindividual variability. Besides, the underground manufactured hCG might be a (little) underdosed, adding to 'round up' this recommendation.
 
M

marshallherd

New Member
Mar 5, 2014
8
0
#2
It makes complete sense and you explained it well. I've never personally used on cycle. Are you saying to start a couple weeks after beginning the cycle or like mid cycle and continue to pct obviously?
 
GetXXL

GetXXL

Member
Oct 3, 2012
27
1
#3
It makes complete sense and you explained it well. I've never personally used on cycle. Are you saying to start a couple weeks after beginning the cycle or like mid cycle and continue to pct obviously?
Start with it the moment you suppress your gonadotropin secretion, i.e. first week of your cycle.
 
dr jim

dr jim

MuscleHead
Apr 7, 2014
785
168
#4
Nice physiologic summary Big Guy but to many mates believe the literature extrapolation from HgHg to AIH is justifiable. Well the truth is, if you look at ALL those studies using HGH for either sterility or "low T" the common pathway involves suppressed TESTOSTERONE SECRETION.

However in no instance do the TT levels become supraphysiologic regardless of the HCG dosing. This is exactly what would be required for HCG to be "effective" during a cycle. Thus I've found HCG has NO IMPACT on TT levels during a cycle providing the level is at least 1000ng/dl. (There are a couple articles that indirectly support this OBSERVATION)

Thus during a cycle when TT levels are supra-physiologic HCG has no significant benefit on "maintaining TT production", although it does reduce testicular atrophy by inducing spermatogenesis. The latter is obviously beneficial during PCT.

Consequently HCG is most effectively used when the cycle is completed.

jim
 
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dr jim

dr jim

MuscleHead
Apr 7, 2014
785
168
#5
Hey understand I'm not knocking BIG BIG GUY (who is obviously a stand up mate, is well read, and willing to share his knowledge) OR others who prefer to use HCG during a cycle (and I know many do).

Does HCG help, perhaps yet over the course of 12 weeks, another 100 bucks will be added to a cycles cost, using a 250IU QOD dosing regimen!

I'm just trying to emphasize, on a comparative basis, it's MUCH more important to utilize HCG AFTER a CYCLE rather than during.

JIM
 
GetXXL

GetXXL

Member
Oct 3, 2012
27
1
#6
Nice physiologic summary Big Guy but to many mates believe the literature extrapolation from HgHg to AIH is justifiable. Well the truth is, if you look at ALL those studies using HGH for either sterility or "low T" the common pathway involves suppressed TESTOSTERONE SECRETION.
Yes, primary hypogonadism is the main culprit, as secondary hypogonadism is usely resolved rather quickly.

However in no instance do the TT levels become supraphysiologic regardless of the HCG dosing. This is exactly what would be required for HCG to be "effective" during a cycle. Thus I've found HCG has NO IMPACT on TT levels during a cycle providing the level is at least 1000ng/dl. (There are a couple articles that indirectly support this OBSERVATION)
Why would you require supraphysiological TT levels? And why even bother with TT levels (which would be irrelevant to measure when you're using testosterone or an analog which crossreacts in the measurement)? All what it's about, is maintaining intratesticular testosterone levels, as testosterone is the primary paracrine regulator in the testes maintaining size and resultingly responsitivity to LH (literally preventing primary hypogonadism).

Thus during a cycle when TT levels are supra-physiologic HCG has no significant benefit on "maintaining TT production", although it does reduce testicular atrophy by inducing spermatogenesis. The latter is obviously beneficial during PCT.
Then how come we aren't on the same page? It prevents testicular atrophy and secondary to that the impaired response to LH after a cycle (i.e. primary hypogonadism). It's not really up to debate for me, as I've seen guys coming off after >1 year without any hassle due to hCG usage during their cycle, but I'm really curious why you advocate it after a cycle rather than during, whilst we are clearly on the same page with all the rest.
 
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dr jim

dr jim

MuscleHead
Apr 7, 2014
785
168
#7
Because HCG does NOT reverse Leydig cell atrophy! What it does do indirectly is maintain sterility during a cycle, which maintains testicular size!

HCG DOES NOT significantly increase TT levels DURING a cycle and I would be happy to entertain any evidence (or view) to the contrary. This should become obvious reviewing studies where upwards of 10K IU was used. The MAX TT level achieved was somewhere between 1-1.5K and DID NOT INCREASE THEREAFTER in spite of the HCG dose used.

The comparison? Someone whom is cycling AAS, their TT levels are almost always above 1.5k so what effect will HCG have, ZIPPO, IME. That opinion is based on labs I've done on several patients and supported by the literature.

Hey BIG GUY, I've nothing but respect for you and your opinion mate! YOUR A WELCOME addition to any evidence based forum IMO!

JIM
 
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dr jim

dr jim

MuscleHead
Apr 7, 2014
785
168
#8
Yes, primary hypogonadism is the main culprit, as secondary hypogonadism is usely resolved rather quickly.


Why would you require supraphysiological TT levels? And why even bother with TT levels (which would be irrelevant to measure when you're using testosterone or an analog which crossreacts in the measurement)? All what it's about, is maintaining intratesticular testosterone levels, as testosterone is the primary paracrine regulator in the testes maintaining size and resultingly responsitivity to LH (literally preventing primary hypogonadism).


Then how come we aren't on the same page? It prevents testicular atrophy and secondary to that the impaired response to LH after a cycle (i.e. primary hypogonadism). It's not really up to debate for me, as I've seen guys coming off after >1 year without any hassle due to hCG usage during their cycle, but I'm really curious why you advocate it after a cycle rather than during, whilst we are clearly on the same page with all the rest.
That is the leap many have assumed BUT the fact is the atrophic reversal is almost exclusively the result of SERITOLI CELL (which encompasses somewhere between 95-99% of the testicular cellular matrix) development and maturation, while those LEYDIG cells ( at roughly 1-2% of the testicular cellular matrix) lie relatively dormant.

This is evidenced by the limited response (a proportional rise of TT) to HCG above the optimal therapeutic dose.

jim
 
dr jim

dr jim

MuscleHead
Apr 7, 2014
785
168
#9
OPTIMAL HCG use is after the cycle has ended but PRIOR to SERM therapy, and in that circumstance HCG is a Godsend BUT during a cycle, NOT !
 
GetXXL

GetXXL

Member
Oct 3, 2012
27
1
#10
Because HCG does NOT reverse Leydig cell atrophy! What it does do indirectly is maintain sterility during a cycle, which maintains testicular size!

HCG DOES NOT significantly increase TT levels DURING a cycle and I would be happy to entertain any evidence (or view) to the contrary. This should become obvious reviewing studies where upwards of 10K IU was used. The MAX TT level achieved was somewhere between 1-1.5K and DID NOT INCREASE THEREAFTER in spite of the HCG dose used.

The comparison? Someone whom is cycling AAS, their TT levels are almost always above 1.5k so what effect will HCG have, ZIPPO, IME. That opinion is based on labs I've done on several patients and supported by the literature.

Hey BIG GUY, I've nothing but respect for you and your opinion mate! YOUR A WELCOME addition to any evidence based forum IMO!

JIM
You're mixing serum testosterone up with intratesticular testosterone. Due to the origin of synthesis, intratesticular testosterone is roughly a hundred fold higher than in circulation, therefor the testosterone you inject will not maintain that concentration required for optimal spermatogenesis and maintaining size of the testes. I also mention this in my article:
As a result, intratesticulair testosterone levels drop immensly (normally they are roughly a 100 times higher than circulating androgens, hence why your exogeneous androgens do not matter concerning this),which is a prime paracrine regulator in the testes. As known, the testes experience, sometimes extremely severe, atrophy.


That is the leap many have assumed BUT the fact is the atrophic reversal is almost exclusively the result of SERITOLI CELL (which encompasses somewhere between 95-99% of the testicular cellular matrix) development and maturation, while those LEYDIG cells ( at roughly 1-2% of the testicular cellular matrix) lie relatively dormant.

This is evidenced by the limited response (a proportional rise of TT) to HCG above the optimal therapeutic dose.

jim
I had roughly different numbers in my head, but besides that, testosterone is the prime factor responsible for maintaining testes size, it works in a paracrine fashion. So it doesn't matter the seminiferous tubules containing the Sertoli cells make up most of the size of the testes, it is testosterone doing the work intratesticular. Not only can it prevent atrophy and the resulting decreased response to LH (as is the case after a cycle),it CAN reverse atrophy as also evidenced by this trial:
Yang, Luo, et al. "Application of hormonal treatment in hypogonadotropic hypogonadism: more than ten years experience." International urology and nephrology 44.2 (2012): 393-399.

However, I advocate usage during a cycle as it prevents atrophy completely with the right dosage. The only problem which remains is that people mix 5000 IU with bacteriostatic water and store it for several weeks. Peptides decay, and so will hCG, moreover fenols such as benzylalcohol tend to promote decay of peptides as we already know from several other peptides. So most people are probably underdosing their hCG due to this. Solution is 'simple' by dosing higher (making up for the loss). I've worked with enough people by now who employed this, and with great success.
 
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