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Avoiding HCG Burnout With NAC

bubbafrombama

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FYI, you can also find the below article in the December 2011 issue of Muscular Development on pages 194-196.

Avoiding HCG Burnout With NAC

Many young bodybuilders blindly begin taking anabolic-androgenic steroids (AAS), focused only on the immediate acquisition of greater strength and muscle mass. Without condoning AAS misuse in an unsupervised fashion, and standing against AAS abuse by adolescents, it is a testament to the effectiveness of AAS that the benefits can be achieved outside of the appropriate environment or dosing schedules. Unfortunately, this greatly increases the risk of adverse side effects.

This article addresses one of the most common adverse effects of supraphysiologic AAS use—suppression of endogenous (natural) testosterone production and testicular atrophy (shrinkage), as well as a relevant and applicable finding recently presented in the scientific literature. This focus is not meant to diminish the impact of other potential adverse effects. It is meant to foster discussion that may lead to a better understanding of a predictable adverse effect common to an underserved population.

Testosterone is naturally produced within the testes, in specialized cells called "Leydig cells" after the German anatomist Franz Leydig who first identified them in 1850. An alternate term, "interstitial cells of Leydig" refers to the same cells. The production of testosterone is regulated by a negative feedback loop system called the Hypothalamic-Pituitary-Gonadal axis, or HPG axis (testes are male gonads, ovaries are female gonads).(1) The hypothalamus and pituitary are two glands located near the brain stem. They release stimulatory "releasing hormones" when monitored hormones that regulate the metabolism are below a threshold concentration in the blood. When a monitored hormone exceeds the "ceiling" concentration, releasing hormones are no longer released until the hormone concentration falls into the lower range of normal.

So, to make it clearer, the negative feedback loop means when there is not enough testosterone in the blood, the brain releases the "GO" signal and when there is too much testosterone, the "GO" signal is shut off and no more testosterone is produced until the excess is cleared from the blood. The "GO" signal that directly affects the Leydig cells of the testes is a pituitary hormone called "LH." It is released when the hypothalamus detects a low testosterone concentration and the hypothalamus then releases its signaling hormone, "LHRH," that orders the pituitary to release LH. So, low testosterone leads to LHRH release, which leads to LH release, resulting in increased testosterone until the hypothalamus says "enough!"

When LH stimulates the Leydig cells, a series of enzymes are activated, creating testosterone from cholesterol. Most people fail to realize that cholesterol is the building block from which all steroids are created. This is why some cholesterol-lowering drugs also lower testosterone.(2) LH is not very potent and is short acting. Thus, the HPG axis is triggered by fluctuations in testosterone multiple times daily. For the average man, the peak testosterone value is approximately 30 percent higher than the low value. Human chorionic gonadotropin (hCG) is approximately four times as potent as LH and stimulates the same receptors, generating a stronger response by the Leydig cells. Typically, hCG — a hormone produced by the placenta of a fetus during pregnancy— is only present in pregnant women. It is used as part of a cocktail of hormones to treat women with fertility challenges.

HCG CUTS BOTH WAYS

There are several indications for hCG use in males: cryptorchidism (undescended testes), infertility and persistent hypogonadism secondary to androgen exposure (i.e., post-cycle recovery). hCG was once considered to be an automatic method for restoring natural testosterone production post-cycle. It is likely that most AAS users would recover natural testosterone production over time anyway. However, several cases emerged of persistent hypogonadism (low testosterone) despite hCG post-cycle treatment.(3,4) Typically, these cases either resolved after many months or responded to hCG in conjunction with clomiphene, hMG, Nolvadex or an aromatase inhibitor. Recently, the use of triptorelin has proven effective in a limited number of refractory cases of AAS-induced hypogonadism (low testosterone post-cycle).(4)

Another trend among both aging-management practitioners and illicit AAS users is the use of low-dose hCG at the same time as testosterone or AAS.(5,6) The intent is to keep the testes stimulated during the period that they would normally be dormant due to the suppressive effect of testosterone replacement or supraphysiologic AAS use on the HPG axis. To be clearer (this is a lesson in endocrinology, after all—expect a little bit of a mental workout), when the testes are shut down by testosterone/AAS, an appropriately scheduled low-dose hCG protocol may maintain testes size, function and hasten post-cycle/therapy recovery of natural testosterone production.

Most AAS users are convinced of the necessity of using hCG post-cycle; many during cycle as well. However, inappropriately dosed, hCG can actually impair natural testosterone production and even cause the Leydig cells to die off.(6,7)

That last sentence should have caused a double take. Use hCG wrongly, and not only do the testes stop making testosterone but the Leydig cells die in a process called apoptosis. This has been shown in animal studies and is consistent with the results observed in cryptorchid men treated with hCG.(8)

Briefly, hCG needs to be used sparingly and at low dose. High doses, and especially prolonged use (greater than 10 days) of high doses, initiate a series of biochemical reactions that result in a great amount of oxidative damage as well as starting the process of apoptosis (cell death).This agrees with observations made in men suffering from tumors that produce hCG. Men with these hCG-producing tumors see an increase in testosterone as well as other steroid hormones (17-hydroxyprogesterone, estradiol, etc.) when hCG concentration is low. When tumor-produced hCG results in a high concentration of hCG, testosterone concentration is actually lower than normal and the testosterone:estradiol concentration also falls.(9)

A trial compared dosing hCG at 1,500, 3,000 and 4,500 IU daily for three days. No difference among the doses was noted, suggesting that the maximal stimulation occurs at or below 1,500 1U.(10) Repeated daily 1,500 IU dosing maintains the testosterone response, but it is not cumulative as testosterone is rapidly cleared. Also, hCG's effect is short-lived, with testosterone peaking within a day or two and then dropping. Compared to a single 1,500 IU injection, five daily injections of 300 IU resulted in a greater total testosterone increase.(11) Another study showed a maximal testosterone increase at 5,000 IU in response to a single injection, but estradiol increased considerably more.(12) This is consistent with the experience some bodybuilders report of gynecomastia flaring up during hCG use.

Anecdotal reports from AAS-using men support dosing hCG at or below 500 IU for daily or alternate day use. Dr. John Crisler utilizes hCG for some of his patients on testosterone replacement therapy (allthingsmale.com) and his protocol describes 250 IU administered twice weekly— two days and one day prior to testosterone injection if administered via injection. He has established a therapeutic limit of 350 IU, noting an adverse increase in testicular aromatase and Leydig cell desensitization.(5)

THE NAC FACTOR

These practical observations lend credence to the findings of Dr. Aggarwal and colleagues reported in the journal Molecular and Cellular Endocrinology.(8) Using rats, they followed the response and cellular effects of hCG administration over 30 days, compared to placebo. They noted that though testosterone initially increased over the first week, by the end of the month there was a significant decrease in circulating (blood) testosterone. Also, the signaling system of the Leydig cells was not generating as strong a response to hCG. Aggarwal et al. noted in an earlier study that hCG induced a significant rise in oxidative stress within the Leydig cells. In fact, when compared to the control group, the Leydig cells had greater lipid peroxidation (damage), reduced glutathione (a major antioxidant) and reduced enzymes and capacity of the antioxidant system. This was associated with a marked increase in the signals that promote apoptosis. Additionally, signals that protect against apoptosis were reduced in the hCG-treated animals' Leydig cells.

Recognizing the role and potency of glutathione in protecting against oxidative damage, Aggarwal's group provided N-acetylcysteine (NAC) to certain groups of rats to look at the effect of NAC given once weekly or twice weekly- either with or without hCG. So, some rats received nothing; others received NAC once weekly; others received NAC twice weekly; others received only hCG daily; others received hCG daily and NAC once weekly and lastly, a group received hCG daily and NAC twice weekly.

NAC is a modified amino acid that is a direct precursor to glutathione. By itself, it had no significant effect upon the rats or the Leydig cells. However, during the oxidative stress induced by hCG, NAC was able to restore Leydig cell function such that it was as responsive and was not spiraling into an apoptotic state- BUT ONLY WHEN DOSED TWICE WEEKLY.(8) As the hCG insult was being administered daily, and glutathione is used up during ongoing oxidative damage, it is understandable that the once-weekly NAC dosing was unable to sustain Leydig cell status under the repeated hCG attack. It would have been of interest to see if more frequent NAC dosing could have provided any further benefit.

Glutathione reduces oxidative damage by allowing itself to be oxidized, rather than essential molecules responsible for keeping cells alive and functioning. It is like a bodyguard that jumps in front of a bullet. After being "shot," glutathione can be regenerated by an enzyme called glutathione reductase. Unfortunately, the pace of regeneration can easily be outstripped by the rate of oxidative damage when a cell is stimulated to a higher rate of function. A similar pattern of oxidative damage in the testes of rats has been noted with the administration of D-aspartic acid.(13) It has been noted that glutathione can be increased through supplementation with NAC, lipoic acid and vitamin D; other products also can positively affect glutathione content in the body.(14)

Thus, it appears that the research of Aggarwal provide a basis for a deeper understanding of the effects of hCG on the Leydig cells, and a method of reducing the desensitization to hCG treatment over a period exceeding approximately 10 days. In agreement with the observations of bodybuilders and aging management clinicians, the benefits of hCG are obtained when used with discretion in moderation. Proper treatment to protect or restore testes function appears to require no more than 350-500 IU per day, with as little as 250 IU twice a week being capable of offering benefit. Even under this limited stimulation, oxidative damage is likely to increase, making it reasonable to suggest the inclusion of NAC, alpha-lipoic acid and vitamin D in the nutritional support protocol during this time. Even when hCG is not being administered, these are practical supplements to take for health purposes, though they are not likely to have a noticeable effect on testosterone production. It is worth noting that there is a documented association between vitamin D and testosterone values in older men.(15)

The take-home message is that short-term hCG for post-cycle treatment will likely achieve maximal effect near 1,500 IU, though elevated aromatase activity will induce unwanted estrogen-related adverse effects. The Leydig cells will face undue oxidative stress, and if such a dose were maintained for greater than one week, apoptosis and reduced testosterone production may ensue. Optimal dosing appears to be within a range between 250-500 IU, administered two to five times weekly with antioxidant support (NAC, lipoic acid and vitamin D). Even done correctly, there remains a risk of long-term suppression with the use of high-dose AAS that does not respond to hCG or other post-cycle therapy. Bodybuilders should not disregard this potential risk, as it may lead to lifetime dependence upon testosterone replacement or testosterone deficiency if it goes undiagnosed or untreated.

By Daniel Gwartney, M.D.

References:
1. Araujo AB, Wittert GA. Endocrinology of the aging male. Best Pract Res Clin Endocrinol Metab, 2011 Apr;25(2):303-19.
2. Corona G, Boddi V, et al.The effect of statin therapy on testosterone levels in subjects consulting for erectile dysfunction. J Sex Med, 2010 Ap r;7 (4 Pt 1):1547-56.
3. Boregowda K, Joels L, et al. Persistent primary hypogonadism associated with anabolic steroid abuse. Fertil Steril, 2011 Jul;96(1):e7-8.
4. Pirola I, Cappelli C, et al. Anabolic steroids purchased on the Internet as a cause of prolonged hypogonadotropic hypogonadism. Fertil Steril, 2010 Nov;94(6):2331.e1-3.
5. Crisler J. An update to the Crisler hCG protocol. Available at allthingsmale.com/publications.html, accessed September 12, 2011.
6. KarilaT, Hovatta 0, et al. Concomitant abuse of anabolic androgenic steroids and human chorionic gonadotrophin impairs spermatogenesis in power athletes. Int J Sports Med, 2004 May;25(4):257-63.
7. Aggarwal A, Misro MM, et al. Adverse effects associated with persistent stimulation of Leydig cells with hCG in vitro. Mol Reprod Dev, 2009 Nov;76(11):1076-83.
8. Aggarwal A, Misro MM, et al. Differential modulation of apoptotic gene expression by N-acetyl-l-cysteine in Leydig cells stimulated persistently with hCG in vivo. Mol Cell Endocrinal, 2011 Aug 12. [E-pub, ahead of print]
9. Rieu M, ReznikY, et al.Testicular steroidogenesis in adult men with human chorionic gonadotropin-producing tumors. J Clin Endocrinol Metab, 1995 Aug;80(8):2404-9.
10. Repcekov6 D, Mikulaj L. Plasma testosterone response to HCG in normal men without and after administration of anabolic drug. Endokrinologie, 1977 Feb;69(1):115-8.
11. Smals AG, Pieters GF, et al. Differential effect of single high dose and divided small dose administration of human chorionic gonadotropin on Leydig cell steroidogenic desensitization. J Clin Endocrinol Metab, 1984 Feb;58(2):327-31.
12. Cailleux-Bounacer A, ReznikY, et al. Evaluation of endocrine testing of Leydig cell function using extractive and recombinant human chorionic gonadotropin and different doses of recombinant human LH in normal men. Eur J Endocrinol, 2008 Aug; 159(2):171-8.
13. Chandrashekar KN, Muralidhara. D-Aspartic acid induced oxidative stress and mitochondria) dysfunctions in testis of prepubertal rats. Amino Acids, 2010 Ma r;38(3):817-27.
14. Exner R, Wessner B, et al. Therapeutic potential of glutathione. Wien Min Wochenschr, 2000 Jul 28;112(14):610-6.
15. Pilz S, Frisch S, et al. Effect of vitamin D supplementation on testosterone levels in men. Horm Metab Res 2011 Mar;43(3):223-5.
 
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I take NAC daily while on orals...hmm. Great info, thanks for the read!
 
I take NAC daily while on orals...hmm. Great info, thanks for the read!

Good to hear! I've been taking NAC for a few months now, so like you, it was nice to pick up MD and read this article. I added in Alpha-Lipoic Acid, as well, right after reading it. I already get a good dose of Vitamin D a day in a multi. I know that my red blood cell count was high on all my bloodwork a couple of weeks ago, and NAC is known for doing that, as well (plus, I've been living at 6k feet for 3 years, too).
 
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Great info. When it comes to protecting yourself and doing things right this hits the nail on the head. There is so many different approaches out there that it is hard to weed though them all and make a educated decision but this seems to sum it up nicely.
 
Really great article. Thank you for sharing this one.

Cheers
An Old Dawg
 
So pretty much stick to 250iu twice a week w/NAC?
 
Important information...good to know. Thanks for posting.
 
Great article. NAC is incredible. Be sure to never take it before you go to bed because it thins out your mucous and you'll want to spit it out. Also, try taking it an hour or so before you go out drinking to drastically reduce a potential hangover. :)

Thanks again for posting this article!
 
Great info!! Great to know that NAC has more benifits besides liver health.
I have been using 600mg ED for years now.
 
It said to take NAC twice a week. Does it hurt the hcg if taken every day? Also what was the dosed amount of NAC in this study?
 
It said to take NAC twice a week. Does it hurt the hcg if taken every day? Also what was the dosed amount of NAC in this study?

Cowboy, good questions to ask! Here's the actual NAC study:

http://www.ncbi.nlm.nih.gov/m/pubmed/21856376/

Differential modulation of apoptotic gene expression by N-acetyl-L-cysteine in Leydig cells stimulated persistently with hCG in vivo.

Abstract
The present study was designed to investigate the molecular mechanisms of NAC (150 mg/kg bw twice/week) action in vivo under repeated hCG (100 IU/rat/day) stimulation to adult rats. Leydig cell refractoriness led to a significant decline in serum testosterone and intracellular cAMP by day 30 of chronic hCG intervention which improved significantly following NAC co-administration. It inhibited the rise in lipid peroxidation, improved the activity of antioxidant enzymes along with intracellular glutathione and total antioxidant capacity in the target cells. Leydig cell apoptosis declined significantly (P<0.001) with down-regulation of upstream, Fas, FasL, caspase-8, Bax and caspase-9, JNK/pJNK and downstream caspase-3 and PARP. On the other hand, anti-apoptotic Bcl2, NF-kβ, and Akt were up-regulated. Taken together, the above findings indicate that the specificity of NAC action was not restricted to regulating marker proteins in the extrinsic and JNK pathways as seen in vitro but extended to include intrinsic pathway of metazoan apoptosis as well.


And to answer your question about taking it every day and it potentially affecting hCG, I'd say no.
 
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Thanks Bubba. Great info..

So basically a 200lb man would take about 300mg of NAC twice a week with HCG (250-500 ius).

I have always used HCG during my cycles but have never used NAC along with it. Most of the studies i have read say that long term use of HCG in low dosages (250-500 ius twice a week), during cycles, has no negative effect on the testes and their ability to rebound and start back up. Sounds like adding the NAC to equation might be even better.
 
Thoughtful and insightful info. I understand well how useful HCG can be and appreciate such articles. There's a lot of opinions around on what to do, but cited articles are always the best! Bump.
 

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