Mechanism of Suppression
By William Llewellyn
By most accounts, nandrolone is an extremely mild steroid. It is likely the least androgenic in nature of all the anabolic/androgenic compounds, often to the point of interfering with libido. And though it does aromatize, it does so at a very slow rate. In fact, it’s probably the least estrogenic of all the steroids that are capable of aromatizing to estrogen. Yet, there is one trait we seem to know well when it comes to nandrolone; it strongly suppresses the Hypothalamic-Pituitary-Testicular Axis (HPTA).
Now, when used in doses sufficient to stimulate muscle growth, pretty much every steroid suppresses the HPTA. However, we have been using nandrolone long enough to know it’s particularly strong in this regard. For such a weakly androgenic and estrogenic steroid, we would expect its suppressive nature to be more on par with anabolics such as Primobolan and oxandrolone. Most often, however, bodybuilders liken Deca to the primary androgen testosterone when speaking of testicular atrophy and HPTA suppression. As of yet, we have had no solid explanation of why. In this article I’ll discuss the functioning and steroid-related suppression of the HPTA, and propose a new mechanism that may account for the strong nature of nandrolone and some of its derivatives.
The Hypothalamic-Pituitary-Testicular Axis is responsible for regulating the output of testosterone in the male body. At the top of the axis is the hypothalamic region of the brain, which releases a hormone called Gonadotropin Releasing Hormone (GnRH, formerly called LHRH). GnRH stimulates the pituitary to release the two gonadotropic hormones LH (Luteinizing Hormone) and FSH (Follicle Stimulating Hormone). Both hormones, but LH primarily, stimulate the Leydig’s cells in the testes to secrete testosterone.
Some of the same sex steroids that are produced as a result of this process are integral in a negative feedback mechanism, however, which works to prevent the oversecretion of testosterone. The primary hormone involved in this suppression is estradiol, which is, of course, the aromatized byproduct testosterone. High estrogen levels serve as a signal to the hypothalamus to slow the release of GnRH, and also desensitize the pituitary to this hormone. This in turn trickles down to the testes receiving less stimulation via LH. In addition, androgens and progestins can also cause a suppression of LH and testosterone output via the same target sites. Were that not the case, most non-aromatizable steroids would be unable to affect endogenous testosterone release. Unfortunately, they are.
Now, when we are taking a steroid such as an injectable testosterone, naturally we expect our body to read the heightened androgen and estrogen levels and slow the release of endogenous testosterone. When we look at studies to try and understand what is happening, we see the drop in testosterone is directly correlated with a drop in the level of LH,1 which again is the primary stimulus for the testes to release testosterone. Studies with Primobolan, a non-aromatizable steroid, also show a drug-induced suppression of gonadotropins, even before testicular functioning is disrupted.2 The same T/LH correlation was seen in studies with oxandrolone3 and methandrostenolone.4
Until fairly recently it was our understanding that HPTA suppression from all anabolic/androgenic steroids occurs the same way, at the top of the axis, through sex steroid induced inhibition of the release of hypothalamic GnRH and pituitary LH. From what we know of the negative feedback inhibition of sex steroids, this seemed like a logical assumption to make. But a study at the University Hospital Utrecht in The Netherlands suggests that nandrolone can suppress endogenous testosterone production though a very different mechanism; one that exists outside of the normal suppression of gonadotropic hormones.
The study was published in Acta Endocrinologica5 and its results were in striking contrast to everything we in the bodybuilding world have assumed about steroid-related HPTA suppression. In this experiment, 11 male patients between ages 44 and 62 were given injections of Deca-Durabolin over the course of 12 weeks. The total dosage given to each subject was only 450 milligrams. However, this was sufficient to suppress testosterone production throughout the course of therapy. In fact, testosterone remained below pre-treated levels three months after the last injection, at which point the study was concluded.
We are left to guess how long full HPTA recovery actually took. What was demonstrated in this investigation is shocking. Nandrolone decanoate strongly suppressed testosterone production but had no impact on serum LH. Suppression was not caused at the top of the axis, with a lowering of LH, as we would have expected. It is probably good that a higher dosage wasn’t used in this experiment, as the drug would likely have started suppressing LH, which would have made noticing this unusual trait difficult. With these results, the investigators were left to conclude that “the constant levels of LH, together with the steep decrease in testosterone levels, suggests an influence of ND [nandrolone decanoate] on testicular level: an impaired sensitivity of the Leydig cells towards LH stimulation, resulting in a decreased testosterone secretion.” No specific explanation was given.
In trying to understand what might be happening, we can note that nandrolone has one noteworthy trait that we would say is not characteristic of the other steroids mentioned in this article. It exhibits measurable progestational activity.6 Is it possible this has something to do with its unusual testosterone suppressing activity? Although progesterone is known to exhibit negative feedback on LH release, the actions of this hormone on the testis are not fully understood. Other studies do suggest that it has a very interesting role in the regulation of testicular function.7
Noting that intratesticular levels of progesterone increase with high-dosed stimulation by HCG, investigators wanted to see if progesterone participated in the desensitization of the testes to LH that also results. To accomplish this they pre-incubated mouse Leydig cells for 24 to 48 hours with progesterone, and then measured the binding of HCG (which attaches to the LH receptor), as well as the AMP production of cells (which HCG stimulates) in its presence. The results were compared to control cells. Both measures were significantly reduced when cells were pre-incubated with progesterone; effects that were shown to be caused by a clear inhibitory effect of this hormone toward LH receptor concentrations. This, in turn, could obviously cause a lowering of testosterone production, as it would interfere with the ability of the testes to respond to luteinizing hormone.
The above raises a plausible explanation for the results of the nandrolone study: The peculiar effect nandrolone has on the HPTA may be a result of its progestational nature. It also seems possible that this model of inhibition would be characteristic of many steroids that are derived from nandrolone and share a similar ability to act as progestins. Norethandrolone8 and trenbolone9 for example, both structurally related to nandrolone, are believed to have measurable progestational activity.
Perhaps these steroids share nandrolone’s ability to desensitize the testes to LH. If our progestational hypothesis is correct, we are still uncertain at this time what impact this knowledge has in the real world. It does seem to suggest an additive effect with many 19-nor androgens in terms of testicular atrophy and testosterone suppression, and perhaps proposes a reason those extremely concerned with post-cycle HPTA recovery should reconsider using such agents. It is also possible that recovery after a good testosterone cycle would not be significantly different than if nandrolone were included, and its importance is ultimately academic. At the very least, we understand that LH activity is not the sole regulator of testosterone synthesis, nor the sole concern for the steroid user wishing to maintain testicular mass or restore a balanced HPTA.
William Llewellyn is widely regarded as one of the world’s foremost authorities on the use of performance-enhancing substances. He is the author of the bestselling anabolic steroid reference guide ANABOLICS and CEO of Molecular Nutrition. William is an accomplished researcher/developer in the field of anabolic substances, and is also a longtime advocate for harm reduction and legislative change. He built the website anabolic.org, an extensive online database of information on anabolic steroids and other performance-enhancing drugs.
References:
1. Comparison of testosterone, dihydrotestosterone, luteinizing hormone, and follicle stimulating hormone in serum after injection of testosterone enanthate or testosterone cypionate. Schulte-Beerbuhl & Nieschlag. Fertil and Steril 33 (1980) 201-3
2. Comparative studies about the influence of methenolonacetate and mesterolone on hypophysis and male gonads. Trenkner, Senge et al. Arzheim-Forsch. 4 (1970) 545-7
3. The effects of oxandrolone on the growth hormone and gonadal axis in boys with constitutional delay of growth and puberty. Clin Endocrinol 38 (1993) 393-8
4. Effect of anabolic steroid (metandienon) on plasma LH-FSH, and testosterone and on the response to intraveinous administration of LRH. Holma, Adlercreuta. Acta Endocrinol 83 (1976) 856-64.
5. Influence of nandrolondecanoate on the pituitary-gonadal axis in males. Bijlsma, Duursma et al. Acta Endocrinol 101 (1982) 108-112
6. Competitive progesterone antagonists: receptor binding and biologic activity of testosterone and 19-nortestosterone derivatives. Reel, Humphrey et al. Fertil Steril 31 (1979) 552-61.
7. Progesterone can participate in down-regulation of the luteinizing hormone receptor gene expression and function in cultured murine Leydig cells. El-Hefnawy, Huhtaniemi. Mol Cell Endocrin 137 (1998) 127-38
8. Structural and hormonal activity of some new steroids. Drill, Riegel. Research laboratories G.D.Searle and Co.
9. Characterization of the affinity of different anabolics and synthetic hormones to the human androgen receptor, human sex hormone binding globulin and to the bovine progestin receptor. Bauer, Meyer et al. Acta Pathol Microbiol Imunol Scand Suppl 108 (2000) 838-46
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