Question: I’ve been thinking about this for a while and don’t have an answer (also, admittedly haven’t researched it for lack of time)...Why do androgens such as Primobolan, Masteron, or Anavar also lead to shutdown of the HPGA when they don’t convert to estrogen? I understand and appreciate the negative feedback induced by estrogen (and this being the theoretical reason why exogenous T shuts you down). However, is this the only factor influencing HPGA shutdown? If so, why do DHT derivatives also lead to shutdown?
All AAS will lead to the shutdown of the HPG axis (even non-aromatizing AAS) due to a direct suppressive effect on the hypothalamus (reduction in GnRH output).
The HPG axis is very sensitive to sex steroids and when using exogenous AAS the hypothalamus will recognize these elevated/excess levels which in turn leads to a shutdown resulting in the suppression of natural endogenous testosterone/sperm production.
AAS can also bind the androgen receptor inside target cells and bring into play the same negative feedback effects as endogenous testosterone.
Also, although some of the milder non-aromatizing oral AAS such as oxandrolone (Anavar), methenolone (Primobolan), stanozolol (Winstrol), mesterolone (Proviron) have been shown to be less suppressive under some therapeutic conditions it because of the therapeutic doses used/duration of therapy and just to be clear this is tossed out the window when any AAS are taken in high enough supra-physiological doses.
WILLIAM LLEWELLYN'S
ANABOLICS
Some of the more potent anabolic/androgenic steroids, including testosterone, nandrolone, trenbolone, and oxymetholone, appear to be more suppressive of testosterone release than many other AAS drugs. This may be explained in part by the additional estrogenic or progestational activity inherent in these steroids, as estrogens and progestins both also provide negative feedback inhibition of testosterone release 306 307. It is important to note, however, that all anabolic/androgenic steroids are capable of suppressing testosterone secretion. This includes primarily anabolic compounds such as methenolone and oxandrolone, which are normally regarded as milder in this regard. While these compounds may be less inhibitive of testosterone synthesis under some therapeutic conditions when taken in the supratherapeutic doses necessary for physique- or performance-enhancement, significant atrophy and suppression are common, and distinctions less pronounced.
The HPTA Axis In the human body, the Hypothalamic-Pituitary-Testicular Axis (HPTA) controls testosterone biosynthesis. The HPTA is a tightly regulated system of checks and balances that works to assure the correct level of testosterone is maintained. We can look at this regulating process as having three levels. At the top is the hypothalamic region of the brain, which releases GnRH (Gonadotropin-Releasing Hormone) when it senses a need for more testosterone. GnRH sends a signal to the second level of the axis, the pituitary, to produce Luteinizing Hormone (LH). LH, in turn, sends a message to the Leydig’s cells in the testes (level three) to secrete testosterone. Given this role, LH is regarded as the primary direct messenger controlling testosterone synthesis. Testosterone and other sex steroids that are produced as a result of this LH stimulation serve as a counterbalance. They provide negative feedback to lower the secretion of LH and testosterone, preventing overproduction. Synthetic anabolic steroids, of course, send the same negative feedback. The serum level of testosterone is, therefore, a reflection of both positive and negative stimulation fighting each other for hormonal control.
The Hypothalamic-Pituitary-Testicular Axis: The hypothalamus releases Gonadotropin- Releasing Hormone (GnRH), which stimulates the pituitary to release luteinizing hormone (LH) and follicle-stimulating hormone (FSH). This (primarily LH) promotes the release of testosterone from the testes. Androgens, as well as estrogens and progestins, in turn, cause negative feedback inhibition at the hypothalamus and pituitary, lowering the output of gonadotropins and testosterone when too much hormone is present.
Reproductive (Male)
Fertility
Anabolic/androgenic steroid use may impair fertility.
The human body strives to maintain balance in its sex hormone levels (homeostasis). This balance is regulated largely by the hypothalamic-pituitary-testicular axis (HPTA), which is responsible for controlling the production of testosterone and sperm. The administration of anabolic/androgenic steroids provides additional sex steroid(s) to the body, which the hypothalamus can recognize as excess. It responds to this excess by reducing signals that support the production of pituitary gonadotropins luteinizing hormone (LH) and follicle-stimulating hormone (FSH). LH and FSH normally stimulate the release of testosterone by the testes(gonads) and also increase the quantity and quality of sperm. When LH and FSH levels drop, testosterone levels, sperm concentrations, and sperm quality may all be reduced.
Testicular Atrophy
Anabolic/androgenic steroids may produce atrophy (shrinkage) of the testicles.
Testosterone is synthesized and secreted by the Leydig cells in the testes. Its release is regulated by the hypothalamic-pituitary-testicular axis, a system that is very sensitive to sex steroids. When anabolic steroids are administered, the HPTA will recognize the elevated hormone levels and respond by reducing the synthesis of testosterone. If the testes are not given ample stimulation, over time they will atrophy, a process that can involve both a loss of testicular volume and shape. This atrophy may or may not be obvious to the individual. In some cases, the testes will appear normal even though their functioning is insufficient. In other cases, shrinkage is very apparent. Visible testicular atrophy is one of the most common side effects of steroid abuse, appearing in more than 50% of all anabolic/androgenic steroid abusers.
300 301
Recovery of spermatogenesis following testosterone replacement therapy or anabolic-androgenic steroid use
J Abram McBride and Robert M Coward
Both TRT and AAS use can lead to suppression of the hypothalamic-pituitary-gonadal (HPG) axis, resulting in a diminution of spermatogenesis and potential infertility. Spontaneous recovery of spermatogenesis after cessation of TRT or AAS is possible but may take several months to several years, and in some cases may be permanent.13,14,15,16 Taken together, the rising use of TRT and AAS in young- to middle-aged men, in conjunction with a societal shift toward greater paternal age,
17 is creating an environment where clinicians are increasingly likely to encounter men seeking treatment for infertility related to prior TRT and/or AAS use or treatment for hypogonadism with interest in preserving their fertility. Meanwhile, men present to infertility specialists for vasectomy reversal (VR) at an average age of 41 (
n = 1300), some of whom may also suffer from hypogonadism and report current or previous TRT use.
18 Therefore, clinicians need to be keenly aware of the effects of TRT and AAS on spermatogenesis and what treatment options are available to reverse these effects to restore spermatogenesis.
NORMAL SPERMATOGENESIS
Normal spermatogenesis is dependent on appropriate signaling from the HPG axis. This signaling initially consists of a pulsatile release of gonadotropin-releasing hormone (GnRH) from the hypothalamus via the portal system to the pituitary gland where stimulation results in gonadotropin release. Luteinizing hormone (LH) from the pituitary stimulates Leydig cells in the testis to produce testosterone and leads to intratesticular production of insulin-like growth factor 1 (IGF-1), which plays an integral role in Leydig cell LH receptor upregulation, steroidogenesis, and maturation.19,20 Follicle-stimulating hormone (FSH) from the pituitary stimulates Sertoli cells in the testis, which supports spermatogonial differentiation and maturation. Both FSH and maintenance of high intratesticular testosterone (ITT) levels (50–100 fold higher than serum) in response to LH are critical for normal spermatogenesis to occur.21,22,23,24 Historically, Sertoli cell-produced androgen-binding protein was thought to be responsible for such high ITT levels, but recent data suggest that other factors are also involved.
25 Interestingly, animal studies have demonstrated that the absence of FSH signaling results in impaired spermatogenesis whereas loss of sufficiently high ITT levels results in the absence of spermatogenesis.
26
Regulation of the HPG axis occurs via feedback inhibition. Endogenous testosterone directly inhibits GnRH and LH release at the hypothalamus and pituitary levels, respectively, leading to downstream attenuation of testosterone production. Testosterone also indirectly regulates gonadotropin secretion via estrogen, derived from testosterone conversion peripherally by aromatase enzyme. Estrogen exhibits a greater effect on LH secretion than FSH although additional FSH feedback inhibition occurs with inhibin B secreted from Sertoli cells. Inhibin B levels have been considered a surrogate for spermatogenesis; for example, men with spermatogenetic defects express lower inhibin B levels.27 Additional autocrine, paracrine, and endocrine factors within the hypothalamus, pituitary, and testis can function to further modulate the HPG axis in complex ways including endocannabinoids, GnRH, kisspeptin, norepinephrine, growth hormone, interleukins, and TGF-β.28 Therefore, the HPG axis represents a dynamic, but tightly regulated, system at multiple levels resulting in spermatogenesis, among other things.
INFLUENCE OF EXOGENOUS ANDROGENS ON SPERMATOGENESIS
The use of exogenous androgens can influence the HPG axis by similar mechanisms as endogenous testosterone by exerting negative feedback in a dose- and duration-dependent fashion, resulting in reductions in ITT, blunting of FSH production, and ultimately decrease or complete cessation of spermatogenesis.29 Data specifically describing the natural history of unassisted spermatogenesis recovery after long-term TRT are lacking, but such information can be extrapolated from the male contraceptive literature.
16 Multiple and international trials using various testosterone preparations have been performed and demonstrate a median time to spermatogenesis suppression to <1 × 106 ml-1 sperm within 3.5 months. Alternatively, the same data demonstrate a median time to recovery of 20 × 106 ml-1 sperm ranging from 3 to 6 months, with probability estimates suggesting recovery in 67%, 90%, 96%, and 100% of men at 6, 12, 16, and 24 months, respectively, after discontinuation of testosterone exposure.
13 These data also suggest that a longer exposure to exogenous testosterone, Asian ethnicity, and older age may result in a prolonged recovery time after treatment cessation.
13,
30,
31,
32 Importantly, one must consider that these data are carefully collected in men within the tightly controlled, clinical trial environment, and may not be generalizable. Certainly, men with a prior, multiple year history of TRT or AAS use may not expect the same rate of recovery.
AAS are synthetic derivatives of testosterone with chemical modifications intended to mimic the anabolic more than the androgenic effects of testosterone. Many abusers use “stacking” regimens with multiple, high-dose AAS agents to maximize muscle mass and weight gain, which are often “cycled” to minimize side effects.
Nevertheless, AAS can still bind the androgen receptor within target cells and exert the same negative feedback effects as endogenous testosterone, often resulting in anabolic steroid-induced hypogonadism (ASIH) and associated reductions in serum gonadotropin levels and ITT.9,15,21,33 With abnormally low ITT and FSH, these patients often exhibit azoospermia or oligospermia with reduced motility and/or morphology on semen analysis.
15
Selective estrogen receptor modulators (SERMs)
SERMs are a group of medications that function to disrupt binding of estrogen at estrogen receptors in the hypothalamus through competitive antagonism. In men, normal binding of estrogen at these receptors functions as an indirect negative feedback mechanism of endogenous testosterone production to downregulate GnRH and subsequently pituitary gonadotropin production. Therefore, SERMs function to block estrogen feedback thereby increasing GnRH and gonadotropin production and ultimately increasing ITT levels in men without evidence of primary hypogonadism.16,63,64 Clinically, tamoxifen and CC are two of the most commonly used SERMs, with the former popularized by use in breast cancer treatment protocols and the latter popularized by its initial development for triggering ovulation in women.
CC exists as a racemic mixture of shorter acting enclomiphene (purely anti-estrogenic effects) and longer acting zuclomiphene (both estrogen agonist and antagonist effects) and exhibits a serum half-life of approximately 5 days.65
Aromatase inhibitors (AIs)
AIs are a class of medications FDA approved for the treatment of early- and late-stage breast cancer and historically include nonselective steroidal, and highly selective nonsteroidal agents, including anastrozole and letrozole. AIs function by inhibiting the aromatase enzyme, which is a cytochrome P450 converter of testosterone-to-estrogen within the testes, liver, brain, and adipose tissues.16 Estrogen is an indirect mediator of testosterone feedback inhibition of the HPG axis. Therefore, aromatase inhibition in men can result in decreased estrogen levels and ultimately increased gonadotropin production. Their use clinically in men is off-label and has focused upon improving male infertility and symptoms of hypogonadism, particularly in obese men or in those with a serum testosterone-to-estrogen (T/E) ratios <10 where improvements of approximately 77% have been observed.
64 In addition, AIs can be prescribed for use with exogenous testosterone or hCG to mitigate side effects of hyperestrogenemia such as gynecomastia.
Anabolic steroid-induced hypogonadism – Towards a unified hypothesis of anabolic steroid action
R.S. Tan, M.C. Scally
The HPTA has two components, both spermatogenesis and testosterone production. In males, luteinizing hormone (LH) secretion by the pituitary positively stimulates testicular testosterone (T) production; follicle-stimulating hormone (FSH) stimulates testicular spermatozoa production. The pulsatile secretion of gonadotropin-releasing hormone (GnRH) from the hypothalamus stimulates LH and FSH secretion. In general, absent FSH, there is no spermatozoa production; absent LH, there is no testosterone production. Regulation of the secretion of GnRH, FSH, and LH occurs partially by the negative feedback of testosterone and estradiol at the level of the hypothalamo-pituitary. Estradiol has a much larger, inhibitory effect than testosterone, being 200-fold more effective in suppressing LH secretion [57–61].
[57] Hayes FJ, Seminara SB, Decruz S, Boepple PA, Crowley F. Aromatase inhibition in the human male reveals a hypothalamic site of estrogen feedback. J Clin Endocrinol Metab 2000;85:3027–35.
[58] Bagatell CJ, Dahl KD, Bremner WJ. The direct pituitary effect of testosterone to inhibit gonadotropin secretion in men is partially mediated by aromatization to estradiol. J Androl 1994;15:15–21.
[59] Finkelstein JS, O’Dea LS, Whitcomb RW, Crowley WF. Sex steroid control of gonadotropin secretion in the human male. II. Effect of estradiol administration in normal and gonadotropin-releasing hormone-deficient men. J Clin Endocrinol Metab 1991;73:621–8.
[60] Veldhuis JD, Dufau ML. Estradiol modulates the pulsatile secretion of biologically active luteinizing hormone in man. J Clin Invest 1987;80:631–8. [61] Schnorr JA, Bray MJ, Veldhuis JD. Aromatization mediates testosterone’s shortterm feedback restraint of 24-h endogenously driven and acute exogenous gonadotropin-releasing hormone-stimulated luteinizing hormone and follicle
[61] Schnorr JA, Bray MJ, Veldhuis JD. Aromatization mediates testosterone’s shortterm feedback restraint of 24-h endogenously driven and acute exogenous gonadotropin-releasing hormone-stimulated luteinizing hormone and follicle stimulating hormone secretion in young men. J Clin Endocrinol Metab 2001;86:2600–6.