Male Central Hypogonadism Secondary to Exogenous Androgens

A Review of the Drugs and Protocols Highlighted by the Online Community of Users for Prevention and/or Mitigation of Adverse Effects

Stamatios Karavolos; Michael Reynolds; Nikoletta Panagiotopoulou; Kevin McEleny; Michael Scally; Richard Quinton

Disclosures

Clin Endocrinol. 2015;82(5):624-632. 

In This Article

Results

Information Available on the Internet

We found that online discussions and advertisements concerning agents that can be used to combat the side effect of hypogonadism are very common. There was a mixture of information available from online communities (forums), AAS user blogs and from websites attempting to sell products such as anabolic steroids and substances directly related to hypogonadal recovery. Roughly one-third of the Internet sites we reviewed also offered to sell these drugs without prescription. Information was also available from official public health websites, such as the Welsh government funded and image-enhancing drugs website (SIEDSinfo.co.uk). The later provided risk reduction advice by providing information on safe injection practices.

Information on forums consisted of anecdotal reports and advice from unverifiable sources (some claiming to be medically qualified). These sources referenced mainstream scientific papers and abstracts on the issues discussed. However, there were clear flaws to this superficially 'evidence-based approach'. The papers quoted were of only limited generalizability to AAS users, ASIH, or to the argument proposed by the 'expert'. Equally most users were unable or unwilling to progress beyond subscription pay-walls, leaving them to draw conclusions from the abstracts or the 'expert opinion' alone.

Sites directly attempting to sell products to consumers could be broken into two groups, those purportedly selling medications and those selling supplements. Websites recommending the use of medications provided a balanced view with reference to current evidence with citations to peer-reviewed articles in the medical literature. Links to 'Frequently Asked Questions' for specific drugs (e.g. clomid) were available in some websites (e.g. steroidology.com), with information including the mechanism of action, instructions on how to use the drugs in relation to a 'steroid cycle', costs in the UK and USA and options to purchase online. Comparison of the efficacy of some drugs was also available in some websites (e.g. nolva vs clomid). We found that the use of these medications was positively discussed on forums.

Supplements advocated ranged from transparent preparations such as milk thistle to blends with a multitude of ingredients, such as vitamins (notably vitamin D), minerals (most often zinc), amino acids, herbal extracts and synthesized compounds such as L-carnitine. These supplements were mostly derided as ineffective on forum discussions.

The rationale behind the different tactics used was the quick restoration of the hypothalamus–pituitary–testicular axis and return of the endogenous steroid production to normal, whilst minimizing 'time lost' to AAS use and/or muscle mass augmentation and avoiding other symptoms of low testosterone in men, namely erectile problems, loss of libido and low mood. Fertility concerns were typically secondary; indeed, plenty of users reported getting their partners pregnant whilst using AASs and most users ignored potentially sustained effects on numbers and quality of sperm.[22] Discussions often lead to misunderstanding the pathophysiology of spermatogenesis and its impairment, leaving users to believe that return to normal serum testosterone levels translated to normal spermatogenesis. In most discussions, men seemed to equate regaining endogenous steroid production to normal fertility, ignoring long-term effects on quality of sperm, such as poor morphology and motility, which might potentially be irreversible.[22]

Purported Methods for Avoiding ASIH

Steroid Cycling. A common method suggested by the websites was the use of steroid 'cycles'. This involves alternating active periods of AAS use with respite intervals. The aim of cycling was to minimize AAS-associated side effects, by facilitating recuperation of the hypothalamus–pituitary–testicular axis, restoring endogenous testosterone production and, hopefully, reversing ASIH during the drug-free interval. Cycling was also suggested to avoid detection during competition in drug-free athletic events. AAS users typically use steroids in cycles of 6–12 weeks, with varying periods of no use.

Nonandrogenic Drugs. Users often combine different preparations of AASs with nonandrogenic drugs (hCG, SERMs or AIs) to counteract the negative side effects of AASs, a method referred to as 'stacking'. In addition to stacking, users will often use substances during the respite intervals, commonly referred to as 'postcycle therapy' (e.g. gonadotrophins), with the aim to restore the hypothalamus–pituitary–testicular axis and testicular function quicker than might have occurred naturally, if at all.

Certain drugs cropped up as being suggested for treatment either during the steroid cycle or postcycle. These included hCG, SERMs, such as clomiphene, toremifene, tamoxifen and raloxifene, and the various AIs (anastrozole, letrozole and exemestane). Other agents were mentioned less often and with controversy, for example mesterolone and FSH-based products, principally human menopausal gonadotrophin (hMG), but also r-hFSH. Drug recommendations partially depended on reported 'off-label' availability.

hCG was advocated for use in two ways. A group of users suggested hCG injections during the steroid cycle to try and maintain testicular volume and function that exogenous amounts of steroids would normally suppress. Others advocated waiting till one's body contained low amounts of AAS and then starting hCG. This could be up to several weeks from the last steroid injection, given the slow half-life of many esterified steroids (although for an oral steroid cycle, this washout period will often be considerably less).

A common theme was that users felt hCG reversed primary gonadal failure (i.e. the atrophy) but perpetuated the hypothalamic failure as it prompted testosterone production, but did not alleviate the underlying secondary failure (low FSH/LH); thus, hCG regimes tended to be recommended for shorter periods than other drugs. Users also differed on dosing schedules. Some argued for 250 IU every other day whilst using AAS, whereas others suggested hCG after stopping AAS and using 2500 IU every other day for a week. Hundreds of more variations were suggested, mainly lower steady doses for longer periods or 'pulsing' the doses, that is high but infrequent doses. Partly, this was down to users perceived differences on effectiveness but also a common fear was that hCG would desensitize Leydig cells to producing testosterone in response to LH, if large amounts of hCG was used, an effect that has been shown in rat studies,[23] often quoted in these websites.

SERMs and AIs stimulate pituitary gonadotrophin secretion, and hence testicular T secretion, by inhibiting negative feedback at the hypothalamus. This is because oestrogen (E2) is the dominant moiety for sex steroid feedback-inhibition of gonadotrophin secretion even in men. It is generated by aromatization from T, both locally (e.g. breast bud) and systemically (principally in adipose tissue), but the testicular E2/T secretory ratio also rises with supraphysiological LH levels (as seen in Klinefelter's), or with hCG-overstimulation. Testosterone and other aromatizable AASs are metabolized in part to E2 and other oestrogen agonists. Indeed, men using high doses of AAS can achieve circulating E2 levels within the normal range for women reproductive age.[24]

Clomiphene users suggested its use primarily as postcycle therapy after a steroid cycle to block the negative feedback of E2 on FSH/LH production, thus restoring hypothalamus–pituitary–testicular axis function. Dosing was often advocated for several weeks up to a month, with doses normally between 25 and 150 mg daily. Almost universally, users suggested not medicating until serum androgen levels were dropping close to normal. One user indicated differing schedules with age, with those over 35 requiring longer dosing schedules, quoting that 'at least 50% of the older men do not fully recover with normal Clomid treatment'.

Tamoxifen use was mainly advocated to prevent gynaecomastia, rather than hypogonadism. Users sometimes reported side effects such as blurred vision, dizziness, headaches and reduced libido, although others claimed that ocular side effects were a myth, quoting papers in support.[25] Some users also suggested using tamoxifen in combination with or just after stopping cycles of hCG injections, with the aim of extending the post-hCG rise in serum T through blockade of E2-mediated negative feedback.

Less commonly, raloxifene was suggested as an equivalent to tamoxifen, but it seemed less well known and available on the websites. Toremifene, a newer drug, is licensed for the treatment of hormone-dependent metastatic breast cancer in postmenopausal women.[26] It was advocated similarly to clomiphene and tamoxifen, as a stimulator of FSH/LH production, with users suggesting greater potency than clomiphene a website where a purported doctor posts paper abstracts linked but not always directly relevant to the issue of ASIH.[27]

Anastrozole, letrozole and exemestane were the typically mentioned AI choices on the websites. AIs were popular with those who suffered side effects from SERMs, or who reported difficulty sourcing alternatives. On occasion users expressed a dislike for AIs because they reduce E2 levels to a point where the users report 'aching joints' that they ascribed to E2-mediated 'lack of lubrication'. Users seemed to draw support from this form of anecdotal reports and menopausal women reporting similar joint problems.

Physiological Effects of Exogenous Testosterone and AAS

Testosterone in supraphysiological blood concentrations increases lean muscle mass, burns fat and increases strength in healthy eugonadal men.[15] This effect is linearly related to blood T levels.[28] Similar effects are seen with synthetic androgens,[7] although serum levels cannot routinely be measured, nor mapped in relation to a physiological male normal range.

The use of exogenous AASs causes hypogonadotrophic hypogonadism by exerting negative feedback both on hypothalamic GnRH release and directly on LH and FSH secretion by pituitary gonadotrophs. At the pituitary level, feedback-inhibition by T is largely mediated by E2, following local aromatization. The overall results are testicular atrophy and impaired spermatogenesis with resultant infertility.[29] Normal spermatogenesis is associated with intratesticular T levels some 30-fold higher than serum T levels. Exogenous administration cannot deliver anything remotely approaching this requisite T concentration within the seminiferous tubules; indeed, it will tend to markedly reduce it by suppressing endogenous LH-mediated T secretion.[30]

The duration of suppression and the resultant central hypogonadism varies between individuals. This is due to factors including the use of multiple drugs, the dose and duration of use. Most AAS users will recover normal HPG function within a few weeks to months, even after prolonged cycles of supraphysiological doses of AAS.[31] However, some users demonstrate prolonged hypogonadism, occasionally persisting more than a year after stopping AAS, although some of these will have persistent low-level spermatogenesis.[32–35] Younger men may recover faster and more completely from ASIH following cessation of AAS use as compared to older men.[36] The symptoms of testosterone deficiency in ASIH typically manifest 'postcycle', when the supraphysiological androgen levels drop. For this reason, AAS users seek the use of ancillary drugs such as hCG, SERMs and AIs in an attempt to hasten the recovery of the hypothalamus–pituitary–testicular axis and T production. SERMS and AIs may also be taken with the primary aim of avoiding AAS- or hCG-induced gynaecomastia.

The pathophysiology of ASIH is likely to be more complex than that of a simple T excess effect, because AAS users are likely to be taking a 'cocktail' of high-dose synthetic androgens and ancillary drugs by a combination of administration routes, as has been revealed by our Internet search. On top of the endocrine disruption that these may cause, they may also contribute to a degree of primary testicular failure through a direct toxic effect, as suggested by animal studies.[37–39]

Effective Treatment of ASIH

hCG is a naturally occurring glycoprotein normally produced by the human placenta. It is available in purified or recombinant forms and is licensed for use in the treatment of female infertility.[26,40] hCG binds to the LH receptor and, having a much longer effective plasma half-life, is a useful analogue of LH to stimulate testosterone secretion by Leydig cells. In men, hCG acts directly on Leydig cells to increase both intratesticular and serum T levels.[41–43] Clinical indications for hCG use in men are for the treatment of T deficiency and/or induction of spermatogenesis in gonadotrophin-deficient adults (typically with concomitant FSH therapy in the latter role) and in treating hypogonadotrophic pubertal delay.[44] There are no other proven uses of hCG for men in routine clinical practice. As discussed above, we found that AAS users misused hCG in two settings: (i) by men with sustained suppression of their hypothalamus–pituitary–testicular axis from prolonged use of high-dose AAS use, in an attempt to increase endogenous testicular T secretion and (ii) by AAS users seeking to avoid detection of exogenous androgens by stimulating endogenous testosterone production. In reality, this merely prolongs suppression of the hypothalamus–pituitary–testicular axis, which is the root cause of the reduction in testicular size and serum T levels.

In a small case series of 13 azoospermic men with acquired gonadotrophin deficiency, hCG in combination with FSH was successful in stimulating and maintaining spermatogenesis in hypogonadotrophic, hypogonadal men.[45] Low-dose hCG with testosterone supplementation has also been shown to be effective in maintaining spermatogenesis, although whether this can translate to successful pregnancies is uncertain.[46] In the context of AAS use, hCG has been shown to be effective in accelerating testicular production of testosterone and reversing azoospermia, but evidence is only available from case reports.[47–49]

SERMs such as clomiphene, tamoxifen and raloxifene stimulate pituitary gonadotropin and, consequently, T secretion by blocking E2 receptors in pituitary gonadotrophs. They have long been used off-label for the treatment of male infertility and gynaecomastia.[50–55] In men, there are no valid clinical indications for the use of SERMs, except in the exceptionally rare case of male breast cancer (unlicensed indication), and there are thus only limited number of studies on their therapeutic use. The use of clomiphene to treat subfertile men was first reported in 1966.[56] Since then, there have been reports of clomiphene use 'off-label' for the treatment of different forms of sperm abnormalities, including unexplained couple infertility, with variable results.[57–59] Much better results, in respect of improvement in T levels and semen, have been reported where clomiphene was targeted in men with nonsyndromic hypogonadotrophic hypogonadism,[60] with similar findings reported for other SERMs.[61] However, individual SERMs vary in their biological effects in men. For instance, standard doses of raloxifene promote a smaller degree of gonadotropin-driven T secretion (E2-antagonist-effect) in men than equivalent doses of tamoxifen, but also induce less inhibition of growth hormone (GH)-mediated IGF1 secretion (E2-agonist-effect).[62] Despite promising data, enclomiphene (the trans-isomer of clomiphene citrate) has not yet obtained regulatory approval in the USA for the desired indication of obesity-related hypogonadotrophic hypogonadism.[63]

Recent meta-analyses do suggest that empiric treatment with clomiphene or tamoxifen for idiopathic male infertility may improve sperm concentration and motility and increase spontaneous pregnancy rates,[64,65] but optimal dosing schedules for the treatment of such patients have not been established, and there are reports of high-dose clomiphene being associated with a decline in spermatogenesis in some men.[66] Based on current published data, there is insufficient evidence to suggest that clomiphene is effective for the treatment of idiopathic male infertility. With regard to treatment of ASIH, we could only find two case reports of the successful clomiphene-induced restoration of FSH, LH and free T levels in men.[67,68] It is therefore difficult to draw any conclusions from these data.

AIs such as anastrozole block the conversion of androgens to oestrogens, conversely leading to increasing serum T levels in a similar fashion to anti-oestrogens. They are licensed for use in the treatment of breast cancer and can be used in men for the prevention of gynaecomastia associated with raised E2 levels.[40] AIs have been used to treat men with idiopathic infertility and hypogonadism related to obesity, with mixed results.[69–72] These studies did not demonstrate any significant negative effects on sperm production; however, the primary concern associated with the prolonged use of AIs in men is oestrogen deficiency that can lead to osteopenia or osteoporosis. On the other hand, inhibition of E2 synthesis tends to impair GH pulsatility, but promote GH-mediated IGF1 synthesis.[73] Overall, strong evidence on the effectiveness of AIs to treat ASIH is currently lacking.

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