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

Abstract and Introduction

Abstract

Androgen- or anabolic steroid-induced hypogonadism (ASIH) is no longer confined to professional athletes; its prevalence amongst young men and teenagers using androgens and/or anabolic steroids (AASs) is rising fast, and those affected can experience significant symptoms. Clinicians are increasingly encountering demanding, well-informed men affected by ASIH, yet lacking authoritative information on the subject may struggle to project a credible message. In this article, we overview the methods and drugs that men use in an attempt to counteract ASIH (with a view to either preventing its onset, or reversing it once it has developed) and summarize the scientific evidence underpinning these. The main channel for obtaining these drugs is the Internet, where they can be readily sourced without a valid prescription. An Internet search using relevant terms revealed a huge number of websites providing advice on how to buy and use products to counteract ASIH. Drugs arising repeatedly in our search included human chorionic gonadotrophin (hCG), selective oestrogen receptor modulators (SERMs) and aromatase inhibitors (AIs). The quality and accuracy of the online information was variable, but review of medical literature also highlighted a lack of scientific data to guide clinical practice. It is important for clinicians to be aware of the AAS user's self-treatment strategies with regard to ASIH side-effect mitigation. By ensuring that they are well-informed, clinicians are more likely to retain the credibility and trust of AAS users, who will in turn likely be more open to engage with appropriate management.

Introduction

Use of performance-enhancing drug is an important aspect of endocrinology that is often overlooked. Anabolic androgenic steroids (AASs) are amongst the most common and serious form of drug used for performance enhancement in sport and bodybuilding[1] and increasingly also for enhancement of physical appearance ('get that sculpted body and six-pack abdomen'). Inappropriate prescribing of native testosterone (T) may also be on the increase and potentially carries the same risk of anabolic steroid-induced hypogonadism (ASIH).[2] The lifetime prevalence of AAS use in men is estimated to be between 3·0 and 4·2%, but is rapidly increasing, with even USA high school students well-represented amongst users.[3] However, clinicians are often unaware just how ubiquitous AAS use has become[4,5] and, due to their knowledge base, may anyway be uncomfortable addressing the issue; indeed, some authors report that over 50% of AAS users are reluctant to disclose their AAS use to clinicians.[6] Moreover, mainstream academic endocrinology rather lost credibility with the 'performance-enhancement community' in the 1980s and 1990s, by persisting overlong in (a) doubting whether further enhancement of athletic performance could be achieved through raising serum T levels above the physiological reference range and (b) questioning whether any therapeutic separation of androgenic and anabolic actions was achievable, due to the single androgen receptor.[6]

AASs are a family of hormones including T, the primary male sex hormone and its derivatives. 'Anabolic' refers to the muscle-building properties of these drugs and 'androgenic' refers to their promotion of male sex characteristics. The anabolic effects represent the principal motivation for the illicit use of AAS, with users attempting to minimize or mitigate the unwanted side effects (principally ASIH and gynaecomastia) arising from the androgenic properties. Although all genomic AAS actions are ultimately transduced by ligand binding to the androgen receptor, selectivity of signalling towards anabolic vs androgenic pathways is mediated by an interacting web of molecular chaperones, co-activators/-repressors and transcription factors.[7,8] Indeed, many users take T alongside nandrolone ('stacking'), specifically because of the latter's perceived inadequate androgenicity in respect of supporting sexual function. AASs can be taken orally, transdermally or by intramuscular injection, the latter being the most popular mode of administration amongst illicit users.

There is an acute dose-dependent suppression of endogenous gonadotropin-driven androgen secretion with exogenous AAS.[9] However, ASIH refers to the phenomenon of hypogonadotrophic hypogonadism persisting even after discontinuation of the exogenous AAS product. It was first described by Boje in 1939,[10] who suggested that AAS might enhance athletic performance but could also have potential health-related side effects. It is biochemically indistinguishable from organic hypogonadotrophic hypogonadism and results from chronic sex steroid-mediated feedback-inhibition of the hypothalamus–pituitary–testicular axis. Although a near-universal consequence of AAS use, its duration and severity are highly variable, reflecting dose, duration and type of prior AAS exposure.[11] A retrospective study of 15 ex-AAS users (the mean time off steroids was 43 months; range 1 to 10 years) found 13 of 15 to be in the lower 20 percentage of the normal reference range for testosterone and 2 of 15 below the normal range.[12] Thus, prolonged, severe ASIH is relatively uncommon amongst former AAS users. In some centres, approximately one-fifth of men seeking treatment for hypogonadism have reported the earlier use of AAS.[13] It is hypothesized (although by no means proven) that addictive behaviour might contribute to users' continuing their regimens even when side effects occur, partly due to psychological dependence and partly through fear of losing muscle mass.[11,14–16]

AAS users are thus necessarily motivated to counteract or reverse the unwanted side effects of exogenous androgens, frequently seeking information on the use of steroidal and nonsteroidal ancillary drugs for this purpose: a therapeutic manoeuvre that users also define as within the category of 'stacking' (i.e. taking more than one agent simultaneously). The most easily accessible source for obtaining such information is the Internet,[14,17,18] wherein we identified numerous websites and forums allowing AAS users around the world to anonymously offer and solicit advice, share drug sources and personal outcomes, and collaborate on dosing schedules. Indeed, many AAS users attending our endocrinology and male infertility clinics will already be 'stacking' and may simply be attempting to have these ancillary agents prescribed; others will just want professional information about their use and effectiveness.

These drugs are steroid, or glycoprotein hormones that should only be available on medical prescription, and yet the typical source of information and procurement for AAS users regarding these substances is the Internet.[14,18–21] Commonly used agents include human chorionic gonadotrophin (hCG), selective oestrogen receptor modulators (SERMs) and aromatase inhibitors (AIs). The off-label illicit use of these medications is concerning, as so little is known about their long-term effects and drug interactions in the context of AAS use.[1] Clinicians should be aware of the methods exogenous androgen users use in an attempt to mitigate the features of ASIH, particularly loss of endogenous testosterone secretion, but also reduced testicle size and infertility secondary to reduced sperm count.

In this paper, we review the beliefs of AAS users, the current best scientific evidence related to these beliefs and the current best scientific evidence for treatment of ASIH. We identified Internet sites and forums offering information on the use of these products and reviewed the methods and drugs advised therein for the self-medication. We then examined the evidence-based medical information currently available to support or refute this advice.

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