Sports Endocrinology

F. Lanfranco, C. J. Strasburger

• Publisher: S. Karger
• Year: 2016
• ISBN:
  9783318058697
• Topic: Medizin
• Subtopic: Endokrinologie & Stoffwechsel

This book is an up-to-date, extensive overview of the effects of physical activity and training on endocrine function. It gives insights into a complex relationship by describing effects with respect to exercise performance, growth, development, and ageing. It includes discussions of the endocrine response depending on exercise mode, intensity, and duration as well as on gender, age, and fitness level. Additionally the book deals with the impact of environmental and psychological factors on endocrine level. A substantial part of Sports Endocrinology is devoted to the 'hot topic' of hormonal doping in sports. The properties of androgens, growth hormone, erythropoietin, and dietary supplements are highlighted. The use and abuse among professional and recreational athletes is discussed and specific methods of detection are presented and explained. All contributors are well-known experts in sports medicine and endocrinology, endocrine physiology, pharmacology, and doping detection, so this book is a must-read for every professional involved in the field.

Use of Performance-Enhancing Endocrine Drugs (Doping) in Competitive and Recreational Sports Activity

Lanfranco F, Strasburger CJ (eds): Sports Endocrinology.
Front Horm Res. Basel, Karger, 2016, vol 47, pp 82-100 (DOI: 10.1159/000445159)

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Androgens

Rakesh Iyer · David J. Handelsman

Department of Andrology, Concord Repatriation General Hospital, and ANZAC Research Institute, University of Sydney, Sydney, N.S.W., Australia

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Abstract

Androgen abuse is the most potent and prevalent form of sports doping detected. It originated from the early years of the Cold War as an epidemic confined to drug cheating within elite power sports. In the decades following the end of the Cold War, it has become disseminated into an endemic based within the illicit drug subcultures serving recreational abusers seeking cosmetic body sculpting effects. Within sports, both direct androgen abuse (administration of androgens), as well as indirect androgen abuse (administration of nonandrogenic drugs to increase endogenous testosterone), is mostly readily detectable with mass spectrometry-based anti-doping urine tests. The ongoing temptation of fame and fortune and the effectiveness of androgen abuse in power sports continue to entice cheating via renewed approaches aiming to exploit androgens. These require ongoing vigilance, inventiveness in anti-doping science, and targeting coaches as well as athletes in order to build resilience against doping and maintain fairness in elite sport. The challenge of androgen abuse in the community among recreational abusers has barely been recognized and effective approaches remain to be developed.

© 2016 S. Karger AG, Basel

Androgens are a class of hormones based on the two canonical endogenous steroids, testosterone (T) and its potent metabolite, dihydrotestosterone (DHT). Androgen effects are produced by binding to, and activating, the androgen receptor (AR) resulting in the development and maintenance of the male reproductive system as well as characteristic nonreproductive effects on classical androgen target tissues such as muscle, skin, and bone, and more subtle effects on most other somatic tissues which ubiquitously express AR [1]. Androgen binding to AR protein results in conformational AR changes, liberation from chaperone protein binding, and AR dimerization which facilitates binding to androgen-response elements in target genes. This allows attachment of coregulators to regulate characteristic patterns of gene expression that represent the actions of androgens [2]. In addition, nongenomic effects of androgens, mediated by postulated non-AR, membrane-binding mechanisms, are widely discussed but not yet well characterized [3].

Testosterone

T was first fully characterized as the principal male sex steroid of testicular origin in 1935 [4] followed rapidly by its first clinical use (1937) [5] and a Nobel Prize (1939). Following the hiatus of World War II, the pharmaceutical industry development of synthetic steroids included pursuing the goal of a nonvirilizing androgen (‘anabolic steroid’) potentially suitable for use to obtain pharmacological androgen effects in women and children. Contrasting with the successful development of synthetic glucocorticoids and oral contraceptives during the golden age of steroid pharmacology, the industrial quest for an ‘anabolic steroid’ based on dissociating the virilizing from the anabolic effects of androgens failed. This is now understood in the light of the later discovery of the singular AR together with the flawed interpretations of relatively nonspecific whole animal bioassays then used to screen synthetic steroids for supposedly distinct anabolic and virilizing effects. Yet, despite the industry’s abandonment of this fruitless endeavor by 1980, and its recent reincarnation under the guise of developing a ‘selective AR modulator’ (SARM) [6], the empty concept of an ‘anabolic steroid’ persists as an ill-defined and misleading scientific terminology [7, 8]. In this paper, the more accurate and clearer term ‘androgen’ is used exclusively for both endogenous and synthetic androgens, but includes references to chemicals loosely defined elsewhere as ‘anabolic steroids’ or ‘anabolic-androgenic steroids’, which confuse by making an obsolete distinction where there is no difference.

The primary therapeutic indication for T is in replacement therapy for men with disorders of the reproductive system that prevent normal synthesis of T. This may be due to either testicular damage that disrupts Leydig cell T synthesis and secretion, or hypothalamo-pituitary disorders which limit pituitary LH secretion that drives Leydig cell T production. The major limitation of T as a therapeutic drug is its short duration of action and minimal oral bioactivity due to first-pass hepatic metabolism. For T replacement therapy, these limitations were overcome by creation of long-acting depot injectable T formed by T esterified with lipophilic, long-chain fatty acids formulated in a vegetable oil vehicle [9]. These remained the most widely used T products for decades until the more recent advent of transdermal gels delivering unesterified T.

Synthetic Androgens

During the postwar decades, thousands of synthetic androgens were invented based on the steroidal structures of the natural androgens, T, and DHT [10]. The vast majority were subjected to 17-α alkylation, which rendered androgens more potent and orally active but suffered from class-specific hepatotoxicity, an adverse effect not shared by endogenous androgens or other classes of synthetic androgens. Only a tiny minority of these synthetic androgens outlined in the pharmaceutical patent literature of the 1950s-1970s were ever marketed. Many more, never-marketed androgens were described and evaluated in research laboratories with no or only preliminary clinical studies.

Due to their hepatotoxicity, most marketed synthetic 17-α alkylated androgens have been progressively eliminated from the market [11]. Yet the ergogenic advantages of androgens for power sports and their efficacy for body sculpting fostered the continuing availability of well-known alkylated androgens such as stanozolol, methandienone and oxandrolone via the internet for illicit use [12-17]. However, in sports, all marketed androgens were readily identified by mass spectrometry (MS)-based doping detection methods [10] making such androgen doping highly risky. Consequently, various alternative strategies were adopted to continue exploiting androgen doping without detection by other means. One approach has been to utilize never-marketed synthetic androgens identified from the old patent literature, but whose structures were unfamiliar and undisclosed while MS-based urine detection tests required a known structure [15, 18, 19]. The first such designer androgen identified in an athlete’s urine was norbolethone, a 17-α alkylated androgen originally synthesized in 1960 but never marketed [20]. Soon after, tetrahydrogestrinone, a previously unknown androgen produced illicitly by a one-step chemical reduction of a marketed alkylated progestin (gestrinone) was identified structurally [21] and then as a potent androgen by an in vitro androgen bioassay [22]. Subsequently, desoxymethyltestosterone (Madol), another never-marketed androgen patented in the 1960s, was identified [23]. A recent review notes at least six designer androgens available over the internet [17]. Nevertheless, once identified, these designer androgens have never again been detected in regular doping tests reflecting effective deterrence. More broadly, similar never-marketed androgens are also commonly found in unregulated, over-the-counter and internet-marketed food supplements, which often do not identify steroids on the label but are promoted as purportedly legal body-building alternatives to androgens [15, 24].

The first nonsteroidal androgen invented was reported in 1998 [25] leading to a new class of structurally diverse AR agonists (SARM) with the overall goal of tissue selectivity, reviving the older attempts to dissociate virilizing from anabolic effects of androgens [6]. This aims to replicate the serendipitous but largely unexplained tissue selectivity of selective estrogen receptor modulators (SERMs). So far, nonsteroidal androgens are not yet approved for clinical use [26-28] and their use in sport was prohibited in 2008. Yet, characteristically, potentially ergogenic drugs in premarketing development become available illicitly over the internet for doping or body building, in breach of law, patents, and doping codes. For example, Andarine (S-4), widely advertised on the internet [29], has been identified in urine samples from athletes [30, 31]. Given the limited clinical trial data available [27], the full safety profile of nonsteroidal androgens, even at conventional let alone doping doses, remains little understood.

Efficacy of Androgen Abuse

The ergogenic effects of androgen doping in eugonadal men were long doubted with the claimed benefits attributed to placebo effects of expectation, athletic training, and nutrition. Even meta-analyses of controlled studies were misleadingly negative [32] as they were restricted, by perceived ethical constraints, to conventional androgen doses but failed to reproduce the supraphysiological doses used in doping. In 1996, Bhasin et al. [33] unequivocally proved that administration of T at sup...