Medical consequences of doping with anabolic androgenic

37 Pages·2015·1.12 MB·English

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Accepted Preprint first posted on 24 March 2015 as Manuscript EJE-15-0080
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1 EN11 2015-03-11
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Medical consequences of doping with anabolic androgenic
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steroids (AAS): effects on reproductive functions.
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6 Eberhard Nieschlag1,2 and Elena Vorona3

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8 1Centre of Reproductive Medicine and Andrology
9 University of Münster, Münster, Germany

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11 2Center of Excellence in Genomic Medicine Research
12 King Abdulaziz University, Jeddah, Saudi Arabia
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14 3Centre of Endocrinology, Diabetology and Rheumatology, Dortmund, Germany
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16 Correspondence should be addressed to E. Nieschlag,
17 Email: [email protected]
18 EN11 2015-03-11
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22 Abstract
23 Anabolic androgenic steroids (AAS) are the favoured appearance and
24 performance enhancing drugs (APED) used in competitive athletics, in
25 recreational sports and by body-builders. The global lifetime prevalence of AAS
26 abuse is 6.4% for males and 1.6% for women. Many AAS, often obtained from the
27 internet and dubious sources, have not undergone proper testing and are
28 consumed at extremely high doses and in irrational combinations, also along
29 with other drugs. Controlled clinical trials investigating undesired side-effects
30 are lacking since ethical restrictions prevent exposing volunteers to potentially
31 toxic regimens, obscuring a causal relationship between AAS abuse and possible
Copyright © 2015 European Society of Endocrinology.
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32 sequelae. Because of the negative feedback in the regulation of the
33 hypothalamic-pituitary-gonadal axis, in men AAS cause reversible suppression
34 of spermatogenesis, testicular atrophy, infertility and erectile dysfunction
35 (anabolic steroid induced hypogonadism). Should spermatogenesis not recover
36 after AAS abuse, a pre-existing fertility disorder may have resurfaced. AAS
37 frequently cause gynecomastia and acne. In women, AAS may disrupt ovarian
38 function. Chronic strenuous physical activity leads to menstrual irregularities
39 and, in severe cases, to the female athlete triad (low energy intake, menstrual
40 disorders and low bone mass),making it difficult to disentangle effects of sports
41 and AAS. Acne, hirsutism and (irreversible) deepening of the voice are further
42 consequences of AAS misuse. There is no evidence that AAS cause breast
43 carcinoma. Detecting AAS misuse through the control network of the World
44 Anti-Doping Agency (WADA) not only aims to guarantee fair conditions for
45 athletes, but also to protect them from medical sequelae of AAS abuse.
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47 Introduction
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49 Medal-winning athletes are the undisputed icons of society. As role models they are
50 also expected to show impeccable character and behaviour. Society rewards them with
51 admiration and dedication, in no way objecting to exorbitant financial gains by their
52 idols; governments and companies consider athletes‟ triumphs as advertisements for
53 their politics and products respectively. In addition to exhaustive training, this places
54 athletes under tremendous pressure, not only to excel in their discipline, but also to
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55 resist the temptation to use any illicit means, e.g. drugs, to enhance performance. “Play
56 true” is the motto of the World Anti-Doping Agency (WADA), appealing to all
57 athletes to refrain from using illicit drugs, but without the elaborate worldwide
58 network of doping controls and sanctions against doping (www.wada-ama.org,1,2),
59 WADA‟s call for fairness would remain without echo. However, doping is not
60 reserved for the small squad of elite athletes, it has spread from the idols at the top to
61 all rank and file participants in sports, from adolescents to seniors. The global lifetime
62 prevalence rate of using AAS is 6.4% for males and 1.6% for females (3). Not only
63 classical sport disciplines are involved, the phenomenon is similarly widespread
64 among bodybuilders, so that the drugs used have been collectively classified as
65 “appearance and performance enhancing drugs” (APEDs) and summarized in the
66 WADA Prohibited List 2015(www.wada-ama.org).
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68 Although doping has been practiced since antiquity, often with placebo or toxic
69 effects, really effective APEDs only became available with the rise of modern
70 pharmacology, and in particular, following the isolation and synthesis of testosterone
71 and anabolic androgenic steroids (AAS). Testosterone came into clinical use shortly
72 after its synthesis in 1935 (4) and its first documented use for doping was by German
73 rowers in 1952 (to maintain their marital duties during exhausting training) and by
74 Russian weight lifters in 1954 to enhance their power. Since then AAS lead the lists of
75 APEDs worldwide and among these testosterone is used in almost 50 %, be it in the
76 4500 doping-positive samples collected by WADA worldwide in 2012 (5) or be it
77 among black market substances confiscated by customs and police (6) (Table 1).
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79 As all licensed testosterone and AAS preparations are available only by prescription,
80 the drug sources remain obscure. In part, these substances are no longer or have never
81 been on the open market. There have been instances of doctors prescribing AAS
82 especially under pressure of bodybuilders, who undertake any risk to become
83 champions. Surveys among fitness center clientele revealed that up to half of APED
84 users obtained the drugs with or without prescription from physicians or pharmacies
85 (7,8). Labs in Eastern Europe, Asia and South America producing multitudes of AAS
86 offer them for sale on the internet which, next to gyms and fitness studios, has become
87 the major source of AAS. When counted in November 2011 there were 328,000
88 internet pages accessible under the search term “steroids for sale” (9)! Furthermore,
89 AAS may be added to food supplements – often undeclared on the label (10,11,12) or
90 found in phytopharmaka and animal organ extracts. For example, musk pods used in
91 Chinese traditional medicine contain 16 different, undeclared AAS, as discovered in
92 doping controls (13). Finally, secret but official programs of sport organisations or
93 states may provide AAS and other APEDs to their athletes, as demonstrated by the
94 systematic doping program of the former German Democratic Republic (GDR) in the
95 1970s and 1980s which became evident after the collapse of that règime in 1989 (14).
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97 AAS – as all other APEDs – may not only have the desired, but also adverse side
98 effects, resulting from the combination of different AAS in extremely high doses with
99 other drugs and from duration of administration over periods ranging from months to
100 many years. Due to the secret nature of this drug abuse type, doses and duration are
101 mostly unknown and properly controlled clinical trials do not exist. Hence the
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102 scientific assessment of the sequelae of AAS abuse relies on case reports and on a few
103 retrospective investigations, making a review of the field in the age of evidence-based
104 medicine extremely difficult and frustrating. Nevertheless, this review is intended to
105 inform the endocrinologist about symptoms and diseases caused by AAS which,
106 without specific knowledge, may be misinterpreted while searching for their origin.
107 Proper diagnosis is further hindered by the reluctance of the doped patient to admit
108 consumption of AAS and ignorance about their possible serious side effects.
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110 This review highlights the effects of testosterone and AAS on male and female
111 reproductive functions and includes effects on the skin and its appendices as secondary
112 sexual characteristics (overview in Table 2). For adverse effects on other organ
113 systems the reader is referred to previous reviews (e.g. 15-19). For the sake of
114 manageability testosterone and AAS (including designer steroids) are referred to
115 collectively as AAS, although both chemical structure and biological profiles of
116 individual AAS differ. In general, the effects and side-effects of specific AAS depend
117 on their chemical structure. The full spectrum of biological action requires that the
118 androgen can be aromatized to estradiol as well as reduced to 5alpha-
119 dihydrotestosterone. As indicated in Figure 1, the most frequently used AAS,
120 testosterone, boldenone, metandione and nortestosterone can be aromatized as well as
121 5alpha-reduced, while fluoxymesterone and formebolone can be 5alpha-reduced but
122 not aromatized, and some AAS can be neither aromatized nor 5alpha-reduced,
123 especially those that are dihydrotestosterone derivatives (Figure 1). In addition, the
124 genetic disposition of the individual athlete may modify the reaction to androgenic
125 substances, as exemplified by the androgen receptor polymorphism modulating
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126 testosterone activity (20). However keeping these apart is difficult due to the varying
127 combinations and doses in addition to the often practiced doping polypharmacy (21,
128 22) including erythropoietin, insulin, IGF-1, thyroxine, clenbuterol, amphetamines,
129 diuretics, etc. However, the unique common feature of alkylation in the 17α-position
130 of the androgen molecule should be pointed out since these AAS are potentially
131 severely liver toxic (Figure 1). AAS abuse is also characterized by “stacking and
132 cycles” i.e. increasing doses over time and changing preparations and their
133 combinations alternating with AAS-free periods in order to maximize desired effects
134 and minimize side-effects. Whether these regimens indeed fulfill their purpose cannot
135 be assessed as they are based on trial and error and appropriate studies do not exist.
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138 Effects of AAS on male reproductive functions
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140 Suppression of spermatogenesis
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142 As endogenous testosterone is the major regulator of the hypothalamo-pituitary-
143 testicular axis, it is not surprising that exogenous testosterone and AAS exert a
144 suppressive effect on the hypothalamo-pituitary system. The resulting suppression of
145 LH and FSH leads to a decrease in intratesticular testosterone and secreted
146 testosterone, as well as to a decrease in spermatogenesis and sperm production. This
147 effect forms the basis for clinical trials in hormonal male contraception. As there are
148 no systematic investigations of the effects of doping with high-dose AAS on testicular
149 function, contraceptive trials may serve as a model for what happens under AAS
150 suppression.
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152 Male hormonal contraceptive trials use testosterone alone in therapeutic doses or in
153 combination with gestagens to induce azoospermia or severe oligozoospermia
154 compatible with contraceptive protection (for review 23). Testosterone derivatives
155 used for doping such as 19-nortestosterone and MENT have also been applied in
156 contraceptive trials (24,25). The kinetics of sperm suppression and recovery are quite
157 well known from these carefully conducted trials using therapeutic doses (26,27). Of
158 1549 healthy eugonadal men o participated in 30 different clinical trials, after
159 cessation of medication, 67% showed a return to sperm concentrations above 20
160 mill/ml within 6 months, 90% within 12 months, 96% within 16 months and 100%
161 within 24 months (26). While the different regimens used in the 30 trials were not
162 identical, they used similar steroid doses and the differences in recovery time appear
163 to be determined more by characteristics of the individual than by the therapeutic
164 regimen. Nevertheless, all men returned to fertile levels of sperm counts. Thus a 6 – 24
165 month span provides a time frame for recovery in AAS abusers, although it has to be
166 kept in mind that doses used for doping far exceed those used for male contraception,
167 and therefore even longer periods may be anticipated.
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169 These results may help to interpret case reports and small retrospective studies in AAS
170 abusers. These show a wide spectrum of sperm counts in AAS users under treatment,
171 as well as after cessation of abuse ranging from normal levels to azoospermia. (Fig. 2)
172 (28,29). LH and FSH correlate grossly with sperm counts, i.e. the lower the
173 gonadotropins, the lower the sperm counts tend to be. Parallel to the decline in
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174 spermatogenesis, testicular volumes decrease significantly since the tubules occupy
175 about 95% of the testes volume and their atrophy causes shrinkage of the testes.
176 Varying doses, preparations and combinations of AAS and other APED make it
177 difficult to draw general conclusions from individual observations, but it is clear that
178 the recovery of sperm counts correlates positively with duration of time since last
179 intake of AAS, as do sperm morphology and motility (Figure 2). As AAS may be
180 abused for many years at high doses and in varying combinations, it is impossible to
181 predict their impact on spermatogenesis without proper investigations.
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183 In some AAS abusers recovery may take irritatingly long. This, in addition to
184 individual predisposition, is most likely due to the depot effects of the huge steroid
185 concentrations consumed (30,31). For example, after termination of nandrolone abuse
186 metabolites could still be detected in urine after more than a year in some men (32). In
187 other candidates sperm counts may not reach the normal range after cessation of
188 doping, possibly due to preexisting fertility problems. When infertile men with
189 subnormal sperm counts were included in a contraceptive trial using testosterone
190 undecanoate alone, all returned to their (subnormal) baseline levels after cessation of
191 testosterone undecanoate administration, but did not become better or worse than
192 before the trial (33). In analogy, those AAS users who apparently do not return to
193 normal sperm counts may never have had normal values before initiation of AAS
194 abuse.
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196 In conclusion, to date there is no indication that AAS abuse causes permanent damage
197 to spermatogenesis, although suppression may cause transient azoospermia and
198 recovery may take up to two years. However, no systematic investigations exist to
199 provide a definitive answer.
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201 Considering the great number of teenage boys using AAS, the question arises whether
202 their use by boys boys around puberty may be harmful to spermatogenesis. Although
203 systematic investigations in pubertal AAS users are lacking, treatment of over-tall
204 boys with high doses of testosterone - close to doping doses - for reduction of final
205 height provides an analogy. Initially it was suspected that this treatment would be
206 harmful to the testes and leave permanent damage. However, when the proper control
207 groups were co-investigated, the incidence of subnormal semen parameters was the
208 same in both groups (34,35), indicating that at this age the testes do not differ from
209 adult men in their capacity to recover from suppression.
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211 Testicular tumours
212 In connection with AAS abuse, testicular germ cell tumours have not been reported in
213 the literature. A single case of a leiomyosarcoma in a former GDR weightlifter has
214 been reported. He used oralturinabol at high doses (up to 20 tablets per day) from 18 to
215 23 years of age. He developed gynaecomastia under the treatment and was, at the age
216 of 32, operated for a unilateral intratesticular leiomyosarcoma (36). As these tumours
217 are extremely rare and have been described in hamsters after treatment with
218 testosterone propionate and diethylstilbestrol (37), the authors suspected a causal
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219 relationship between AAS abuse and the sarcoma. As this remains the only reported
220 case, possible involvement of AAS in the pathogenesis of the tumour remains unclear.
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222 Hypogonadism induced by anabolic steroids
223 In addition to decreased sperm counts and testes volumes, some AAS abusers
224 experience lack of libido and erectile function as well as other signs of hypogonadism.
225 This occurs especially in those men abusing aromatizable AAS, resulting in high
226 estrogen levels. Although physiological levels of estrogens are necessary for normal
227 sexual function (38), the extremely high doses and the imbalance between testosterone
228 and estradiol appear to be the cause of sexual dysfunction in these cases. This may also
229 occur during the recovery phase after termination of exogenous AAS supply, when
230 endogenous production has not yet resumed full activity. This type of hypogonadism
231 (31) has been referred to as “anabolic steroid induced hypogonadotropic
232 hypogonadism” (39 and more recently, simply as “anabolic steroid induced
233 hypogonadism” (ASIH) (40, 41). In a large US urology department, 96 of 6033
234 (=1.6%) patients consulting for hypogonadism suffered from ASIH. One quarter of
235 these patients presented with infertility and three quarters with sequelae of
236 hypogonadism (41). Many of these AAS abusers were first overlooked and only
237 diagnosed after renewed interviewing following inconclusive investigations. This
238 reflects the fact that patients seeking medical care only reluctantly admit to AAS abuse
239 and targetting AAS abuse directly should be part of the routine work-up of
240 hypogonadal men (17).
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