Anabolic steroids and semen parameters in bodybuilders

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1 FERTILITY AND STERILITY Copyright C> 1989 The American Fertility Society Printed on acid-free paper in U.S.A. Anabolic steroids and semen parameters in bodybuilders Ulrich A. Knuth, Dr.med. Harald Maniera, Cand.med. Eberhard Nieschlag, Prof. Dr.med. * Max Planck Clinical Research Unit for Reproductive Medicine and Institute of Reproductive Medicine of the University, Munster, Federal The influence of high-dose anabolic steroid administration on endocrine and semen parameters of 41 bodybuilders (age, 26.7 ±.7 years [mean ± SEM]; height, 182 ± 1 cm; weight, 97.5 ± 2. kg) was investigated. History of anabolic steroid administration was recorded retrospectively, and results of semen analysis were compared with data from 41 consecutively recruited normal volunteers not using any steroids or other drugs. Doses of anabolic steroids taken by bodybuilders exceeded those generally applied for clinical purposes by up to 4-fold. Although only 5 of the normal volunteers had sperm counts below the lower normal limit of 2 X 1 6 sperm/ml, 24 of the bodybuilders showed subnormal values. Depending on the duration of anabolic steroid use and the period since last drug intake before the investigation, percentages of motile and normally formed sperm were significantly reduced in bodybuilders compared with normal volunteers. In those bodybuilders who had stopped consumption of anabolic steroids> 4 months previously, sperm numbers were in the normal range. Results suggest that even after prolonged use of extremely high doses of anabolic steroids, sperm production may return to normal. Fertil SteriI52:141, 1989 Administration of steroids at doses used frequentlyby athletes is so high that controlled clinical studies under similar conditions appear prohibited for ethical reasons. The possibility of impaired liver function during anabolic steroid treatment is well documented,i,2 and both malignant and benign liver tumors and peliosis hepatis have been reported in relation to the use of anabolic steroids (for review, see Reference 3). Thus the only way to detect long-term effects of high-dose administration of anabolic steroids is the use of retrospective case-control studies. 4 In the present cross-sectional investigation, we used this approach to elucidate the influence of anabolic steroids on seminal and reproductive endocrine parameters in bodybuilders. Received April 3, 1989; revised and accepted July 27, * Reprint requests: Eberhard Nieschlag, Prof. Dr.med., Institute of Reproductive Medicine of the University, Steinfurter Strasse 17,44 Miinster, Federal. Recruitment MATERIALS AND METHODS Contacts with bodybuilding studios were established by one of the authors (H.M.), who is an active athlete himself. The aim of the study was explained to potential volunteers. Free medical examination, hormone investigation, and semen analysis were offered. Study Design Forty-one bodybuilders (age, 26.7 ±.7 years [mean ± SEM]; height, 182 ± 1 cm; weight, 97.5 ± 2. kg) agreed to participate. They were asked to complete a detailed questionnaire on history of drug intake, diet habits, and training performance. These questionnaires formed the basis for the final interview concerning information as detailed as possible about time course, doses, and kind of drugs taken in the past. In addition, a detailed medical Knuth et ai. Anabolic steroids and semen parameters 141

2 Table 1 Generic and Trade Names of Anabolic Steroids Used by 41 Bodybuilders Investigated in the Present Study Systematic name Generic name + ester Trade name Manufacturer/location Injectable substances Testosterone-derived 17tJ-Hydroxyandrost-4-en -3-one Testosterone propionate Testoviron Oreton Durateston Organon, Oss, Netherlands cyclopentylpropionate Depot testosterone Upjohn, Heppenheim, Federal cypionate enanthate Delatestryl Squibb, Frankfurt, Federal Testoviron Depot Mixture of Omnadren Organon, Oss, Netherlands propionate Sustanon Polva-Chemie, Warsaw, phenylpropionate Poland decanoate isocapronate 4-Chloro-17tJ-hydroxy-androst-4- Clostebol en-3-one acetate Steranabol Farmitalia, Freiburg, Federal Megagrisevit Farmitalia, Freiburg, Federal 17tJ-Hydroxy-androsta-1,4-dien-3- Boldenone Boldane Squibb, Frankfurt, Federal one 19-N ortestosterone-derived 17tJ-Hydroxyestr-4-en-3-one Equipoise Squibb, Frankfurt, Federal Nandrolone phenylpropionate Durabolin Organon, Oss, Netherlands Nerobolil Richter, Milano, Italy Superanabol hexyloxyphenylpropionate Anadur Pharmacia, Helsingborg Sweden laurate Laurabolil Organon, Oss, Netherlands decanoate Deca-Durabolin Organon, Oss, Netherlands Retabolil Richter, Milano, Italy 4,17tJ-Dihydroxyestr-4-en-3-one Oxabolone Steranabol-Depot Farmitalia, Freiburg, Federal 17tJ-Hydroxy-estratrien-4,9,l1-3- Trenbolone one acetate Finaject Hoechst, Frankfurt, Federal cyclohexylacetate Parabolone Negmar Heterocyclic anabolic steroids 17a-Methyl-5a-androstano-[3,2-c J- Stanozolol Strombaject Winthrop, Norderstedt, pyrazol-17tj-ol Miscellaneous structure 17tJ-Hydroxy-1-methyl-5a-androst- 1-en-3-one Substances for oral use Testosterone-derived 17tJ-Hydroxyandrost-4-en-3-one Methenolone Acetate Primobolan Enanthate Primobolan Depot Testosterone undecanoate Andriol Organon, Oss, Netherlands 17tJ-Hydroxy-17 -methyl-androsta- Methandrostenolone Dianabol Ciba, Wehr, Federal Republic 1,4-dien -3-one Nerobil Metanabol of Richter, Milano, Italy Polva-Chemie, Warsaw, Poland 142 Knuth et al. Anabolic steroids and semen parameters Fertility and Sterility

3 Table 1 (Continued) Systematic name Generic name + ester Trade name Manufacturer/location 19-Nortestosterone-derived 17 p-hydroxy-19-norpregn-4-en-3- one Androstane-derived 17P-Hydroxy-1a-methyl-5aandrostan-3-one 17P-Hydroxy-17-methyl- 2(hydroxymethylene )-5a-androstan-3-one Heterocyclic anabolic steroids 17a-Methyl-5a-androstano-[3,2-c]- pyrazol-17p-ol 17p-Hydroxy-1-methyl-5a-androst- 1-en-3-one Miscellaneous structure 17 p-hydroxy-1-methyl-5a-androst- 1-en-3-one Norethandrolone Mesterolone Oxymetholone Stanozolol Oxandrolone Methenolone Nilevar Proviron Mestoran Plenastril Oxytosona Anadrol Androyd Winstrol Stromba Omnisterin Anavar Primobolan Searle, Dreieich-Sprintlingen, Griinenthal, Stolberg, Federal Syntex, Palo Alto, California Syntex, Palo Alto, California Winthrop, Norderstedt, Winthrop, Norderstedt, Searle, Dreieich-Sprintlingen, history was taken with special reference to reproductive function and gynecomastia. During physical examination testicular size was determined by comparison with an orchidometer. Varicoceles were excluded by palpation and Valsalva maneuver. A blood sample for endocrine parameters was drawn from an antecubital vein, and a semen specimen obtained by masturbation at the hospital was analyzed according to World Health Organization (WHO) guidelines 5 after 48 hours to 5 days of sexual abstinence. The mean time of abstinence was 2.7 ±.4 days. In cases of extremely low sperm counts, the ejaculates were centrifuged and analyses performed on the sediment. Data from semen analysis in athletes were compared with results from a group of normal, drugfree volunteers (n = 41; age, 25.9 ±.5 years; weight, 8.7 ± 2.9 kg; height, 184 ± 1 cm) screened consecutively during the recruitment phase of a different study.s These semen samples were analyzed by the same technicians around 6 months earlier. Hormone Measurements Serum for the endocrine evaluation was separated at 8 X g and stored at -2 C until assayed. Serum -luteinizing hormone (LH), follicle-stimu- lating hormone (FSH), and estradiol (E2) were determined in duplicate by radioimmunoassay (RIA). The detection limits for FSH and LH were 1. and 1.5 U/L, respectively. World Health Organization International Reference Preparations (IRPs) 68/ 4 and 78/549 were used as standards for LH and FSH, respectively. Testosterone (T) and dihydrotestosterone (DHT) were measured by RIA7 after isolation and separation by high-performance liquid chromatography to avoid cross-reactivity of unknown steroid metabolites. Steroid concentrations are given in international units. For conversion to nanograms per deciliter, multiply T values by 28.9; E2 values multiplied by 3.7 give results in picograms per milliliter. Statistics Statistical analysis was performed on a Zeilith AT personal computer using the SPSS PC+ program (SPSS, Inc., Chicago, IL). Throughout the paper means ± SEM are used. Values of sperm concentrations were normalized by square root transformation. To detect differences in measured parameters among individual groups, analysis of variance (ANOVA) followed by a Student-Newman-Keul (SNK) test was applied. For the purpose of data reduction and further Knuth et ai. Anabolic steroids and semen parameters 143

4 analysis, three subgroups were formed within the group of bodybuilders. Allocation was based on the time course of anabolic steroid administration and duration ofthe spermatogenic cycle. Nineteen men were still taking anabolic steroids when the investigation was performed. Eight of them had been taking steroids for only ~2 months after a drug-free interval from 1 to 5 months, together with 3 additional men who had stopped anabolic steroid administration between 1 and 3 months earlier after a treatment phase of only 2 months. These 11 men were considered to be most likely in an incomplete phase of spermatogenic suppression and were classified as group I. Group II comprised those 11 athletes who reported uninterrupted administration of anabolic steroids for 3 to 12 months up to the time of investigation and another 8 bodybuilders who had stopped taking steroids within the last 3 months after continuous administration for 3 to 9 months. In these men (n = 19), a maximal inhibition of spermatogenesis was expected. Group III was formed by the remaining 11 athletes, who had abandoned the use of anabolic drugs for >4 months before semen analysis. Steroids and Doses RESULTS Details of the steroids taken are given in Table 1. Testosterone and 19-nortestosterone esters were used most frequently, followed by methandrostenolone, methenolone acetate, and stanozolol (Table 2). Based on the duration of administration over the last 12 months, these five steroids comprised around 88% of anabolics used. In addition, trenbolone, boldenone, oxandrolone, chlorotestosterone mesterolone, and oxymetholone were used. Three men had used human chorionic gonadotropin (hcg) at doses of 1,5 to 3, IV on one or two occasions to stimulate endogenous T production. On average, the amounts of anabolic steroids taken per month were considerably higher than therapeutically recommended doses and reached extreme ranges in some men (Fig. 1). As a general pattern, different anabolic steroids were taken simultaneously for intervals of 3 to 4 months, interrupted by drug-free periods of similar length. This "stacking," as referred to by the athletes themselves, increased the total drug exposure per month even more. Side Effects and Semen Parameters In spite of these enormous doses, no side effects were reported, and only one man revealed gynecomastia during the physical examination. Compared with the control group of normal men, in which only two volunteers showed severe oligozoospermia (sperm concentrations < 5 X 1 6 jml) in addition to three men with sperm concentrations between 5 and 2 X 1 6 jml (moderate oligozoospermia), sperm concentrations in bodybuilders taking anabolic steroids were severely impaired (Fig. 2). There was no difference in semen volume between controls and "bodybuilders" (3.9 ±.2 versus 3.8 ±.3 ml; P >.5). In group I (n = 11), one man was azoospermic, three showed severe oligozoospermia, and one revealed sperm concentrations in the oligozoospermic range. Percentage of motile sperm in athletes with detectable sperm was significantly impaired in comparison with the control group, whereas no differences could be detected for the proportion of normally formed sperm. Within group II (n = 19), in which the most serious impact on spermatogenesis was expected, 7 men were azoospermic, 2 had only single sperm per high-power field in the sediments of their ejaculates, 5 were severely oligospermic, and 2 showed moderately impaired sperm concentrations. However, in spite oflong-iasting steroid administration at high doses, 2 athletes revealed normal sperm concentrations at 41.8 and 71. X 1 6 jml, respectively. In comparison with controls, percentage of motile as well as normally formed sperm was significantly reduced in this group. In contrast to those men allocated to groups I and II, athletes in group III (n = 11), who had stopped the usage of anabolic steroids for >4 months, had sperm concentrations within the range of normal controls. Only 3 men were severely oligozoospermic and 1 showed moderate oligozoospermia. However, a significant reduction in sperm motility and morphology compared with normal controls was apparent (Fig. 2). Hormone VaIues Those men still taking anabolic steroids when tested (n = 19) showed significantly reduced values for LH (1.9 ±.3 V) and FSH (1.4 ±.2 V) compared with athletes, who had stopped drug consumption >4 months previously (n = 11; LH, 4.5 ± 1.1 V; FSH, 3.2 ±.5 V;P<.5).Allotherbodybuilders (n = 11) with a drug-free interval of <3 144 Knuth et al. Anabolic steroids and semen parameters Fertility and Sterility

5 Table 2 Anabolic Steroids Taken by 41 Bodybuilders Drug Steroid use TEa NT b MAc MEd ST' TR' BOg OX h CL' MSi Oyk Total months of overall use Average use/ 1, month ± 125 ±68 (mg) I Highest dose 1,55 3, used/month (mg) ,98 ±82 ± 18 4,5 7, ± 19 3, ± 13 ± 195 1,8 1, ,225 ± 255 ±97 ± 125 ±522 2, ,2 3, a TE, testosterone esters. b NT, 19-nortestosterone esters. c MA, methandrostenolone. d ME, methenolone. est, stanazolol. 'TR, trenbolone. months showed intermediate values not different statistically from values given above (LH, 2.7 ±.6 U; FSH, 2.1 ±.6 U). No statistically significant differences could be detected for serum T (25.3 ± 5.9 versus 16.1 ± 5.1 versus 13.2 ± 1.8 nmol/l) and DHT concentrations (2.7 ±.3 versus 2.7 ±.9 versus 2. ±.3 nmol/l) depending on duration of the drug-free interval due to high variations within groups (AN OVA: P >.5). However, those men who were still taking anabolic steroids revealed significantly increased serum E2 concentrations (274 ± 21 pmol/l) compared with men with ~4 months of drug abstinence (184 ± 17 pmol/l; SNK: P <.5). Drug-free intervals of ~3 months in athletes were accompanied by E2 serum levels not different from both other groups (211 ± 9.6 pmol/l). g BO, boldenone. h OX, oxandrolone. i CL, clostebol. i MS, mesterolone. k OY, oxymetholone. I Values for average use are means ± SEM. DISCUSSION Today the use of anabolic steroids among athletes has reached almost epidemic proportions, as revealed by the last olympic games.s Although a wealth of literature exists about their influence on athletic performance and side effects, 3 the use of anabolic steroids by athletes is still quite controversial. Many men interviewed during the present study were convinced that strength and performance were improved by the use of anabolic steroids, although in general, this notion is not supported by the available scientific publications (for review, see Reference 3). However, well-controlled randomized trials under double blind conditions are difficult to perform, because athletes seem to be able to differentiate anabolic steroid treatment from placebo administration and use exceedingly Figure 1 Comparison of clinically used doses (according to manufacturer's recommendations) versus mean and maximal monthly doses of some anabolic steroid used by bodybuilders. The mean represents the average dose taken by all men, whereas the maximal dose represents the highest consumption by one individual in the study. For abbreviations of steroids, see Table 2. 12,..., m!. 1 CD.:::t..E 8 c ~ o ~ CD... U1 > L-... C o E o TE - D maximal average clinical dose NT ME ST ox anabolic steroid dose used by bodybuilder Knuth et al. Anabolic steroids and semen parameters 145

6 '=' 12 n: E c,d..., ~ M =... 1 E >-... C» -.2 a.r. D C 8 a,b - a.. ~ ~ 6 c E u c... >- 4 u = ;: 2 ~ E., a.. a,b,c sperm conc. motility morphology Figure 2 Sperm concentration (mean ± SEM), percentage of motile sperm, and proportion of normally formed sperm in controls (black bars) in bodybuilders with short duration of anabolic steroid consumption (group I of text, hatched bars), in bodybuilders with extended anabolic steroid consumption (group II of text, horizontauy lined bars), and in athletes after >4 months of drug-free interval (group III of text, open bars). Identical letters above two bars indicate those pairs of values that are statistically different by analysis of variance and SNK test. For analysis of motility and morphology, azoospermic ejaculates were treated like missing values. high doses that clinical investigators find difficult to administer for ethical reasons. Androgenic steroids are known to cause impaired spermatogenesis Nortestosterone has even been suggested for male contraception.lo.n Although the suppressive effects of anabolic steroids on testosterone and gonadotropin secretion have been studied to some extent, detailed trials on their influence on spermatogenesis are virtually nonexistent. In most instances, only endocrine parameters were measured.l2-l8 A general decrease of gonadotropins was reported, which is confirmed by our data. Spermatogenesis is under the control of FSH and LH, whose secretion is regulated by gonadal steroids and possibly by inhibin. Based on this negative feedback mechanism, administration of anabolic steroids suppresses gonadotropin secretion. Although this is the principle underlying an endocrine approach to male contraception with androgenic steroids (for review, see References 19 and 2), only few studies report seminal parameters in athletes using anabolic steroids. Studies are limited to case reportsl4 or were conducted after too short a duration of treatment.2l.22 The only controlled trials on the influence of anabolic steroids on seminal parameters used 19-nortestosterone at moderate doses with the aim of developing a male antifertility agent.lo.n In these trials, azoospermia or severe oligozoospermia with sperm counts < 5 X 1 6 /ml was observed in 83% of all participants.23 In the present study, this value was shown by 65% of those 26 men who had taken anabolic steroids long enough immediately before the investigation so that an impact on spermatogenesis could be expected. As in trials with steroids for male contraception (for review, see References 19 and 2), some men were able to maintain spermatogenesis in spite of long-term steroid administration at high doses. This could corroborate the hypothesis that androgens alone may be sufficient to maintain or reinitiate spermatogenesis,24.25 although the diversity of compounds and doses used and their unknown metabolism complicate a definite conclusion. Most of the athletes in subgroup III (7/1) who had stopped taking anabolic steroids > 3 months before the investigation showed sperm counts> 2 X 1 6 /ml, the lower limit of normality according to the WHO guidelines.5 Two athletes with sperm counts at 3.6 and 6.1 X 1 6 /ml had ceased anabolic steroid usage 4 and 6 months earlier. Only 1 man displayed severely suppressed sperm concentrations 12 months after the latest use of anabolic steroids. Although the rate of 3% oligozoospermia in exusers of anabolic steroids versus 12% in unselected normal volunteers seems higher, numbers of subjects are small and normalization of spermatogenesis after trials for hormonal male antifertility agents may take >1 year. Apparent recovery time is severely influenced by the half-life of anabolic steroids used, which may be extremely long, as in the case of some 19-nortestosterone esters.n The reported results of the present study are based on data of anabolic steroid use in bodybuild- 146 Knuth et al. Anabolic steroids and semen parameters Fertility and Sterility

7 ers collected retrospectively and suffer from all disadvantages of this type of uncontrolled studies. In addition to the wide variety of drugs used, their different doses and durations of administration, diet habits, and training conditions may affect the results. It did not seem reasonable to put these factors into account systematically, because the report consists basically of 41 independent case studies. Within these limitations, however, the data suggest that in spite of severe suppression of gonadotropins, spermatogenesis may still continue in some men when high amounts of androgens are administered exogenously. Even after prolonged use of high doses of anabolic steroids, sperm production may return to normal levels. Ackrwwledgments. Semen analyses and hormone determinations were performed by Christa Kriisemann, Ingrid Upmann, Ulrike Oberdiek, and Mathilde Moller. Language editing was provided by Susan Nieschlag, M.A. (all working at Institute of Reproductive Medicine, Miinster). REFERENCES 1. O'Shea JP, Winkler W: Biochemical and physical effects of an anabolic steroid in competitive swimmers and weight lifters. Nutr Rep Int 2:351, Shephard RJ, Killinger D, Fried T: Responses to sustained use of anabolic steroid. Br J Sports Med 11:17, Haupt HA, Rovere GD: Anabolic steroids: a review of the literature. Am J Sports Med 12:469, Cowar VS: Study proposes to examine football players, power lifters for possible long term sequelae from anabolic steroid use in 197s competition. J Am Med Assoc 257: 321, World Health Organization: WHO Manual for the Examination of Human Semen and Semen-Cervical Mucus Interaction. 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In Fertility Regulation Today and Tomorrow, Edited by E Diczfalusy, M Bygdeman. New York, Raven Press, 1987, p Johnson LC, Fisher G, Silvester LJ, Hotheins CC: Anabolic steroid: effects on strength, body weight, oxygen uptake and spermatogenesis upon mature males. Med Sci Sports 4:43, Holma PK: Effects of an anabolic steroid (metandienone) on spermatogenesis. Contraception 15:151, Knuth UA, Behre H, Belkien L, Bents H, Nieschlag E: Clinical trials with 19-nortestosterone for male fertility control. In Male Contraception: Advances and Future Prospects, Edited by GI Zatuchni, A Goldsmith, JM Spieler, JJ Sciarra. Philadelphia, Harper and Row, 1986, p Marshall GR, Wickings EJ, Liidecke DK, Nieschlag E: Stimulation of spermatogenesis in stalk-sectioned Rhesus monkeys by testosterone alone. J Clin Endocrinol Metab 57:152, Weinbauer GF, GOckeler E, Nieschlag E: Testosterone prevents complete suppression of spermatogenesis in the Gn RH-antagonist treated non-human primate macaca fascicularis. J Clin Endocrinol Metab 67:284, 1988 Knuth et ai. Anabolic steroids and semen parameters 147