110 Review Article DOI: 10.1111/j.1610-0387.2007.06176.x

Abuse of anabolic-androgenic steroids and bodybuilding acne: an underestimated health problem Bodo Melnik1,Thomas Jansen2, Stephan Grabbe2 (1) Department of Dermatology, Environmental Medicine and Health Science, Division of Human Sciences, University of Osnabrück, Germany (2) Department of Dermatology,Venereology and Allergy, University of Essen, Germany

JDDG; 2007 • 5:110–117 Submitted: 3.7.2006 | Accepted: 6.9.2006

Keywords Summary • anabolics Abuse of anabolic-androgenic steroids (AAS) by members of fitness centers • anabolic-androgenic steroids and others in Germany has reached alarming dimensions. The health care • bodybuilding acne system provides the illegal AAS to 48.1 % of abusers. Physicians are involved in • doping acne illegal prescription of AAS and monitoring of 32.1 % of AAS abusers. Besides • health risk health-threatening cardiovascular, hepatotoxic and psychiatric long-term side effects of AAS, acne occurs in about 50 % of AAS abusers and is an important clinical indicator of AAS abuse, especially in young men 18-26 years of age. Both acne conglobata and acne fulminans can be induced by AAS abuse. The dermatologist should recognize bodybuilding acne, address the AAS abuse, and warn the patient about other potential hazards.

Introduction acne fulminans [4–9]. Further, healing of non-therapeutic indications and for use Sports can promote good health as well as acne may be prevented by anabolic steroids. in sports. The World Anti-Doping pose a health hazard. Various skin diseases AAS abuse has detrimental effects on lipid Agency lists them among prohibited can be improved or worsened by sports metabolism. The AAS-induced drop substances and methods [20]. [1]. Intake or administration of doping of HDL cholesterol and rise of LDL cho- agents, especially anabolic-androgenic lesterol increase the cardiovascular risk. Doping prevalence and anabolic- steroids (AAS ) lead to unwanted derma- Exacerbation of other skin diseases such androgenic steroids tological effects such as bodybuilding or as hereditary coproporphyria, linear Use of doping agents, especially of AAS, doping acne with increased seborrhea, keloids and psoriasis has been reported as is no longer limited to competitive striae distensae, gynecomastia, hypertri- side effects of AAS [10–12]. Therapeutic sports, but has, as medical studies in chosis, hirsutism, androgenetic alopecia, applications of AAS in dermatology USA show, spread to leisure sports, espe- seborrheic dermatitis, cutaneous infec- include long-term prophylaxis of heredi- cially to fitness sports and bodybuilding tions including furunculosis as well as tary angioedema (, ), [21–34]. The main reason for taking reduction of testicular volume and sperm treating cryofibrinogenemia, use of anti- AAS is the identification of adolescents count (Table 1) [2, 3]. In doping acne catabolic effects in burns and extensive and young adults with the exaggerated the clinical picture ranges from the ini- wounds and in wasting syndrome in ad- ideal body image suggested by western tial manifestation of acne or a worsening vanced HIV infection [13–19]. mass media [25, 26, 34]. Striegel et al. of preexistent acne up to features of acne Anabolic ergogenic substances such as [27] estimate that visitors of fitness cen- conglobata or the sudden occurrence of AAS and clenbuterol are prohibited for ters in Germany spend about 85 million

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totoxic substances were taken, mainly Table 1: Most common clinical side effects of anabolic-androgenic procured on the black market, but pre- steroids, modified from O´Sullivan et al. [45]. scribed by physicians in 14 % (Table 2). As the return of questionnaires in the Side effects Percent (%) of users effected Lübeck study was 52 %, a much higher rate of use must be anticipated. A re- Changes of libido 61 cently published report by Striegel et al. Mood swings 57 [27] from the Institute for Sports Medi- cine of the University of Tübingen, Ger- Reduced testicular volume 46 many, revealed the results of a nation- Acne 43 wide poll of 113 fitness centers. Of participants, 13.5 % admitted to having Erectile dysfunction 21 used anabolic ergogenic substances at Headaches 9 least once. Abuse correlates with cocaine abuse, years of training, frequency of Edema, water retention 5 training and showed negative correlation Change in hair growth 5 with educational status and alcohol con- sumption. Especially disturbing is the fact that 48.1 % of the users of anabolic Euros yearly for anabolic ergogenic sub- athletes in the USA is reported to be ergogenic agents obtain them through stances. In the USA, 11 % of boys in 17–20 % [26, 32], among amateur health care providers and 32.1 % of grades 11 and 12 consume AAS, as do bodybuilders even 80 % in men and 40 % these are under physician supervision. 2.5 % of girls [24, 30]. In England, 9 % in women [24, 29]. An increase in the A similar situation can be found in Swe- of male fitness studio attendants take prevalence in AAS abuse has also been den. An analysis of 25,835 calls to the AAS [31, 32]. The drugs are known observed in Italy and Sweden [37, 38]. anti-doping hotline of the Institute for among users as ‘‘Sus’’ and ‘‘Deca’’. ‘‘Sus’’ The doping prevalence in Northern Ger- Clinical Pharmacology of the Huddinge (sustanon) is a mixture of four testos- many is best represented by the Lübeck University Hospital in Stockholm from terone esters, ‘‘Deca’’ is de- study, a survey of 24 fitness studios in 1993 to 2000 shows that most calls were canoate [33].The prevalence of AAS Schleswig-Holstein and Hamburg [39]. in regard to side effects of AAS, especially, among Australian high school students is The average age of the athletes was 27.9 , , reported at 3.2 % [35]. In the subgroup years with users being most frequently methandienone and stanozolol [40]. Of of bodybuilders and weightlifters in (37 %) in the age group 21–25 years. Of the ten most common side effects of Flanders, the prevalence of AAS abuse the interviewed men 24 % and of the AAS, acne was third following psycho- between 1988 and 1993 was 38–58 % women 8 % admitted to using anabolic logical changes such as aggression and [36]. Doping prevalence among college drugs. In 94 % potentially highly hepa- depression, among clinically visible symptoms it even ranked first (Table 3).

Table 2: Most commonly used anabolic-androgenic steroids in German fitness clubs (Lübeck study), modified from Boos et al. [39]. Sources of and substance groups of anabolic-androgenic steroids In the Lübeck study 94 % of abusers took Anabolic-androgenic Cases Average dose Trade name AAS, of these 96 % in oral form and steroid (AAS) (%) (mg/day) 64 % additionally via a parental route [39]. Among oral drugs, stanozolol, Methandrostenolone Dianabol, Metanabol 37.5 36.6 methandrostenolone and predominated. Among parenterally ad- Nandrolone Deca-Durabolin 37.5 4.0 ministered AAS, stanozolol, and decanoate and nan- drolone were favored. Table 2 informs on Testosterone Systanon, Testoviron 37.5 58.5 the frequency of use of the AAS and the average daily dose, which ranged from Oxandrolone Anavar, Oxitosona 15.0 25.0 35 to 75 mg. The majority of athletes use drug combinations over a period of 7.5 Stanozolol Winstrol, Stromba 39.0 37.4 weeks on average as a course of treatment. The drug dose is generally increased up Methenolone Primobolan 27.5 75.6 to the middle of the course and tapered again towards the end. A recently pub- Other AAS Omnadren, Proviron 60.9 53.3 lished internet-based survey from the USA also shows that of the 207 participants most used AAS in combinations [41].

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terone. AAS lead to hypertrophy of seba- Table 3: 10 side effects most commonly reported by 4,339 users of ceous glands together with increased se- anabolic-androgenic steroids in Sweden 1996–2000 [40]. bum excretion, increased production of skin surface lipids and an increased pop- Reported side effects Number of reports ulation of Propionibacterium acnes [2, 48–51]. The mechanism of action of Aggression 835 AAS is dependent on the chemical mod- Depression 829 ification of each individual derivative as Acne 770 this affects the affinity to the receptor and the interaction with various Gynecomastia 637 steroid-metabolizing enzymes and trans- Fear 637 port proteins [sex -binding Impotence 413 globulin (SHBG)] [58–62]. Regarding interactions of AAS with intracellular Testicular atrophy 404 steroid receptor proteins, different bind- Sleep disturbances 328 ing affinities are known [52, 53, 55, 56]. AAS with high binding affinity to the an- Edema 318 drogen receptor are considered potent an- Mood swings 302 drogens such as 19-nortestosterone and methe-nolone; substances with lower binding affinity to the On average, 3.1 different drugs were of AAS are made available by licensed are weak such as stanozolol or used in the 5–10 week course of treat- health care providers. [56]. Some AAS such as ment. Physiological substitution doses Further correlations exist between con- do not bind at all to the were exceeded by a factor of 5 to 29. Di- sumption of AAS and of other drugs such androgen receptor and possess other verse bodybuilding online forums and as alcohol, cigarettes, cocaine, marihuana mechanisms of action. Androgen recep- internet services provide exchanges and chewing tobacco. It probably also tors have been found in sebocytes and among users, information on procurement, paves the way to steroid dependency, as 72 follicular keratinocytes [57]. It is signifi- use, combination of drugs, dosages, % of users plan to continue taking AAS in cant that AAS can be enzymatically con- side effects and, in part, sell products the future [43, 44]. This observation con- verted by steroid-metabolizing enzymes (e.g. www.bodybuilding-online.com, firms the experience gained by an Aus- in sebaceous glands and keratinocytes of http://steroidanabolic.com./germany/ste tralian survey that showed that only 19 % the follicular epithelium, which posses roideoraldoping.php, www.muscle.de24/ of AAS users informed about side effects 3- and 17-hydroxysteroid dehydroge- de/muskelaufbau/anabolics). and their own lab test results by physicians nase. The key enzyme of androgen In up to 50 % AAS are obtained on the wanted to avoid AAS in the future [45]. biosynthesis, 5-reductase, can produce black market. Sources range from the Interim results of the ‘‘Growing Up To- AAS metabolites with a higher receptor ‘‘house dealer’’ to users who finance their day Study’’ in the USA with 4,237 boys binding affinity. The AAS-androgen re- own need by further selling. The sub- and 6,212 girls aged 12 to 18 years ceptor complex translocates to the cell’s stances are imported via the former Eastern showed that 4.7 % of boys and 1.6 % of nucleus where it modifies protein syn- bloc countries. They can also be obtained girls already were taking protein drinks, thesis of androgen-dependent genes [58, on vacation in Spanish pharmacies or creatine, amino acids, hydroxymethyl bu- 63]. Even the androgenic prohormone supermarkets in Thailand [39, 47]. Often tyrate, , growth dehydroepiandrosterone (DHEA) plays anabolic agents from veterinary sources hormone or injectable anabolic steroids a role in the pathogenesis of acne, as it is are used. They are often cheaper and easier at least once weekly to improve their converted into the potent dihydrotestos- to obtain, bur carry additional risks as appearance or strength [46]. Media- terone by 3- and 17-hydroxysteroid they are not produced with the same care oriented adolescents wanting to copy the dehydrogenase and 5-reductase type I as are drugs for human consumption. ideals propagated by health magazines found in sebocytes [59–62]. Morphome- Sources named by the users in the Lübeck are particularly susceptible for diverse tric analysis of sebaceous glands in AAS- survey were in 14 % physicians, in 12 % supplementation. In the ‘‘United States treated athletes in a 4 week training the trainer, in 16 % pharmacies, in 56 % Centers for Disease Control and Preven- phase showed a significant increase of acquaintances and in 53 % fellow athletes tion’s 1997 Youth Risk Behavior Survey’’ size of the sebaceous glands by 89.2 % [39]. The latest nationwide data from it is shown that certain behavioral pecu- with the number of sebocytes in the dif- the Tübingen survey show a shocking liarities such as being quarrelsome in ferentiating as well as the undifferenti- participation by health care professionals girls and taking sexual risks in boys are ated cell pools both increasing signifi- in distributing AAS to users in 48.1 % predictors of future AAS abuse [47]. cantly [50]. of cases [27]. Of these, about one-half During a 12-week power training with receive the substances through physicians’ Pathophysiology of doping or AAS administration the sebum secretion prescriptions and one-third through the bodybuilding acne rate rose significantly from 0.989 ± pharmacist – often without prescription. It Anabolic-androgenic steroids (AAS) are 0.191 g/cm2/min to 1.171 ± 0.076 g/ is a very grave situation that about 50 % derivatives of the male hormone testos- cm2/min [49]. The relative distribution

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of the main lipid classes of sebum (free ance or exacerbation of seborrhea, the not go unmentioned [81]. Psychiatric fatty acids, squalene, triglycerides, wax development of acne up to the develop- complications of AAS abuse such as in- esters) on the forehead showed no ment of acne papulopustulosa, acne con- creased aggression and depression should significant difference before or after AAS globata or acne fulminans (Figures 1 and 2). be viewed in a sociological context and use. A significant increase in cholesterol Acne conglobata or acne fulminans can from the point of view of safety in driv- to 4.2 ± 0.7 % compared to the initial develop under exogenous AAS even in ing and handling machines [82]. An au- level of 2.4 ± 0.1 % was observed. Be- the absence of previous acne [4, 5, 7, 8, topsy study by the Institute for Forensic yond effects of androgens on the andro- 73]. Further, AAS-induced acne can be Medicine of the Swedish Karolinska In- gen receptor, other nuclear receptors, the worsened by oral or parenteral adminis- stitute on 52 AAS abusers proved the as- peroxisome proliferator-activated recep- tration of vitamin preparations contain- sociation of AAS abuse and the abuse of tors (PPAR), are involved in develop- ing high doses of vitamin B2, B6 and other psychoactive substance in 79 % of ment, proliferation and differentiation of B12 [74]. Iatrogenic administration of the cases [83]. AAS can also pave the way sebocytes. The nuclear receptors PPAR-, testosterone or other AAS to treat exces- to opiate dependency [84]. In compari- PPAR- and PPAR- induce lipogenesis sive height in children and adolescents son to other drug abusers, AAS abusers and differentiation of sebocytes during can cause acne conglobata or acne fulmi- died at a significantly earlier age of various differentiation phases [54, 64]. nans just as in doping acne (Figure 2) [5, 24.5 years, more frequently due to Here, androgen-induced gene expression 6, 75, 76]. Associated psychological dis- murder or suicide and possessed a higher of PPAR- 1 appears to play an important turbances, gynecomastia, striae disten- body mass index. role in sebocyte differentiation. AAS sae, edema, increased body mass index increase sebum synthesis directly by and decrease in testicular volume point Underestimating the dangers of binding to the androgen receptor of the to doping acne [40]. anabolic-androgenic steroids by sebocyte and indirectly by induction of When suspecting doping acne, drug- physicians the nuclear hormone receptor PPAR- 1, induced acneiform exanthemas, especially The uncritical and careless approach to whose natural ligand 15-deoxy-12, due to halogens, B vitamins, lithium non-therapeutic use of AAS is evident in 14-prostaglandin J2 was recently identified salts, isoniazid, glucocorticosteroids or the Lübeck study [39] and in the re- in sebocytes of hamsters and in adipocytes tetracyclines, should be considered as a cently published Tübingen study [27], [65, 66]. Plewig and Luderschmidt [67] differential diagnosis. They are usually where 14 % and 32.1 % of physicians, observed that hamster sebocytes were monomorphous consisting of follicular respectively, played an assisting role in similar to human sebocytes in terms of size, papules and pustules and lacking pri- AAS abuse. Similar results were obtained turnover time and androgen dependency. mary comedos [77]. in an Australian survey of 143 general Iwata et al. [66] recently showed that practitioners in Sydney [85]. Two per- 15-deoxy-12,14-prostaglandin J2 is an Treatment and preventive measures cent of physicians admitted to prescrib- important effector of lipogenesis in hamster The most important measure in doping ing AAS for bodybuilding, 6 % were in- sebocytes. It increases triglyceride produc- acne is the immediate cessation of exoge- clined to do the same if requested. Of the tion by increasing the activity of diacylglyc- nous administration of AAS. Treatment Australian colleagues, 77 % showed in- erol acyl transferase (DGAT), the rate- of the various acne forms conforms to terest in obtaining more information on determining enzyme of triglyceride syn- the general guidelines for treating acne effects and side effects of AAS. thesis. Production of 15-deoxy-12, [78]. Systemic retinoids are first-line 14-prostaglandin J2 is via COX-2- and therapy for acne conglobata or acne ful- Conclusions cytochrome-P-450-mediated metabolic minans. Isotretinoin is the most potent Law makers are concerned about the in- pathways. AAS are indirectly involved in sebosuppressive agent. Possible liver creased use of doping agents and meth- prostaglandin metabolism in lipogenesis damage induced by AAS must be taken ods by sportsmen and –women in the through increased expression of PPAR- into consideration. When AAS abuse is whole field of sports and the resulting 1. Pharmacological manipulation of detected, the physician should give de- dangers to health and to the future of prostaglandin metabolism opens new tailed counseling on the long-term risks sports [Law to the Agreement of Novem- ways in acne therapy and sebum suppres- of AAS abuse and provide for profes- ber 16, 1989 against Doping (of March sion, as was shown for the 5-lipoxyge- sional psychological intervention. AAS 3, 1994, BGBl. II p. 334)]. In the decla- nase inhibitor zileuton by Zouboulis et abuse can be confirmed by detecting ration of the new version of the Attach- al. [68–71]. Zileuton inhibits the syn- the substances and their metabolites ment to the Agreement of November 16, thesis of leukotriene B4, the natural lig- in urine and, more recently, by gas 1989 against Doping of January 21, and of PPAR- [72], which is also in- chromatography-mass spectrometry of 2002, anabolic-androgenic steroids are volved in lipogenesis in sebaceous glands hair [79]. listed in the group of illicit drugs in the [54, 64]. chapter ‘‘C’’ [63]. Nevertheless, use of Risks of long-term abuse of anabolic-androgenic steroids has reached Clinical features of doping acne anabolic-androgenic steroids a troubling high prevalence in leisure Administration of AAS leads to stimula- The cardiovascular toxicity of AAS is sports and bodybuilding in Germany. tion of the sebaceous glands even in indi- known; an exhaustive and up-to-date re- Due to the cult of body image propa- viduals who already display seborrhea. view is found by Dhar et al. [80]. The gated by the mass media and the internet The spectrum of AAS-induced sebaceous sudden cardiac death of two body- marketing of these substances, further gland diseases ranges from the appear- builders with long-term AAS use should increases in AAS abuse can be anticipated.

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Dr. med. Dr. h.c. Gerd Plewig, for his teaching and his extensive scientific contri- butions on acne and sebaceous gland dis- eases on the occasion of his retirement. <<<

Conflict of interest None.

Correspondence to Prof. Dr. B. Melnik Dermatology Office Eickhoffstraße 20–22 D-33330 Gütersloh, Germany Tel.: +49-52 41-98 80-80 Fax: +49-52 41-25 80-1 E-mail: [email protected]

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