Curr Urol Rep (2016) 17:72 DOI 10.1007/s11934-016-0629-8

MEN’S HEALTH (A DABAJA, SECTION EDITOR)

Novel Uses for the Anabolic Androgenic Steroids Nandrolone and Oxandrolone in the Management of Male Health Christopher Wu 1 & Jason R. Kovac 2

# Springer Science+Business Media New York 2016

Abstract There has recently been renewed interest in novel clinical applications of the anabolic-androgenic steroid (AAS) testosterone and its synthetic derivatives, particularly given with the rising popularity of testosterone supplementation therapy (TST) for the treatment of male hypogonadism. In this manuscript, we provide a brief review of the history of AAS and discuss clinical applications of two of the more wellknown AAS: nandrolone and oxandrolone. Both agents exhibit favorable myotrophic/androgenic ratios and have been investigated for effectiveness in numerous disease states. We also provide a brief synopsis of selective androgen receptor modulators (SARMs) and postulate how these orally active, non-aromatizing, tissue-selective agents might be used in contemporary andrology. Currently, the applications of testosterone alternatives in hypogonadism are limited. However, it is tempting to speculate that these agents may one day become accepted as alternatives, or adjuncts, to the treatment of male hypogonadism. Keywords Hypogonadism . Androgenic anabolic steroids . Nandrolone . Oxandrolone . SARMS

Abbreviations AAS Anabolic-androgenic steroid TST Testosterone supplementation therapy This article is part of the Topical Collection on Men’s Health * Jason R. Kovac [email protected] 1

McMaster Institute of Urology, Hamilton, ON, Canada

2

Men’s Health Center, 8240 Naab Road, Suite #220, Indianapolis, IN 46260, USA

SARMS

Selective androgen receptor modulator

Introduction Testosterone was first characterized, isolated, and synthesized in 1935 [1]. The biologic effects of this hormone on target tissues are largely categorized into androgenic and anabolic effects. Anabolic effects of testosterone include increases in skeletal muscle mass, strength, and exercise recovery [2]. Traditionally, testosterone and its derivatives (testosterone cypionate, propionate, and enanthate) are the prototypical anabolic-androgenic steroids (AASs). Athletes and body builders popularized these medications in the 1950s, with the intention of improving athletic performance and/or aesthetics. Early documented uses of AAS for the purposes of gaining advantages in sports was with the German rowing team in 1952 and the Russian weight-lifting team in 1954 [3]. The prevalence of AAS use in athletics resulted in the International Olympics Committee (IOC) commencing screening programs for AAS and its derivatives in the 1960s. The use of AAS has been banned since 1974 [3]. The World Anti-Doping Agency (WADA) was established in 1999 under the auspices of the IOC to fight against doping in international elite sports. A comprehensive list of performance-enhancing drugs, including numerous AASs, is currently on the list of prohibited substances (https://www. wada-ama.org). In the USA, anabolic steroids are listed as a Schedule IIIcontrolled substance since the advent of the Steroid Control Act of 1990. The original act was further ammended in 2004 and 2014 with the addition of numerous compounds into the Schedule III list [4]. In the USA, an estimated 3.6 % of high school students have reported ever using steroids at some time in their life [5], with a recent study suggesting an estimated

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lifetime prevalence of three to four million Americans having ever used AAS [6]. There has been a shift from AAS use primarily for competitive athletics to recreational users seeking to enhance appearance and self-esteem [7]. In fact, some suggest that up to 30 % of gym attendees have been postulated to use AAS [8]; however, methodological issues such as confusion of AAS with corticosteroids or over-the-counter nutritional supplements represent false positives [6, 9].

Mechanism of AAS Action The effects of AAS are separated mainly into androgenic and anabolic effects. The androgenic effects of the most common AAS, testosterone, include effects on male secondary sexual characteristics, effects on the reproductive tract, hair growth pattern, and sebaceous gland activity. AAS also has anabolic effects, with increased nitrogen fixation and protein synthesis, leading to increases in collagen synthesis, muscle hypertrophy, and bone metabolism. AAS use, in supra-physiological doses, has been associated with effects on the cardiovascular system. Some studies have reported adverse changes in the serum lipid profile including reductions in high-density lipoprotein cholesterol (HDL-C) and elevation in low-density lipoprotein cholesterol (LDL-C) levels. With prolonged, highdose AAS use, it can thus be postulated that atherosclerosis, with subsequent coronary artery and cerebrovascular disease, could develop [10]. Associations between supra-physiological AAS use and alterations in psyche and behavior have also been observed with manic behavior, increased aggression, elevated self-confidence, and psychotic symptoms possibly resulting [11]. Physiologically, Leydig cells in the testes produce endogenous testosterone. Physiological testosterone production amounts to roughly 2.1–11.0 mg per day in males, with normal plasma levels of 300–1000 ng/dL [12]. There is an agerelated decline in these levels with age, reflected by a higher incidence of testosterone deficiency in older males. Testosterone penetrates the cellular membrane and then binds the intra-cystosolic target molecule, the androgen receptor. The hormone-receptor complex is then translocated into the nucleus, where it forms a homodimer that then binds to androgen response elements on target genes, promoting gene transcription and, ultimately, protein synthesis. These synthesize proteins and then mediate the actions of the hormone. Testosterone has been long utilized by athletes for its muscle building and performance-enhancing (i.e., anabolic) properties. As evidenced by a study in 1996 by Bhasin et al. [2], the authors found that in eugonadal males, administration of supra-physiological levels of IM testosterone enanthate (600 mg/week) resulted in increased fat-free mass, muscle size, and strength [2]. Erythropoiesis is also increased in a

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dose-dependent fashion with testosterone therapy [13, 14], results that might further augment exercise capacity in endurance athletes [15]. Testosterone may also undergo different metabolic fates, with conversion by 5α-reductase into dihydrotestosterone (DHT) and conversion by aromatase into 17β-estradiol. Further metabolism by these enzymes plays a significant role in the actions of testosterone at different target tissues. Tissues expressing 5α-reductase include the prostate, testes, liver, skin, and brain. DHT has a threefold greater affinity for the androgen receptor than testosterone does [16], contributing to the androgenic effects of testosterone such as acne, alopecia, and benign prostate enlargement [17]. Tissues expressing high levels of aromatase include bone, brain, and adipose, and elevation of serum 17β-estradiol can lead to adverse side effects including fluid retention, gynecomastia, and worsening sleep apnea [17]. Testosterone may also impart anti-catabolic effects through competitive inhibition of glucocorticosteroid receptors reducing protein synthesis during stressful physical activity that may help with exercise recovery [18]. Lastly, neuropsychiatric effects have been associated with AAS use including euphoria and increased aggressiveness that might help drive further training and increased competitiveness in athletes [19].

Evidence Behind the Benefits of AAS As a way of assessing the potency of AAS, Kicman [16] initially proposed a myotrophic/androgenic index in 1950. In his pioneering work, the author compared the increase in levator ani weight (anabolic or myotrophic response) to the increase in weight of the seminal vesicles (androgenic response) to devise a ratio [16]. Modifications were then later proposed to compare the myotrophic response to change in ventral prostate weight as an androgenic metric, resulting in an index ratio. Testosterone, the prototypical AAS, has a myotrophic/androgenic index ratio of 1:1 [12]. Through the modification of the basic steroid structure of testosterone, attempts to separate the anabolic from androgenic activity have yielded numerous different testosterone derivatives. Unfortunately, despite all chemical modifications, all AAS have androgenic effects at high dosages [20]. One common modification of the testosterone molecule is through 17α-alkylation. Testosterone, when administered orally, has a short half-life, with a rapid clearance through first-pass liver metabolism. The introduction of a methyl group at the C17α position retards hepatic inactivation, allowing for oral administration of AAS [21]. These oral steroids usually have a short half-life and require daily dosing. Common synthetic agents in this class include stanozolol, methyl-testosterone, and oxandrolone [12].

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Another common modification to the basic testosterone structure is through 17β-esterification. When this 17βhydroxyl group is esterified, this variation delays the release and subsequent biodegradation of testosterone, prolonging the duration of action [21]. The length of the ester will determine the half-life of anabolic action. Typically, these steroids are administered parenterally, usually in an oil-based vehicle. There is less hepatic stress associated with these AAS, but intramuscular administration of this product can be associated with pain at the injection site, due a reaction to the oil base. Common parenteral AASs include testosterone bound to esters such as undecanoate, cypionate, and propionate as well as nandrolone.

Adverse Effects of AAS As with any medication that has been around for decades, the adverse effects of AAS, including testosterone, are well reviewed and will be only briefly touched upon here. They include effects on the cardiovascular (including hypertension, cardiomyopathy, arrhythmias, myocardial infarction, strokes, and systemic thrombosis), hepatic, hematologic, neuropsychiatric, musculoskeletal, endocrine, and dermatologic systems [3, 13, 16, 17, 19, 20]. AAS have also been shown to decrease HDL cholesterol levels and increase LDL levels, placing AAS/testosterone users at an increased risk for coronary artery disease. These effects may vary with the types and regimens of AAS/testosterone used, and these levels tend to normalize with cessation of use [22, 23]. AAS/testosterone use in children and adolescents can cause premature epiphyseal closure, leading to decreased adult height [24]. There are also concerns about higher risks of tendon rupture with AAS use [25]. With regard to AAS/testosterone use and hepatic dysfunction, this relationship is most commonly related to the 17αalkylated steroids and is manifested as elevations in the levels of liver transaminases, with reports of cholestatic jaundice, peliosis hepatis, and hepatocellular carcinomas that occur [26–28]. Lastly, the reproductive effects of AAS use are also well studied. The use of steroids in men decreases endogenous testosterone production through inhibition of the hypothalamicpituitary-gonadal axis, leading to decreased spermatogenesis and testicular atrophy [12]. Lastly, rare reports of priapism have also been documented with AAS/testosterone use [29] along with adverse effects on the dermatologic system including diffuse acne and male pattern alopecia [30].

AAS Usage When discussing AAS and their potential benefits, some consideration must be taken as to how they are used in the nonmedical community. Indeed, a large number of AAS users are non-medical, self-treating individuals. This has lead to a poor

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pool of research information and significant challenges for the medical community to accurately document usage and administration while correlating outcomes and side effects. The majority of the literature available on AAS usage has self-reported measures, which are inherently unreliable. Mistrust of medical professionals among AAS users and active Internet forums has further diluted research on AAS outcomes. Currently, there are hundreds of AAS available, and these are usually used orally or via injection while being stacked together and taken in short durations, or Bcycles,^ lasting 4–12 weeks. The combinations of substances used typically depends on the purpose of the cycles, varying from mass-building regimens to weight shedding, or cutting, regimens. The types as well as dosages are passed down from user to user based on individual experience and results. Since possession of unauthorized and non-prescribed AAS is prohibited, the habits of AAS users are largely unsupervised. Studies have suggested that the Internet is the most popular source for anabolic steroid procurement, with numerous websites dedicated to promoting AAS use [31] with fellow gym users also providing users with medications [32]. Lastly, since the 1970s, the availability of underground handbooks made popular in the bodybuilding subculture has helped guide AAS regimens with self-administered poly-drug regiments ranging from 5 to 20 times higher than traditional studies [15].

Clinical Application of AAS Nandrolone 19-Nortestosterone (or nandrolone) is an anabolic steroid that was first synthesized in 1950 [33]. One of the main biochemical differences between nandrolone and testosterone is the substitution of a hydrogen atom in the C19 methyl group of testosterone, a change that imparts a favorable myotrophic/ anabolic ratio of nearly 11:1 [16]. It is administered via an intramuscular injection and is metabolized in a similar manner to testosterone, with conversion into 3-norandrosterone by 5α-reductase [34]. Unlike DHT, this metabolite has a weak binding affinity to the androgen receptor [16]. Through this fundamental difference between nandrolone and its metabolite, as well as the significant anabolic-androgenic dissociation of nandrolone, there have been renewed investigations into the use of nandrolone in clinical situations of chronic catabolic disorders such as anemia and muscle wasting secondary to hemodialysis, COPD, or HIV [35–37]. Due to the weak affinity for the androgen receptor after 5α-reductase reduction, there is also a possibility that nandrolone may be used in the context of male hypogonadism, androgenic alopecia, and management of shoulder pain in men with rotator cuff injury

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[34]. It could also serve to augment testosterone’s effects in improving body composition and possibly decreasing the risk of type 2 diabetes and metabolic syndrome in hypogonadal men [34]. Furthermore, given that prior research has noted that exercise enhances serum total testosterone levels in young men [38] and loss of muscle mass correlates with decreases in androgen levels [39], it is tempting to speculate that gains in muscle mass could be beneficial in warding off, and even treating, male hypogonadism. Specifically, a Finnish study investigated the effects of heavy strength/power training on serum hormone levels in elderly men and women. A significant response in serum testosterone was noted after 24 weeks of resistance training in the elderly male population [40]. In another study by the same group, significant increases in testosterone were noted in a middle-aged and elderly population of men, but not women [41]. It is suggested that the low levels of serum testosterone might be a limiting factor in muscle hypertrophy and strength development in these older populations. Thus, it is tempting to speculate that short-term administration of nandrolone, coupled with a structured exercise program in the hypogonadal male, could lead to sustained improvements in both muscle mass and strength, thus resulting in long-term elevations in native testosterone levels. Further studies, however, are needed to investigate this phenomenon. Caution should be taken with the use of any AAS in males of reproductive age desiring fertility. Though no formal studies on reproductive effects have been conducted with nandrolone, rat studies have shown impaired spermatogenesis [42]. A case report on a patient with 10 years of supra-physiological nandrolone use also demonstrated prolonged testicular dysfunction with severe oligospermia [43]. Oxandrolone Oxandrolone, known by its chemical name 17β-hydroxy17α-methyl-2-oxa-5α-androstane-3-one, was first synthesized in 1962 [44]. Characterized by a modification in the basic structure of testosterone to include a substitution of an oxygen atom in place of the methylene group at the C2 position in the steroid ring, this molecule has a 17α-alkylated group at the C17 position that prevents deactivation of this steroid by hepatic first-pass metabolism - allowing for oral administration. Given these alterations, oxandrolone also shows resistance to hepatic metabolism further enhancing action [20]. While mild elevations in hepatic transaminases have been noted [45], oxandrolone is not known for significant hepatic side effects such as cholestasis, peliosis hepatis, hepatic adenomas, and hepatocellular carcinomas. Minor adverse events have been noted in clinical trials on oxandrolone including alterations in cholesterol levels [20]. Similar to nandrolone, oxandrolone has marked anabolic activity, with a myotrophic/androgenic ratio of 10:1 [46]. It

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has shown clinical efficacy in acute catabolic disorders such as severe burn injuries, after extensive surgery, and severe trauma. There have also been positive clinical outcomes in chronic catabolic disorders such as the treatment of HIV/AIDSassociated wasting [47], neuromuscular diseases such as Duchenne muscular dystrophy [48], amyotrophic lateral sclerosis [45], and COPD [49]. Oxandrolone is also used to offset the protein catabolism associated with long-term corticosteroid use and relief of the bone pain accompanying osteoporosis [20]. As with nandrolone, the reproductive effects of oxandrolone are not well studied. Several case reports note reversible steroid-induced azoospermia with oxandrolone use in combination with other AAS [50, 51]. Caution should be employed in all men of reproductive age given known effects on the LH/FSH axis and the potential resultant effects on spermatogenesis. Selective Androgen Receptor Modulators In the quest to develop agents that have selective anabolic effects without significant androgenic action, pharmaceutical companies have been developing a new class of drugs called selective androgen receptor modulators (SARMs). The concept of this class of drugs arose from selective estrogen receptor modulators (SERMs), which have been in clinical use for decades. A number of pharmaceutical compounds are currently in the pipeline, with companies developing compounds for the treatment of conditions including sarcopenia, chronic disease-associated cachexia, osteoporosis, and hypogonadism [52–54]. Ideal features of SARMs include good oral bioavailability, tissue specificity, and minimal off-target effects [55]. The ability to stimulate anabolism without a risk of androgenic effects significantly increases the therapeutic options open to men and women. Non-steroidal SARMs comprise a chemically diverse group of compounds, with current SARMs under development based on analogues of quinolinone [56], aryl propionamide [57], hydantoin [58], and tetrahydroquinoline [59]. Their tissue selectivity arises from their AR selectivity while, at the same time, avoiding action as a substrate for aromatase and/or 5α-reductase enzymes. The best-studied SARM to date is enobosarm (GTx Inc.), first identified in 2004. Rat studies showed increases in levator ani muscle weight with increased strength while lacking the significant increases in prostate and seminal vesicle weights characteristic of androgenic contribution. Adverse effects were reported as alterations in serum cholesterol levels, with decreased serum SHBG, HDL, and triglycerides reported. Enobosarm has also been evaluated in two phase III clinical trials entitled Prevention and treatment Of muscle Wasting in patiEnts with Cancer 1 and 2 (POWER1 (NCT01355484) and POWER2 (NCT01355497)). These trials enrolled men ≥30 years of age

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and postmenopausal women with stage III/IV non-small cell lung cancer (NSCLC) at the initiation of platinum-based chemotherapy to evaluate for its effect on the prevention and treatment of muscle wasting associated with NSCLC. POWER1 evaluated patients with platinum and taxane chemotherapy, while POWER2 evaluated patients with platinum and nontaxane chemotherapy [60]. The co-primary endpoints of this trial were lean body mass (LBM) response and physical function response for enobosarm vs. placebo after 3 months of treatment. Beneficial effects on both LBM and physical function were found in POWER1, and benefit to LBM but equivocal effects on physical function were found in POWER2. Enobosarm was approved by the US Food and Drug Administration as a fast track development program for the prevention and treatment of muscle wasting in patients with NSCLC in 2013. Aromatase inhibitors (AIs) such as anastrozole and letrozole have also been found to increase testosterone production [61]. Acting via the inhibition testosterone to estradiol conversion in peripheral tissues, negative feedback signals at the hypothalamus and pituitary are decreased, leading to increases in GnRH and LH release and subsequently increased serum testosterone. Side effects from estradiol, such as gynecomastia, can be mitigated with AI administration. Moreover, since testosterone and estradiol both play roles in the maintenance of bone health in men, prospective studies have shown decreased bone mineral density (BMD) associated with long-duration AI monotherapy in older hypogonadal men [62]. As such, caution should be employed in men with osteopenia or osteoporosis; regular monitoring of BMD is also recommended [62].

Page 5 of 7 72 Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by any of the authors.

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Conclusions AASs have been subject to adverse publicity and negative perceptions due to associations with doping in sports and use by recreational athletes. However, there are many clinical conditions in which the judicious administration of AAS has demonstrated clinically meaningful improvements in muscle mass, strength, nutritional status, bone strength, and recovery from acute catabolic insults. Such gains in muscle mass could be postulated to attenuate decreases in serum total testosterone levels. In this manuscript, we have reviewed the use of nandrolone and oxandrolone. With favorable myotrophic/ androgenic ratios, these AASs have relatively low adverse risk profiles due less potent metabolites that are attractive molecules that could be potentially beneficial in the setting of men’s health in general and hypogonadism in particular. Compliance with Ethical Standards Conflict of Interest Christopher Wu declares no potential conflicts of interest. Jason R. Kovac reports personal fees from Abbvie.

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