1 Running head: TREATMENT OF HIV ASSOCIATED CACHEXIA USING ANDROGENIC-ANABOLIC STEROIDS

Treatment of HIV associated cachexia using androgenic-anabolic steroids Matthew E. Simhon Northeastern University

2 TREATMENT OF HIV ASSOCIATED CACHEXIA USING ANDROGENIC-ANABOLIC STEROIDS

Abstract
HIV-infected individuals often develop cachexia, or wasting, during the course of their disease. This wasting is associated with lower survival rates and lower quality of life. Low testosterone levels in HIVinfected individuals are common and have been shown to be a contributing factor to cachexia; low testosterone is associated with increased weight loss, reduced lean body mass and bone mineral density, and poorer quality of life in both men and women. Treatment of cachexia in HIV-infected individuals with anabolic-androgenic steroids (AAS) may be beneficial for increasing survival and quality of life due to their ability to promote increases in lean body mass and body weight. While AAS have been known to cause serious adverse effects including hepatic toxicity and altered lipid profiles, these side effects have been overstated. Therefore, it is recommended that AAS be used in patients with HIV associated cachexia.

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Introduction
Anabolic-androgenic steroids (AAS) comprise a large class of synthetic derivatives of testosterone with a variety of anabolic and androgenic effects including growth of sexual organs, development of secondary sex characteristics, fertility, and increases in bone and muscle mass (Mooradian, Morley, & Korenman, 1987). In males, testosterone is mainly secreted by the testicular Leydig cells upon stimulation by gonadotropins. Normal male plasma concentration of testosterone ranges from 300 1000 ng/dl. In females, circulating testosterone levels are 10% of those in men, with the ovaries and adrenal glands being the main site of secretion (Woerdeman & Ronde, 2011). AAS are transported through the plasma membrane and into the cytoplasm of target cells where they bind to androgen receptor (AR) or they are reduced to 5-dihydrotestosterone (DHT) which can also bind to androgen receptor. This steroid-AR complex travels into the nucleus and binds to and enhances transcription of certain genes which mediate the androgenic and anabolic effects of AAS (Hiipakka & Liao, 1998). Because of their anabolic effects, AAS are frequently taken at supraphysiologic doses by professional and amateur athletes in order to increase muscle mass and athletic performance far beyond what is attainable by natural means (Kouri, Pope, Katz, & Oliva, 1995). The anabolic effects of AAS are well documented; supraphysiologic doses of testosterone enanthate administered to males over 10 to 20 weeks increased lean body mass, muscle strength, and muscle size, with or without exercise (Evans, 2004). The anabolic effects of AAS administration are dose-dependent, with significant increases in muscle size occurring with doses of 300 mg per week and higher (Sinha-Hikim, et al., 2002). This increase in muscle size is due to an increase in cross sectional area of both type I and type II muscle fibers and an increase in myonuclear number (Sinha-Hikim, et al., 2002).

4 TREATMENT OF HIV ASSOCIATED CACHEXIA USING ANDROGENIC-ANABOLIC STEROIDS While the safety and efficacy of AAS for uses other than androgen replacement therapy for male hypogonadism are not absolute, recent studies suggest that these compounds may have therapeutic benefit for a variety of other conditions such as HIV, chronic obstructive pulmonary disease, severe burns, muscular dystrophy, trauma following major surgery, and even age-related sarcopenia. AAS may be able to play a vital role in promoting anabolism in patients suffering from cachexia induced by these conditions. Cachexia, or wasting, is the progressive loss of skeletal muscle and adipose tissue associated with fatigue and weakness. Weight loss associated with wasting in HIV infected individuals significantly decreases survival as well as quality of life (Bhasin & Javanbakht, 1999). Furthermore, many HIV-infected individuals display reductions in testosterone levels that correlate with weight loss, which strongly suggests that testosterone depletion leads to wasting syndrome (Coodley, Loveless, Nelson, & Coodley, 1994). Therefore, AAS should be given for the treatment of cachexia associated with wasting syndromes in HIV-infected patients as therapeutic use may be beneficial in increasing body weight, quality of life, and overall survival.

Clinical Efficacy
The limited number of studies on androgen replacement therapy for the treatment of cachexia in HIV-infected patients has met with varying success depending on route of administration and dosage. In one randomized, double blind study, testosterone enanthate was given at 100mg/wk to HIV-infected men with hypogonadism. The AAS treated patients gained 2.6 kg of weight with an increase in lean body mass of 2.3 kg while the placebo group lost weight (Bhasin, et al., 2000). Studies using oxandrolone, an oral AAS that is resistant to liver metabolism and shows marked anabolic activity, have shown positive clinical outcome for cachexia. One such study demonstrated a significant dose-dependent relationship between bodyweight and quality of life in women with an increase in nitrogen retention, lean body mass, and muscle strength (Pharo, et al., 1997). Transdermal

5 TREATMENT OF HIV ASSOCIATED CACHEXIA USING ANDROGENIC-ANABOLIC STEROIDS testosterone patches have also shown efficacy in women. Miller et al. (1998) has shown that treatment of HIV-infected women with testosterone patches results in improvement in weight and quality of life with no adverse effects. A more recent study has shown that long term administration of AAS in HIVinfected women resulted in significant improvements in lean body mass, weight, and bone mineral density without increases in liver function tests or lipid levels. Furthermore, treatment improved quality of life; significant beneficial effects on depression and mood scores were seen along with significant decreases in problems affecting sexual function (Looby, Collins, Lee, & Grinspoon, 2009). The effectiveness of AAS in treating HIV associated cachexia was investigated in a 2005 Cochrane review which included 13 clinical trials with both HIV-infected men and women (Johns, Beddall, & Corrin, 2005). The results demonstrated that AAS increased lean body mass and total weight with supraphysiologic doses resulting in larger treatment effects. The review also showed that no significant effect was seen in deaths or withdrawals from adverse events. A much larger multicenter, randomized, double blind, placebo-controlled trial following the Cochrane review resulted in significant increases in weight and lean body mass compared with placebo and testosterone using nandrolone in HIV-infected males (Gold, et al., 2006). This study was significant in that it addresses the concern that AAS may increase serum lipids and liver function test results in HIV patients undergoing ART; no significant differences were found between placebo and nandrolone groups for changes in serum lipid levels or hepatic enzymes. This is significant because ART alters lipid metabolism and is commonly associated with hypercholesterolemia and hepatic enzyme elevation (Mehta, et al., 2005; Souza, Luzia, Santos, & Rondo, 2013). Additionally, adverse events thought to be related to the study medication were rare.

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Harmful Effects
Little is currently known about complications of AAS use in patients with cachexia. Much of what is known about the adverse effects of AAS results from studies in athletes, where supraphysiologic doses were used. Most adverse events reported from clinical trials using AAS therapeutically for cachexia were described as mild and reversible (Woerdeman & Ronde, 2011). Nevertheless, there remains a potential for serious adverse effects. These effects fall under several categories including cardiovascular, hepatic, endocrine, behavioral, and dermatologic. Cardiovascular effects such as hypertension, left ventricular hypertrophy, impaired diastolic filling, arrhythmia, erythrocytosis, and thrombosis have all been reported with AAS use (Kutscher, Lund, & Perry, 2002). Additionally, reductions in high-density lipoprotein and increases in low-density lipoprotein cholesterol levels are frequently seen (Woerdeman & Ronde, 2011). This may be of particular concern to HIV-infected individuals; patients undergoing antiretroviral therapy (ART) typically display altered serum lipid levels which may be exacerbated by AAS use (Souza, Luzia, Santos, & Rondo, 2013). While many cardiovascular events have been reported among AAS users (Melchert & Welder, 1995), these reports are largely anecdotal and do not establish a causative role of AAS in these events. Furthermore, therapeutic AAS are usually administered for limited periods which may minimize any cardiovascular effects. Heavy use of the oral 17-alpha alkylated androgenic steroids is also associated with elevated hepatic enzymes with dose-dependent jaundice and hepatic dysfunction likely after administration for at least 1 month (Ishak & Zimmerman, 1987). However, this risk is not present with parenterally administered testosterone or its esters. The risk of hepatic dysfunction has probably been overstated, being [that it is] extremely uncommon in individuals receiving parenteral androgens (Hoffman, et al., 2000). While some patients in clinical trials showed increased liver enzymes, the degree of change was

7 TREATMENT OF HIV ASSOCIATED CACHEXIA USING ANDROGENIC-ANABOLIC STEROIDS usually mild and did not warrant an interruption in treatment (Woerdeman & Ronde, 2011). Nevertheless, hepatic dysfunction is common in HIV patients undergoing ART (Mehta, et al., 2005) and therefore, liver enzymes in this population would need to be closely monitored during treatment with AAS. Of particular concern with AAS use in males is the depression of luteinizing hormone and follicle stimulating hormone through the negative feedback loop of the hypothalamic-pituitary-gonadal axis (Maclndoe, et al., 1997). This can lead to hypogonadotropic hypogonadism and as a result, decreased sperm density and count, abnormal sperm morphology and testicular atrophy. After discontinuing AAS use, free testosterone concentrations may fall to very low levels before endogenous production recovers. This leads to dose-dependent symptoms such as depression and hot flashes which causes many abusers to revert back to AAS use, leading to vicious cycles of abuse (Hoffman, et al., 2000). Additionally, testosterone can convert to estrogen through aromatization resulting in gynecomastia (Hickson, Ball, & Falduto, 1989). The psychological effects of AAS administration remain controversial. Many studies in athletes have linked AAS use to behavioral problems such as increased aggression, mood changes, depression, and psychosis at supraphysiologic doses (Pope & Katz, 1988), while some studies have shown AAS to improve mood and depression while decreasing anger and irritability (Yates, 2000). The instruments used to measure aggressive behavior have varied across trials, and many utilized self-reporting questionnaires that may have been unable to detect changes in aggression. Other factors such as concurrent use of drugs and alcohol and preexisting personality disorders may have also affected the results of these studies. No controlled trials using replacement doses of AAS have reported significant changes in aggression, while many trials using supraphysiologic doses report that a majority of participants show no change (Hoffman, et al., 2000).

8 TREATMENT OF HIV ASSOCIATED CACHEXIA USING ANDROGENIC-ANABOLIC STEROIDS Dermatologic effects of AAS use are common and can include acne, striae, and alopecia. Increases in acne are caused by increasing skin surface lipids and cutaneous populations of acne-causing bacteria (Scott & Scott, 1992) while striae are caused by rapid changes in body mass that stretch the skin. There are also specific concerns for adverse effects from AAS use in women. Women taking AAS may undergo masculinization and experience hirsutism, deepening of the voice, clitoral enlargement, breast atrophy, menstrual irregularities, and widening of the upper torso (Hoffman, et al., 2000). However, a recent study has found that even long term use of AAS is well tolerated in women. Looby, Collins, Lee, and Grinspoon (2009) demonstrated that AAS administration in HIV-infected women over 18 months did not result in significant differences in hirsutism, acne, or changes in menstrual pattern between the testosterone treatment group and the placebo group.

Further Research
Further studies are needed to evaluate the potential serious adverse effects of AAS use in HIVinfected individuals. Of specific concern are the effects of AAS on HIV-infected individuals with pretreatment elevations in lipids, elevated liver function enzymes, and poor glycemic control. The efficacy of AAS in eugonadal men in treating HIV-associated cachexia as opposed to hypogonadal men also needs to be determined. Additional studies on the efficacy of AAS therapy in HIV-infected women with wasting are also warranted. Optimal anabolic agents and dosages as well as duration need to be determined for specific populations. Most importantly, studies need to be done in order to find a correlation between increases in weight with increases in quality of life and survival rate in HIV-infected individuals. The number of studies evaluating these outcomes is limited.

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Conclusion
Diseases such as HIV that result in weight and muscle loss contribute to functional impairment and increased mortality. Because AAS have a dose-dependent effect on increasing muscle mass and weight, they may be able to reverse the effects of cachexia and improve outcome. However, it is difficult to draw firm conclusions from the studies on the treatment of HIV-associated cachexia for several reasons. The number of randomized, controlled trials is relatively small and these studies were conducted with different types of agents using varying dosing regimens. Additionally, the number of studied patients was small. Nevertheless, despite the heterogeneity of these studies there was a statistically significant increase in both lean body mass and body weight with AAS treatment in nearly all studies without major adverse events (Johns, Beddall, & Corrin, 2005). This may increase survival and quality of life in HIV-infected patients with cachexia. Because cachexia is associated with hypogonadism in HIV-infected men, those found to be hypogonadal should be given testosterone replacement therapy. While therapy with AAS in eugonadal HIV-infected men with cachexia has been effective at increasing lean body mass (Strawford, et al., 1999), more research needs to be done in order to confirm the safety and efficacy of this treatment in this population. Until such time, eugonadal HIV-infected men should only be given AAS when cachexia is severe. While more research on the effects of AAS on HIV-infected women with cachexia is needed, AAS that display limited androgenic effects and have shown previous efficacy with little or no adverse effects in women such as oxandrolone should be given to counter the devastating wasting effects of HIV. Treatment of patients suffering from HIV associated cachexia with AAS appears to be relatively safe; concerns related to serious side effects have been overstated and are probably a result of reports of abuse of AAS by athletes.

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