madman
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Pope Jr. has been at this for decades!
Body Image Disorders and Anabolic Steroid Withdrawal Hypogonadism in Men (2022)
Harrison G. Pope Jr, MD, Gen Kanayama, MD, PhD
INTRODUCTION AND HISTORICAL BACKGROUND
The anabolic-androgenic steroids (AAS) are a family of hormones that includes the natural hormone testosterone together with its many analogs (Box 1). Testosterone was originally isolated in the 1930s and synthetic derivatives quickly followed.1 By the early 1950s, elite athletes had discovered the potential of these drugs, and AAS use spread rapidly through the Olympics and other high-level sporting events. However, it was not until the 1980s and 1990s that AAS use began to spread from the elite athletic world and into the general population. Most of these new general population AAS users were young men who simply wanted to get bigger, often purely for personal appearance, and who had no plans to use AAS for competitive athletics. Today, probably about 80% of the world’s AAS users fall into this latter category, with only about 20% representing competitive athletes.2–4 However, many clinicians, and many members of the general public, still think of AAS as largely a problem of doping by athletes and remain unaware of the much larger, less visible population of nonathlete AAS users.5 Most of these latter men are relatively young; even the older members of this group—those who first started using AAS as youths in the late 1980s or early 1990s—are only now reaching middle-age, and thus entering the age of risk for long-term consequences of AAS use, including persistent hypogonadism.
Other historical trends in the last few decades have helped to further potentiate AAS use. One of these developments has been the rise of the Internet.6 Unlike other drugs of abuse, such as cocaine and heroin, AAS can be legally purchased without a doctor’s prescription in many countries, such as in Latin America, former Eastern Bloc countries, and various countries in Asia. Thus, AAS dealers located in one of these countries can purchase any amount of AAS and then sell them via the Internet to buyers in countries where possession of nonprescribed AAS is illegal. In the authors’ anecdotal experience with numerous studies of AAS users in the United States, such illicit purchases are really interdicted.
Even in countries where they are illegal, AAS are nevertheless present in a substantial percentage of “dietary supplements,” sold over the counter in nutrition stores or on the Internet.7–10 In some cases, these supplements contain AAS that represent small chemical variations on illegal AAS molecules, but which can still be sold openly because they are not technically outlawed. These variant compounds may be identified on the label of the supplement bottle, or a supplement may contain legal or illegal AAS that are not disclosed on the label at all. Men using these supplements are often not aware that they are ingesting AAS and unwittingly exposing themselves to AAS-induced toxicity.
Also starting roughly in the 1980s, another important historical trend began to develop, namely an increasing focus on male body image, and particularly male muscularity, throughout many Western societies.11 Over the last 4 decades, people have seen more and more images of ideal muscular male bodies in movies, television, advertising, and even in children’s “action toys” (Fig. 1). For example, the American “G.I. Joe” toy, when he first appeared on the market in the 1960s, had an ordinary-looking male body, but by the 1970s he had become distinctly more muscular, and by the 1990s more muscular still.12 A similar trend occurred with the smaller versions of G.I. Joe, culminating in the “G.I. Joe extreme,” who, if he were extrapolated to the height of an actual man, sported biceps bigger than those of any natural human being. Similarly, the toys representing Luke Skywalker and Han Solo from “Star Wars,” when they first appeared in the late 1970s, portrayed normal-looking male bodies—but the equivalent figures 20 years later were dramatically more muscular. Similar trends have appeared in many other settings.11,13 The possible causes of this mounting cultural focus on muscularity have been discussed elsewhere.11,14–17
These 2 parallel developments—the increasing availability of AAS and the growing cultural focus on male muscularity—have created a fertile soil for the development of AAS use, especially in younger men concerned about their body image. Particularly vulnerable are men who have developed so-called muscle dysmorphia, a form of body dysmorphic disorder in which the individual develops a pathologic concern that he is not sufficiently muscular. Men with muscle dysmorphia may devote long hours to weightlifting and other exercises, often with meticulous attention to diet.18–20 Even when they become markedly muscular, these men may still feel that they are too small and will avoid being seen in situations where their bodies are visible, such as at the beach or in a locker room. Not surprisingly, such men are strongly attracted by AAS, and may indeed develop an AAS dependence syndrome, wherein they continue to use these drugs for years, often persisting despite adverse effects.21,22 A recent study of adult male weightlifters found that men who retrospectively reported prominent body image concerns in early adolescence (between the ages of 13 and 16 years) were significantly more likely to have gone on to initiate AAS use than were men reporting lower levels of adolescent body image concern (Fig. 2).23
One study estimated that as of 2013, between 2.9 and 4.0 million men in the United States alone had used AAS at some time in their lives, and that about 1 million of these men had developed an AAS dependence syndrome.24 Notably, these estimates did not include the substantial number of additional men who may have used “dietary supplements” containing AAS, as described earlier. About 98% of all AAS users are men, as women rarely aspire to become extremely muscular, and are also vulnerable to the virilizing effects of AAS, such as beard growth, deepening of the voice, and masculinization of secondary sexual characteristics.24 Thus, the present article refers only to male AAS users unless specified otherwise.
AAS-WITHDRAWAL HYPOGONADISM
All AAS suppress the hypothalamic-pituitary-testicular (HPT) axis via feedback inhibition. Thus, men who have used AAS for a few months or more will typically exhibit hypogonadism upon AAS withdrawal. AAS-withdrawal hypogonadism, like hypogonadism due to other causes, is associated with loss of libido, sometimes loss of erectile function, and occasionally, symptoms of depression. Interestingly, hypogonadism-associated depressive episodes appear to be idiosyncratic, with most men experiencing few depressive symptoms while a minority may develop prominent depression, sometimes even associated with suicidal ideation.25,26 This idiosyncratic pattern of depressive symptoms has been found in laboratory studies where hypogonadism was deliberately induced in male volunteers by administration of depot leuprolide acetate,27 in men administered reversible chemical castration for treatment of prostate cancer,28 and in men undergoing AAS withdrawal.29–31
AAS withdrawal hypogonadism has been noted in the literature at least since the 1980s, and by 1989 was cited as a possible mechanism contributing to AAS dependence, whereby AAS users would be tempted to resume AAS in order to self-treat the dysphoric symptoms attendant on AAS withdrawal.32 Nevertheless, before the last decade, most of the literature on AAS-withdrawal hypogonadism consisted of individual case reports or small case series (eg, see Refs. 33–39), with little to suggest that this phenomenon might be widespread, persistent, and sometimes perhaps irreversible. Recent years, however, have seen reports from urologists, endocrinologists, and substance-abuse researchers demonstrating that AAS-induced hypogonadism is potentially a more serious problem than was once supposed. For example, Coward and colleagues40 reviewed a database of 6033 cases of men seeking treatment for hypogonadism of any etiology. Of these men, 97 (1.6%) displayed profound hypogonadism, defined as a total testosterone level of 50 ng/dL or less. Remarkably, 42 (43%) of these severe cases were attributed to prior AAS use. The investigators subsequently conducted an anonymous survey of 382 men in their current hypogonadal patient population and found that 80 (21%) reported prior AAS exposure. These findings suggest the importance of seeking a history of AAS exposure in men presenting for treatment of hypogonadism, especially in cases of men under the age of 50 years and in men exhibiting profound hypogonadism as defined earlier.
Kanayama and colleagues30 assessed indices of hypogonadism among 24 long-term AAS users who had discontinued AAS at least 3 months before the time of evaluation (mean, 58.9 months) and compared this group with 36 non–AAS-using weightlifters. Five of the former AAS users (21%) were receiving physiologic doses of exogenous testosterone as maintenance therapy to treat hypogonadism, leaving 19 untreated former AAS users for comparison with the 36 nonusers. Among these former users, 5 (26%) displayed testosterone levels of less than 200 ng/dL despite abstinence from AAS for 3, 7, 8, 16, and 26 months, respectively. On the “sexual desire” subscale of the International Index of Erectile Function, 7 former users (37%) scored 4 or less, indicating moderate to severe impairment. Five displayed major depressive disorder during AAS withdrawal; 3 of these 5 had never displayed major depressive disorder at any other time in their lives.
Rasmussen and colleagues41 compared 37 current AAS users, 30 former users (mean duration of abstinence 2.5 years), and 30 non-users. The men in all groups were aged 18 to 50 years and engaged in recreational strength training. Among the former AAS users, 28% displayed plasma testosterone levels below the reference limit of 12.1 nmol/L (350 ng/dL) as compared to none of the nonusers (P<.01). The former AAS users also displayed higher levels of depressive symptoms, erectile dysfunction, and decreased libido when compared with either of the other 2 groups.
These reports, together with other recent studies42 and reviews,43,44 suggest that AAS-induced hypogonadism is common but underrecognized, and may often be persistent and severe. Thus, it seems likely that as more of today’s long-term AAS users begin to enter middle age, such cases of hypogonadism will become increasingly common, presenting in the clinics of primary care physicians, urologists, endocrinologists, and mental health clinicians involved in substance abuse treatment.
DIAGNOSIS AND DETECTION
The diagnosis and detection of AAS-induced hypogonadism is complicated by the fact that AAS users may be reluctant to disclose their AAS use to the clinician. In our experience, AAS use is arguably the most secret of the major forms of substance use disorders, perhaps for several reasons. First, AAS are illicit drugs in many countries. Second, if a man admits that he is using, say, illicit cocaine or opiates, he is simply revealing an illegal activity. But if he admits to using AAS, he is not only revealing illegal behavior but also admitting that his muscular prowess is merely a result of taking chemicals—a confession that he may be loath to make. Third, AAS users often have disdain for medical professionals. They recall that the medical community claimed for years, well into the 1970s and even 1980s, that AAS were ineffective for muscle gains or athletic improvement, even though athletes everywhere knew that these claims were false.1 If doctors had been so misinformed, why should a patient confide to them about his AAS use?
This mistrust of physicians is illustrated by one study of 43 AAS users who were asked questions about how they trusted various sources of information about AAS.45 Remarkably, 41% of these men users reported that they would trust information from their local drug dealer at least as much as information from their physicians, and 56% reported that they had never disclosed their AAS use to any physician that they had ever seen. Other writers have commented similarly on the physician’s difficult task of securing trust with an AAS-using patient.46,47 In light of the above, clinicians should use a careful, nonjudgmental approach with men reporting AAS use, as well as men who appear likely to have used AAS, but who are reluctant to disclose this fact.
Signs and Symptoms
If a patient does not initially disclose AAS use, several signs and symptoms may heighten the clinician’s index of suspicion. First, does the patient exhibit marked muscularity? There is a clear upper limit to the amount of muscularity that a lean man can achieve without AAS use. We have developed and published a formula for calculating the so-called fat-free mass index in men, together with data suggesting that a man with low body fat (say <10%) cannot exceed a fat-free mass index of about 26 kg/m2 without the use of drugs.48
It should be remembered that a man might exceed 26 kg/m2 with low body fat, even though he has not knowingly taken AAS, because he may have used “nutritional supplements” containing surreptitious AAS or other anabolic substances, as discussed earlier in this article. Thus, clinicians should question carefully about supplement use when encountering an unusually muscular man who denies AAS consumption.
In addition to muscularity, various clinical signs and symptoms, such as truncal acne, gynecomastia, striae above the pectoralis muscles, and testicular atrophy may suggest AAS use.49 Certain laboratory findings may also heighten the clinician’s index of suspicion (Table 1).3,50,51 Clinicians should be particularly alert upon finding abnormally low testosterone in conjunction with low follicle-stimulating hormone (FSH) and luteinizing hormone (LH) (ie, hypogonadotropic hypogonadism), in a young man who appears muscular. Any of these clues should prompt a gentle and sympathetic attempt to elicit a possible history of AAS use and to assess whether the patient is willing to discontinue future AAS use and consider treatment.
Laboratory Detection of AAS Use
A substantial literature has addressed the detection of AAS use by laboratory methods, but this approach is often of limited value to practicing clinicians. The only AAS detectable in blood samples with commercial testing is testosterone, and thus individuals taking multiple AAS in the absence of testosterone will be missed. Urine testing, on the other hand, can detect a wide range of AAS, but this testing is much more expensive (in the range of hundreds of dollars per sample), and available in only a few reference laboratories. Also, urine testing can detect only current or relatively recent use of many AAS, such as orally administered compounds—although long-acting depot preparations (eg, nandrolone decanoate) may sometimes be detected many months after last use. Furthermore, commercial urine testing may fail to detect novel “designer” AAS, such as those sometimes present in “nutritional supplements,” as described earlier.
TREATMENT
The literature on the treatment of AAS-induced hypogonadism remains limited. Most cases appear to be associated with low levels of gonadotropic hormones, LH, and FSH. This may be addressed by administering clomiphene, which stimulates the pituitary to secrete these 2 hormones, thus, in turn, stimulating testicular production of testosterone and spermatozoa. One early article52 reported successful use of clomiphene, 100 mg per day for 2 months, to restore HPT function in a 30-year-old man with AAS-induced hypogonadism. Other articles have also described success with this medication in various cases of hypogonadism (eg, see Refs. 53,54). Importantly, Tan and Scally55 have noted that clomiphene has 2 enantiomers with different actions. The trans enantiomer, enclomiphene, is an estradiol antagonist, whereas the cis enantiomer, zuclomiphene, is an estradiol agonist. Therefore, these authors have suggested that the addition of an estrogen receptor blocker, such as tamoxifen, might increase the overall antagonism of the estradiol receptor and hence improve the net effect of clomiphene on pituitary function, and secondarily on testicular function.
Another treatment for AAS-induced hypogonadism is human chorionic gonadotropin (hCG), which simulates the effect of pituitary gonadotropins by stimulating testicular Leydig cells to produce testosterone. Unfortunately, hCG must be administered parenterally and has a relatively short half-life, thus requiring injections every second day. However, for men prepared to self-administer hCG on a regular basis, this substance can fairly quickly increase serum testosterone levels. Moreover, hCG can be combined with clomiphene to achieve a dual stimulus on the HPT axis, hopefully resulting in more rapid return of testicular function in AAS users undergoing withdrawal. Various authorities (eg, see Refs. 44,56) have proposed combination treatment protocols of this nature for attempting to restore both testosterone levels and fertility in men with AAS-induced hypogonadism.
Clinicians should be aware that many AAS users are already familiar with these treatments via their own personal research on the Internet. Karavolos and colleagues57 have noted the vast number of Web sites providing information for users on how to self-treat AAS-withdrawal hypogonadism. These Web sites typically recommended the same compounds described in the scientific literature—hCG, selective estrogen receptor modulators such as clomiphene, and aromatase inhibitors. In our experience, users often obtain these compounds on the black market and self-treat their own cases of hypogonadism without coming to the attention of clinicians. Similarly, a well-known “underground” guide to AAS use58 provides a detailed discussion of AAS-induced hypogonadism and offers a specific “postcycle therapy” program to treat AAS withdrawal, wherein the user takes 2000 international units of hCG every second today for 20 days, plus clomiphene citrate 50 mg twice a day for 30 days, and tamoxifen 20 mg twice a day for 45 days.
Practical Considerations
Patient motivation: In our experience, many AAS users, especially those under age 40 years, have little interest in stopping these drugs. This is particularly the case for men with body-image concerns or frank muscle dysmorphia, and who have become obsessed with looking lean and muscular. Such men may attempt to discontinue AAS but become panicky and resume the drugs when they perceive that they have lost even a few pounds of muscle.
However, symptoms of hypogonadism may eventually trump body-image concerns and bring the patient to the clinician. At this point, the clinician may be confronted with an ambivalent patient who recognizes that his loss of libido, erectile dysfunction, and possible depression are caused by AAS-induced hypogonadism, but who dreads stopping AAS entirely. Many such patients will ask for simple testosterone replacement therapy and will be content to self-administer physiologic or mildly supraphysiologic doses of testosterone (eg, 100–200 mg of testosterone cypionate intramuscularly once per week). However, maintenance testosterone represents an endless proposition, in that the patient’s own HPT axis remains chronically suppressed and is never given the opportunity to recover on its own. AAS users, in our studies, are generally aware of this problem, and often report that they are resigned to taking testosterone for the remainder of their lives.
A happier alternative for willing AAS users is to attempt to regain their own HPT function and be freed from dependence on maintenance testosterone. Such men must be prepared to undergo a potentially prolonged regimen of drugs such as hCG, clomiphene, and antiestrogens, using protocols such as those cited earlier,44,56 hoping that the HPT axis will recover and that the medication treatments can be gradually withdrawn. However, as discussed earlier, clinicians cannot assure users that they will be successful in this process. This is especially the case given our still incomplete knowledge of the pathophysiology of AAS-induced hypogonadism, which may have different subtypes and may reflect lesions at one or more different levels of the HPT axis (eg, in the hypothalamus, the pituitary, the testis, or the androgen receptor).
Psychiatric issues: As noted earlier, prominent depressive symptoms occur only in a minority of men with AAS-induced hypogonadism, but some depressive episodes are severe and require treatment with antidepressant medications.29,59 One report has described a patient with suicidal depression attendant upon AAS withdrawal who failed to respond to successive trials of antidepressant medications but ultimately responded well to electroconvulsive therapy.60 In cases of this nature, an endocrinologist should attempt to collaborate with a psychiatrist who can address these problems. Ideally, such a psychiatrist should be experienced in psychopharmacological interventions for major mood disorders, should have experience with substance use disorders in general, and should also be conversant with the particular psychiatric issues commonly encountered in AAS users, such as body-image disorders
Patient commitment and compliance: Given the dysphoric symptoms associated with hypogonadism, together with the slow and difficult process of restoring normal HPT function, many AAS users will surreptitiously resume taking black-market AAS to supplement the drugs that they have been prescribed. In our anecdotal experience, as many as half of AAS users undergoing treatment for hypogonadism have engaged in at least some surreptitious AAS use in addition to prescribed medications. Clinicians who discover such behavior may be tempted to summarily refuse to treat the patient further. However, loss of medical treatment may plunge the patient back into repeated cycles of AAS use with worsening and more refractory symptoms of hypogonadism whenever he attempts to stop. In our experience, there is no simple answer in situations of this nature, and the physician will need to have a frank discussion with the patient about how to proceed. Again, it may be useful to seek the input of a psychiatrist familiar with substance use and body-image disorders.
SUMMARY
AAS are used by millions of men worldwide to achieve muscle growth for athletic performance or (more commonly) for personal appearance. The increasing availability of AAS, coupled with an increasing societal focus on male body image, has caused AAS use to spread widely since the 1980s and 1990s, especially in Western societies.
AAS suppress the HPT axis via feedback inhibition, thus resulting in AAS-induced hypogonadism after prolonged AAS exposure. Though little studied before the 21st century, AAS-induced hypogonadism has now been shown to be common, underrecognized, and often severe, persistent, and perhaps sometimes irreversible. As larger numbers of AAS users accumulate years of AAS exposure and begin to enter middle age, clinicians are likely to encounter increasing numbers of cases of this disorder.
The literature on treatment of AAS-induced hypogonadism remains limited, but strategies using hCG, selective estrogen receptor modulators, and estrogen receptor blockers may help to restore HPT axis function in men attempting to discontinue the use of AAS. However, treatment of such men involves several issues unique to this population, outlined earlier, that must be considered by endocrinologists and other clinicians who encounter such patients.
Body Image Disorders and Anabolic Steroid Withdrawal Hypogonadism in Men (2022)
Harrison G. Pope Jr, MD, Gen Kanayama, MD, PhD
INTRODUCTION AND HISTORICAL BACKGROUND
The anabolic-androgenic steroids (AAS) are a family of hormones that includes the natural hormone testosterone together with its many analogs (Box 1). Testosterone was originally isolated in the 1930s and synthetic derivatives quickly followed.1 By the early 1950s, elite athletes had discovered the potential of these drugs, and AAS use spread rapidly through the Olympics and other high-level sporting events. However, it was not until the 1980s and 1990s that AAS use began to spread from the elite athletic world and into the general population. Most of these new general population AAS users were young men who simply wanted to get bigger, often purely for personal appearance, and who had no plans to use AAS for competitive athletics. Today, probably about 80% of the world’s AAS users fall into this latter category, with only about 20% representing competitive athletes.2–4 However, many clinicians, and many members of the general public, still think of AAS as largely a problem of doping by athletes and remain unaware of the much larger, less visible population of nonathlete AAS users.5 Most of these latter men are relatively young; even the older members of this group—those who first started using AAS as youths in the late 1980s or early 1990s—are only now reaching middle-age, and thus entering the age of risk for long-term consequences of AAS use, including persistent hypogonadism.
Other historical trends in the last few decades have helped to further potentiate AAS use. One of these developments has been the rise of the Internet.6 Unlike other drugs of abuse, such as cocaine and heroin, AAS can be legally purchased without a doctor’s prescription in many countries, such as in Latin America, former Eastern Bloc countries, and various countries in Asia. Thus, AAS dealers located in one of these countries can purchase any amount of AAS and then sell them via the Internet to buyers in countries where possession of nonprescribed AAS is illegal. In the authors’ anecdotal experience with numerous studies of AAS users in the United States, such illicit purchases are really interdicted.
Even in countries where they are illegal, AAS are nevertheless present in a substantial percentage of “dietary supplements,” sold over the counter in nutrition stores or on the Internet.7–10 In some cases, these supplements contain AAS that represent small chemical variations on illegal AAS molecules, but which can still be sold openly because they are not technically outlawed. These variant compounds may be identified on the label of the supplement bottle, or a supplement may contain legal or illegal AAS that are not disclosed on the label at all. Men using these supplements are often not aware that they are ingesting AAS and unwittingly exposing themselves to AAS-induced toxicity.
Also starting roughly in the 1980s, another important historical trend began to develop, namely an increasing focus on male body image, and particularly male muscularity, throughout many Western societies.11 Over the last 4 decades, people have seen more and more images of ideal muscular male bodies in movies, television, advertising, and even in children’s “action toys” (Fig. 1). For example, the American “G.I. Joe” toy, when he first appeared on the market in the 1960s, had an ordinary-looking male body, but by the 1970s he had become distinctly more muscular, and by the 1990s more muscular still.12 A similar trend occurred with the smaller versions of G.I. Joe, culminating in the “G.I. Joe extreme,” who, if he were extrapolated to the height of an actual man, sported biceps bigger than those of any natural human being. Similarly, the toys representing Luke Skywalker and Han Solo from “Star Wars,” when they first appeared in the late 1970s, portrayed normal-looking male bodies—but the equivalent figures 20 years later were dramatically more muscular. Similar trends have appeared in many other settings.11,13 The possible causes of this mounting cultural focus on muscularity have been discussed elsewhere.11,14–17
These 2 parallel developments—the increasing availability of AAS and the growing cultural focus on male muscularity—have created a fertile soil for the development of AAS use, especially in younger men concerned about their body image. Particularly vulnerable are men who have developed so-called muscle dysmorphia, a form of body dysmorphic disorder in which the individual develops a pathologic concern that he is not sufficiently muscular. Men with muscle dysmorphia may devote long hours to weightlifting and other exercises, often with meticulous attention to diet.18–20 Even when they become markedly muscular, these men may still feel that they are too small and will avoid being seen in situations where their bodies are visible, such as at the beach or in a locker room. Not surprisingly, such men are strongly attracted by AAS, and may indeed develop an AAS dependence syndrome, wherein they continue to use these drugs for years, often persisting despite adverse effects.21,22 A recent study of adult male weightlifters found that men who retrospectively reported prominent body image concerns in early adolescence (between the ages of 13 and 16 years) were significantly more likely to have gone on to initiate AAS use than were men reporting lower levels of adolescent body image concern (Fig. 2).23
One study estimated that as of 2013, between 2.9 and 4.0 million men in the United States alone had used AAS at some time in their lives, and that about 1 million of these men had developed an AAS dependence syndrome.24 Notably, these estimates did not include the substantial number of additional men who may have used “dietary supplements” containing AAS, as described earlier. About 98% of all AAS users are men, as women rarely aspire to become extremely muscular, and are also vulnerable to the virilizing effects of AAS, such as beard growth, deepening of the voice, and masculinization of secondary sexual characteristics.24 Thus, the present article refers only to male AAS users unless specified otherwise.
AAS-WITHDRAWAL HYPOGONADISM
All AAS suppress the hypothalamic-pituitary-testicular (HPT) axis via feedback inhibition. Thus, men who have used AAS for a few months or more will typically exhibit hypogonadism upon AAS withdrawal. AAS-withdrawal hypogonadism, like hypogonadism due to other causes, is associated with loss of libido, sometimes loss of erectile function, and occasionally, symptoms of depression. Interestingly, hypogonadism-associated depressive episodes appear to be idiosyncratic, with most men experiencing few depressive symptoms while a minority may develop prominent depression, sometimes even associated with suicidal ideation.25,26 This idiosyncratic pattern of depressive symptoms has been found in laboratory studies where hypogonadism was deliberately induced in male volunteers by administration of depot leuprolide acetate,27 in men administered reversible chemical castration for treatment of prostate cancer,28 and in men undergoing AAS withdrawal.29–31
AAS withdrawal hypogonadism has been noted in the literature at least since the 1980s, and by 1989 was cited as a possible mechanism contributing to AAS dependence, whereby AAS users would be tempted to resume AAS in order to self-treat the dysphoric symptoms attendant on AAS withdrawal.32 Nevertheless, before the last decade, most of the literature on AAS-withdrawal hypogonadism consisted of individual case reports or small case series (eg, see Refs. 33–39), with little to suggest that this phenomenon might be widespread, persistent, and sometimes perhaps irreversible. Recent years, however, have seen reports from urologists, endocrinologists, and substance-abuse researchers demonstrating that AAS-induced hypogonadism is potentially a more serious problem than was once supposed. For example, Coward and colleagues40 reviewed a database of 6033 cases of men seeking treatment for hypogonadism of any etiology. Of these men, 97 (1.6%) displayed profound hypogonadism, defined as a total testosterone level of 50 ng/dL or less. Remarkably, 42 (43%) of these severe cases were attributed to prior AAS use. The investigators subsequently conducted an anonymous survey of 382 men in their current hypogonadal patient population and found that 80 (21%) reported prior AAS exposure. These findings suggest the importance of seeking a history of AAS exposure in men presenting for treatment of hypogonadism, especially in cases of men under the age of 50 years and in men exhibiting profound hypogonadism as defined earlier.
Kanayama and colleagues30 assessed indices of hypogonadism among 24 long-term AAS users who had discontinued AAS at least 3 months before the time of evaluation (mean, 58.9 months) and compared this group with 36 non–AAS-using weightlifters. Five of the former AAS users (21%) were receiving physiologic doses of exogenous testosterone as maintenance therapy to treat hypogonadism, leaving 19 untreated former AAS users for comparison with the 36 nonusers. Among these former users, 5 (26%) displayed testosterone levels of less than 200 ng/dL despite abstinence from AAS for 3, 7, 8, 16, and 26 months, respectively. On the “sexual desire” subscale of the International Index of Erectile Function, 7 former users (37%) scored 4 or less, indicating moderate to severe impairment. Five displayed major depressive disorder during AAS withdrawal; 3 of these 5 had never displayed major depressive disorder at any other time in their lives.
Rasmussen and colleagues41 compared 37 current AAS users, 30 former users (mean duration of abstinence 2.5 years), and 30 non-users. The men in all groups were aged 18 to 50 years and engaged in recreational strength training. Among the former AAS users, 28% displayed plasma testosterone levels below the reference limit of 12.1 nmol/L (350 ng/dL) as compared to none of the nonusers (P<.01). The former AAS users also displayed higher levels of depressive symptoms, erectile dysfunction, and decreased libido when compared with either of the other 2 groups.
These reports, together with other recent studies42 and reviews,43,44 suggest that AAS-induced hypogonadism is common but underrecognized, and may often be persistent and severe. Thus, it seems likely that as more of today’s long-term AAS users begin to enter middle age, such cases of hypogonadism will become increasingly common, presenting in the clinics of primary care physicians, urologists, endocrinologists, and mental health clinicians involved in substance abuse treatment.
DIAGNOSIS AND DETECTION
The diagnosis and detection of AAS-induced hypogonadism is complicated by the fact that AAS users may be reluctant to disclose their AAS use to the clinician. In our experience, AAS use is arguably the most secret of the major forms of substance use disorders, perhaps for several reasons. First, AAS are illicit drugs in many countries. Second, if a man admits that he is using, say, illicit cocaine or opiates, he is simply revealing an illegal activity. But if he admits to using AAS, he is not only revealing illegal behavior but also admitting that his muscular prowess is merely a result of taking chemicals—a confession that he may be loath to make. Third, AAS users often have disdain for medical professionals. They recall that the medical community claimed for years, well into the 1970s and even 1980s, that AAS were ineffective for muscle gains or athletic improvement, even though athletes everywhere knew that these claims were false.1 If doctors had been so misinformed, why should a patient confide to them about his AAS use?
This mistrust of physicians is illustrated by one study of 43 AAS users who were asked questions about how they trusted various sources of information about AAS.45 Remarkably, 41% of these men users reported that they would trust information from their local drug dealer at least as much as information from their physicians, and 56% reported that they had never disclosed their AAS use to any physician that they had ever seen. Other writers have commented similarly on the physician’s difficult task of securing trust with an AAS-using patient.46,47 In light of the above, clinicians should use a careful, nonjudgmental approach with men reporting AAS use, as well as men who appear likely to have used AAS, but who are reluctant to disclose this fact.
Signs and Symptoms
If a patient does not initially disclose AAS use, several signs and symptoms may heighten the clinician’s index of suspicion. First, does the patient exhibit marked muscularity? There is a clear upper limit to the amount of muscularity that a lean man can achieve without AAS use. We have developed and published a formula for calculating the so-called fat-free mass index in men, together with data suggesting that a man with low body fat (say <10%) cannot exceed a fat-free mass index of about 26 kg/m2 without the use of drugs.48
It should be remembered that a man might exceed 26 kg/m2 with low body fat, even though he has not knowingly taken AAS, because he may have used “nutritional supplements” containing surreptitious AAS or other anabolic substances, as discussed earlier in this article. Thus, clinicians should question carefully about supplement use when encountering an unusually muscular man who denies AAS consumption.
In addition to muscularity, various clinical signs and symptoms, such as truncal acne, gynecomastia, striae above the pectoralis muscles, and testicular atrophy may suggest AAS use.49 Certain laboratory findings may also heighten the clinician’s index of suspicion (Table 1).3,50,51 Clinicians should be particularly alert upon finding abnormally low testosterone in conjunction with low follicle-stimulating hormone (FSH) and luteinizing hormone (LH) (ie, hypogonadotropic hypogonadism), in a young man who appears muscular. Any of these clues should prompt a gentle and sympathetic attempt to elicit a possible history of AAS use and to assess whether the patient is willing to discontinue future AAS use and consider treatment.
Laboratory Detection of AAS Use
A substantial literature has addressed the detection of AAS use by laboratory methods, but this approach is often of limited value to practicing clinicians. The only AAS detectable in blood samples with commercial testing is testosterone, and thus individuals taking multiple AAS in the absence of testosterone will be missed. Urine testing, on the other hand, can detect a wide range of AAS, but this testing is much more expensive (in the range of hundreds of dollars per sample), and available in only a few reference laboratories. Also, urine testing can detect only current or relatively recent use of many AAS, such as orally administered compounds—although long-acting depot preparations (eg, nandrolone decanoate) may sometimes be detected many months after last use. Furthermore, commercial urine testing may fail to detect novel “designer” AAS, such as those sometimes present in “nutritional supplements,” as described earlier.
TREATMENT
The literature on the treatment of AAS-induced hypogonadism remains limited. Most cases appear to be associated with low levels of gonadotropic hormones, LH, and FSH. This may be addressed by administering clomiphene, which stimulates the pituitary to secrete these 2 hormones, thus, in turn, stimulating testicular production of testosterone and spermatozoa. One early article52 reported successful use of clomiphene, 100 mg per day for 2 months, to restore HPT function in a 30-year-old man with AAS-induced hypogonadism. Other articles have also described success with this medication in various cases of hypogonadism (eg, see Refs. 53,54). Importantly, Tan and Scally55 have noted that clomiphene has 2 enantiomers with different actions. The trans enantiomer, enclomiphene, is an estradiol antagonist, whereas the cis enantiomer, zuclomiphene, is an estradiol agonist. Therefore, these authors have suggested that the addition of an estrogen receptor blocker, such as tamoxifen, might increase the overall antagonism of the estradiol receptor and hence improve the net effect of clomiphene on pituitary function, and secondarily on testicular function.
Another treatment for AAS-induced hypogonadism is human chorionic gonadotropin (hCG), which simulates the effect of pituitary gonadotropins by stimulating testicular Leydig cells to produce testosterone. Unfortunately, hCG must be administered parenterally and has a relatively short half-life, thus requiring injections every second day. However, for men prepared to self-administer hCG on a regular basis, this substance can fairly quickly increase serum testosterone levels. Moreover, hCG can be combined with clomiphene to achieve a dual stimulus on the HPT axis, hopefully resulting in more rapid return of testicular function in AAS users undergoing withdrawal. Various authorities (eg, see Refs. 44,56) have proposed combination treatment protocols of this nature for attempting to restore both testosterone levels and fertility in men with AAS-induced hypogonadism.
Clinicians should be aware that many AAS users are already familiar with these treatments via their own personal research on the Internet. Karavolos and colleagues57 have noted the vast number of Web sites providing information for users on how to self-treat AAS-withdrawal hypogonadism. These Web sites typically recommended the same compounds described in the scientific literature—hCG, selective estrogen receptor modulators such as clomiphene, and aromatase inhibitors. In our experience, users often obtain these compounds on the black market and self-treat their own cases of hypogonadism without coming to the attention of clinicians. Similarly, a well-known “underground” guide to AAS use58 provides a detailed discussion of AAS-induced hypogonadism and offers a specific “postcycle therapy” program to treat AAS withdrawal, wherein the user takes 2000 international units of hCG every second today for 20 days, plus clomiphene citrate 50 mg twice a day for 30 days, and tamoxifen 20 mg twice a day for 45 days.
Practical Considerations
Patient motivation: In our experience, many AAS users, especially those under age 40 years, have little interest in stopping these drugs. This is particularly the case for men with body-image concerns or frank muscle dysmorphia, and who have become obsessed with looking lean and muscular. Such men may attempt to discontinue AAS but become panicky and resume the drugs when they perceive that they have lost even a few pounds of muscle.
However, symptoms of hypogonadism may eventually trump body-image concerns and bring the patient to the clinician. At this point, the clinician may be confronted with an ambivalent patient who recognizes that his loss of libido, erectile dysfunction, and possible depression are caused by AAS-induced hypogonadism, but who dreads stopping AAS entirely. Many such patients will ask for simple testosterone replacement therapy and will be content to self-administer physiologic or mildly supraphysiologic doses of testosterone (eg, 100–200 mg of testosterone cypionate intramuscularly once per week). However, maintenance testosterone represents an endless proposition, in that the patient’s own HPT axis remains chronically suppressed and is never given the opportunity to recover on its own. AAS users, in our studies, are generally aware of this problem, and often report that they are resigned to taking testosterone for the remainder of their lives.
A happier alternative for willing AAS users is to attempt to regain their own HPT function and be freed from dependence on maintenance testosterone. Such men must be prepared to undergo a potentially prolonged regimen of drugs such as hCG, clomiphene, and antiestrogens, using protocols such as those cited earlier,44,56 hoping that the HPT axis will recover and that the medication treatments can be gradually withdrawn. However, as discussed earlier, clinicians cannot assure users that they will be successful in this process. This is especially the case given our still incomplete knowledge of the pathophysiology of AAS-induced hypogonadism, which may have different subtypes and may reflect lesions at one or more different levels of the HPT axis (eg, in the hypothalamus, the pituitary, the testis, or the androgen receptor).
Psychiatric issues: As noted earlier, prominent depressive symptoms occur only in a minority of men with AAS-induced hypogonadism, but some depressive episodes are severe and require treatment with antidepressant medications.29,59 One report has described a patient with suicidal depression attendant upon AAS withdrawal who failed to respond to successive trials of antidepressant medications but ultimately responded well to electroconvulsive therapy.60 In cases of this nature, an endocrinologist should attempt to collaborate with a psychiatrist who can address these problems. Ideally, such a psychiatrist should be experienced in psychopharmacological interventions for major mood disorders, should have experience with substance use disorders in general, and should also be conversant with the particular psychiatric issues commonly encountered in AAS users, such as body-image disorders
Patient commitment and compliance: Given the dysphoric symptoms associated with hypogonadism, together with the slow and difficult process of restoring normal HPT function, many AAS users will surreptitiously resume taking black-market AAS to supplement the drugs that they have been prescribed. In our anecdotal experience, as many as half of AAS users undergoing treatment for hypogonadism have engaged in at least some surreptitious AAS use in addition to prescribed medications. Clinicians who discover such behavior may be tempted to summarily refuse to treat the patient further. However, loss of medical treatment may plunge the patient back into repeated cycles of AAS use with worsening and more refractory symptoms of hypogonadism whenever he attempts to stop. In our experience, there is no simple answer in situations of this nature, and the physician will need to have a frank discussion with the patient about how to proceed. Again, it may be useful to seek the input of a psychiatrist familiar with substance use and body-image disorders.
SUMMARY
AAS are used by millions of men worldwide to achieve muscle growth for athletic performance or (more commonly) for personal appearance. The increasing availability of AAS, coupled with an increasing societal focus on male body image, has caused AAS use to spread widely since the 1980s and 1990s, especially in Western societies.
AAS suppress the HPT axis via feedback inhibition, thus resulting in AAS-induced hypogonadism after prolonged AAS exposure. Though little studied before the 21st century, AAS-induced hypogonadism has now been shown to be common, underrecognized, and often severe, persistent, and perhaps sometimes irreversible. As larger numbers of AAS users accumulate years of AAS exposure and begin to enter middle age, clinicians are likely to encounter increasing numbers of cases of this disorder.
The literature on treatment of AAS-induced hypogonadism remains limited, but strategies using hCG, selective estrogen receptor modulators, and estrogen receptor blockers may help to restore HPT axis function in men attempting to discontinue the use of AAS. However, treatment of such men involves several issues unique to this population, outlined earlier, that must be considered by endocrinologists and other clinicians who encounter such patients.
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