Androgens and anabolic steroids

Androgen replacement therapy in men

The notion that many men in later life require androgen supplementation to counter the effects of the “andropause” is more widespread in some countries than others, both among practitioners and the public, and it is heavily debated [ , ]. Much of the evidence adduced to support the use of so-called “androgen supplementation” in older men, such as an attempt to demonstrate its use as a supportive treatment in depression [ ], is far from convincing. Proponents of this therapy call for the development of more specific formulations for this purpose, while others argue that such treatment is rarely justified and should be strictly limited to a minority of men with severe and evident hypogonadism. It has, after all, to quote a sober review, “never been definitively established that the decline in testosterone seen in most aging men results in an androgen deficient state with health-related outcomes that can be improved by androgen therapy” [ ]. In that situation it is indefensible to run risks. A thorough review of the literature has turned up much evidence for the benefit of short-term testosterone treatment in selected subjects, provided prostate cancer can be excluded, but also marked reservations regarding the safety or otherwise of long-term use. Potential risks include erythrocytosis, edema, gynecomastia, and prostate stimulation. The possibility of significantly increased risks of prostate cancer and cardiovascular disease has been considered [ ]. Another thorough review has concluded that there is no place for such treatment in healthy older men [ ]. It is not clear to what extent the less favorable aspects of aging are really attributable to androgen decline; nor is it clear that aged tissues remain androgen sensitive, nor that such treatment is necessarily safe. However, certain idiosyncratic adverse effects of androgen treatment, which can include disordered sleep and breathing, as well as polycythemia, are clearly dose related, suggesting that dose escalation to increase efficacy may create or aggravate undesirable adverse effects.

Hormonal contraception in men

The use of intramuscular testosterone + oral desogestrel for hormonal contraception in men is discussed in a separate monograph (Hormonal contraceptives—male).

General adverse effects and adverse reactions

Adverse reactions to pharmacological doses of androgens include, as one would expect from male hormones, hirsutism with acne and other signs of virilization, along with adverse lipoprotein profiles, endometrial hyperplasia in women, and an increased risk of cardiovascular disease. Some compounds are particularly likely to cause liver disorders.

Male hormone replacement therapy has been reviewed [ ]. Hypogonadism can be accompanied by hot flushes, similar to those seen in postmenopausal women, and gynecomastia. The potential risks of testosterone replacement in adult men are precipitation or worsening of sleep apnea, hastened onset of clinical significant prostate disease, benign prostatic hyperplasia, prostatic carcinoma, gynecomastia, fluid retention, polycythemia, exacerbation of hypertension, edema, and an increased risk of cardiovascular disease.

Adverse reactions to long-term testosterone therapy in HIV-positive men include irritability, weight gain, fatigue, hair loss, reduced volume of ejaculate, testicular atrophy, truncal acne, breast tenderness, and increased aggression [ ].

Supraphysiological concentrations of androgen hormones can cause acne, hirsutism, and deepening of the voice.

Adverse reactions to androgens in men

The safety of androgen therapy for cardiovascular and prostatic disease is uncertain. Kraus, after a careful review of the literature from a German perspective, has pointed out that androgen substitution must be approached with caution; even if the hazards are dubious, the need for such treatment is even more doubtful: “…The lack of clear hazards from testosterone substitution in the aging male does not indicate unrestricted treatment safety. Until all doubts are cleared, each treatment should be carefully documented and monitored” [ ].

While opinions are many and varied, only a few groups have made an adequate effort to acquire firm data on relative benefits and harms. In a randomized study using the anabolic androgen oxandrolone, 32 men aged 60–87 took oxandrolone 20 mg/day for 12 weeks or placebo [ ]. Oxandrolone produced significant increases in lean body mass and muscle strength during treatment, but 12 weeks after the treatment had ended these measures were no long different from baseline; however, there was some improvement in fat mass during the study, which was largely discernible 12 weeks later. These modest short-term effects hardly seem to provide a justification for anabolic treatment of the elderly in view of the risks involved.

Adverse reactions to androgens in women

There are clear differences of opinion about the use of androgens in women. An Australian reviewer has argued that women may have symptoms secondary to androgen deficiency and that “prudent” androgen replacement can be effective in relieving both the physical and psychological symptoms of such insufficiency [ ]. The reviewer suggested that testosterone replacement for women is safe, with the caveat that doses should be restricted to the “therapeutic” window for androgen replacement in women, such that the beneficial effects on well-being and quality of life are achieved without incurring undesirable virilizing effects. The predominant symptom of women with androgen deficiency is claimed to be loss of sexual desire after a premature or natural menopause, while other indications for androgens include premenopausal iatrogenic androgen deficiency states, glucocorticoid-induced bone loss, management of wasting syndromes, and possibly premenopausal bone loss, premenopausal loss of libido, and the treatment of the premenstrual syndrome.

Some reservations about this approach arise when one considers the possible adverse effects and the doubts that have been raised as to whether there is in fact a safe therapeutic window when treating women with androgens. This comes clearly to the fore in a thoughtful paper by another Australian author, a speech therapist [ ]. For women treated with androgens or related compounds for any reason, virilization of the voice, which soon becomes permanent, is a distressing complication that has not received a great deal of specific study. This review provides some pointers for clinical practice. She reports on four women aged 27–58 years who sought otolaryngological examination because of significant alterations to their voices, the primary concerns being hoarseness, lowering of habitual pitch, difficulty in projecting their speaking voices, and loss of control over their singing voices. Otolaryngological examination with a mirror or flexible laryngoscope showed no apparent abnormality of vocal fold structure or function, and the women were referred for speech pathology with diagnoses of functional dysphonia. Objective acoustic measures using the Kay Visipitch showed significant lowering of the mean fundamental frequency in each woman, and perceptual analysis of the patients’ voices during quiet speaking, projected voice use, and comprehensive singing activities showed a constellation of features typically noted in pubescent men. The original diagnosis of functional dysphonia was queried, prompting further exploration of each woman’s medical history. In each case the vocal symptoms had started shortly after the beginning of treatment with medications containing virilizing agents, notably danazol, nandrolone decanoate, and testosterone. Although some of the vocal symptoms abated in severity with 6 months of voice therapy and after withdrawal of the drugs, a number of symptoms remained permanent, suggesting that each subject had suffered significant alterations in vocal physiology, including muscle tissue changes, muscle coordination dysfunction, and proprioceptive dysfunction. The study showed that both the projected speaking voice and the singing voice proved highly sensitive to virilizing effects.

It has been known for more than 30 years that some 50% of women have voice changes with anabolic steroids. While it has sometimes been thought that safe doses can be identified, studies of individual patients, including one of the cases documented here, throw doubt on this. The effects can be disastrous for any woman and incapacitating to a singer; clearly the use in women of any product having any androgenic potency must be undertaken with great reticence.

Placebo-controlled studies

A well-founded indication for the cautious use of androgens in women is to treat those who have much reduced sexual desire after a surgical menopause and are troubled by it. In a 24-week, randomized, double-blind, placebo-controlled, parallel-group, study, 447 women aged 24–70 years were randomized to receive placebo or transdermal testosterone patches in dosages of 150, 300,or 450 micrograms twice weekly, and 318 subjects completed the study [ ]. There were marginally significant successes in restoring sexual desire and activity, but only in the two higher dose groups. There were no serious safety concerns, but adverse effects were not discussed in detail.

Cardiovascular

Particularly when androgens/anabolics are misused to promote extreme muscular development, there is a risk of cardiomegaly and ultimate cardiac failure. Androgen-induced hypertension may be due to a hypertensive shift in the pressure-natriuresis relation, either by an increase in proximal tubular reabsorption or by activation of the renin–angiotensin system [ ]. This effect is not related to higher doses or longer treatment and can develop after a few months but can also be delayed for many years.

Respiratory

There has been a single published report, which could have been coincidental, of obstructive sleep apnea during use of testosterone [ ].

Nervous system

Use of androgenic steroids is likely to produce a sensation of energy and euphoria, but also with a tendency to sleeplessness and irritability [ ]. More extreme changes in mental state can result in extreme swings in mood, ranging from depression to aggressive elation. An unusual complication in one case was a toxic confusional state and choreiform movements caused by an anabolic steroid [ ], but it may have been due to the non-specific results of endocrine stress in a susceptible individual.

• A 40-year-old Korean woman who had taken oxymetholone for aplastic anemia (doses not stated) developed cerebral venous thrombosis accompanied by a tentorial subdural hematoma [ ].

Hiccups have been classified as a neurological reaction that can be triggered by many factors. There have been a few published reports of persistent hiccups associated with oral and intravenous glucocorticoids and one of progesterone-induced hiccups, which were thought to be secondary to the glucocorticoid-like effects of progesterone on the brainstem.

• Anabolic steroid-induced hiccups have been reported in a champion power lifter [ ]. The hiccups occurred within 12 hours of an increase in the dose of oral methandrostenolone from 50 to 75 mg/day, and persisted for 12 consecutive hours until medical attention was sought. The hiccups abated rapidly after the dose of methandrostenolone was reduced, but he was unwilling to abandon it completely.

Psychological, psychiatric

In the late 1980s various reports seemed to show that the use of anabolic steroids was linked to aggressive behavior and mood changes, even to the extent of inducing or potentiating violent crime [ , ]. During the decade that followed, a series of other papers similarly linked high circulating concentrations of testosterone to increased degrees of aggression and related changes in mood. Undoubtedly, some of these findings are well-founded, but one must always be alert to the fallacy that individuals with particular pre-existent personality traits might be more susceptible than others to become bodybuilders, to use anabolic steroids, or to take testosterone. This possibility remains open after the completion of a thorough study of weightlifters at various American academic centers. In 20 male weightlifters, 10 of whom were taking anabolic steroids (methandrostenolone, testosterone, and nandrolone), supranormal testosterone concentrations were associated with increased aggression [ ]. Users tended to have a greater degree of depression, agitation, psychic or somatic anxiety, hypochondriasis, and hopelessness on the Hamilton Depression Scale; on the Modified Manic State Rating Scale, users showed more talkativeness, restlessness, threatening language, irritability, and sexual preoccupation. However, the results of the Personality Disorder Questionnaire suggested that this finding, while valid, was to some extent confounded by the personality disorder profile of the steroid users. The latter showed “cluster B” personality disorder traits for antisocial, borderline, and histrionic personality disorder, significantly differing in this respect from non-users. Men who use androgenic anabolic steroids to enhance their sporting achievements seem to be more likely to have cyclic depression [ ], but young men who have stopped using anabolic steroids can also develop depression and fatigue as withdrawal effects [ ].

In a useful review of the entire field there is particular reference to the contested evidence on the behavioral effects of these compounds [ ]. The authors observed that certain of these complications, in particular hypomania and increased aggressiveness, have been confirmed in some, but not all, randomized controlled studies. Epidemiological attempts to determine whether anabolic steroids trigger violent behavior have failed, primarily because of high rates of non-participation. Studies of the use of anabolic steroids in different populations typically report a prevalence of repeated use of 1–5% among adolescents. The symptoms and signs of the use of anabolic steroids seem to be often overlooked by health-care professionals, and the number of cases of complications is virtually unknown. The authors suggested that future epidemiological research in this area should focus on retrospective case–control studies and perhaps also on prospective cohort studies of populations selected for a high prevalence of anabolic steroid use, rather than large-scale population-based studies.

Androgens can rarely cause psychotic mania.

• A 28-year-old man with AIDS and a history of bipolar disorder was given a testosterone patch to counter progressive weight loss and developed worsening mania with an elevated mood, racing thoughts, grandiose delusions, and auditory hallucinations [ ]. His condition improved in hospital after removal of the patch and the administration of antipsychotic drugs. No cause for the psychosis, other than the use of testosterone, was found.

Suicide—or attempted suicide—in eight users of anabolic steroids has been described in Germany; the cases were related variously to hypomanic states during use of anabolic steroids or depression after withdrawal [ ]. Some of the users had committed acts of violence while using the drugs. In all cases, there were risk factors for suicidality and the drugs may simply have triggered the suicidal decision.