0021-972X/91/7301-0004$03.00/0 Journal of Clinical Endocrinology and Metabolism Copyright © 1991 by The Endocrine Society

Vol. 73, No. 1 Printed in U.S.A.

SPECIAL ARTICLE Androgens: Risks and Benefits C. WAYNE BARDIN, RONALD S. SWERDLOFF, AND RICHARD J. SANTEN The Population Council (C.W.B.), New York, New York 10021; Department of Medicine/Endocrinology (R.S.S.), Harbor/UCLA Medical Center, Torrance, California 90509; and Department of Medicine (R.J.S.), Penn State University, Hershey, Pennsylvania 17033

Extensive studies have evaluated the risks, benefits,

and indications for progestins and estrogens, but androgens have received minimal attention. Currently, physicians prescribe testosterone as replacement therapy for hypogonadism, and athletes often receive pharmacological amounts of androgens without medical supervision. Androgen use is prevalent and likely to increase. Concerns about the risks and benefits of androgen therapy thus led to a workshop conference on current knowledge and to target key areas for future study. This workshop conference was attended by over 180 experts in the field. This report summarizes the consensus that was developed.1 The conference was sponsored by the Contraceptive Research and Development Program of the Eastern Virginia Medical School (Norfolk, VA), the Special Progamme of Research Development and Research Training in Human Reproduction of the World Health Organization, the U.S. Food and Drug Administration, and the National Institute of Child Health and Human Development of the National Institutes of Health. Mechanism of action of androgens Recent studies on hormone action provide a basis for understanding risks and benefits. Testosterone, the most important androgen in blood, acts via the androgen receptor. Inherited alterations of this receptor change the sensitivity of tissues to androgens and result in pathologic states; 10 separate mutations of the androgen receptor have been identified. Androgen binding converts an inactive androgen receptor to a DNA binding protein that activates specific genes. In some organs, testosterone is metabolized to estradiol and 5a-dihydrotestosterone, which are effective via the estrogen and androgen Received February 7,1991. Address requests for reprints to: C. Wayne Bardin, M.D., The Population Council, 1230 York Avenue, New York, New York 10021. 1 A detailed report of the meeting prepared with the support of the Contraceptive Development Branch of NICHD is available upon request.

receptors, respectively. Since receptors a r e n o t entirely

specific, part of the effects of supraphysiological amounts of testosterone and other androgens are mediated via estrogen and progestin receptors. Thus, the risks and benefits of androgens are determined by interactions of androgens and their metabolites with multiple receptors which act on multiple genes. Potential adverse effects of androgens Prostate cancer and benign prostatic hypertrophy (BPH):

Prostate cancer and BPH are major areas of concern in men receiving androgens. These conditions do not develop without testosterone exposure during puberty. There are no data demonstrating how androgen blood levels after puberty influence the incidence of these disorders. Prostate cancer is the most commonly diagnosed cancer in the United States and the cause of death of 28,000 men annually. This cancer arises by a two-step process, which in turn is influenced by multiple factors. The first step is development of microscopic foci or preclinical cancer. The prevalence of this entity increases with age, reaching approximately 50% by the seventh decade in men throughout the world. The role of androgens on the initiation of preclinical cancer is not known, but studies in animals suggest that they are promoters. The second step is progression to clinical cancer. The fact that there is a 10-fold greater prevalence of clinical prostate cancer in the United States than in Japan, even though the prevalence of preclinical cancer is the same, suggests that some of the factors that influence progression are geographically distributed. There are no data to indicate whether androgens enhance the progression of preclinical to clinical cancer. BPH is the most common form of prostatic enlargement in humans. More than 80% of men will develop BPH if they live to the seventh decade and many will require surgery. Although both androgens and estrogens

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SPECIAL ARTICLE are believed to be required to produce maximal prostate enlargement, the influence of androgen therapy is unknown. Two years ago, the current belief was that androgen deprivation would not lead to a regression of BPH. Notably, a variety of studies presented at the meeting indicated that androgen deprivation of the prostate by 5a-reductase inhibitors, LHRH analogs, or antiandrogens reduces prostate size and improves urine flow in men with BPH. These encouraging results could markedly improve the methods of treating BPH in the next several years. Nonreproductive organs

Part of the 5-fold increase in mortality due to cardiovascular disease in men us. premenopausal women may be attributable to androgens. Men have lower high density lipoprotein (HDL) cholesterol and higher low density lipoprotein (LDL):HDL cholesterol ratios than premenopausal women. These observations suggest that some of the difference in mortality between men and women is attributable to hormone-induced differences in lipids. Observations suggesting that such an interpretation may be too simplistic include findings that women can tolerate higher LDL-HDL ratios than men without developing coronary artery disease, and that hormones that induce decreases in HDL or increases in the LDL:HDL ratio may not necessarily be deleterious. For example, combination oral contraceptives protect against atherogenesis in primates even in the presence of steroidinduced suppression of HDL and increase in LDL:HDL. The concern as to whether androgens influence cardiovascular disease may relate to the type of androgen administered. Orally administered 17-alkylated steroids, such as stanozolol and danazol, markedly lower HDL and increase LDL, whereas parenteral testosterone esters do not affect lipoprotein levels. The latter observations may be due to testosterone conversion to estradiol, which opposes the effect of androgens on serum lipids and to a first-pass effect on the liver of orally administered 17-alkylated steroids, which induce greater lipid changes. Part of the unfavorable changes in serum lipids induced by 17-alkylated androgens may be counterbalanced by a favorable increase in fibrinolysis. Whether testosterone has a beneficial effect on fibrinolysis is not certain at this time. It was concluded that future studies on androgens should focus on how steroid structure and estrogenic metabolites influence adverse reactions. Sleep apnea is seven times more common in men than in women and androgens potentiate this process. It was concluded that testosterone administration to hypogonadal men increases the incidence of sleep-related breathing disorders as compared to that observed in normal men. The risk factors for clinically significant sleep

apnea are obesity, chronic obstructive pulmonary disease, and advancing age. Similarly, androgens increase red blood cell mass but almost never lead to frank polycythemia unless there is associated sleep apnea, pulmonary disease, or obesity. Potential benefits of androgens Osteoporosis

Osteoporosis develops in men with long-term hypogonadism. One-third of such men have reduction in bone density sufficient to result in fracture. Androgen replacement before puberty leads to increases in both trabecular and cortical bone and after puberty only on cortical bone. A beneficial effect of androgen replacement in hypogonadal patients is prevention of osteoporosis. The effects of androgen on bone density in eugonadal individuals are unknown. Androgens and sexuality

Androgens are necessary though not sufficient for normal sexual desire in men. The relationship between androgens and erectile function is more complex. Spontaneous erections as measured by nocturnal penile tumescence are androgen dependent. They are impaired in hypogonadism and are improved with androgen replacement. However, erections in response to certain erotic stimuli, such as movies, are not androgen dependent. It is not clear whether androgen effects on sexuality are dose-related or reach a plateau once a threshold is achieved. There are limited placebo-controlled studies of androgen administration to eugonadal men suggesting a positive effect on sexuality. Thus, further controlled trials are required. Evidence from rodents suggests that the major metabolites of testosterone, dihydrotestosterone (DHT) and estradiol may have some influence on sexuality but there is little evidence for effects of these metabolites in humans. Although it is clear that androgens increase aggression in some species, the evidence for such an effect in primates and humans, whereas suggestive during adolescence, is inconclusive in adults possibly due to the confounding effects of social learning. Studies to define the role of androgens in sexual and aggressive behavior were identified as a priority. Androgens and aging

Cross-sectional studies show that testosterone production rates, spermatic venous testosterone concentrations, and tissue androgen levels decrease in many but not all elderly men. The reasons for low testosterone in healthy elderly men are decreased sensitivity of Leydig cells to

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BARDIN ET AL.

gonadotropin and a decreased sensitivity of the hypothalamo-pituitary axis to a fall in androgen levels. Testosterone levels can also be decreased by illness, medications, and stress. A decline in sexual function with age can be correlated with reduced spontaneous erections as measured by nocturnal penile tumescence. Even when one excludes individuals with neural and vascular causes for impotence, there remains a large group of elderly men with either impotence or reduced sexual function of unknown cause. A question considered by the conference was whether sexual function could be improved in elderly men with androgen treatment. There are ongoing studies on the effects of testosterone on elderly men. There are limited data from placebocontrolled trials suggesting a beneficial effect of testosterone on sexual response in a proportion of individuals. As yet, it is not possible to predict which men will respond. A consensus emerged that clinical trials should be conducted to determine whether some elderly men may benefit from androgen therapy in terms of both sexuality and well being. Such studies should monitor the effects of androgens on BPH and prostate cancer. Controversial use of androgens

The benefits and risks of androgenic steroid use by the athlete have not been documented by controlled studies. Most information about androgen abuse is anecdotal. Nonetheless, there is a consensus that there is increasing use by athletes. Abuse has changed from continuous use of physiological amounts to cyclic use of supraphysiological doses. The beginning of each cycle is characterized by escalating, followed by declining, doses of orals plus injectables. Some agents that are being abused are veterinary preparations that have toxic or unknown effects. Some androgens used by athletes are produced in underground laboratories and hence do not have the quality control of approved drugs. Abusers not only seek increased performance, but improved appearance. Over 6% of adolescent males in the United States may use anabolic steroids at some time. Some studies of androgenic steroids on athletic performance have shown effects and others have not. The observed effects seem small compared to those claimed by athletes. A major problem is that few definitive controlled clinical trials with supraphysiological doses of androgens have been conducted. In spite of the problems with the scientific data, there is a common belief on the part of athletes, coaches, sports physicians, and the public at large that androgens do enhance athletic performance. Thus, clinical scientists and the sports community have diverging opinions as to the effects of these agents and the need for further study. There are also

JCE & M • 1991 Vol 73 • No 1

ethical concerns about experiments on athletes using androgens. Nonetheless, the issues regarding the use of other abused agents have been resolved by carefully controlled clinical trials that were approved by properly constituted human investigation committees. The possibility that large doses of androgenic steroids have effects that have not been observed in scientific studies was considered. Possible reasons include: first, the effects of anabolic steroids are uniform but of small magnitude so that they are statistically difficult to demonstrate; such effects, however, could be a major benefit to a top athlete. Second, effects are related to the log of the dose, and benefits on performance are observed at 10 or more times the replacement dose for hypogonadal men. Studies showing that maximal effects of androgens in animals are only observed at supraphysiological doses support this hypothesis. Third, there is genetic polymorphism among individuals such that only a small subset will show a large response to administered androgens. Studies in inbred mice show that some strains have as much as a 20-fold greater response to androgens. Finally, the effects of androgens are mediated by one or more metabolites that are formed from some but not all drugs, or by some but not all individuals; there is no evidence for or against the latter possibility. Standard indications for androgens Treatment of male hypogonadism is the major medical indication for use of androgens. Participants generally agreed that parenteral androgen treatment is superior because of favorable pharmacokinetics. Administration of testosterone esters at 3- to 4-week intervals results in a wide swing in testosterone levels that may be associated with emotional lability. There is, therefore, a search for preparations that produce constant serum androgen levels. Androgen replacement therapy for children with hypogonadism should be coupled with a careful plan to induce complete puberty and maximal height. Most patients can be maintained on existing formulations although there was consensus that none are entirely optimal. Alternative methods for delivering testosterone include testosterone pellets, new testosterone esters, transdermal delivery systems, and microspheres. Of these, the transdermal system is most advanced and should be available for widespread clinical use in the near future. Future indications for androgens Widespread use of androgens can be expected in normal men if a male contraceptive based on the hormonal suppression of spermatogenesis is developed. Androgens used alone or in combination with progestins do not

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SPECIAL ARTICLE routinely produce azoospermia. Results using LHRH antagonist plus testosterone were reported. These agents appear to suppress gonadotropin levels better than LHRH agonists. In nonhuman primates, antagonists produced azoospermia in most animals. In two ongoing human studies, 10 out of 11 men developed azoospermia. Such observations, along with studies in monkeys, suggest that an antagonist plus testosterone may be effective as a male contraceptive. The high doses of antagonist required, however, indicate that more potent peptides will have to be developed before a practical contraceptive can be formulated. An unresolved issue is how much testosterone should be administered with an LHRH agonist or antagonist. If there is a synergistic action of either LHRH or the analogs with testosterone in humans, a high normal physiological dose may have the optimal effect on sperm suppression. Alternatively, if an analog alone can maintain azoospermia, then physiological replacement of tes-

tosterone may be optimal for contraception. If, on the other hand, physiological amounts of androgens can directly stimulate spermatogenesis as studies in monkeys suggest, then replacement therapy on the lower side of normal would be desirable. It should be emphasized that ideal methods for administration of androgen and LHRH agonists or antagonists have not been developed. Conclusion Since past use of androgens was by individuals with rare diseases, the long-term effects of these agents on the cardiovascular system, prostate, central nervous system, and other organs, were not defined. The use of androgens by athletes, by aging men, and for potential contraception indicates that the risks and benefits of androgens should now be evaluated in the same detail as were those of estrogens and progestins after introduction of oral contraceptives and use of these drugs as replacement therapy in postmenopausal women.

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Androgens: risks and benefits.

0021-972X/91/7301-0004$03.00/0 Journal of Clinical Endocrinology and Metabolism Copyright © 1991 by The Endocrine Society Vol. 73, No. 1 Printed in U...
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