Antiandrogen Pharmacotherapy

Although it is the primary goal of various psychotherapeutic interventions to alter deviant or unconventional sexual behavior, currently available pharmacotherapies directly target the intensity of sexual arousal. The antiandrogens cyproterone acetate and medroxyprogesterone acetate were developed during the 1960s and have been used to ameliorate abnormal uterine bleeding in women and to retard the progression of prostatic carcinoma in men. Because these medications have diverse endocrinological and medical effects, it is advisable that patients receiving them have a physical examination and laboratory tests, including a complete blood count, a general serology panel, total testosterone, follicle-stimulating hormone (FSH), and luteinizing hormone (LH).

Antiandrogens are currently the most commonly prescribed agents for the control of repetitive, deviant sexual behaviors and severe PRDs. Although neither cyproterone nor medroxyprogesterone has been specifically approved by the U.S. Food and Drug Administration for the treatment of paraphilias, both agents are available in oral and parenteral preparations. Both can be prescribed in Canada and Europe, but only medroxyprogesterone is available in the United States. In multiple studies, parenterally administered antiandrogens have been shown to reduce recidivism rates in male sexual aggressors (Berlin and Meinecke 1981; Bradford and Pawlak 1993a; Cooper et al. 1992; Federoff et al. 1992; Gagne 1981; Kravitz et al. 1996; Langevin et al. 1979; Maletzky 1991c; Meyer et al. 1992), the group most commonly prescribed these drugs.

Cyproterone acetate inhibits testosterone directly at androgen receptor sites and also exhibits antigonadotrophic effects (Liang et al. 1977). In the drug’s oral form, the usual prescribed dosage range is 50-200 mg/day. Parenterally, it is usually administered every 1-2 weeks at dosages of 300-600 mg/injection. Side effects can include weight gain, fatigue, hypersomnia, gallstones, depression, and decreased spermatogenesis and gynecomastia.

Medroxyprogesterone acetate, an analog of progesterone, lowers serum testosterone by reducing the production of testosterone from its precursors and by significantly increasing its metabolic clearance rate from serum by interfering with the binding of testosterone to a sex hormone-binding globulin (Albin et al. 1973). It is most commonly prescribed in the parenteral-depot form and injected weekly or biweekly at dosages ranging from 100-800 mg (usually 200-500 mg). Although less data are available on the use of oral medroxyprogesterone, encouraging results have been reported (Gottesman and Schubert 1993; Langevin et al. 1979) with dosages from 20 to 120 mg/day. Side effects associated with medroxyprogesterone acetate may include weight gain, fatigue, gallstones, hypertension, headaches, hyperglycemia, leg cramps, diminished spermatogenesis, and an increased risk of thrombosis. Rarely, feminization effects, such as breast swelling and changes in hair distribution, may occur during prolonged treatment with either drug. Because antiandrogens diminish serum testosterone and affect its synthesis, these medications are generally not prescribed to adolescent sex offenders.

The effects of antiandrogens on sexual desire and associated fantasies, erections, urges, and other sexual behaviors are usually evident by 2-6 weeks after initiation of pharmacotherapy (Cooper et al. 1992; Kravitz et al. 1996), and pharmacological tolerance to these effects has not been described. In addition, in the only study that compared the two available antiandrogens, both were equivalent in reducing sexual thoughts, frequency of masturbation, and erections (Cooper et al. 1992). Inasmuch as there does not appear to be a linear relationship between lowered serum testosterone and diminished deviant sexual behavior, some clinicians try to lower serum testosterone to prepubertal levels (<100 ng/dL) (Cooper 1981), whereas others target a 50% reduction of circulating testosterone (Gagne 1981) as adequate for a therapeutic effect. Although reducing serum testosterone is a measurable clinical goal associated with the reduction of sex-offending behaviors, on occasion, men will continue to offend despite current prepubertal levels of serum testosterone.

After a period of symptom stabilization, the maintenance dose of antiandrogen can sometimes be carefully adjusted upward or downward to minimize side effects and, in some cases, to permit a more selective mitigation of deviant sexuality in comparison with normal sexual desire (Bradford and Pawlak 1993b). Antiandrogens can also be tapered without a rebound increase in sexual or aggressive behaviors but there can be a significant lag time (e.g., 10 months or more) in the full recovery of pretreatment sexual behavior in male sex offenders after depo-medroxyprogesterone taper (Kravitz et al. 1996).

It is common practice for antiandrogen pharmacotherapy to be used early (e.g., in the first 3-12 months, in conjunction with cognitive, behavioral, and group therapies) in the treatment of sex-offending paraphilic individuals. In some circumstances, however, antiandrogens have been prescribed for periods longer than 10 years in selected men with no significant untoward effects and with continued beneficial mitigation of deviant sexual arousal.

Despite its demonstrated effect on reducing sexual offender recidivism (Grossman et al. 1999; Hall 1995), antiandrogen medication remains a controversial treatment associated with a high dropout rate. In my clinical experience, some of the adverse effects of antiandrogens - as well as the stigmatization of “chemical castration” - can be relieved by administering antiandrogens orally instead of parenterally in motivated subjects with PAs and PRDs.

Mr. L was a 30-year-old man who had been incarcerated for 10 years after raping an elderly female when he was 20. He was not intoxicated at the time of his offense. In fact, he did not meet criteria for any Axis I disorder except PA not otherwise specified (repetitive, intensely sexually arousing rape fantasies). In addition, there was no history of physical, sexual, or overt psychological abuse or neglect. While incarcerated in a specialized sex offender treatment center, Mr. L was intensively treated with cognitive-behavior therapy for several years in both group and individual formats and demonstrated authentic progress. Unfortunately, within 6 months of his discharge, recurrent rape fantasies insidiously returned and then intensified. He was fired from a job in a nursing home for suspicious sexual behavior.
As a teenager and into his early 20s, Mr. L had masturbated at least 5 times per week, although at the time he was referred to me, his masturbation rate was only twice per week. Mr. L had previously experienced side effects from three different SSRI antidepressants, and none of these medications affected his deviant sexual arousal. Oral medroxyprogesterone was prescribed, with the dosage gradually raised (over a period of 3 months) to 120 mg/day. As a result of this treatment, serum testosterone decreased by more than 50%, and there was a marked reduction in all socially deviant sexual arousal. In addition, Mr. L experienced no discernible side effects and continued to have sexual relations with his female partner. Ammonia aversion therapy proved to be a helpful adjunct to pharmacological reduction of deviant sexual arousal, and Mr. L rejoined a relapse prevention group therapy program as well.

Recently, a different class of antiandrogens has been reported to be beneficial to sex-offending paraphilic individuals. This group of medications, called either gonadotropin-releasing hormone (GnRH) or luteinizing hormone-releasing hormone (LHRH) agonists, work directly by first selectively stimulating and then depleting the hypothalamic hormones necessary to trigger the anterior pituitary gland’s production of FSH and LH, the hormones that directly stimulate androgen production by the testes. The net effect, then, is selective inhibition of testosterone production without the usual side effects associated with antiandrogens. First suggested by Berlin (1983), this approach has been reported as successful in case reports (Dickey 1992; Rousseau et al. 1990; Thibaut et al. 1993) and an open trial of 30 men with treatment-resistant paraphilias (Rosler and Witztum 1998).

Currently, the two GnRH agonists reported as effective are triptorelin (3.75 mg administered intramuscularly once a month) (not available in the United States) and leuprolide (7.5 mg intramuscularly, once every 4 weeks). Because these interventions could cause a “testosterone surge” prior to the depletion of testosterone production, it has also been recommended that flutamide (250 mg three times a day) be taken during the first 2 weeks of administration of either triptorelin or leuprolide. To prevent significant hypocalcemia and associated loss of bone density, it is advisable to obtain a baseline bone density study prior to starting any antiandrogenic treatment, especially GnRH agonists. It would be helpful to also prescribe a calcium supplement or alendronate sodium to preserve bone density.

Although treatment with GnRH agonists appears quite promising, several caveats apply. First, GnRH agonists are costly and may not always be covered by medical insurance when administered to males. Second, the long-term therapeutic and/or medical effects of GnRH agonists in males are unknown. Third, as is the case with the use of any of the suggested medical interventions in sex-offending paraphilic individuals, concurrent psychotherapy is recommended. Finally, until we have more data about the use of these promising medications, it is wisest to work with an internist or endocrinologist familiar with the medical management issues of prescribing GnRH agonists.