Background: Paraphilias are characterized by recurrent, intense, sexually arousing fantasies, urges, or behaviors, over a period of > or =6 months, generally involving nonhuman objects, suffering or humiliation of oneself or one's partner, or children or other nonconsenting persons. These fantasies, urges, and behaviors produce clinically significant distress or impairments in social, occupational, and other important areas of functioning.

Objective: The goal of this article was to provide an in-depth review of the clinical pharmacology of the main antiandrogens (cyproterone acetate, medroxyprogesterone acetate [MPA], and the luteinizing hormone-releasing hormone [LHRH] agonists) used in the treatment of the paraphilias, as well as a discussion of the relevant clinical case reports, case series, and controlled trials. Treatment recommendations are also provided.

Methods: Relevant publications were identified through a search of the English-language literature indexed on MEDLINE/PubMed (1966-September 2008) using the search terms paraphilia, sex offender, hypersexuality, sexual behaviors, fetish, transvestic fetishism, sexual addiction, sexual compulsivism, selective serotonin reuptake inhibitors, tricyclic antidepressants, antiandrogens, cyproterone acetate, medroxyprogesterone acetate, LHRH agonists, and estrogens. Additional publications were identified from the bibliographies of retrieved publications.

Results: In vitro and in vivo (animal) studies have revealed that serotonin and prolactin inhibit sexual arousal, while norepinephrine (via alpha(1)-adrenoceptor activation), dopamine, acetylcholine (via muscarinic receptor activation), enkephalins, oxytocin, gonadotropin-releasing hormone, follicle-stimulating hormone, luteinizing hormone, testosterone/dihydrotestosterone, and estrogen/progesterone stimulate it. Most of the currently used pharmacologic treatments of the paraphilias have serotonin and testosterone/dihydrotestosterone as their targets. Cognitive-behavioral psychotherapy should be initiated in all offenders. In those at the highest risk of reoffending, psychotherapy should be initiated at the same time as drug therapy because their combination is associated with better results compared with either as monotherapy (especially in pedophiles). In offenders committing non-"hands-on" or violent paraphilias and those at low risk of reoffending, serotoninergic monotherapies (selective serotonin reuptake inhibitors [SSRIs] or tricyclic antidepressants) are reasonable choices (SSRIs are preferred). In other offenders, initial dual combination therapy (serotoninergic plus antiandrogenic) is recommended. Progestogens should be used before LHRH agonists or estrogens. Cyproterone acetate and MPA are preferred as oral and IM progestogens, respectively. Failure of dual combination serotoninergic/ progestogen therapy should prompt a change in one or both of the components (eg, SSRI to tricyclic antidepressants or vice versa, or cyproterone acetate to MPA or vice versa) or the addition or substitution of an LHRH agonist (leuprolide or triptorelin) for the progestogen. Estrogens are second- or third-line agents. Rarely, triple combination therapy is necessary (serotoninergic plus LHRH agonist or progestogen plus estrogen). It appears that recidivism rates are reduced by the use of psychotherapy alone, drug therapy alone, and more so by their combination.

Conclusions: Although some progress has been made in the therapy of paraphilic and nonparaphilic sexual disorders, much work remains to be done. The development of more specific, more effective, and better-tolerated medications for these disorders should be recognized as a program worthy of greater support from government and pharmaceutical industry sources. Clinical studies performed to date have largely been of poor design, making the recommendations provided in this review tentative at best.