A number of psychotherapeutic drugs have been noted to affect the ability of women to attain orgasm. The selective serotonin reuptake inhibitors (SSRIs) frequently affect orgasmic functioning, leading to delayed orgasm or anorg-asmia. There is variability, however, in that some antidepressants have been associated with anorgasmia less frequently than others. For example, the anti-depressant, nefazodone, has been reported to produce fewer sexual side effects in women (34) than many of the earlier-generation SSRIs. Nephazodone increases serotonin activity in general while simultaneously inhibiting serotonin activity at the serotonin2 (5-HT2) receptor. Stimulation of 5-HT2 receptors has been reported to inhibit the release of both norepinephrine and dopamine from several brain areas (35). Because dopamine and norepinephrine have been reported to facilitate sexual behavior, the decrease in serotonergic activity at 5-HT2 receptors (and consequent possible increase in dopamine and nor-epinephrine) could explain the decreased incidence of anorgasmia noted with nefazodone. Cyproheptadine is also a 5-HT2 receptor antagonist and has been used with some success as an antidote to SSRI-induced orgasmic dysfunction.
Among the typical SSRIs, paroxetine has been reported to delay orgasm more frequently than fluvoxetine, fluoxetine, and sertraline (36) and more than nefazadone, fluoxetine and venlafaxine (37). One explanation for this greater impairment may be that paroxetine is a more potent inhibitor of the serotonin transporter than are fluoxetine and fluvoxetine, and does not inhibit the dopamine transporter, as does sertraline and, to a lesser degree, fluoxetine and fluvoxetine (38). As noted earlier, dopamine antagonists impair several aspects of sexual function. Women treated with fluoxetine, paroxetine, and sertraline for anxiety disorders reported delays in reaching orgasm and decreased quality of orgasm at 1 and 2 month follow-ups (39). However, the impairments in the fluoxetine group decreased by the end of the third month. In contrast to these findings of impaired orgasm with fluoxetine, one multicenter open-label study of fluoxetine reported an improvement in women's orgasmic ability associated with the amelioration of depression (40).
Several factors may explain the discrepancy between such studies. First, there may be individual differences in the numbers and anatomical distributions of receptor subtypes, and in the influence of the SSRI on subsequent dopamine and norepinephrine release. In addition, for some women, improvements in mood and interpersonal functioning, which result from the antidepressant properties of these drugs, may offset neurochemical changes that may adversely impact orgasmic ability.
Antipsychotic medications have also been reported to inhibit orgasm in women (41). This is likely attributable to the blockade of dopamine receptors in areas critical for sexual function (e.g., medial preoptic area, paraventricular nuclei), or indirectly from increased prolactin levels, extrapyramidal side effects, or sedation. A retrospective clinical study of women taking antiepilepsy drugs (primarily benzodiazepines) reported they found orgasm less satisfying than did the healthy, unmedicated controls (42). These effects were not attributable to alterations in free testosterone levels with antiepilepsy medication use.
Nitric oxide stimulates guanylate cyclase release, which triggers the conversion of guanosine triphosphate to cGMP. cGMP activity relaxes the smooth muscles of the penile tissue allowing vasocongestion and erection. Sildenafil (Viagra®) potentiates the activity of cGMP by inhibiting phosphodiesterase type 5, the endogenous substance responsible for cGMP deactivation. This increases and prolongs cGMP activity, which increases and prolongs vasoconges-tion, and enables erection. There have been mixed reports of the effects of sildenafil on women's orgasmic function. Caruso et al. (43) found improved sexual arousal and orgasm with sildenafil. However, only a minority of women responded positively in several other studies (44,45). A number of case studies have reported a reversal of antidepressant-induced anorgasmia with sildenafil (46-49) but, to date, no placebo-controlled studies have been conducted.
Drugs that inhibit beta-adrenergic receptors do not seem to adversely impact women's orgasmic ability. In a retrospective questionnaire study of 1080 women, there were no reports of significant increases in difficulty achieving orgasm while taking hydralazine, beta-adrenergic antagonists, or methyldopa (50). In a prospective randomized double-blind study of 345 women over a period of 24 months (51), antihypertensive medications did not substantially impact orgasm ability. Similarly, atropine, a cholinergic acting agent, did not affect subjective sexual arousal or orgasm in women (52).
In an uncontrolled, open-label study, estrogen was reported to facilitate orgasmic function in 25% of 188 premenopausal women (53). However, a retrospective study of 66 women who had undergone hysterectomy and oophorectomy found no difference in orgasmic ability between the 33 who received conjugated estrogens and the 33 who did not (54). In a single blind study comparing estrogen plus progestin hormone replacement therapy (HRT) to tibolone, a drug which can be metabolized into estrogenic, androgenic, and progestogenic compounds, there was no effect of HRT or tibolone in 50 postmenopausal women (55). An open-label study of 48 women found a significant improvement after 3 months of tibolone treatment, but not HRT (56).
In a 3 month, prospective, open-label study of 44 women who had undergone hysterectomy and oophorectomy, monthly injections of estrogen and testosterone increased the rates of orgasm during the first 3 weeks following treatment, compared with the woman's own baseline and compared to estrogen alone or no treatment (57). Similar results were noted in a well-controlled study of 75 women who had undergone hysterectomy and oophorectomy (58). Conjugated estrogens were administered either alone or with testosterone (150 or 300 mg/day) in transdermal patches. The higher dose of testosterone improved orgasm pleasure. However, as was the case in the Sherwin and Gelfand study, the testosterone levels noted in this study were substantially greater than that regarded as being within the normal range for intact women. In an open-label, uncontrolled study, dehydroepiandrosterone (DHEA) (50mg/day orally) was used to treat 113 women with low levels of testosterone and DHEA and complaints of orgasmic difficulty. After 3 months of treatment, the women reported a greater frequency of orgasm compared with pretreatment levels (59).
In summary, drugs that increase serotonergic activity (e.g., antidepressants), or decrease dopaminergic activity (e.g., antipsychotics) adversely impact female orgasm. The degree to which the former of these influences orgasm appears to be dependent upon which serotonin receptor subtype they activate/inhibit.
Beta-adrenergic drugs and estrogenic compounds do not seem to have a substantial impact on women's orgasm ability. High doses of testosterone seem to facilitate orgasmic ability but future controlled studies are needed to assess the impact of more moderate doses of testosterone on women's orgasmic ability.
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