PDE5 inhibitors

Content written by Irwin Goldstein MD

When women undergo sexual stimulation, peripheral arousal results in part following increased blood flow to genital tissues such as the clitoris, vagina, and labia. Such genital tissue engorgement is thought to be regulated by neurochemicals such as nitric oxide and cyclic guanosine monophosphate that are involved in a comparable genital tissue engorgment response in male genital tissues. For example, in clitoral and vaginal erectile tissues, researchers have identified high concentrations of the enzymes that regulate genital tissue vasodilation, nitric oxide synthase and phosophodiesterase type 5. Nitric oxide synthase utilizes the amino acid L-arginine and molecular oxygen to synthesize nitric oxide. Nitric oxide stimulates the synthesis of cyclic guanosine monophosphate, a key messenger that facilitates the release of calcium out of the cell thereby causing smooth muscle cells to relax. The enzyme phosophodiesterase type 5 regulates the degradation of cyclic guanosine monophosphate.

Numerous multi-institutional double-blind, placebo-controlled clinical studies using phosphodiesterase type 5 inhibitors, such as sildenafil (Viagra), tadalafil (Cialis) and vardenafil (Levitra), in men with erectile dysfunction have shown that these pharmaceutical agents safely and effectively facilitate the arousal response in men. Similar double-blind, placebo-controlled clinical studies using phosphodiesterase type 5 inhibitors in women with sexual arousal disorder have yielded confusing clinical results. There are several reasons for the variable clinical responses in women. One explanation is that sex steroid hormones are required for structure and function of men and women’s genital tissues. What was not fully appreciated at the time of the early (1990’s) clinical studies in men (and women) with sexual dysfunction was that phosphodiesterase type 5 inhibitors do not work efficiently in men without normal testosterone values. Phosphodiesterase type 5 inhibitors do not appear to effectively vasodilate in women without normal testosterone (and estrogen) values. Most of the early (mid-late 1990’s) clinical studies of phosphodiesterase type 5 inhibitors in women with sexual dysfunction did not take into account the androgen blood test values.

Two large multi-center, placebo-controlled, randomized trials with 577 estrogenized and 204 estrogen-deficient women affected by at least one sexual complaint (superficial/introital dyspareunia due solely to lack of lubrication, female sexual arousal disorder, hypoactive sexual desire disorder with associated arousal disorder, or female orgasmic disorder with associated arousal disorder) investigated the effects of administration of sildenafil. The women were treated for 12 weeks (10, 50 or 100 mg in the estrogenized and 50 mg in the estrogen-deficient women). Efficacy has been assessed with two global efficacy questions, the Life Satisfaction Checklist, an event log of sexual activity, and a 31-item sexual function questionnaire. Testosterone blood test values were not assessed. Differences between sildenafil and placebo were not significant for any patient end-point. Adverse events included mild to moderate headache, flushing, rhinitis, nausea, visual disturbances and dyspepsia.The following studies assessed safety and efficacy of phosphodiesterase type 5 inhibitor drugs in women with normal androgens and estrogens. A double-blind, crossover, placebo-controlled safety and efficacy study of sildenafil was performed in pre-menopausal women affected by female sexual arousal disorder who did not have problems with sexual interest and had normal levels of steroid hormones. Subjects benefited from treatment with the sildenafil showing improvement in sexual arousal, orgasm, frequency, and enjoyment of sexual intercourse versus placebo.

A double-blind, placebo-controlled safety and efficacy study with sildenafil was performed in post-menopausal women with female sexual arousal disorder who had adequate serum estradiol and testosterone values. Women with female sexual arousal disorder and no problems with sexual interest that were assigned the active drug sildenafil had a significantly greater improvement in sexual arousal, orgasm, intercourse, and overall satisfaction with sexual life, compared with placebo. A double-blind, crossover, placebo-controlled randomized safety and efficacy study with sildenafil was performed in pre-menopausal women asymptomatic for sexual disorders, with normal ovulatory cycles and with normal levels of steroid hormones. Sildenafil improved general sexual behavior including sexual arousal, orgasm, and enjoyment versus placebo. The study suggested that phosphodiesterase type 5 inhibitors improved women’s sexual experience.

Sildenafil has been studied as an antidote to psychotropic-induced sexual dysfunction in women. A recently published prospective, parallel-group, randomized, double-blind, placebo-controlled clinical trial investigated the effect of sildenafil on pre-menopausal women whose major depression was remitted by selective serotonin reuptake inhibitor antidepressants but who were also experiencing sexual dysfunction. Primary and secondary outcome measures were psychometrically validated questionnaires such as the Clinical Global Impression sexual function scale, the Female Sexual Function Questionnaire, the Arizona Sexual Experience scale-female version, the University of New Mexico Sexual Function Inventory-female version, and the Hamilton Depression Rating scale. Testosterone blood levels were also assessed. Sildenafil treatment was associated with a significant improvement in orgasmic function and the response was best in women with the highest free testosterone values.Based on the above, it is suggested that phosphodiesterase type 5 inhibitors may have clinical therapeutic benefit, especially for selected female patients with sexual arousal and orgasm disorders with normal values of testosterone. Further research is needed, but it is strongly recommended that the critical influence of sex steroids on women’s sexual responses be better appreciated and accounted for.

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