Pharmacotherapy

In the relatively short time span, compared to psychologic treatments, that pharmacological treatments have become available for men, since 1998, the effect of pharmacological treatments in women with sexual arousal problems has been investigated in several controlled and uncontrolled studies. To date, none of the treatments listed here have been approved.

Phosphodiesterase Inhibitors

Sildenafil is the first pharmacological treatment that has been investigated on a reasonable scale in controlled studies with female subjects. In the very first laboratory study, 12 healthy premenopausal women without sexual dysfunction were randomized to receive a single oral 50 mg dose of sildenafil or matching placebo in the first session and alternate medication in a second session (107). Although sildenafil was found effective in enhancing vaginal engorgement (VPA) during erotic stimulus conditions, these changes were not associated with an effect on subjective sexual arousal. The first large controlled at home study in 557 estrogenized and 204 estrogen-deficient pre- and postmenopausal women with sexual problems that included, but were not limited to, sexual arousal disorders, found no improvement with 10-100 mg of sildenafil on subjective sexual arousal and subjective perception of genital arousal, as assessed by several different measures (108). Women identified as having DSM-IV arousal disorder without concomitant hypoactive sexual desire disorder did show benefit of sildenafil beyond placebo (109). Also, an Italian study found improvement on subjective sexual arousal, pleasure, orgasm, and even on frequency of orgasm, in premenopausal women with sexual arousal complaints, although these results were obtained with unvalidated questionnaires (110). A second study from the same group in sexually functional women showed benefit of sildenafil over placebo on arousal, orgasm, and enjoyment, now with a validated questionnaire (111). A small, recent placebo-controlled laboratory study of women diagnosed with genital arousal disorder suggested only a small minority of them might benefit from sildenafil (112). The controlled laboratory study of Sipski et al. (113) in women with SCI found an enhancing effect of sildenafil on genital (VPA) and subjective sexual arousal. The beneficial effects of sildenafil over placebo were most evident in the strongest stimulus condition of both visual and manual stimulation. Several, yet unpublished, controlled studies in women with FSAD found no improvement of sildenafil.

These conflicting findings have probably led to Pfizer's recent decision to end their program of testing efficacy of sildenafil in women (114). It would be theoretically and clinically meaningful to investigate which factors may have been responsible for these inconsistent findings. Possible candidates are: inadequate sexual stimulation (sildenafil will not be effective without sexual stimulation); inadequate outcome measures; wrong patient group (e.g., women with sexual problems unrelated to genital responsiveness); estrogen depletion. In most studies, women with a medical condition were excluded from the trials. This may have been an unfortunate choice. We have argued that women with various medical conditions may have an impaired genital response and may therefore have more to gain from a genital arousal enhancing agent such as sildenafil than medically healthy women.

Prostaglandines

One placebo-controlled, single-blind, dose response study has been published investigating the effect of a local application of alprostadil in women with arousal difficulties (115). No significant differences with placebo were found. A comparison of the lowest with the highest dose did show some effects in the expected direction, but these effects were estimated by visual inspection by an MD. It is unknown whether that MD was also blinded to treatment. Apparently a larger, as yet unpublished study, in postmenopausal women did find significant improvement over placebo on genital sensation, subjective sexual arousal, and sexual satisfaction (116).

Phentolamine

Two controlled studies have investigated the effect of the alpha-1 and alpha-2 adrenergic receptor antagonist phentolamine on the basis of the hypothesis that, as in men, the smooth muscle surrounding the vaginal arterial vascular bed is mainly alpha adrenergically innervated. In the first study, an oral application was used that showed a positive effect on subjective and genital sexual arousal (VPA) in postmenopausal women with sexual arousal difficulties (117). A second placebo-controlled study studied both oral and vaginal applications in estrogen-ized and nonestrogenized postmenopausal women (118). Genital response was higher with the highest dose of vaginally applied phentolamine than with placebo, in estrogenized postmenopausal women only. Subjective sexual arousal was higher with the highest doses of both applications of phentolamine than with placebo, again in the estrogenized women only.

Dopamine Agonists

Dopaminergic drugs might be interesting because unlike the previously discussed drugs, they have a direct effect on the brain and may therefore have a positive influence on sexual arousal and desire. The only controlled study published to date found an enhancing effect of levodopa on an index of somatic motor preparation, the Achilles tendon reflex, in men, but not in women (119). Sumanirole is a dopamine agonist that specifically targets D2-receptors. We investigated the effect of this drug in women with complaints of sexual arousal and desire in a placebo-controlled laboratory study, but found no effects on genital or subjective sexual arousal (data not published). Buproprion was used in one uncontrolled study to counteract the sexual side-effects of selective serotonine reuptake inhibitors. Keeping in mind that no adequate control was used, the authors conclude that the results point to relief of the sexual complaints (120).

Androgens

Several companies have begun to study the effects of various androgen products and androgen-estrogen combinations. The relationship between declining androgens and sexual response has not been clarified. Sexual problems related to androgen deficiency are to be expected only when there is a real deficiency of biologically available testosterone. Recently, a consensus conference has tried to establish clear criteria for such an androgen insufficiency syndrome (64). Fourcroy (116) recently published a detailed overview of androgen treatments that are being developed, and concluded that it remains to be seen whether these products will show promise in female sexual dysfunction. Besides efficacy, there are increasing concerns about safety. For an overview of a small number of other treatments and a listing of pharmaceutical companies that are involved in these treatments, see Ref. (116).

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