Introduction
Female sexual dysfunction (FSD) is a common disorder: in the US, the prevalence is often quoted to be 30–40%.1, 2, 3 In Europe the prevalence is similar: 33% lack sexual interest, 25% lack pleasurable sex, and 24% have difficulty reaching orgasm.4 According to the International Classification of Diseases (ICD-10),5 FSD is classified either by physiological or psychogenic causes. Studies have noted, however, that sexual problems associated with personal distress are not as frequent as those without associated distress: FSD as a result of personal distress was found to make up 8.3% of cases in a study by West et al.3 and 12% in a study by Shifren et al.2 The Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR)6 classifies FSD as disorders in desire, arousal, orgasm, and pain, which causes marked distress or interpersonal difficulties. This classification is based on the original arousal sequence delineated by Masters and Johnson7 in 1966, which was updated by Kaplan8 the following decade. Newer definitions of FSD have removed distress and interpersonal problems from the diagnostic criteria. Although this change in definition will increase the number of women who would meet the criteria for a diagnosis of FSD, the diagnosis would be clinically irrelevant in women who have very low or no distress.
Several consensus meetings have been held to update the definitions of FSD. Most recently, the second International Consultation on Sexual Medicine expert panel convened in 2003.9, 10, 11 Following this meeting, Basson et al.10, 12 highlighted the need for definitions to reflect the nuances of desire experienced by women. These experts noted that a woman is initially in sexually neutral states, but is receptive to sexual stimuli that cause arousal, which lead to desire and sexual enjoyment. Here, desire is not the starting point of the sexual response cycle.9
Female sexual arousal disorder (FSAD), as defined by DSM-IV-TR, is a persistent or recurrent inability to attain or maintain adequate lubrication and genital swelling until completion of sexual activity. This definition stresses the importance of genital events in sexual arousal; however, Basson et al.9, 10 suggested separating the definition of FSAD into subjective and genital sexual arousal disorders, in light of studies that showed that women with difficulty in feeling aroused often had similar physical genital responses to sexual stimuli as healthy women without arousal disorders.9, 13
Several pharmacological agents have been studied as possible treatments for FSAD, though none have received regulatory approval from the US FDA. These drugs include topical alprostadil, 
-adrenergic receptor antagonists, melatonin receptor agonists and phosphodiesterase inhibitors. Past and current studies are attempting to delineate the place of these drugs in treating FSAD. Sildenafil citrate (Viagra®; Pfizer, New York, NY) is a phosphodiesterase type-5 (PDE5) inhibitor that is used for the treatment of male erectile dysfunction. Since the approval of sildenafil citrate by the US FDA in 1998, hundreds of articles regarding the safety and efficacy of sildenafil citrate for male erectile dysfunction have been published; however, only a handful of randomized trials have assessed the use of sildenafil citrate in women with FSAD. The aim of this Review is to provide the rationale for using sildenafil citrate in the treatment of FSAD, and to discuss the clinical trials examining the efficacy of treating FSAD with this drug. The manufacturer of sildenafil citrate, Pfizer, is not currently conducting any clinical trials for FSAD, nor have they announced funding of any future FSAD trials. This article, however, will discuss past trials that indicate particular etiologies of FSAD that might be amenable to treatment with sildenafil citrate.
Rationale for sildenafil citrate therapy
PDE5 acts in the nitric oxide pathway to break down cyclic GMP (Figure 1). Nitric oxide production via nitric oxide synthase activates guanylyl cyclase to form cGMP from GTP, which in turn activates a cGMP-dependent protein kinase G. Ex vivo studies have shown that the activated protein kinase acts upon large-conductance, calcium-activated potassium channels to promote smooth-muscle relaxation in the clitoris, which is also thought to cause vasodilation and engorgement in vivo.14 PDE5 inhibitors prevent breakdown of cGMP, extending the period of effect of cGMP on smooth-muscle cells.
Figure 1 | Mechanism of sildenafil citrate in promoting smooth-muscle relaxation.
NO production via NOS activates soluble guanylyl cyclase to form cGMP from GTP, which in turn activates cGMP-dependent protein kinase G. Activated protein kinase G acts upon large-conductance, calcium-activated potassium channels to promote smooth-muscle relaxation in the clitoris, and is also thought to cause vasodilation and engorgement. PDE5 promotes the formation of GMP from cGMP and, therefore, prevents activation of protein kinase G. Sildenafil citrate, a PDE5 inhibitor, promotes protein kinase G activation and smooth-muscle relaxation. Abbreviations: cGMP, cyclic guanosine monophosphate; GMP, guanosine monophosphate; GTP, guanosine triphosphate; NO, nitric oxide; NOS, nitric oxide synthase; PDE, phosphodiesterase. Permission obtained from Nature Publishing Group © Ghofrani, H. A. et al. Nat. Rev. Drug Discov. 5, 689–702 (2006).
PDE5 has been found to be expressed in vaginal, clitoral and labial smooth muscle, which indicates that PDE5 is involved in female sexual function, particularly genital arousal.15, 16, 17 PDE5, however, is expressed in far smaller quantities in the female clitoris than in the male corpus cavernosum.16, 17 Nevertheless, the presence of PDE5 in female genital tissue has helped support the hypothesis that sildenafil citrate may be useful in treating some forms of FSD, such as FSAD. In addition, the mechanism of action that sildenafil citrate has on cellular tissue indicates that greater success would be achieved in the treatment of genital rather than subjective arousal disorder. Sildenafil citrate might not, however, be successful for treating female desire disorders: the drug has been shown to have no effect on libido in men,18, 19 and its mechanism as a vasodilator does not seem to lend itself to treatment of desire disorders.
Studies in the late 1990s showed that sildenafil citrate was successful in treating erectile dysfunction due to spinal cord injuries,20, 21 and erectile dysfunction induced by serotonin reuptake inhibitors.22 These studies, in addition to the rationale provided by the preclinical studies mentioned above, were the impetus for expanding the use of sildenafil citrate to women with FSAD resulting from spinal cord injuries.
Clinical trials of sildenafil citrate
One of the earliest clinical trials of sildenafil citrate in women was by Sipski et al.23 in 2000. The trial recruited 19 premenopausal women with spinal cord injuries affecting the sacral cord. Participants were defined as having FSD on the basis of previous evidence of upper motor neuron disease and spinal cord injuries affecting S2 through S5 spinal segments, with preserved reflex but not psychogenic genital vasocongestion.24 This study was a double-blind, crossover study; each participant received either sildenafil citrate 50 mg or placebo on the first day, and the alternate medication on the second day. The protocol began 1 h after drug administration, and included two 12 min sessions of audiovisual stimulation followed by two 12 min sessions of audiovisual plus manual stimulation. A 6 min period separated each session in which there was no stimulation. Vaginal pulse amplitude (VPA) was measured via vaginal photoplethysmography continuously throughout the protocol, as were heart rate and blood pressure. Physiologic data were averaged over 3 min periods, whereas subjective levels of arousal were measured by a verbal scale of 0–10 every 3 min. In both the visual and manual stimulation sessions, VPA was markedly increased in the sildenafil citrate group compared with placebo (P <0.07), and subjective arousal was significantly greater with sildenafil citrate than placebo (P <0.01). The trial also demonstrated significant heart rate increases of 4–5 beats per min, and systolic and diastolic blood pressure decreases of 2–4 mmHg during sexual stimulation. This trial was the first to evaluate the cardiovascular effects of sildenafil citrate in women during sexual stimulation. This study had a small sample size, and additional studies would be beneficial to assess success in this subgroup of women.
A study published in 2001 by Caruso et al.25 included 53 premenopausal women being seen for sexual arousal disorders at the investigators' clinic; the women denied any subjective desire problems with their partners. Women who were taking hormone therapy or oral contraceptives were excluded from the study. The trial was a randomized, double-blind, crossover study. Each participant was assigned to one of six groups, with each group receiving the following three medications in different sequences: sildenafil citrate 25 mg, sildenafil citrate 50 mg, and placebo. Each participant took medication 1 h prior to sexual intercourse for a 4-week period, followed by a 1-week washout period before starting the next medication. The Personal Experience Questionnaire (PEQ)26, 27 was used to evaluate changes in qualitative and quantitative information of interest (arousal, frequency of coitus and orgasm, enjoyment, and so on), and revealed that both doses of sildenafil citrate significantly increased the frequency of arousal compared with placebo (P <0.001). Participants also had more enjoyment (P <0.05), more satisfaction with frequency of coitus (P <0.05), increased frequency of coitus (P <0.05) and increased frequency of fantasies (P <0.05) with sildenafil citrate than with placebo. Only orgasm was shown to increase in frequency in the placebo group compared with baseline (P <0.05). Overall, participants were found to have an improved sexual quality of life during the sildenafil citrate sequences.
In 2002, however, a study published by Laan et al.28 found no subjective difference between sildenafil citrate and placebo in arousal or vaginal wetness, even though an increase in VPA was reported following the sildenafil citrate sessions compared with placebo. This study was a randomized, double-blind, placebo-controlled crossover trial, which included 12 healthy, premenopausal volunteers with no history of FSD. Each participant received sildenafil citrate 50 mg or placebo; the following week, the alternative medication was administered. Participants watched 60 min of neutral video content, 30 min of erotic video content, and then another 15 min of neutral video content. VPA was measured by vaginal photoplethysmography continuously, starting 15 min prior to dosing. Subjective sexual arousal was measured after each session by a verbal scale of 0 to 4 (0 indicating no arousal and 4 indicating extremely intense arousal). Vaginal wetness was measured after each session by a similar rating scale of 0 to 4 (0 indicating no wetness and 4 indicating extreme wetness). In addition, participants were asked which treatment they thought they had received during their session. Fifty percent of the women guessed correctly. A significant placebo effect was observed in this study compared with baseline. Participants indicated increased sexual arousal (P <0.01) and vaginal wetness (P <0.05) during the session in which they suspected sildenafil citrate had been administered versus the suspected placebo session. The study is limited by the small sample size and the fact that women included did not have FSD: women without FSD may have different subjective arousal responses to women with FSD.
In 2002, Basson et al.29 performed a large, double-blind, placebo-controlled study in women with FSD, including women with FSAD, dyspareunia due to lack of lubrication, hypoactive sexual desire disorder (HSDD) with associated arousal disorder, or female orgasmic disorder with associated arousal disorder. All women were eventually diagnosed with FSAD, but only 48% of the women had FSAD as the primary diagnosis. In total, 577 estrogenized women (either premenopausal or postmenopausal receiving estrogen) and 204 estrogen-deficient women were randomly assigned into two parallel studies. The estrogenized women received sildenafil citrate 10 mg, 50 mg or 100 mg, or placebo. The estrogen-deficient women received sildenafil citrate 50 mg or placebo, with one opportunity to adjust the dose of sildenafil citrate to 25 mg or 100 mg as tolerated. Each group was evaluated using the Global Efficacy Questions (GEQ; GEQ1: Did treatment improve physical response during sexual activity? GEQ2: Did treatment improve ability to participate in sexual activity?), Life Statistical Checklist (LSC)30 and the Sexual Function Questionnaire (SFQ).31 Both the estrogenized and estrogen-deficient groups had a matched control group without FSD; these groups were used solely to provide validation of the SFQ within the study. No significant increase was reported in the number of women who answered 'yes' to GEQ1 or GEQ2 with sildenafil citrate, compared with placebo, in either the estrogenized or estrogen-deficient groups; however, the heterogeneous group in this trial may have influenced the end results.
Caruso et al.32 followed up their study from 2001 with another study in 2003 that assessed the effects of sildenafil citrate on 68 premenopausal women without FSD. This study had a similar design to their first trial: it was a randomized, double-blind, placebo-controlled crossover study with end points derived from the PEQ. The questionnaire was given at baseline, after washout and after treatments. Each woman was randomly assigned to receive a medication sequence that included sildenafil citrate 50 mg and placebo, with a 2-week washout period in between. The women had significant subjective improvement in arousal (P <0.001), orgasm (P <0.05), and enjoyment of sexual intercourse (P <0.001); however, no improvement in desire was reported. These findings contradict earlier data from Laan et al.,28 who showed that healthy, premenopausal women did not have an increase in subjective arousal when given sildenafil citrate compared with placebo.
A study performed by Basson and Brotto33 in 2003 included 34 postmenopausal women who had been receiving menopausal estrogen replacement therapy for at least 6 months, and who had a confirmed diagnosis of acquired genital FSAD and a loss, delay or reduction in orgasm intensity. In this randomized, double-blind crossover study, the women were given sildenafil citrate 50 mg or placebo 1 h prior to vibratory and visually erotic stimulation. Primary outcome measures were orgasm latency and intensity and subjective genital arousal. Latency was measured in time elapsed from initiation of erotic sensory material and completion of orgasm, intensity was measured on a subjective 7-point scale from 1 (not at all) to 7 (intensely felt), and a subjective questionnaire was given before and after the erotic film to assess arousal and perception of autonomic activity.34 VPA was also measured via vaginal photoplethysmography. The data showed no significant improvement in orgasm latency, intensity or subjective genital arousal with sildenafil citrate treatment compared with baseline values and placebo. However, multiple regression analysis found that age and VPA were independent predictors of whether women would attain orgasm with sildenafil citrate. Age was positively correlated with orgasm attainment with sildenafil citrate (P = 0.014). In order to identify the relationship between VPA and orgasm attainment, participants were stratified at baseline into groups of low responders (VPA score increase <114%) and high responders (VPA score increase >156%). The authors found that women who had a low VPA response at baseline were more likely to experience a decrease in orgasm latency with sildenafil citrate than were women with high VPA response at baseline. Both groups had similar demographic variables and questionnaire data, and no indicators predicted the magnitude of increase in VPA score. This study showed that, although no overall group effect on orgasm latency was detected, women who were low VPA responders at baseline had significant improvements following sildenafil citrate treatment. This finding may indicate an opportunity to use VPA to identify women who would benefit from this treatment.
Another double-blind, randomized clinical trial of sildenafil citrate, published in 2003, included 202 postmenopausal women (either spontaneous or surgically induced), with or without oophorectomy. The women's testosterone levels were >0.9 pg/ml and estradiol levels were >40 pg/ml; these levels were maintained during the study.35 Participants had a primary diagnosis of FSAD, with possible secondary diagnoses of female orgasmic disorder, HSDD, or dyspareunia due to vaginal dryness. The women were randomly allocated to receive 12 weeks of treatment with sildenafil citrate 50 mg (with one opportunity to adjust dose to 25 mg or 100 mg) or placebo. Each woman completed the SFQ at baseline and study end, and the Female Intervention Efficacy Index36 at study end. Participants' response to treatment was self reported: women were asked to engage in sexual activity once per week on average, and to keep a log of events and dosing. The SFQ data determined that women without HSDD had a significant improvement in the primary end points arousal sensation (P <0.001), arousal lubrication (P = 0.003) and orgasm (P = 0.01) with sildenafil citrate treatment, although these women had no significant improvements in desire, pain or enjoyment. Women with HSDD did not experience any significant improvements in any of these end points.
The efficacy of sildenafil citrate treatment has also been addressed in women with FSD secondary to multiple sclerosis (MS). Dasgupta et al.37 conducted a randomized, double-blind, placebo-controlled crossover study in 2004. Nineteen premenopausal women with MS and FSD (including arousal and orgasm problems) were randomly allocated to receive either sildenafil citrate 50 mg (with one opportunity to change the dose to 25 mg or 100 mg) or placebo for 12 weeks, and then the alternative medication was given for an additional 12 weeks. The SFQ was administered at baseline and after each session. Only lubrication (P <0.03) and sensation (P <0.059) were significantly improved with sildenafil citrate compared with placebo. No improvement in orgasm, desire or overall quality of life was reported by participants.
A pilot study performed in 2006 in premenopausal women with type 1 diabetes and FSAD (according to the American Foundation of Urologic Disease38) found significant improvements in sexual function with sildenafil citrate treatment.39 This double-blind, randomized, placebo-controlled crossover study included 32 women. Participants were randomly assigned to receive sildenafil citrate 100 mg or placebo for 8 weeks, followed by the alternative treatment for 8 weeks, with a 7-day washout period before crossover. The PEQ was given at baseline, after washout, and after both treatment periods. Levels of HbA1c were measured weekly to monitor glucose control, and color Doppler ultrasonography of clitoral blood flow was performed at baseline and during each 8-week treatment session. The data showed improvements in arousal (P <0.01) and orgasm (P <0.05), and increased clitoral blood flow (P <0.05) with sildenafil citrate treatment compared with placebo. HbA1c levels remained similar to baseline values at each treatment, indicating well-controlled diabetes in all women.
Lastly, a trial published in 2008 by Nurnberg et al.40 demonstrated the efficacy of sildenafil citrate in treating FSD associated with serotonin reuptake inhibitors in premenopausal women. In total, 98 premenopausal women who were taking antidepressants for major depressive disorder, had reported sexual dysfunction for at least 4 weeks, and who had no pre-existing sexual dysfunction prior to initiation of antidepressant therapy, were included. The women were randomly allocated to receive either sildenafil citrate 50 mg (with the option to increase the dose to 100 mg) or placebo. Each participant was assessed at baseline, 2 weeks, 4 weeks, and at the end of the trial (8 weeks) using the Clinical Global Impression Scale,41 the SFQ, the Arizona Sexual Experience scale (female version),42 and the University of New Mexico Sexual Function Inventory (female version).43 With a conservative intention-to-treat baseline-carry-forward analysis, a significant improvement in the Clinical Global Impression scale of sexual function (P = 0.03) was reported with sildenafil citrate. The SFQ, Arizona and University of New Mexico scales all showed significant improvement in orgasm with sildenafil citrate compared with placebo (P = 0.01). The results of this trial confirm those of earlier open trials44, 45 and case reports.46, 47
Sildenafil citrate was well tolerated by patients in all the studies: adverse events were mild-to-moderate. The most common adverse events reported in all studies were headache, flushing, nausea, rhinitis, and visual disturbances.23, 25, 28, 29, 32, 33, 35, 39, 40 A summary of the clinical trials can be found in Table 1.
Conclusions
Data are emerging that support the use of sildenafil citrate in women diagnosed with FSAD; however, one of the hurdles to recommending sildenafil citrate treatment in these women is that FSAD is proving to be a heterogeneous disorder. Studies have shown mixed results regarding success in treating FSAD with sildenafil citrate, largely based on the type of population chosen for each trial. The new definitions separate FSAD into a subjective and genital subtype, and those women suffering from subjective arousal disorder will probably not benefit from sildenafil citrate. Even the subgroup of women with genital arousal disorder show heterogeneity within the diagnosis, as discovered by Basson and Brotto.33 All the participants in this study received a diagnosis of genital arousal disorder, but the women responded differently to erotic stimuli (VPA response increase), which affected the success of treatment. The authors could not use demographic data or pretrial interviews to predict which women would have a relatively low or high increase in VPA following visual stimulation. VPA response may be clinically useful to identify women who are more likely to benefit from sildenafil citrate, although the practicality for day-to-day clinical use remains to be seen. In order to effectively evaluate sildenafil citrate as a possible treatment for FSAD, a greater understanding of arousal disorders is required, and patients most likely to respond should be identified. Large studies could possibly reveal a subset of women with FSAD who naturally have lower VPA changes in response to sexual stimulation, and thus would benefit from sildenafil citrate treatment.
Although PDE5 is present in vaginal and clitoral tissue, it is present in much smaller quantities than in male erectile tissue.16, 17 The smaller quantities of PDE5 in women could account for the lower response to sildenafil citrate in women with FSAD, relative to the response achieved in men with erectile dysfunction. Even though some studies have shown success, sildenafil citrate might never be as effective in women with FSAD as in men with erectile dysfunction, as a result of the concentration differences of PDE5 in the respective tissues.
Several studies point to an increase in clitoral blood flow with sildenafil citrate,23, 39, 47, 48 so future studies could show that sildenafil citrate is useful in treating certain subgroups of women who have FSAD with vasculogenic causes. Further research would be especially beneficial in diabetic women with FSAD, as patients with diabetes often suffer from vascular complications49 and have been shown to have improvements in sexual function with sildenafil citrate.39 Several case reports,46, 47 open-label studies,44, 45 and now a randomized controlled trial40 have shown that sildenafil citrate improves orgasm in women with sexual dysfunction secondary to antidepressant use. Further studies in this area may make sildenafil citrate a realistic therapy for clinicians treating therapy-related sexual complications. Lastly, the investigation of sildenafil citrate treatment in women with arousal disorders of neurogenic origin is incomplete. The small studies performed in these women23, 37 showed some small but significant improvements; a larger study to evaluate the efficacy of sildenafil citrate in this population would be clinically useful.
In conclusion, the clinical trials discussed in this Review demonstrate a modest improvement in arousal with sildenafil citrate treatment, compared with placebo (albeit with caveats in the Basson and Brotto study33). Further studies to identify which patients with FSAD would be most likely to respond to sildenafil citrate could be beneficial.
Review criteria
A search of PubMed was performed using the following terms: "female sexual dysfunction", "female sexual function", "female sexual arousal disorder", "female orgasmic disorder" and "sildenafil". We limited our review criteria to randomized, double-blind, placebo-controlled studies published between January 1998 and October 2008.
