Topical Sildenafil Cream for Female Sexual Arousal Disorder

Female sexual dysfunction includes female sexual interest/arousal disorder, genito-pelvic pain/penetration disorder, and female orgasmic disorder. These disorders may be lifelong or acquired, and generalized or situational. The dysfunction may be due to sociocultural factors, religious factors, drugs, substances, medical disorders, menopause, or other etiologies; or, no etiology may be apparent.

Managing female sexual dysfunction is complex. Dimensions that require addressing include psychosocial factors, other etiopathological factors, and the specific symptoms that manifest. Symptom-driven approaches include behavioral and medical options.

Among medical options, oral flibanserin and subcutaneous bremelanotide are approved treatments for hypoactive sexual desire in women.^1,2 Personalized pharmacotherapy, comprising testosterone to increase interest and desire, sildenafil to increase arousal, and buspirone to reduce anxiety and inhibition, as appropriate, has also been trialed, with some success, for female sexual interest/arousal disorder. ³ Recently, a simpler and more intuitive approach has been examined: the use of topical sildenafil.

Topical Treatments for Sexual Dysfunction

Topical application of creams, such as nitrate creams, has for decades been mooted to treat erectile dysfunction in men ⁴ ; however, these have not been very successful. ⁵ In contrast, EMLA cream, containing lidocaine and prilocaine, has been found effective against premature ejaculation. ⁶ Tangentially, a decade and a half ago, the use of sildenafil cream was proposed to treat cellulite. ⁷ A variety of creams, including anesthetic creams (procaine, lidocaine, prilocaine, benzocaine), phosphodiesterase 5 inhibitor creams (sildenafil, tadalafil, vardenafil), and testosterone cream, rapidly became available on internet websites for direct purchase and use for erectile dysfunction in men and genital arousal in women. ⁸ Whereas alprostadil cream was suggested to improve hardness of erection, ⁹ sildenafil cream even came to be used in the treatment of anal fissure, ¹⁰ palmar-plantar erythrodysesthesia,^11,12 and the Raynaud phenomenon. ¹³

With regard to female sexual dysfunction, a new focus of drug development has been on the use of sildenafil cream to improve arousal in women who have difficulties with sexual arousal. These women experience inadequate genital blood flow and inadequate lubrication; lubricating creams that are marketed do not resolve the underlying problem of inadequate arousal, and no treatment has yet been approved for the condition. In principle, topical sildenafil cream could improve the genital vascular response and could be faster acting and better tolerated (with a lower risk of systemic adverse effects) than oral sildenafil. ¹⁴

In this context, an industry-driven, phase 2b, randomized, double-blind, placebo-controlled study of 3.6% topical sildenafil cream was conducted by Johnson et al. during 2021–2023 at 49 centers in the United States. ¹⁵

Sildenafil Cream: Randomized Controlled Trial

These authors ¹⁵ recruited healthy adult premenopausal women diagnosed with female sexual arousal disorder. Two hundred women successfully completed a 4-week no-treatment run-in phase and another 4-week placebo treatment run-in phase. The mean age of these women was 36 years. The mean body mass index was 27, indicating that the average woman was overweight. The sample was 83% White. Nearly a third of the women also had decreased sexual desire, and nearly 60% also had orgasmic dysfunction.

These women were randomized to receive treatment with sildenafil (n = 101) or placebo (n = 99) cream for 12 weeks. Sildenafil cream (2 g) was required to be applied 10-20 min before planned sexual activity; 1 g was to be applied to the external genitalia and 1 g was to be applied in the outer third of the vagina. Treatment was permitted not more than once a day and on not more than 9 days in a month.

There were two coprimary efficacy endpoints: change from 0 to 12 weeks in the Arousal Sensation domain of the SFQ28 (Sexual Function Questionnaire) and Question 14 of the FSDS-DAO (Female Sexual Distress Scale-Desire, Arousal, Orgasm). Secondary and exploratory endpoints included the number and proportion of satisfactory sexual events per month and evaluation of the SFQ28 desire domain. Results were additionally analyzed every 4 weeks until treatment endpoint.

There were 11 dropouts in the sildenafil group and 15 dropouts in the placebo group. Reasons for dropout were not presented. In a separate article, ¹⁶ however, the authors reported that adverse effects among subjects and their partners did not differ much between the sildenafil and placebo groups.

Study Findings

The results were disappointing. In the intent-to-treat analysis of women (n = 193) who had used at least one dose of study medication, sildenafil cream did not separate from placebo cream on any of the primary, secondary, and exploratory endpoints examined at 4, 8, and 12 weeks. The only exception was that, in one of the exploratory analyses, sildenafil was associated with a greater improvement in the SFQ28 Desire domain score at Week 8, but this statistical significance would not have survived correction for multiple hypothesis testing.

The authors performed exploratory subgroup analyses, examining outcomes in women with different diagnostic combinations. They found that, when women with genital pain and orgasmic dysfunction were removed, the remaining women, comprising those with decreased arousal alone, or decreased desire and arousal together, fared significantly better at Week 12 with sildenafil cream (n = 33) than with placebo cream (n = 32). This advantage was observed for the arousal outcome but not for desire or orgasm. The magnitude of advantage was large: the sildenafil vs placebo change in least-squares means was approximately 2 (which was about 25% of the baseline arousal score). However, precision was poor; the standard error was nearly half of this value.

In further exploratory analyses, in this subgroup of women, treatment with sildenafil cream was also associated with significantly lower embarrassment, guilt, and stress related to sex on the FSDS-DAO. Finally, in yet another set of exploratory analyses published separately, age, race, and baseline use of hormonal contraception did not influence outcomes. ¹⁷

How might one interpret these results? On the one hand, the significant findings were “discovered” in exploratory analyses of various combinations of female sexual dysfunctions, and so the findings could very likely be Type 1 errors. Additionally, the number of women (n = 65) in the two subgroups was small. On the other hand, there is no prima facie reason to expect that sildenafil would reduce genital pain or orgasmic dysfunction in women, and there are biological reasons to expect that the treatment might improve arousal, ¹⁴ so examination of outcomes in the specified subgroups could be considered reasonable. At best, therefore, the findings may point to a subgroup of women to focus on in future studies.

The take-home message is that sildenafil cream did not succeed for female sexual interest/arousal disorder, but potential leads have been obtained. That is, the treatment may improve arousal in women with decreased arousal, with or without decreased desire. On a parting note, partner compatibility and behavioral interventions that include the partner need to be considered in any management plan for this difficult-to-treat disorder.