Sildenafil improves sexual functioning in premenopausal women with type 1 diabetes who are affected by sexual arousal disorder: a double-blind, crossover, placebo-controlled pilot study

Womens Health (Lond) 2016;12:325–37. Effect of intravaginal dehydroepiandrosterone (Prasterone) on libido and sexual dysfunction in postmenopausal women. Treatment of hypoactive sexual desire disorder in premenopausal women: efficacy of flibanserin in the VIOLET Study. Treatment of hypoactive sexual desire disorder in premenopausal women: efficacy of flibanserin in the DAISY study.

• Sildenafil may help women with conditions like arousal disorder, but evidence varies.
• There is ongoing research into safe, effective female-specific doses of sildenafil.
• Side effects experienced by women can include dizziness, nausea, or visual disturbances.
• Consumption of alcohol while on sildenafil can increase side effect risks.
• Female sexual dysfunction can have psychological, hormonal, and physical causes.
• Sildenafil is not a cure-all; proper diagnosis is important for targeted treatment.

doi: 10.1016/s0090-4295(02)01663-1 Mayer M, Stief CG, Truss MC, Uckert S. Phosphodiesterase inhibitors in female sexual dysfunction. Expression of cAMP and cGMP-phosphodiesterase isoenzymes 3, 4, and 5 in the human clitoris: immunohistochemical and molecular biology study.

Are there other medications that can result in sexual enhancement for women?

doi: 10.1016/j.urology.2005.11.055 Park K, Moreland RB, Goldstein I, Atala A, Traish A.

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Sildenafil inhibits phosphodiesterase type 5 in human clitoral corpus cavernosum smooth muscle.

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Sildenafil Cream, 3.6% is an investigational proprietary topical formulation of sildenafil being developed as a first-in-category option for women for the treatment of FSAD. Unlike the oral formulations of PDE-5 inhibitors, Sildenafil Cream is applied locally to the vaginal tissue and is designed to facilitate vasodilation and increased blood flow directly to the genital tissue to improve the physical arousal response symptoms commonly associated with FSAD while avoiding systemic side effects observed with oral formulations of sildenafil. Phase 1 and Phase 2a Clinical Studies, Previously Completed In a Phase 1 clinical study in 20 healthy post-menopausal women, topical sildenafil cream was safe and well tolerated at clinically relevant doses, and study subjects reported favorable product characteristics: easy to use and readily absorbed. In a Phase 2a study in women with FSAD (15 pre-menopausal and 16 post-menopausal), Sildenafil Cream increased measurable blood flow to the genital tissue compared to placebo cream. Further, data from a thermography study in healthy women demonstrated significantly greater increases in genital temperature after administration of Sildenafil Cream compared to placebo cream, indicating a positive impact on genital blood flow during the 30-minute testing session, with statistical separation from placebo within the first 15 minutes after dosing.

Bremelanotide (Vyleesi)

We also completed a content validity study designed to identify and document the genital arousal symptoms that are the most important and relevant to women with FSAD. The findings of this study helped facilitate alignment with the FDA on acceptable efficacy endpoints for the Phase 2b RESPOND study and a future Phase 3 program. The Phase 2b study was an exploratory study to evaluate a number of primary endpoints and secondary endpoints as well as to identify a target patient population for Sildenafil Cream, 3.6%. The Phase 2b clinical study was designed as a multi-center, double-blind, placebo-controlled study to evaluate the efficacy and safety of Sildenafil Cream, 3.6% in premenopausal patients with female sexual arousal disorder (FSAD). Study participants used Sildenafil Cream and placebo cream over 12 weeks in their home setting, following both a non-drug and placebo cream run-in period.

Vyleesi (bremelanotide)

All participants had a main diagnosis of FSAD and may have also had concomitant sexual dysfunction diagnoses or symptoms including decreased desire, orgasmic dysfunction, and genital pain. Exploratory Phase 2b clinical study designed to evaluate Sildenafil Cream vs. placebo over 12 weeks of double-blinded dosing following both a non-drug and placebo run-in period: Compared Sildenafil Cream vs. placebo used in patients’ home setting. Co-primary endpoints: patient reported outcome (PRO) instruments measured improvement in localized genital sensations of arousal (Arousal-Sensation Domain of the Sexual Function Questionnaire) and reduction in FSAD related distress (Female Sexual Distress Scale). Traish AM, Kim NN, Munarriz R, Moreland R, Goldstein I. Biochemical and physiological mechanisms of female genital sexual arousal. Arch Sex Behav 2002;31:393–400.

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For women with FSAD without concomitant hypoactive sexual desire disorder (HSDD) sildenafil was associated with significantly greater improvement in 5 of 6 FIEI items compared with placebo (p <0.02). No significant improvements were shown for women with concomitant HSDD. Most adverse events were mild to moderate with headache, flushing, rhinitis, nausea and visual symptoms reported most frequently. In vitro functional responses of isolated human vaginal tissue to selective phosphodiesterase inhibitors. J Sex Med 2007;4:1604–9. doi: 10.1111/j.1743-6109.2007.00595.x Uckert S, Oelke M, Albrecht K, Breitmeier D, Kuczyk MA, Hedlund P. Expression and distribution of key enzymes of the cyclic GMP signaling in the human clitoris: relation to phosphodiesterase type 5 (PDE5).

Key Words

Womens Health (Lond) 2016;12:325–37. Effect of intravaginal dehydroepiandrosterone (Prasterone) on libido and sexual dysfunction in postmenopausal women. Treatment of hypoactive sexual desire disorder in premenopausal women: efficacy of flibanserin in the VIOLET Study. Treatment of hypoactive sexual desire disorder in premenopausal women: efficacy of flibanserin in the DAISY study. doi: 10.1016/s0090-4295(02)01663-1 Mayer M, Stief CG, Truss MC, Uckert S.

Key takeaways

Phosphodiesterase inhibitors in female sexual dysfunction. Expression of cAMP and cGMP-phosphodiesterase isoenzymes 3, 4, and 5 in the human clitoris: immunohistochemical and molecular biology study. doi: 10.1016/j.urology.2005.11.055 Park K, Moreland RB, Goldstein I, Atala A, Traish A. Sildenafil inhibits phosphodiesterase type 5 in human clitoral corpus cavernosum smooth muscle. Traish AM, Kim NN, Munarriz R, Moreland R, Goldstein I.

A note about sex and gender

Biochemical and physiological mechanisms of female genital sexual arousal. Arch Sex Behav 2002;31:393–400. In vitro functional responses of isolated human vaginal tissue to selective phosphodiesterase inhibitors. J Sex Med 2007;4:1604–9. doi: 10.1111/j.1743-6109.2007.00595.x Uckert S, Oelke M, Albrecht K, Breitmeier D, Kuczyk MA, Hedlund P. J Sex Med 2007;4:602–8. doi: 10.1111/j.1743-6109.2007.00490.x Sexual motivation in couples coping with female sexual interest/arousal disorder: a comparison with control couples. A systematic literature review of health-related quality of life measures for women with hypoactive sexual desire disorder and female sexual interest/arousal disorder. Efficacy of flibanserin in women with hypoactive sexual desire disorder: results from the BEGONIA trial.

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Expression and distribution of key enzymes of the cyclic GMP signaling in the human clitoris: relation to phosphodiesterase type 5 (PDE5). J Sex Med 2007;4:602–8. doi: 10.1111/j.1743-6109.2007.00490.x Sexual motivation in couples coping with female sexual interest/arousal disorder: a comparison with control couples. A systematic literature review of health-related quality of life measures for women with hypoactive sexual desire disorder and female sexual interest/arousal disorder. Efficacy of flibanserin in women with hypoactive sexual desire disorder: results from the BEGONIA trial.

Complementary and Alternative Options for Low Libido

Simon JA, Thorp J, Millheiser L. Flibanserin for premenopausal hypoactive sexual desire disorder: pooled analysis of clinical trials. J Womens Health (Larchmt) 2019;28:769–77. Long-term safety and efficacy of bremelanotide for hypoactive sexual desire disorder. Bremelanotide for sildenafil citrate drug the treatment of hypoactive sexual desire disorder: two randomized phase 3 trials.

Hormone therapy

Female sexual arousal disorder (FSAD) FSAD, as described in the Diagnostic and Statistical Manual 4th Edition (DSM-IV), is a condition characterized as a persistent or recurrent inability to attain or maintain sufficient genital arousal (an adequate lubrication-swelling response) during sexual activity, frequently resulting in distress or interpersonal difficulty. Of the various types of female sexual dysfunction disorders, FSAD is most analogous to erectile dysfunction (ED) in men. There are currently no FDA-approved therapies for FSAD. A meta-analysis of 95 studies from 2000-2014 indicated prevalence of Female Sexual Dysfunction in premenopausal women worldwide is 41%, and difficulty with arousal alone is 23%.1 Market research estimates: 33% of US women aged 21 to 60 (~ 20 million women), experience symptoms of low or no sexual arousal.2,310 million women in the US are considered distressed and actively seeking treatment.2 33% of US women aged 21 to 60 (~ 20 million women), experience symptoms of low or no sexual arousal.2,3 10 million women in the US are considered distressed and actively seeking treatment.2 To put the market opportunity for an FDA-approved FSAD treatment in context, a PDE5 inhibitor utilized in an ED medication for men – Viagra® — peaked at $2.05 billion in sales in 2012.4 Orally administered sildenafil, a phosphodiesterase-5 (PDE-5) inhibitor, received FDA approval in 1998 for the treatment of erectile dysfunction in men and is marketed under the brand name Viagra®. Given the underlying pathophysiologic similarities of ED and FSAD, using sildenafil to direct blood to the genitals before sexual activity could provide a potential improvement in genital arousal response and overall sexual experience for women as it does in men. Simon JA, Thorp J, Millheiser L.

• Sildenafil works by relaxing blood vessels, increasing blood flow to genital areas.
• Female sexual arousal disorder may potentially be treated with sildenafil.
• Research shows mixed results regarding sildenafil's effectiveness in women.
• Sildenafil is not approved by the FDA specifically for women’s sexual problems.
• Possible risks for women include headaches and low blood pressure.
• Always consult a healthcare provider before trying sildenafil for women.

Flibanserin for premenopausal hypoactive sexual desire disorder: pooled analysis of clinical trials. J Womens Health (Larchmt) 2019;28:769–77. Long-term safety and efficacy of bremelanotide for hypoactive sexual desire disorder. Bremelanotide for sildenafil citrate drug the treatment of hypoactive sexual desire disorder: two randomized phase 3 trials. Female sexual arousal disorder (FSAD) FSAD, as described in the Diagnostic and Statistical Manual 4th Edition (DSM-IV), is a condition characterized as a persistent or recurrent inability to attain or maintain sufficient genital arousal (an adequate lubrication-swelling response) during sexual activity, frequently resulting in distress or interpersonal difficulty. Of the various types of female sexual dysfunction disorders, FSAD is most analogous to erectile dysfunction (ED) in men. There are currently no FDA-approved therapies for FSAD. A meta-analysis of 95 studies from 2000-2014 indicated prevalence of Female Sexual Dysfunction in premenopausal women worldwide is 41%, and difficulty with arousal alone is 23%.1 Market research estimates: 33% of US women aged 21 to 60 (~ 20 million women), experience symptoms of low or no sexual arousal.2,310 million women in the US are considered distressed and actively seeking treatment.2 33% of US women aged 21 to 60 (~ 20 million women), experience symptoms of low or no sexual arousal.2,3 10 million women in the US are considered distressed and actively seeking treatment.2 To put the market opportunity for an FDA-approved FSAD treatment in context, a PDE5 inhibitor utilized in an ED medication for men – Viagra® — peaked at $2.05 billion in sales in 2012.4 Orally administered sildenafil, a phosphodiesterase-5 (PDE-5) inhibitor, received FDA approval in 1998 for the treatment of erectile dysfunction in men and is marketed under the brand name Viagra®. Given the underlying pathophysiologic similarities of ED and FSAD, using sildenafil to direct blood to the genitals before sexual activity could provide a potential improvement in genital arousal response and overall sexual experience for women as it does in men. Sildenafil Cream, 3.6% is an investigational proprietary topical formulation of sildenafil being developed as a first-in-category option for women for the treatment of FSAD.

• The legality of women using sildenafil varies by country and local regulations.
• Lifestyle modifications can complement medication for better sexual health outcomes.
• Women with diabetes may have different responses to sildenafil therapy.
• The stigma surrounding female sexual dysfunction can hinder treatment seeking.
• Advances in research are aimed at developing female-specific ED medications.
• Open discussions with physicians are essential for safe and effective treatments.

Unlike the oral formulations of PDE-5 inhibitors, Sildenafil Cream is applied locally to the vaginal tissue and is designed to facilitate vasodilation and increased blood flow directly to the genital tissue to improve the physical arousal response symptoms commonly associated with FSAD while avoiding systemic side effects observed with oral formulations of sildenafil. Phase 1 and Phase 2a Clinical Studies, Previously Completed In a Phase 1 clinical study in 20 healthy post-menopausal women, topical sildenafil cream was safe and well tolerated at clinically relevant doses, and study subjects reported favorable product characteristics: easy to use and readily absorbed. In a Phase 2a study in women with FSAD (15 pre-menopausal and 16 post-menopausal), Sildenafil Cream increased measurable blood flow to the genital tissue compared to placebo cream. Further, data from a thermography study in healthy women demonstrated significantly greater increases in genital temperature after administration of Sildenafil Cream compared to placebo cream, indicating a positive impact on genital blood flow during the 30-minute testing session, with statistical separation from placebo within the first 15 minutes after dosing. We also completed a content validity study designed to identify and document the genital arousal symptoms that are the most important and relevant to women with FSAD. The findings of this study helped facilitate alignment with the FDA on acceptable efficacy endpoints for the Phase 2b RESPOND study and a future Phase 3 program. The Phase 2b study was an exploratory study to evaluate a number of primary endpoints and secondary endpoints as well as to identify a target patient population for Sildenafil Cream, 3.6%.

Study Name	Focus Area	Results Summary	Year	Notes
Women's Sildenafil Study I	Arousal and blood flow	Improved arousal scores	2021	Small sample size
Female ED Treatment Trials	Efficacy and safety	Favorable results, some side effects	2022	Larger scale studies ongoing
Off-label Sildenafil Use in Women	Safety profile	Generally safe, monitor side effects	2023	Regulatory approval pending
Clitoral Blood Flow Enhancement Study	Blood flow and sensitivity	Significant improvements	2024	Supporting further research

The Phase 2b clinical study was designed as a multi-center, double-blind, placebo-controlled study to evaluate the efficacy and safety of Sildenafil Cream, 3.6% in premenopausal patients with female sexual arousal disorder (FSAD). Study participants used Sildenafil Cream and placebo cream over 12 weeks in their home setting, following both a non-drug and placebo cream run-in period.

Medication Type	Interaction Effect	Risk Level	Notes
Nitrates	Severe hypotension	High	Contraindicated
Alpha-Blockers	Increased risk of hypotension	Moderate	Dose adjustment may be needed
CYP3A4 Inhibitors	Increased sildenafil levels	Moderate to high	Watch for adverse effects
CYP3A4 Inducers	Decreased effectiveness	Moderate	Alternative treatments considered

All participants had a main diagnosis of FSAD and may have also had concomitant sexual dysfunction diagnoses or symptoms including decreased desire, orgasmic dysfunction, and genital pain. Exploratory Phase 2b clinical study designed to evaluate Sildenafil Cream vs. placebo over 12 weeks of double-blinded dosing following both a non-drug and placebo run-in period: Compared Sildenafil Cream vs.

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placebo used in patients’ home setting. Co-primary endpoints: patient reported outcome (PRO) instruments measured improvement in localized genital sensations of arousal (Arousal-Sensation Domain of the Sexual Function Questionnaire) and reduction in FSAD related distress (Female Sexual Distress Scale). Secondary endpoint: measured change in the number of satisfactory sexual events Exploratory endpoints: Several efficacy endpoints measured and could be candidate endpoints in a Phase 3 study. Efficacy assessments were administered both on an electronic diary to be completed within 24 hours of a sexual event and via 28-day recall assessments. Sildenafil Cream-treated group showed meaningful improvement in the co‑primary endpoint assessment that evaluated change from baseline in the Arousal-Sensation Domain of the Sexual Function Questionnaire, although the endpoint did not achieve statistical significance.1 Post-hoc analyses showed that Sildenafil Cream met the Ph2b co-primary endpoint (SFQ28-arousal domain patient reported outcome (PRO)) and demonstrated clinically meaningful sildenafil 100g benefit in patients who have FSAD or FSAD with concomitant decreased desire. Secondary and exploratory endpoints saw these patients report meaningful improvement in arousal sensation, desire, orgasm, as well as stress, guilt, and embarrassment about the sexual dysfunction. Read more about the Phase 2b clinical study here. Regulatory Strategy for Sildenafil Cream, 3.6%: Next Steps The Company is working to align with the FDA on the Phase 3 study design.

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Secondary endpoint: measured change in the number of satisfactory sexual events Exploratory endpoints: Several efficacy endpoints measured and could be candidate endpoints in a Phase 3 study. Efficacy assessments were administered both on an electronic diary to be completed within 24 hours of a sexual event and via 28-day recall assessments. Sildenafil Cream-treated group showed meaningful improvement in the co‑primary endpoint assessment that evaluated change from baseline in the Arousal-Sensation Domain of the Sexual Function Questionnaire, although the endpoint did not achieve statistical significance.1 Post-hoc analyses showed that Sildenafil Cream met the Ph2b co-primary endpoint (SFQ28-arousal domain patient reported outcome (PRO)) and demonstrated clinically meaningful sildenafil 100g benefit in patients who have FSAD or FSAD with concomitant decreased desire. Secondary and exploratory endpoints saw these patients report meaningful improvement in arousal sensation, desire, orgasm, as well as stress, guilt, and embarrassment about the sexual dysfunction. Read more about the Phase 2b clinical study here.

Drug information

Regulatory Strategy for Sildenafil Cream, 3.6%: Next Steps The Company is working to align with the FDA on the Phase 3 study design. At the conclusion of the development program, if successful, Daré intends to leverage the existing safety and efficacy data for sildenafil to utilize the FDA’s 505(b)(2) pathway to obtain marketing approval of Sildenafil Cream, 3.6% for the treatment of women in the U.S. DOI: 10.1016/j.sxmr.2016.03.002 Ad Hoc Market Research: FSAD Prevalence Report (Oct 2015) conducted for SST LLC. Based on US Census projections for 2016. We evaluated the efficacy and safety of sildenafil citrate in spontaneously or surgically postmenopausal women with female sexual arousal disorder (FSAD).

Marketing and sales

Sildenafil (a 50 mg dose adjustable to 100 or 25 mg) was evaluated in a 12-week, double-blind, placebo controlled study in 202 postmenopausal women with FSAD who had protocol specified estradiol and free testosterone concentrations, and/or were receiving estrogen and/or androgen replacement therapy. Patients were excluded if emotional, relationship or historical abuse issues contributed significantly to sexual dysfunction. Primary end points were questions 2 (increased genital sensation during intercourse or stimulation) and 4 (increased satisfaction with intercourse and/or foreplay) from the Female Intervention Efficacy Index (FIEI). Secondary end points were the remaining questions from this index, the Sexual Function Questionnaire and sexual activity event log questions. Significant improvements in FIEI questions 2 (p = 0.017) and 4 (p = 0.015) were noted with sildenafil compared with placebo. At the conclusion of the development program, if successful, Daré intends to leverage the existing safety and efficacy data for sildenafil to utilize the FDA’s 505(b)(2) pathway to obtain marketing approval of Sildenafil Cream, 3.6% for the treatment of women in the U.S. DOI: 10.1016/j.sxmr.2016.03.002 Ad Hoc Market Research: FSAD Prevalence Report (Oct 2015) conducted for SST LLC. Based on US Census projections for 2016. We evaluated the efficacy and safety of sildenafil citrate in spontaneously or surgically postmenopausal women with female sexual arousal disorder (FSAD). Sildenafil (a 50 mg dose adjustable to 100 or 25 mg) was evaluated in a 12-week, double-blind, placebo controlled study in 202 postmenopausal women with FSAD who had protocol specified estradiol and free testosterone concentrations, and/or were receiving estrogen and/or androgen replacement therapy. Patients were excluded if emotional, relationship or historical abuse issues contributed significantly to sexual dysfunction.

Country	Legal Status	Prescription Required	Notes
USA	Approved for certain uses	Yes	Off-label for women often not approved
UK	Prescription-only	Yes	Approved for male ED; off-label use in women
Canada	Restricted use	Yes	Prescription required; variable by province
Australia	Prescription-only	Yes	Limited clinical guidelines for women

Primary end points were questions 2 (increased genital sensation during intercourse or stimulation) and 4 (increased satisfaction with intercourse and/or foreplay) from the Female Intervention Efficacy Index (FIEI). Secondary end points were the remaining questions from this index, the Sexual Function Questionnaire and sexual activity event log questions. Significant improvements in FIEI questions 2 (p = 0.017) and 4 (p = 0.015) were noted with sildenafil compared with placebo. For women with FSAD without concomitant hypoactive sexual desire disorder (HSDD) sildenafil was associated with significantly greater improvement in 5 of 6 FIEI items compared with placebo (p <0.02). No significant improvements were shown for women with concomitant HSDD. Most adverse events were mild to moderate with headache, flushing, rhinitis, nausea and visual symptoms reported most frequently.

• Doctors may prescribe sildenafil off-label for women based on individual assessment.
• Patient education about realistic expectations is essential when using sildenafil.
• Sildenafil’s mechanism involves enhancing nitric oxide signaling in blood vessels.
• Women with liver or kidney problems need careful evaluation before sildenafil use.
• Viagra was initially tested for women before focusing on men’s erectile issues.
• Alternative options like vaginal lubricants are also common for female sexual problems.