Sildenafil in women with sexual arousal disorder following spinal cord injury

Sexual dysfunction is recognized as being associated with selective and nonselective serotonin reuptake inhibitor (SRI) antidepressants, which are the most frequently prescribed medications for outpatients aged 18 to 65 years and represent 90% of the 180 million antidepressant prescriptions filled in the United States.1 Antidepressant treatment–associated sexual dysfunction is estimated to occur in 30% to 70% of men and women treated for major depression with first- or second-generation agents,2 a principal reason for a 3-fold increased risk of nonadherence that approaches 70% in the first months of treatment and leads to increased relapse, recurrence, disability, and resource utilization by affected patients.3 However, the literature in this field is less developed for women with more highly variable prevalence rates and less conclusive data compared with men. In women, sexual dysfunction is associated with decreased sexual interest, genital sensitivity, and vaginal lubrication; delayed or absent orgasm; dyspareunia; reduced sexual activity; and overall dissatisfaction or loss of pleasure in sexual relations. Among the numerous strategies proposed for managing sexual dysfunction associated with SRI treatment, selective phosphodiesterase type 5 inhibitors, which have been limited to studies involving men, have demonstrated the best evidence-based data to support broad-based and clinically meaningful treatment efficacy.4 However, to our knowledge, no randomized controlled trial (RCT) has demonstrated effectiveness for women experiencing sexual dysfunction associated with SRI treatment.

Compared with men, women are prescribed antidepressants at rates of 2 to 1 and can be expected to represent a significant number of patients needing relief.5 Without evidence-based data to treat sexual function associated with SRIs in women, clinicians may lack the confidence to manage it effectively, which leaves patients exposed to excess random pharmacology.6 Although sexual dysfunction is a major influence in determining the selection or switching of antidepressants, it is frequently overlooked because clinicians fail to inquire, misattribute it as a symptom of depression that will improve with treatment, or because 80% of women do not discuss adverse sexual effects with their physician.7,8 Sexual dysfunction associated with SRIs is dose related, usually occurs early in treatment, and rarely remits spontaneously.

Methods and Objectives

Selective phosphodiesterase type 5 inhibitors (sildenafil, vardenafil, tadalafil), which are effective and well tolerated for treatment of erectile dysfunction in men,9 including men with depression10 and associated with SRI treatment,11 are not approved by the US Food and Drug Administration (FDA) for women with sexual dysfunction.

However, interest in their potential use in women was encouraged by reports that nitric oxide synthase isoforms, nitric oxide, and phosphodiesterase type 5 inhibitors are present in female genital tissue, and phosphodiesterase type 5 inhibitor enhancement of nitric oxide–cyclic guanosine monophosphate in nonadrenergic-noncholinergic signaling for women seems similar to men.12 When several trials involving premenopausal and postmenopausal women treated with sildenafil failed to demonstrate significant improvements for sexual arousal disorder,13 the manufacturer abandoned pursuit of FDA approval for treating women.

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Subsequent RCTs narrowed their focus on more specific hormonal factors and demonstrated efficacy with improved frequency of sexual sildenafil citrate 120 mg intercourse, arousal, orgasm, and satisfaction. One trial involved premenopausal women with sexual arousal disorder but with normal sexual desire.

They were randomized to receive 1 of 3 treatments: 25 mg or 50 mg of sildenafil or placebo.14 A protocol-specified trial involved premenopausal or postmenopausal women with sexual arousal disorder without concomitant hypoactive sexual desire disorder. Women with low baseline estrogen and androgen levels received therapy, so their hormone levels would be within the range of normal therapy and were randomly assigned to receive either a flexible dose of between 25 mg and 100 mg of sildenafil or placebo.15 In a third trial, postmenopausal women receiving estrogen hormone therapy and who had acquired sexual arousal disorder and impaired orgasm found that a single dose of 50 mg of sildenafil compared with placebo reduced orgasm latency and increased subjective arousal in those having the lowest vaginal pulse amplitude percentage change.16 In a fourth trial involving asymptomatic premenopausal women, a sildenafil-placebo crossover reported increased arousal and orgasm function.17 Case reports18 and open-label studies19 have also suggested efficacy for phosphodiesterase type 5 inhibitor treatment of women with sexual dysfunction associated with SRI treatment.

• Sildenafil is primarily approved for erectile dysfunction in men.
• Some studies explore its potential to treat female arousal disorder.
• Its use for women remains off-label in many regions.
• Long-term safety data for women is limited.

The objective of our current trial was to use a protocol—similar to our previous RCT11 involving men with sexual dysfunction associated with SRI treatment—to assess the efficacy of sildenafil in the treatment of women, specifically women whose major depressive order is in remission while taking a stable dose of SRI antidepressants and who did not have a preexisting sexual dysfunction but due to the treatment had sexual dysfunction manifest as dysfunction of orgasm (delay) or arousal (lubrication).5 Recognizing the importance of the hormonal variability on nitric oxide signaling in sexual function in women20 and depression on hypothalamic-pituitary–adrenal axis regulation,21 we also examined endocrine measures. The following were our specific aims: (1) to compare the efficacy of sildenafil with placebo for treatment of sexual dysfunction associated with SRI treatment in women with remitted major depressive disorder; (2) to determine whether sildenafil treatment is associated with change in depression severity; and (3) to compare adverse events occurring with sildenafil and placebo treatment.

4. Bottom Line

The study received an investigational new 200mg sildenafil citrate drug approvable letter from the FDA. Women were eligible if they (1) were between 18 and 50 years, (2) were premenopausal, (3) had a diagnosis of major depressive disorder in remission, (4) were taking an antidepressant with a selective or nonselective SRI mechanism for at least 8 weeks (at a stable dose for at least 4 weeks), and (5) were experiencing persistent sexual dysfunction for at least 4 weeks. Other eligibility criteria were good health, some form of regular sexual activity (ie, masturbation, oral sex, intercourse) at least twice monthly before the antidepressant treatment, willingness to continue efforts at sexual activity at least once weekly for the duration of the study, and satisfactory sexual function before onset of depression or antidepressant treatment. In addition, any prior sexual dysfunction must have been limited to previous episodes of depression or antidepressant treatment and must have remitted on clinical improvement and discontinuation of medication. Major depressive disorder in remission was diagnosed according to Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) (DSM-IV) criteria.22 Women had to score no more than 10 points on the Hamilton Rating Scale for Depression, which consists of 17 items that are clinician rated on a 5-point scale from 0 (absent) to 4 (severe).23 The remission threshold score of 10, rather than 7, was selected to adjust for sexual dysfunction associated with SRI treatment potentially inflating the score.24 In addition, women had to score no more than 10 on the Hamilton Rating Scale for Anxiety, indicating absence of significant symptomatic anxiety.25 Sexual dysfunction associated with SRI antidepressant treatment is defined by DSM-IV criteria for substance-induced sexual dysfunction,22 which includes impaired desire, arousal (lubrication), and orgasm and sexual pain.

Increased genital blood flow

Women had to have substantial impaired sexual function defined by at least 1 of the following criteria that caused significant distress: (1) inability to have an orgasm (anorgasmia), according to the woman's opinion; (2) clinically significant orgasm delay with masturbation or intercourse that, according to the woman's opinion, represents a meaningful delay compared with her usual time to achieve orgasm in response to sexual stimulation before antidepressant medication interfered with her sexual function; or (3) inability to attain or maintain until completion of sexual activity an adequate lubrication or swelling response of sexual excitement that, according to the woman's opinion, interferes with her sexual function (compared with before taking antidepressant medication). Women were excluded for any of the following reasons: diagnosis of a sexual disorder other than one associated with SRI treatment or onset of major depressive disorder, genital anatomical deformity, hysterectomy with or without oophorectomy, and at least 6 months of established normal sexual function after the procedure and before onset of depression and antidepressant treatment, uncontrolled psychiatric disorder, diabetes mellitus, cardiovascular disease, alcohol or substance abuse or dependence, stroke, unstable cardiac condition, arrhythmia, or myocardial infarction within the last 6 months, current or anticipated use of nitrate or nitric oxide donor in any form, major relationship changes, proliferative retinopathy, investigational drug use within 3 months, current use of other therapies or medications to treat sexual dysfunction, a sexual partner who has or is receiving treatment for sexual dysfunction, or change in SRI antidepressant agent or prescribed dose during the study.

Eur. Urol.

This prospective, parallel group, randomized, double-blind, placebo-controlled, 8-week trial to test the efficacy of a flexible dose of between 50 mg and 100 mg of sildenafil for sexual dysfunction in women was conducted from September 2003 to January 2007, at 7 US outpatient clinic medical centers. Each center's institutional review board approved the protocol.

• Some women report increased genital sensitivity after sildenafil.
• Research suggests possible benefits for women with vascular sexual dysfunction.
• Its use is still controversial and not widely recommended.
• Women should evaluate risks and benefits with their doctor.

Before enrollment, each woman provided written informed consent to the investigator, who had explained the nature, purpose, and risks of the trial and who provided her with a copy of the information sheets. The study received an investigational new 200mg sildenafil citrate drug approvable letter from the FDA. Women were eligible if they (1) were between 18 and 50 years, (2) were premenopausal, (3) had a diagnosis of major depressive disorder in remission, (4) were taking an antidepressant with a selective or nonselective SRI mechanism for at least 8 weeks (at a stable dose for at least 4 weeks), and (5) were experiencing persistent sexual dysfunction for at least 4 weeks. Other eligibility criteria were good health, some form of regular sexual activity (ie, masturbation, oral sex, intercourse) at least twice monthly before the antidepressant treatment, willingness to continue efforts at sexual activity at least once weekly for the duration of the study, and satisfactory sexual function before onset of depression or antidepressant treatment.

What Would Viagra Do to a Woman?

Anatomy and physiology of female sexual function and dysfunction: classification

Curr. Opin. Neurobiol.

In addition, any prior sexual dysfunction must have been limited to previous episodes of depression or antidepressant treatment and must have remitted on clinical improvement and discontinuation of medication. Major depressive disorder in remission was diagnosed according to Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) (DSM-IV) criteria.22 Women had to score no more than 10 points on the Hamilton Rating Scale for Depression, which consists of 17 items that are clinician rated on a 5-point scale from 0 (absent) to 4 (severe).23 The remission threshold score of 10, rather than 7, was selected to adjust for sexual dysfunction associated with SRI treatment potentially inflating the score.24 In addition, women had to score no more than 10 on the Hamilton Rating Scale for Anxiety, indicating absence of significant symptomatic anxiety.25 Sexual dysfunction associated with SRI antidepressant treatment is defined by DSM-IV criteria for substance-induced sexual dysfunction,22 which includes impaired desire, arousal (lubrication), and orgasm and sexual pain. Women had to have substantial impaired sexual function defined by at least 1 of the following criteria that caused significant distress: (1) inability to have an orgasm (anorgasmia), according to the woman's opinion; (2) clinically significant orgasm delay with masturbation or intercourse that, according to the woman's opinion, represents a meaningful delay compared with her usual time to achieve orgasm in response to sexual stimulation before antidepressant medication interfered with her sexual function; or (3) inability to attain or maintain until completion of sexual activity an adequate lubrication or swelling response of sexual excitement that, according to the woman's opinion, interferes with her sexual function (compared with before taking antidepressant medication). Women were excluded for any of the following reasons: diagnosis of a sexual disorder other than one associated with SRI treatment or onset of major depressive disorder, genital anatomical deformity, hysterectomy with or without oophorectomy, and at least 6 months of established normal sexual function after the procedure and before onset of depression and antidepressant treatment, uncontrolled psychiatric disorder, diabetes mellitus, cardiovascular disease, alcohol or substance abuse or dependence, stroke, unstable cardiac condition, arrhythmia, or myocardial infarction within the last 6 months, current or anticipated use of nitrate or nitric oxide donor in any form, major relationship changes, proliferative retinopathy, investigational drug use within 3 months, current use of other therapies or medications to treat sexual dysfunction, a sexual partner who has or is receiving treatment for sexual dysfunction, or change in SRI antidepressant agent or prescribed dose during the study.

Statistical Analysis

Sexual dysfunction is recognized as being associated with selective and nonselective serotonin reuptake inhibitor (SRI) antidepressants, which are the most frequently prescribed medications for outpatients aged 18 to 65 years and represent 90% of the 180 million antidepressant prescriptions filled in the United States.1 Antidepressant treatment–associated sexual dysfunction is estimated to occur in 30% to 70% of men and women treated for major depression with first- or second-generation agents,2 a principal reason for a 3-fold increased risk of nonadherence that approaches 70% in the first months of treatment and leads to increased relapse, recurrence, disability, and resource utilization by affected patients.3 However, the literature in this field is less developed for women with more highly variable prevalence rates and less conclusive data compared with men. In women, sexual dysfunction is associated with decreased sexual interest, genital sensitivity, and vaginal lubrication; delayed or absent orgasm; dyspareunia; reduced sexual activity; and overall dissatisfaction or loss of pleasure in sexual relations. Among the numerous strategies proposed for managing sexual dysfunction associated with SRI treatment, selective phosphodiesterase type 5 inhibitors, which have been limited to studies involving men, have demonstrated the best evidence-based data to support broad-based and clinically meaningful treatment efficacy.4 However, to our knowledge, no randomized controlled trial (RCT) has demonstrated effectiveness for women experiencing sexual dysfunction associated with SRI treatment. Compared with men, women are prescribed antidepressants at rates of 2 to 1 and can be expected to represent a significant number of patients needing relief.5 Without evidence-based data to treat sexual function associated with SRIs in women, clinicians may lack the confidence to manage it effectively, which leaves patients exposed to excess random pharmacology.6 Although sexual dysfunction is a major influence in determining the selection or switching of antidepressants, it is frequently overlooked because clinicians fail to inquire, misattribute it as a symptom of depression that will improve with treatment, or because 80% of women do not discuss adverse sexual effects with their physician.7,8 Sexual dysfunction associated with SRIs is dose related, usually occurs early in treatment, and rarely remits spontaneously. Selective phosphodiesterase type 5 inhibitors (sildenafil, vardenafil, tadalafil), which are effective and well tolerated for treatment of erectile dysfunction in men,9 including men with depression10 and associated with SRI treatment,11 are not approved by the US Food and Drug Administration (FDA) for women with sexual dysfunction.

Prevalence of and recent developments in female sexual dysfunction

However, interest in their potential use in women was encouraged by reports that nitric oxide synthase isoforms, nitric oxide, and phosphodiesterase type 5 inhibitors are present in female genital tissue, and phosphodiesterase type 5 inhibitor enhancement of nitric oxide–cyclic guanosine monophosphate in nonadrenergic-noncholinergic signaling for women seems similar to men.12 When several trials involving premenopausal and postmenopausal women treated with sildenafil failed to demonstrate significant improvements for sexual arousal disorder,13 the manufacturer abandoned pursuit of FDA approval for treating women. Subsequent RCTs narrowed their focus on more specific hormonal factors and demonstrated efficacy with improved frequency of sexual sildenafil citrate 120 mg intercourse, arousal, orgasm, and satisfaction. One trial involved premenopausal women with sexual arousal disorder but with normal sexual desire. They were randomized to receive 1 of 3 treatments: 25 mg or 50 mg of sildenafil or placebo.14 A protocol-specified trial involved premenopausal or postmenopausal women with sexual arousal disorder without concomitant hypoactive sexual desire disorder. Women with low baseline estrogen and androgen levels received therapy, so their hormone levels would be within the range of normal therapy and were randomly assigned to receive either a flexible dose of between 25 mg and 100 mg of sildenafil or placebo.15 In a third trial, postmenopausal women receiving estrogen hormone therapy and who had acquired sexual arousal disorder and impaired orgasm found that a single dose of 50 mg of sildenafil compared with placebo reduced orgasm latency and increased subjective arousal in those having the lowest vaginal pulse amplitude percentage change.16 In a fourth trial involving asymptomatic premenopausal women, a sildenafil-placebo crossover reported increased arousal and orgasm function.17 Case reports18 and open-label studies19 have also suggested efficacy for phosphodiesterase type 5 inhibitor treatment of women with sexual dysfunction associated with SRI treatment.

A Note on Gender and Sex Terminology

The objective of our current trial was to use a protocol—similar to our previous RCT11 involving men with sexual dysfunction associated with SRI treatment—to assess the efficacy of sildenafil in the treatment of women, specifically women whose major depressive order is in remission while taking a stable dose of SRI antidepressants and who did not have a preexisting sexual dysfunction but due to the treatment had sexual dysfunction manifest as dysfunction of orgasm (delay) or arousal (lubrication).5 Recognizing the importance of the hormonal variability on nitric oxide signaling in sexual function in women20 and depression on hypothalamic-pituitary–adrenal axis regulation,21 we also examined endocrine measures. The following were our specific aims: (1) to compare the efficacy of sildenafil with placebo for treatment of sexual dysfunction associated with SRI treatment in women with remitted major depressive disorder; (2) to determine whether sildenafil treatment is associated with change in depression severity; and (3) to compare adverse events occurring with sildenafil and placebo treatment. This prospective, parallel group, randomized, double-blind, placebo-controlled, 8-week trial to test the efficacy of a flexible dose of between 50 mg and 100 mg of sildenafil for sexual dysfunction in women was conducted from September 2003 to January 2007, at 7 US outpatient clinic medical centers. Each center's institutional review board approved the protocol. Before enrollment, each woman provided written informed consent to the investigator, who had explained the nature, purpose, and risks of the trial and who provided her with a copy of the information sheets.