Sildenafil cream demonstrates safety, efficacy in phase 2b study for female sexual arousal disorder
Systematic review for any protocol deviations in patient enrollment was undertaken before unbinding.
Author information
The 98 randomized women constituted the last-observation-carried-forward analysis.
| 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 |
Seventy-six women (77.6%) completed the study: with 75.5% (37 of 49) in the placebo group and 79.6% (39 of 49) in the sildenafil group and constituted the completer population. Nine women in the placebo group and 4 in the sildenafil group discontinued prematurely for lack of efficacy. The other 6 in sildenafil and 3 in the placebo groups were lost to follow-up. No discontinuations for intolerable or serious adverse events were reported (Figure). As determined by the inclusion criteria, the prevalence of sexual problems was high and the mean (SD) number of problems reported was 3.0 (0.7) for the sildenafil group and 2.8 (0.7) the placebo group (P = .21), with 95.8% of women reporting more than 1 complaint. They reported disturbances in desire (87.8%), subjective arousal (80.6%), lubrication (79.6%), orgasm delay (98.7%), and other difficulties (23.6%), which included anorgasmia, lack of pleasure, and pain. Prior to study entry, the women self-reported a mean (SD) of 6.0 (5.2) sexual attempts per month, of which 1.4 (2.0), or 29.6% (34.9%), were considered successful. There were no statistically significant differences between treatment groups in number or type of sexual problems or in number or percentage success of sexual attempts at baseline (Table 1).
| 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 |
The difference from baseline to end point in the mean (SD) change in the Clinical Global Impression scale sexual function improvement by intent-to-treat last-observation-carried-forward analyses (ie, lower ordinal score) was 4.8 (0.7) to 2.8 (1.0) with a difference of 1.91 (95% CI, 1.57-2.26) for the sildenafil group vs 4.7 (0.9) to 3.6 (0.9) with a difference of 1.10 (95% CI, 0.75-1.46) for the placebo group, which showed a significant difference of 0.8 (95% CI, 0.6-1.0, P = .001) between groups (Table 2). To adjust for potential bias introduced by patients who prematurely discontinued, a more conservative intent-to-treat analysis assigning return-to-baseline values carried forward of those who did not complete the study showed a baseline-to-end point mean difference in the Clinical Global Impression scores of 1.5 (95% CI, 1.1-1.9) among women taking sildenafil vs 0.9 (95% CI, 0.6-1.3) for women taking placebo and a significant 0.6 (95% CI, 0.3-0.8) mean change difference between groups (P = .03). Clinically, 73% of women taking placebo compared with 28% of women taking sildenafil reported no improvement with treatment (Clinical Global Impression score >3 was rated as no improvement). Sexual Function Questionnaires.Table 2 shows the mean (SD) scores on canadian sildenafil citrate the secondary outcome measures from baseline to study end for both treatment groups.
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In comparing the baseline sexual function questionnaire domain scores with those at the end of the study, women in the sildenafil group had a higher mean (SD) improvement (orgasm, P=.01) than women taking placebo for all domains except for pain. In the Arizona and the University of New Mexico questionnaires, the ability to reach orgasm and experience orgasm satisfaction was significantly better for those in the sildenafil group than for those in the placebo group for a mean difference from baseline of 0.5 (95% CI, 0.1-1.0; P = .01) for reaching orgasm for the Arizona questionnaire and 0.7 (95% CI, 0.1-1.3; P = .01) for the New Mexico questionnaire.
- Some women seek sildenafil for increasing genital blood flow and sensation.
- The placebo effect can influence perceived benefits in women using sildenafil.
- Women with cardiovascular risk should avoid sildenafil unless approved by a doctor.
- Topical or alternative therapies might be considered alongside or instead of sildenafil.
- Scientific consensus on sildenafil’s safety for women remains under development.
- Proper dosing and medical oversight are key to minimizing risks.
In measuring depression, at baseline, women in both groups had nearly identical Hamilton scores. At the end of the study, their scores remained similar (P=.90) indicating persisting remission in depression.
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Competing interests
Sexual Function after Spinal Cord Injury: Innervation, Assessment, and Treatment
The difference in change scores between treatment groups did not achieve statistical significance (P = .86). Among women who received treatment according to protocol, 3 women in the placebo group and 1 in the sildenafil group developed intermittent Hamilton depression scores of between 10 and 15. These were self-limited, transient, symptomatic changes distinguished from major depressive disorder relapse and not considered clinically meaningful to warrant intervention. No recurrence or relapse of major depressive disorder occurred in any of the women continuing a stable dose of antidepressants during the trial (Table 2). Mean (SD) baseline values for all endocrine values were within the normal range without significant differences between groups (Table 3). Independent of treatment assignment, a comparison of women whose sexual function improved with those whose sexual function did not improve showed higher mean baseline levels of free testosterone (P ≤ .01) and thyroxine sildenafil 25mg tablets (P ≤ .01) among SRI-associated sexual dysfunction treatment responders. At study end, 76.9% (30 of 39) of women took a mean (SD) dose of 91.7 (19.8) mg of sildenafil and 86.5% (32 of 37) took 93.1 (17.5) mg of placebo.
Material and methods
No serious adverse events related to trial medication were reported (Table 4). To our knowledge, this is the first randomized trial to demonstrate a significant reduction in adverse sexual effects, measured by the Clinical Global Impression sexual function, that compared sildenafil with placebo among women with SRI-associated sexual dysfunction, specifically including delayed orgasm responses and inadequate lubrication, while continuing stable-dose antidepressant treatment. These findings support earlier open-label reports involving women with SRI-associated sexual dysfunction and builds on the results of previous trials involving men, with benefits not limited to erectile function, and including delayed ejaculation or orgasm and satisfaction.11 These findings are important not only because women experience major depressive disorder at nearly double the rate of men5 and because they experience greater resulting sexual dysfunction than men31 but also because it establishes that selective phosphodiesterase type 5 inhibitors are effective in both sexes for this purpose. By treating this bothersome treatment-associated adverse effect in patients who have been effectively treated for depression, but need to continue on their medication to avoid relapse or recurrence, patients can remain antidepressant-adherent, reduce the current high rates of premature medication discontinuation, and improve depression disease management outcomes. Baseline pituitary, thyroid, adrenal, ovarian hormone, and sex hormone–binding globulin levels were within normal limits and were not different to a statistically significant extent between groups.
Exploratory Phase 2b RESPOND Study, Completed in 2023
It should be noted that the endocrine levels, especially those of the menstrual cycle, are estimates of general levels because they were taken in the follicular phase, when levels are at their nadir.32 Within this restriction, there were treatment differences due to assignment suggesting phosphodiesterase type 5 inhibitor treatment likely benefitted women with SRI-associated sexual dysfunction by reducing some of the confounds that women encountered in other trials; for example, low free-testosterone and hypoactive sexual desire,15 low estrogen–decreasing secretory lubrication,13 exogenous estrogen–increasing sex hormone–binding globulin and decreasing free testosterone, hypothyroid hyperprolactinemia–inhibiting neuronal nitric oxide–cyclic guanine monophosphate,33,34 mixed menopausal status, and other conditions that reportedly interfere with nitric-oxide synthase isoforms activating nitric oxide–cyclic guanine monophosphate and phosphodiesterase type 5 in female genital tissue.35 Independent of treatment assignment, a positive treatment response was associated with higher free testosterone and thyroxine. Secondary efficacy measures revealed improved orgasm delay with sildenafil treatment, which is considered a central feature of SRI-associated sexual dysfunction. Orgasm function has received far less attention than sexual arousal, perhaps due to erectile dysfunction being the only FDA indication and primary marketing focus for selective phosphodiesterase type 5 inhibitors. Significant improvement in orgasm function found in this trial is consistent with findings of improved orgasm in trials involving premenopausal and postmenopausal women with sexual arousal disorder,14,15,17 in open-label studies reporting reversal of delayed orgasm in SRI-associated sexual dysfunction,18,19 in trials involving men with erectile dysfunction,9 in trials that include treated or untreated depression,10,11 and in reports showing that enhanced nitergic activity (direct or indirect) can improve inadequate smooth muscle relaxation involved in orgasm delay with SRIs and serotonin norepinephrine reuptake inhibitors.36 Another consideration is whether the dose range of 50 mg to 100 mg of phosphodiesterase type 5 inhibitor was sufficient because reports on treating ejaculatory delay in men with SRI-associated sexual dysfunction suggest that higher doses of between 100 mg and 200 mg can be more effective.37,38 Independent of a significant effect on arousal in women with SRI-associated sexual dysfunction, it would seem unlikely for sexual function to globally improve without some effect on physiological sexual arousal, ie, lubrication, or tumescence. This study may not be generalizable to women who did not meet the criteria of this study.
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The maximum dose for the study was 100 mg. The mean (SD) number of doses per 2-week interval was 5.0 (2.5) mg for sildenafil and 5.2 (2.5) for placebo, which supports the notion that the lack of efficacy in placebo patients was not due to a lack of attempts (P = .67). The most common adverse event was headache, reported by 43% of women taking sildenafil and 27% taking placebo (P = .09). Less frequent were flushing, 24% vs 0% (P<.001); dyspepsia, 12% vs 0% (P = .01); nasal congestion, 37% vs 6% (P<.001); and transient visual disturbances, 14% vs 2% (P = .03), respectively. Adverse events more common in the placebo group than in the sildenafil group were nausea 16% vs 2% (P = .01) and anxiousness 6% vs 2% (P = .31).
| Side Effect | Severity | Frequency | Management Tips |
|---|---|---|---|
| Headache | Mild to moderate | Frequent | Hydration, pain relievers |
| Flushing | Mild | Common | Cooling measures |
| Nasal Congestion | Mild | Occasional | Decongestants |
| Dizziness | Mild | Less common | Sitting or lying down |
| Visual Disturbances | Rare | Rare | Seek medical attention |
No serious adverse events related to trial medication were reported (Table 4). To our knowledge, this is the first randomized trial to demonstrate a significant reduction in adverse sexual effects, measured by the Clinical Global Impression sexual function, that compared sildenafil with placebo among women with SRI-associated sexual dysfunction, specifically including delayed orgasm responses and inadequate lubrication, while continuing stable-dose antidepressant treatment. These findings support earlier open-label reports involving women with SRI-associated sexual dysfunction and builds on the results of previous trials involving men, with benefits not limited to erectile function, and including delayed ejaculation or orgasm and satisfaction.11 These findings are important not only because women experience major depressive disorder at nearly double the rate of men5 and because they experience greater resulting sexual dysfunction than men31 but also because it establishes that selective phosphodiesterase type 5 inhibitors are effective in both sexes for this purpose.
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Systematic review for any protocol deviations in patient enrollment was undertaken before unbinding. The 98 randomized women constituted the last-observation-carried-forward analysis. Seventy-six women (77.6%) completed the study: with 75.5% (37 of 49) in the placebo group and 79.6% (39 of 49) in the sildenafil group and constituted the completer population. Nine women in the placebo group and 4 in the sildenafil group discontinued prematurely for lack of efficacy. The other 6 in sildenafil and 3 in the placebo groups were lost to follow-up.
Erectile dysfunction
No discontinuations for intolerable or serious adverse events were reported (Figure). As determined by the inclusion criteria, the prevalence of sexual problems was high and the mean (SD) number of problems reported was 3.0 (0.7) for the sildenafil group and 2.8 (0.7) the placebo group (P = .21), with 95.8% of women reporting more than 1 complaint. They reported disturbances in desire (87.8%), subjective arousal (80.6%), lubrication (79.6%), orgasm delay (98.7%), and other difficulties (23.6%), which included anorgasmia, lack of pleasure, and pain. Prior to study entry, the women self-reported a mean (SD) of 6.0 (5.2) sexual attempts per month, of which 1.4 (2.0), or 29.6% (34.9%), were considered successful. There were no statistically significant differences between treatment groups in number or type of sexual problems or in number or percentage success of sexual attempts at baseline (Table 1).
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The difference from baseline to end point in the mean (SD) change in the Clinical Global Impression scale sexual function improvement by intent-to-treat last-observation-carried-forward analyses (ie, lower ordinal score) was 4.8 (0.7) to 2.8 (1.0) with a difference of 1.91 (95% CI, 1.57-2.26) for the sildenafil group vs 4.7 (0.9) to 3.6 (0.9) with a difference of 1.10 (95% CI, 0.75-1.46) for the placebo group, which showed a significant difference of 0.8 (95% CI, 0.6-1.0, P = .001) between groups (Table 2). To adjust for potential bias introduced by patients who prematurely discontinued, a more conservative intent-to-treat analysis assigning return-to-baseline values carried forward of those who did not complete the study showed a baseline-to-end point mean difference in the Clinical Global Impression scores of 1.5 (95% CI, 1.1-1.9) among women taking sildenafil vs 0.9 (95% CI, 0.6-1.3) for women taking placebo and a significant 0.6 (95% CI, 0.3-0.8) mean change difference between groups (P = .03). Clinically, 73% of women taking placebo compared with 28% of women taking sildenafil reported no improvement with treatment (Clinical Global Impression score >3 was rated as no improvement). Sexual Function Questionnaires.Table 2 shows the mean (SD) scores on canadian sildenafil citrate the secondary outcome measures from baseline to study end for both treatment groups. In comparing the baseline sexual function questionnaire domain scores with those at the end of the study, women in the sildenafil group had a higher mean (SD) improvement (orgasm, P=.01) than women taking placebo for all domains except for pain. By treating this bothersome treatment-associated adverse effect in patients who have been effectively treated for depression, but need to continue on their medication to avoid relapse or recurrence, patients can remain antidepressant-adherent, reduce the current high rates of premature medication discontinuation, and improve depression disease management outcomes. Baseline pituitary, thyroid, adrenal, ovarian hormone, and sex hormone–binding globulin levels were within normal limits and were not different to a statistically significant extent between groups. It should be noted that the endocrine levels, especially those of the menstrual cycle, are estimates of general levels because they were taken in the follicular phase, when levels are at their nadir.32 Within this restriction, there were treatment differences due to assignment suggesting phosphodiesterase type 5 inhibitor treatment likely benefitted women with SRI-associated sexual dysfunction by reducing some of the confounds that women encountered in other trials; for example, low free-testosterone and hypoactive sexual desire,15 low estrogen–decreasing secretory lubrication,13 exogenous estrogen–increasing sex hormone–binding globulin and decreasing free testosterone, hypothyroid hyperprolactinemia–inhibiting neuronal nitric oxide–cyclic guanine monophosphate,33,34 mixed menopausal status, and other conditions that reportedly interfere with nitric-oxide synthase isoforms activating nitric oxide–cyclic guanine monophosphate and phosphodiesterase type 5 in female genital tissue.35 Independent of treatment assignment, a positive treatment response was associated with higher free testosterone and thyroxine.
- Sildenafil is often known by the brand name Viagra, primarily for men.
- Researchers are exploring other PDE5 inhibitors for women’s sexual health.
- Efficacy of sildenafil in women might depend on underlying health conditions.
- Women with cardiovascular issues should be particularly cautious with sildenafil.
- Some women report increased sexual satisfaction after using sildenafil.
- Medical advice is crucial before women consider sildenafil as a treatment.
Secondary efficacy measures revealed improved orgasm delay with sildenafil treatment, which is considered a central feature of SRI-associated sexual dysfunction. Orgasm function has received far less attention than sexual arousal, perhaps due to erectile dysfunction being the only FDA indication and primary marketing focus for selective phosphodiesterase type 5 inhibitors.
- Female patients should be cautious with sildenafil due to lack of approval.
- Erectile dysfunction medications can interact with other drugs, affecting women as well.
- Some studies suggest sildenafil may help women with arousal issues but are inconclusive.
- Sildenafil may improve clitoral blood flow, enhancing sensitivity.
- Libido enhancement from sildenafil varies based on individual health factors.
- Self-medicating women with sildenafil without supervision can be risky.
Significant improvement in orgasm function found in this trial is consistent with findings of improved orgasm in trials involving premenopausal and postmenopausal women with sexual arousal disorder,14,15,17 in open-label studies reporting reversal of delayed orgasm in SRI-associated sexual dysfunction,18,19 in trials involving men with erectile dysfunction,9 in trials that include treated or untreated depression,10,11 and in reports showing that enhanced nitergic activity (direct or indirect) can improve inadequate smooth muscle relaxation involved in orgasm delay with SRIs and serotonin norepinephrine reuptake inhibitors.36 Another consideration is whether the dose range of 50 mg to 100 mg of phosphodiesterase type 5 inhibitor was sufficient because reports on treating ejaculatory delay in men with SRI-associated sexual dysfunction suggest that higher doses of between 100 mg and 200 mg can be more effective.37,38 Independent of a significant effect on arousal in women with SRI-associated sexual dysfunction, it would seem unlikely for sexual function to globally improve without some effect on physiological sexual arousal, ie, lubrication, or tumescence.
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In the Arizona and the University of New Mexico questionnaires, the ability to reach orgasm and experience orgasm satisfaction was significantly better for those in the sildenafil group than for those in the placebo group for a mean difference from baseline of 0.5 (95% CI, 0.1-1.0; P = .01) for reaching orgasm for the Arizona questionnaire and 0.7 (95% CI, 0.1-1.3; P = .01) for the New Mexico questionnaire. In measuring depression, at baseline, women in both groups had nearly identical Hamilton scores. At the end of the study, their scores remained similar (P=.90) indicating persisting remission in depression. The difference in change scores between treatment groups did not achieve statistical significance (P = .86). Among women who received treatment according to protocol, 3 women in the placebo group and 1 in the sildenafil group developed intermittent Hamilton depression scores of between 10 and 15.
Sexual Health in the Neurogenic Patient
These were self-limited, transient, symptomatic changes distinguished from major depressive disorder relapse and not considered clinically meaningful to warrant intervention. No recurrence or relapse of major depressive disorder occurred in any of the women continuing a stable dose of antidepressants during the trial (Table 2). Mean (SD) baseline values for all endocrine values were within the normal range without significant differences between groups (Table 3). Independent of treatment assignment, a comparison of women whose sexual function improved with those whose sexual function did not improve showed higher mean baseline levels of free testosterone (P ≤ .01) and thyroxine sildenafil 25mg tablets (P ≤ .01) among SRI-associated sexual dysfunction treatment responders. At study end, 76.9% (30 of 39) of women took a mean (SD) dose of 91.7 (19.8) mg of sildenafil and 86.5% (32 of 37) took 93.1 (17.5) mg of placebo.
Drug information
The maximum dose for the study was 100 mg. The mean (SD) number of doses per 2-week interval was 5.0 (2.5) mg for sildenafil and 5.2 (2.5) for placebo, which supports the notion that the lack of efficacy in placebo patients was not due to a lack of attempts (P = .67). The most common adverse event was headache, reported by 43% of women taking sildenafil and 27% taking placebo (P = .09). Less frequent were flushing, 24% vs 0% (P<.001); dyspepsia, 12% vs 0% (P = .01); nasal congestion, 37% vs 6% (P<.001); and transient visual disturbances, 14% vs 2% (P = .03), respectively. Adverse events more common in the placebo group than in the sildenafil group were nausea 16% vs 2% (P = .01) and anxiousness 6% vs 2% (P = .31). This study may not be generalizable to women who did not meet the criteria of this study.