Safety and Efficacy of Sildenafil Citrate for the Treatment of Female Sexual Arousal Disorder: A Double-Blind, Placebo Controlled Study

The PEQ was used at baseline, at the washout, and after treatments. Arterial clitoral color Doppler ultrasound was performed at baseline and during the usage of drugs. All adverse events reported by the woman were recorded, irrespective of any random relationship with the study drug. Intention-to-treat analyses were performed for all efficacy variables and included all patients who had a baseline evaluation and had at least one efficacy assessment after the baseline visit.

Key takeaways:

Each woman took sildenafil or placebo 1 sildenafil citrate tablets 150 mg hour before each sexual intercourse. The usage of the drug was not more than once daily. Each woman received each treatment for 8-week periods. There was a 7-day washout period between treatments. We chose a 1-week washout period on the basis of our previous studies using a similar intervention by which we did not observe any carryover effect (22, 34). We included in the analysis the subjects that had missing information on one or more questionnaire items.

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The last observation carried forward was used to select data such that missing data were replaced by values from the last available assessment during treatment before the respective assessment. Furthermore, women who stopped treatment for adverse events were included in the analysis.

• Some studies suggest sildenafil might help women with sexual arousal disorder.
• The drug's vasodilating effects can have cardiovascular implications in women.
• Women should be cautious of counterfeit or unapproved sildenafil products.
• Combining sildenafil with other ED drugs in women is not recommended without medical advice.
• Psychological support remains an important aspect of treating female sexual dysfunction.
• Ongoing clinical trials aim to establish the safety and efficacy of sildenafil for women.

For comparisons among baseline, sildenafil 100 mg, and placebo sexual PEQ scores, the nonparametric Wilcoxon’s rank-sum test was used. Separate analyses were performed for the arousal score (primary end point) and desire, orgasm, enjoyment of sexual activities, satisfaction with frequency, and frequency of intercourse.

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A double-blind, crossover, placebo-controlled study design was performed. The efficacy of treatment was the primary end point based on the proportion of successful attempts, defined as sexual arousal levels, occurring after dosing. Safety was considered a further end point of this study, data being collected throughout the study period, and included recording adverse events, vital signs, and changes in laboratory test values for standard hematology and biochemistry variables. Patients provided information recorded on diary cards and were reviewed at each study visit concerning sexual activity. After defining inclusion criteria at the screening, according to a computer-generated list of random number groups, each woman was randomly allocated to one of the two possible sequences, each of which constituted two medication series: sildenafil 100 mg/placebo (A sequence) and placebo/sildenafil 100 mg (B sequence).

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Women were assessed before being treated and during each treatment by one investigator. Both the woman and the attending doctor carrying out the procedure were blinded to the two drugs. The investigator was not involved in the recruitment of the women and did not know the computer-generated randomization list and the assignment of the treatment group according to the sequence of recruitment. The codes were broken after the study was completed. The crossover study design was used to define whether the treatment with sildenafil was effective with respect to placebo. Paired Student’s t-test was performed to compare changes between baseline sildenafil and placebo values of clitoral arterial blood flow. Considering the order in which the treatments were allocated, data was analyzed by Student’s t-test, using the Bonferroni method of correction for multiple comparisons if a significant F ratio was found. Statistical analysis was carried out using the Primer of Biostatistics statistical computer package (29). Of the 36 women enrolled in the study, 32 women aged 27–41 with a mean age (±SD) of 33 (±3.1) and a BMI 25.0 ± 3.5 provided information at each treatment to be included in the analyses. Four women were excluded after assessment at baseline: [1] two for anovulatory cycles and [2] two for refused treatment. The mean duration of diabetes was 12.1 ± 8.5 years, and the mean HbA1c value was 8.0% ± 1.8%. Plasma concentrations of T (0.4 ± 0.6 ng/mL; normal range, 0.3–1.2 ng/mL), FT (1.3 ± 0.7 pg/mL; normal range, 0.3–3.2 sildenafil 100mg hexal pg/mL)19, and PRL (10.5 ± 3.5 ng/mL; normal range, 5–25 ng/mL) were normal.

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Moreover, 4 (12.5%) of 32 women in the B sequence did not complete the study for adverse events, all during sildenafil usage. They stopped taking the drug for [1] headache, vision problems, and nausea (n = 1), [2] vision problem and headache (n = 1), and [3] headache and nausea (n = 2). Therefore, the incidences of the most commonly recorded adverse events reported by subjects during the use of sildenafil were headache (12.5%), nausea (6.2%), and vision problem (6.2%).

Medical uses

Women with dysphoric arousal, a sensation of unpleasant genital engorgement (25), were excluded from the study. The American Foundation for Urologic Disease definition of Female Sexual Function Disorders (26) was used to define SAD, that is, the persistent or recurring inability to attain or maintain sufficient sexual excitement, causing personal distress, which may be expressed as a lack of subjective excitement or genital (lubrication/swelling) or other somatic responses. The women with acquired sexual dysfunction and SAD were the focus of our study. Finally, one of our hypotheses was that if arousal were enhanced, orgasm could possibly be facilitated. To measure sexuality we used the Personal Experiences Questionnaire (PEQ) (27), a self-reporting questionnaire based on the McCoy Female Sexuality Questionnaire (28).

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Using the PEQ, it was possible to assess the efficacy of each treatment with respect to baseline values. Qualitative items were answered on a 5-point Likert scale, ranging from 1, not at all, to 5, a great deal. Quantitative items were answered as 0, never; 1, less than once a week; 2, once or twice a week; 3, several times a week; 4, once a day/sometimes twice; and 5, several times a day. The PEQ was completed by each woman and handed back to the fieldworker. Finally, each woman underwent color Doppler ultrasound to measure clitoral blood flow.

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Ultrasound was performed using a SonoAce 8800 (Medison Co., Seoul, Korea) with sildenafil 12 5 mg a 7.5-MHz linear transducer by the same investigator. Each woman was scanned in the gynecological position. The Doppler translabial probe was placed sagittally on the clitoris at an angle of <20 degrees, without exerting any significant pressure on the tissues. After identifying the clitoral artery using color flow mapping, the Doppler probe was positioned over the vessel and at least three sequential Doppler waveforms were obtained. The peak systolic velocity (PSV), the end diastolic velocity (EDV), the resistance index (RI = PSV − EDV/PSV), and the pulsatility index (PI = PSV − EDV/mean flow velocity of clitoral artery) were calculated. Each adverse event was predominantly transient and mild in nature.

OUR PRE-FULFILLMENT PRESCRIPTION PERIOD HAS BEGUN.

Women were excluded from the study if they had a history of hypertension, coronary artery disease, or thromboembolic disorder; impaired hepatic and renal function and neoplasia; were taking hormone therapy or oral contraceptives; had a history of smoking and alcohol abuse; did not have a sexual partner; were affected by situational sexual dysfunction with their partner; or had a partner with sexual dysfunction. All patients admitted to the screening phase had regular menstrual cycles (mean cycle length 26.7 ± 4.2 days), with ovulation. To confirm the ovulatory cycle, ultrasound was performed on days 10, 12, and 15 of the cycle and serum P concentrations were measured at days 21 and 25 of the cycle. Menstrual cycle was defined as ovulatory when the serum P was >18 IU/mL. The P level was measured using commercially available enzyme-linked immunoassorbent assay (ELISA) kits (Elecsys System 2010; Roche, Monza, Italy).

Regional issues

Moreover, during the screening period subjects underwent a physical examination, including assessment of vital signs and an ECG. A venous blood sample was collected on the day of enrollment to determine hemoglobin glycosylated (HbA1c). HbA1c was determined using the Cobas Integra assay (Roche, Basel, Switzerland), where the normal rage is 4.0%–6.0%. Subjects with HbA1c ≥10% were excluded from the study because they were considered to be affected by diabetes that was not well-controlled. Blood samples were obtained from all study participants to measure hormonal levels of T, FT, and PRL.

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Hormones were sampled during the morning on cycle days 12–17. Plasma T and PRL were measured using commercially available ELISA kits (Elecsys Systems 2010). Plasma levels of FT were also measured using ELISA kits (DSX System; DRG Instruments GmbH, Marburg/Lahn, Germany). Each woman underwent a Sexual History Interview (SHI) (24) that was conducted in a private room alone with the female sexual disorder therapist: 60–90 minutes were needed for the interview, and 15–30 minutes to write the justification. Information was sought about any changes in number of sexual fantasies and arousal and about other sexual experiences such as orgasmic and coital frequency and enjoyment of sexual activities. During the study, each women had well-controlled diabetes.

• Clinical research into sildenafil for women includes various dosage trials.
• Women using sildenafil should monitor blood pressure to avoid adverse effects.
• The safety profile of sildenafil in women is less documented than in men.
• Sildenafil’s impact on female sexual desire is still under scientific investigation.
• Women should avoid sildenafil if pregnant or breastfeeding unless prescribed.
• Alternative therapies for female sexual dysfunction include counseling and hormone therapy.

The mean HbA1c value obtained during each treatment was similar to that observed at baseline (P=NS). The BMI did not show any significant variation with respect to baseline values (P=NS). The sexual interview showed that the mean duration of sexual dysfunction was 3.5 years (range, 2.2–4.5 years). Subjects mainly reported arousal and orgasm difficulties and dyspareunia. Moreover, they reported a decrease in sexual satisfaction and in sexual activity. The mean (±SD) usage of sildenafil and placebo was, respectively, 2.1 (±0.4) and 2.9 (±0.4) times weekly. It is interesting to note that all women recorded using each drug for all sexual activities. Changes in sexuality produced by drug administrations were noticed though the analysis of PEQ items. Table 1 shows the changes from baseline of qualitative and quantitative sexual behaviors according to the treatment and the efficacy of sildenafil and placebo. Data indicate that sildenafil improved [1] the experience of arousal (P<.001), orgasm (P<.001), and enjoyment (P<.001) with respect to baseline; and [2] the experience of arousal (P<.01) and orgasm (P<.05) with respect to placebo.

Parameter	Description	Typical Values	Notes
Absorption Rate	Time to reach peak plasma levels	30-120 minutes	Varies with food intake
Half-Life	Duration of drug activity	4 hours	Metabolized mainly in liver
Bioavailability	Percentage of drug absorbed	40-50%	Affected by gastric pH
Metabolism	Enzymes involved	CYP3A4	Liver metabolism mainly
Excretion	How drug is eliminated	Feces and urine	Mainly fecal excretion