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

aDepartment of Microbiological Science and Gynaecological Science, School of Medicine, University of Catania, Catania, Italy bResearch Group for Sexology, School of Medicine, University of Catania, Catania, Italy Received June 18, 2005; Revised October 5, 2005; Accepted October 5, 2005; Published online March 30, 2006 DOI: 10.1016/j.fertnstert.2005.10.043 External LinkAlso available on ScienceDirect External Link Copyright: © 2006 American Society for Reproductive Medicine. There is evidence that women with sexual dysfunction will commonly have physiologic abnormalities such as vasculogenic dysfunction (1) or diabetes (2) that contribute to their overall sexual health problems. The sexual function of diabetic women has received little attention in clinical research, even though diabetes recently has been shown to increase the risk of female sexual dysfunction (3, 4). In diabetic rats, diabetes induces vaginal tissue fibrosis and adverse effects on the hemodynamic mechanism of clitoral engorgement (5). Diabetic women could have decreased sexual desire depending on the indirect effect of diabetes resulting from the increased prevalence of depression (6). On the other hand, changes in sexual genital pathways such as diminished clitoral sensation, vaginal dryness, vaginal discomfort, orgasmic dysfunction, and dyspareunia might be the mechanisms that involve damage to the vascular and autonomic nervous system (4, 7) and cause alterations in the nitric oxide (NO) production and its efficacy (8). The most commonly reported sexual problem in women with diabetes is sexual arousal disorder (SAD) (4, 9). Physiologically, in the sexual arousal phase, sexual excitement is accompanied by pelvic vasocongestion and swelling of the external genitalia, including clitoral and vaginal engorgement; clitoral engorgement appears to be mainly a hemodynamic phenomenon characterized by smooth muscle relaxation (10–12). Diabetes is usually associated with atherosclerosis and microangiopathy (13), and diabetic subjects may have chronic cavernous arterial insufficiency. This could also be the case of male erectile dysfunction (ED). Men with diabetes have an approximately threefold higher risk for ED than men without diabetes (14). The pathophysiology of ED in diabetic men is known to be related to vascular and neuronal origin (15). In male rabbits, diabetes produces penile cavernous trabecular smooth muscle fibrosis based on the degree of hyperglycemia (16). Several pharmacological agents, some with central-acting mechanisms and some with locally acting vascular effects, are therapeutically useful in the treatment of ED (17). Selective phosphodiesterase type 5 (PDE5) inhibitors, taken orally, are effective for men with ED and concomitant type 1 diabetes (18–21). Previous studies suggested that sildenafil, which acts by inhibiting cyclic GMP-specific PDE5, may improve the sexual health of women affected by sexual difficulties such as arousal disorders and may indirectly improve other aspects of sexual life (22, 23). Because subjects affected by chronic illness such as diabetes may suffer from a sexual dysfunction due to neurovascular alterations, research needs to be carried out to find drugs that are effective in treating the pathological effects to improve the quality of sexual life. This double-blind crossover placebo-controlled study was designed to determine whether sildenafil, taken orally, was able to improve sexual genital arousal in type 1 diabetic women with SAD using subjective and objective instruments to measure the efficacy of the drug.

• Female sexual dysfunction affects millions worldwide, prompting research into treatments.
• Sildenafil is part of a broader conversation about women’s sexual health innovations.
• The role of sildenafil in improving orgasm quality is still being studied.
• It is essential to distinguish between clinical trial results and off-label use.
• Some women experience mood improvement alongside physical effects with sildenafil.
• Education about both benefits and risks is crucial for women considering sildenafil.

This was an independent study performed at the Research Group for Sexology of the Department of Microbiological and Gynaecological Science, School of Medicine, University of Catania, Catania, Italy. The Institutional Review Board of the department approved the study.

Thus 36 consecutive premenopausal women aged 27–43 years, with a mean age (±SD) of 34 (±3.6) and a body mass index of 25.3 ± 3.8, affected by type 1 diabetes that was being treated with insulin therapy, and visiting the outpatient Sexology Service for SAD were invited to participate. All the subjects gave their written informed consent before entering the study, which was conducted in accordance with the Helsinki Declaration. However, the subjects could terminate participation at any time.

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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 study was not advertised, and no remuneration was offered. The sample consisted of volunteers who had had a stable, satisfying heterosexual relationship for at least 6 month and subjectively normal sexual desire toward their partners (see Instruments section).

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.

Related questions

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. To confirm the ovulatory cycle, ultrasound was performed on days 10, 12, and 15 of the sildenafil citrate 150 mg red pill cycle and serum P concentrations were measured at days 21 and 25 of the cycle.

Efficacy of Sildenafil Citrate on Female Sexual Dysfunction in A Sample of Egyptian Females, A Prospective Placebo Controlled Study

Men with diabetes have an approximately threefold higher risk for ED than men without diabetes (14). The pathophysiology of ED in diabetic men is known to be related to vascular and neuronal origin (15). In male rabbits, diabetes produces penile cavernous trabecular smooth muscle fibrosis based on the degree of hyperglycemia (16). Several pharmacological agents, some with central-acting mechanisms and some with locally acting vascular effects, are therapeutically useful in the treatment of ED (17). Selective phosphodiesterase type 5 (PDE5) inhibitors, taken orally, are effective for men with ED and concomitant type 1 diabetes (18–21).

What special precautions should I follow?

Previous studies suggested that sildenafil, which acts by inhibiting cyclic GMP-specific PDE5, may improve the sexual health of women affected by sexual difficulties such as arousal disorders and may indirectly improve other aspects of sexual life (22, 23). Because subjects affected by chronic illness such as diabetes may suffer from a sexual dysfunction due to neurovascular alterations, research needs to be carried out to find drugs that are effective in treating the pathological effects to improve the quality of sexual life. This double-blind crossover placebo-controlled study was designed to determine whether sildenafil, taken orally, was able to improve sexual genital arousal in type 1 diabetic women with SAD using subjective and objective instruments to measure the efficacy of the drug. This was an independent study performed at the Research Group for Sexology of the Department of Microbiological and Gynaecological Science, School of Medicine, University of Catania, Catania, Italy. The Institutional Review Board of the department approved the study. 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). 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. Hormones were sampled during the morning on cycle days 12–17.

Why is this medicine prescribed?

Thus 36 consecutive premenopausal women aged 27–43 years, with a mean age (±SD) of 34 (±3.6) and a body mass index of 25.3 ± 3.8, affected by type 1 diabetes that was being treated with insulin therapy, and visiting the outpatient Sexology Service for SAD were invited to participate. All the subjects gave their written informed consent before entering the study, which was conducted in accordance with the Helsinki Declaration. However, the subjects could terminate participation at any time. The study was not advertised, and no remuneration was offered. The sample consisted of volunteers who had had a stable, satisfying heterosexual relationship for at least 6 month and subjectively normal sexual desire toward their partners (see Instruments section).

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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 sildenafil citrate 150 mg red pill 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). Plasma T and PRL were measured using sildenafil citrate tablets for female 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.

• Sildenafil is a medication primarily used to treat erectile dysfunction in men.
• Women sildenafil is an off-label use aimed at improving female sexual arousal.
• Clinical trials are ongoing to assess efficacy of sildenafil for women.
• Side effects of sildenafil may include headaches, flushing, and nasal congestion.
• Women may experience increased blood flow and libido with sildenafil.
• Proper dosage and medical consultation are essential before use.

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. 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). Using the PEQ, it was possible to assess the efficacy of each treatment with respect to baseline values.

Is Viagra an Option for Female Sexual Dysfunction?

aDepartment of Microbiological Science and Gynaecological Science, School of Medicine, University of Catania, Catania, Italy bResearch Group for Sexology, School of Medicine, University of Catania, Catania, Italy Received June 18, 2005; Revised October 5, 2005; Accepted October 5, 2005; Published online March 30, 2006 DOI: 10.1016/j.fertnstert.2005.10.043 External LinkAlso available on ScienceDirect External Link Copyright: © 2006 American Society for Reproductive Medicine. There is evidence that women with sexual dysfunction will commonly have physiologic abnormalities such as vasculogenic dysfunction (1) or diabetes (2) that contribute to their overall sexual health problems. The sexual function of diabetic women has received little attention in clinical research, even though diabetes recently has been shown to increase the risk of female sexual dysfunction (3, 4). In diabetic rats, diabetes induces vaginal tissue fibrosis and adverse effects on the hemodynamic mechanism of clitoral engorgement (5). Diabetic women could have decreased sexual desire depending on the indirect effect of diabetes resulting from the increased prevalence of depression (6).

A Note on Gender and Sex Terminology

On the other hand, changes in sexual genital pathways such as diminished clitoral sensation, vaginal dryness, vaginal discomfort, orgasmic dysfunction, and dyspareunia might be the mechanisms that involve damage to the vascular and autonomic nervous system (4, 7) and cause alterations in the nitric oxide (NO) production and its efficacy (8). The most commonly reported sexual problem in women with diabetes is sexual arousal disorder (SAD) (4, 9). Physiologically, in the sexual arousal phase, sexual excitement is accompanied by pelvic vasocongestion and swelling of the external genitalia, including clitoral and vaginal engorgement; clitoral engorgement appears to be mainly a hemodynamic phenomenon characterized by smooth muscle relaxation (10–12). Diabetes is usually associated with atherosclerosis and microangiopathy (13), and diabetic subjects may have chronic cavernous arterial insufficiency. This could also be the case of male erectile dysfunction (ED). 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. Ultrasound was performed using a SonoAce 8800 (Medison Co., Seoul, Korea) with 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.

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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.

Raynaud's phenomenon

Hormones were sampled during the morning on cycle days 12–17. Plasma T and PRL were measured using sildenafil citrate tablets for female 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. 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. 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.

What are the potential side effects of Viagra for women?

Ultrasound was performed using a SonoAce 8800 (Medison Co., Seoul, Korea) with 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.

Study Design

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). 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). 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.