The Effect of Sildenafil Citrate on Uterine and Clitoral Arterial Blood Flow in Postmenopausal Women

Abstract

Objective

The aim of this study was to determine the effect of sildenafil on the uterine circulation and clitoral artery blood flow in postmenopausal women using color Doppler sonography.

Methods

The study population consisted of 25 volunteer naturally postmenopausal women (mean age, 50.2 ± 3.6 years). Color Doppler sonography was performed to measure the resistance and pulsatility indexes of the uterine arteries and peak systolic velocity, resistance, and pulsatility indexes of the clitoral arteries. One hour after administration of a single oral dose of 50 mg sildenafil citrate, the Doppler sonographic examination was repeated.

Results

After sildenafil administration, the mean resistance and pulsatility indexes of uterine artery were significantly lower (0.73 ± 0.08 vs 0.80 ± 0.07, P < .001 and 1.66 ± 0.50 vs 2.08 ± 0.52, P < .001, respectively) in comparison to baseline values, and the mean peak systolic velocity of clitoral artery was significantly higher (17.9 ± 8.6 cm/sec vs 12.9 ± 5.8 cm/sec, P < .001). Sildenafil did not cause any significant change in the mean resistance and pulsatility indexes of the clitoral artery (P = .683 and P = .714, respectively).

Conclusion

Sildenafil improves the clitoral and uterine blood flow in healthy postmenopausal women without any erotic stimulus. Further studies are needed to determine whether there are roles for sildenafil therapy in postmenopausal women and evaluation of clitoral blood flow by Doppler sonography.

Introduction

Female sexual dysfunction (FSD) is a multicausal and prevalent problem that can significantly affect the quality of life and interpersonal relationships of postmenopausal women.[1,2] Aging and the decline of ovarian hormonal secretion during the menopausal transition may alter libido and sexual response and functioning.[3-5] This decline relates more to decreasing estradiol concentrations than to androgen levels.[6] In addition to hormonal changes, chronic diseases and medications may also negatively affect vascular response of the end genital organs. Potential therapeutic options for some categories of FSD include hormonal and pharmacologic agents.[7-9] Since nitric oxide (NO) synthase isoforms have been identified in the uterine[10] and clitoral tissues,[11] the NO–cyclic guanosine monophosphate (cGMP) pathway, which is involved in penile erection and enhanced by sildenafil,[12,13] may also play a role in some components of female sexual arousal response. Sildenafil has been demonstrated to be safe and effective in treatment of male erectile dysfunction.[13,14] However, there are little data about the influence of sildenafil on vascular hemodynamics of genital tissues in women. A single randomized placebo-controlled trial of sildenafil treatment for female sexual arousal disorder (FSAD) in postmenopausal women suggests that the agent may be effective for a select population of women (ie, without concomitant lack of sexual desire or contributory emotional, relationship, or historical abuse issues).[15] Pfizer, the company that developed the drug, however, decided against seeking regulatory approval for its use in the treatment of FSAD because several large-scale placebo-controlled studies yielded inconclusive results.[16]

Measuring penile blood flow by color Doppler sonography has become a first-line test for evaluation of erectile dysfunction,[17] which is considered the male analogue to some components of FSAD. Clitoral blood flow measurements by color Doppler sonography may also be a reliable method to assess female sexual response.[18] The purpose of this study was to determine the effect of sildenafil on the uterine circulation and clitoral artery blood flow in postmenopausal women, by color Doppler ultrasound.

Materials and Methods

A total of 25 healthy postmenopausal women who had not undergone a hysterectomy, with a mean age of 50.2 ± 3.6 years (age range, 43-58 years), enrolled in this study. All participants had been amenorrheic for a minimum of 6 months before entering the study and had a high plasma level of follicle-stimulating hormone (FSH > 40 mIU/mL). The study population was drawn from patients undergoing routine gynecologic sonographic examination for measurement of endometrial thickness during a 5-month period. Exclusion criteria included significant cardiovascular disease, history of stroke or myocardial infarction, nitrate therapy or use of any cardiovascular medication, hypotension (blood pressure < 90/50 mm Hg), serious liver disease or renal failure, poorly controlled diabetes mellitus, history of alcohol or substance abuse, gynecologic operative intervention, morbid obesity, and history of using hormone replacement therapy. Informed consent was obtained from each participant after a detailed explanation of the procedure. Approval for the study was obtained from the Ethics Committee of our Faculty of Medicine.

Doppler sonography measurements were performed using a commercially available color Doppler scanner (Logic 500 Pro, General Electric, Milwaukee, Wisconsin) with a 6.0 to 9.0-MHz linear transducer for the clitoral arteries and a 2.0 to 5.0-MHz transabdominal convex transducer for the uterine arteries. The measurements were performed by the same investigator immediately before and 1 hour after administration of a single oral dose of 50 mg sildenafil citrate (Viagra, Pfizer, Inc, New York, NY). The standard dose for men younger than 65 is 50 mg orally 1 hour before sexual activity (see footnote 1). Doppler measurements were taken at the end of the first hour because the peak serum levels of sildenafil after oral intake are achieved within 1 hour.[19]

The uterine arteries were studied first. All women were scanned in the supine position with a moderate distended urinary bladder; pelvic sono-anatomy was identified. Color flow mapping was used to visualize the uterine arteries, laterally to the uterine wall. When the proper color signal of uterine artery was located, the pulsed Doppler sample volume was positioned over the vessel of interest and at least 3 similar, sequential Doppler waveforms were obtained. The Doppler angle was maintained at between 30 and 60 degrees during the spectral analyses. After measuring the peak systolic velocity (PSV), end diastolic velocity (EDV), and the mean velocity of the uterine artery, the resistance index (RI = PSV-EDV/PSV) and pulsatility index (PI = PSV-EDV/mean) were calculated.

Subsequently, the clitoral arteries were studied. All women were scanned in the lithotomy position. The Doppler probe was placed sagittally on the clitoris without exerting any significant pressure on genital tissues. The clitoral artery was quickly identified using color flow mapping. Once a clitoral artery was located, the pulsed Doppler sample volume was positioned over the vessel of interest and at least 3 similar, sequential Doppler waveforms were obtained. A Doppler angle of < 20 degrees was ensured during the spectral analyses. After measuring the peak systolic velocity, end diastolic velocity, and the mean velocity of the clitoral artery, the resistance index and pulsatility index were calculated. The total examination time for the clitoral artery was limited to approximately 1 minute for each woman.

The statistical analysis was performed with the Statistical Package for Social Sciences computer program version 9.0 (SPSS, Inc., Chicago, Illinois). The results of the study are shown as the mean plus or minus standard deviation. Paired Student t test was performed to investigate whether values of the uterine and clitoral arteries were significantly different between pre- and post-sildenafil studies. P values ≤ .05 indicated a statistically significant difference.

Results

Table 1 shows the results of the color Doppler sonography measurements and statistical analysis. At least 1 of the uterine arteries was visualized, and satisfactory recordings of the Doppler signals from the uterine arteries were obtained in all subjects. Before sildenafil administration, the mean resistance and pulsatility indexes of the uterine arteries studied were 0.80 ± 0.07 and 2.08 ± 0.52, respectively. Clitoral artery circulation was easily detectable by color Doppler sonography, and good quality flow velocity waveforms were obtained. The basal mean peak systolic velocity, resistance index, and pulsatility index of the clitoral arteries studied were 12.9 ± 5.8 cm/sec, 0.80 ± 0.11, and 2.44 ± 1.32, respectively.

Table 1.

Effect of Single Oral-Dose Sildenafil Citrate on Clitoral Artery (CA) and Uterine Artery (UA)

	Before Sildenafil	After Sildenafil	P
PSV of CA (cm/sec)	12.9 ± 5.8	17.9 ± 8.6	< .001
RI of CA	0.80 ± 0.11	0.79 ± 0.10	.683
PI of CA	2.44 ± 1.32	2.51 ± 1.44	.714
RI of UA	0.80 ± 0.07	0.73 ± 0.08	< .001
PI of UA	2.08 ± 0.52	1.66 ± 0.50	< .001

Data are presented as mean ± standard deviation.

PI = pulsatililty index; PSV = peak systolic velocity; RI = resistance index

One hour after the administration of a single oral dose of 50 mg sildenafil citrate, the mean uterine arterial resistance index (0.73 ± 0.08) and pulsatility index (1.66 ± 0.50) were significantly lower and the mean peak systolic velocity of the clitoral arteries (17.9 ± 8.6 cm/sec) was significantly higher compared with baseline values (P < .001). Sildenafil did not cause any significant change in the mean resistance index (0.79 ± 0.10) and pulsatility index (2.51 ± 1.44) of the clitoral artery (P = .683 and P = .714, respectively).

After sildenafil administration, we observed side effects including headache (n = 4), dizziness (n = 2), flushing (n = 2), and tachycardia (n = 1), none of which were serious.

Discussion

Recently, attention has been directed toward understanding the neurovascular events associated with clitoral and vaginal function and dysfunction. Even hysterectomy alone, for example, without the removal of the ovaries, can result in sexual dysfunction because of neurovascular injuries. Removal of the uterus and ligation of the arterial supply at the uterine pedicles can result in ovarian atrophy and fibrosis of the vaginal wall and clitoral cavernosal smooth muscle.[7] Vasculogenic impairment of the ilio-hypogastric-pudendal arterial bed to the vagina and clitoris, as a result of atherosclerotic vascular disease for instance, is associated with vaginal engorgement insufficiency and clitoral erectile insufficiency.[20] Histomorphometric analysis of clitoral cavernosal tissue shows that aging and vascular risk factors may adversely affect the clitoral cavernosal erectile tissue.[21] Diabetes mellitus produces significant adverse effects on the hemodynamic mechanism of clitoral engorgement and leads to diffuse clitoral cavernous fibrosis in a rabbit model.[22]

It is well known that the release of NO from the cavernous nerves and from endothelial cells activates guanylate cyclase to form cGMP, which relaxes the corpus cavernosum of the penis. Sildenafil, widely used in the treatment of male erectile dysfunction, is a potent cGMP-specific phosphodiesterase (PDE) type 5 inhibitor and selectively inhibits cGMP catabolism in cavernous smooth muscle tissue and augments penile erection.[12-14,23] There has been increasing interest in a possible role for PDE type 5 inhibitors in the treatment of female sexual response disorders. Immunohistochemical studies show that the corporal tissue organization and the anatomic sites of NO synthase isoforms in the human clitoris are similar to those in the penis.[11,24] During the excitement phase, vascular engorgement in female genital tissues occurs, mediated by the parasympathetic nervous system and the NO-cGMP pathway. The relaxation of corporal vascular smooth muscles leads to clitoral tumescence and dilation of the perivaginal arterioles, with seeping of vascular transudate to the vaginal wall resulting in lubrication.[25,26] The uterine and cervical glands also secrete mucus during sexual arousal to lubricate the vagina. Sildenafil enhances electrical field stimulation-elicited relaxation of rabbit clitoral corpus cavernosum by a NO-cGMP dependent pathway.[27] Sildenafil also seems to improve physiologic parameters of the female sexual response, including genital blood flow.[15,28] Sildenafil has been reported to be effective in enhancing vaginal engorgement during erotic stimulus conditions in healthy women without sexual dysfunction.[29] Two studies suggest that sildenafil may improve sexual performance of women affected by sexual problems, such as arousal disorder, and may directly improve other aspects of sexual life.[15,30] One study has shown that sildenafil partially reverses the sexual dysfunction associated with spinal cord injury in women.[31] Oral sildenafil also improves sexual function in some patients with psychotropic-induced sexual dysfunction.[26] Although an improvement of sexual function was reported in most of these studies, randomized controlled clinical trials in this field are limited. In 1 randomized trial, it was found that sildenafil did not improve the sexual response among women with female sexual arousal disorder.[32] However, 2 randomized trials do suggest there may be a select population of women diagnosed with sexual arousal disorder who may benefit from sildenafil.[15,33]

In preliminary Doppler sonographic studies of healthy young women, it was demonstrated that the clitoral arterial blood flow increases following vaginal pressure stimulation,[34] slightly increases at the ovulation phase of menstrual cycle,[35] and significantly increases in women taking hormonal contraception.[35] The postmenopausal changes associated with aging and chronic vascular diseases may alter both clitoral and vaginal blood flow and decrease the vascular response to sexual stimulations. In oophorectomized rabbits, decreased circulating levels of estrogen impairs the hemodynamic mechanism of clitoral engorgement and leads to histopathologic changes, including a decrease in clitoral cavernosal smooth muscle content and diffuse fibrosis.[36] Postmenopausal-aged women not on hormone replacement therapy have worse physiologic sexual response, including a lower increase in genital blood peak flow velocity.[8] We have also found that basal clitoral blood flow is higher in postmenopausal women who have been on hormone replacement therapy in comparison with postmenopausal women who had not taken hormonal therapy (unpublished results).

To the best of our knowledge, this is the first study examining the effects of sildenafil on both clitoral and uterine blood flow in healthy women by color Doppler sonography. In our study of postmenopausal women, we observed that a single oral dose of sildenafil significantly increases the mean peak systolic velocity of clitoral artery and significantly decreases the mean resistance and pulsatility indexes of the uterine artery. These changes seem to be due to a vasodilator effect of sildenafil on female genital tissues. Recently, NO synthase isoforms have also been identified in the uterus and interest has been focused on the role of NO as a modulator of uterine blood flow.[10,37] In our study, the degrees to which sildenafil affected the results of the Doppler measurements of the clitoris and uterus are not equal. The difference is possibly explained by the dense concentration of PDE5 in clitoris, which is highly expressed in erectile tissue in comparison to other tissues. In 2 preliminary reports of the use of vaginal sildenafil in a small group of infertile patients with prior failed assisted reproduction therapy cycles attributed to poor endometrial response, sildenafil improved sonographic endometrial appearance or thickness. Although Sher[10] reported an improvement in uterine artery blood flow, Paulus and colleagues[37] reported no difference in PI values. However, the conflicting results of these studies about the effect of sildenafil on uterine artery blood flow need to be refined with further studies.[10,37] Improvement of the blood flow by sildenafil may play a role in therapy of the vasculogenic component of female sexual arousal disorder, such as clitoral erectile insufficiency syndromes. On the other hand, the decrease in the impedance to blood flow in the uterine artery indicates the increased blood flow to uterus and endometrium. This knowledge may be useful in case of any requirement to improve the uterine blood flow, such as infertility patients with poor endometrial response.

There is a lack of an objective, quantitative, and simple method for physiologic measurements in female sexual arousal response assessment. The color Doppler sonographic examination is a simple, reliable, reproducible, quantitative and noninvasive technique that provides continuous real-time imaging of genital circulation with a high anatomic resolution. However, the technique requires presence of a user to hold the probe in the examination room. Although a perineal approach seems to be more acceptable and comfortable than a transvaginal examination, the ultrasonographer's presence may increase the variability of the data and cause embarrassment.

In conclusion, sildenafil improves the clitoral and uterine blood flow without any erotic stimulus. Further studies are needed to determine whether there are clinically useful roles for evaluation of clitoral blood flow by Doppler sonography and for sildenafil therapy in postmenopausal women.