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

Erkan Alataş, MD; A. Baki Yağci, MD

Disclosures
In This Article

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.[12,13,14,23] 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.

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