In order for successful implantation to occur, an adequately prepared endometrium has to be built up during the menstrual cycle. Endometrial development is regulated by steroid hormones and various growth factors and cytokines. Some of these factors are produced locally and act via paracrine mechanisms; others have to be transferred to the endometrium. Sufficient uterine blood supply is required for these factors to reach the endometrium, especially to its functional layer. Several studies have tried to evaluate the association between the morphologic characteristics of the endometrium and pregnancy rates in assisted reproduction therapy (ART) cycles. Although the results are sometimes conflicting, most studies agree that the endometrium has to reach a certain thickness for successful pregnancy to occur. We have found that endometrial thickness was significantly associated with in vitro fertilization (IVF) outcome. In addition, pregnancy rates were higher when the endometrium was thicker than 8-10 mm.
Various agents that influence blood flow have been evaluated to determine whether their use during ART has an impact on implantation/ pregnancy rates. Antithrombotic agents, aspirin, and heparin have been evaluated by several groups. Two prospective, randomized studies reported opposing results with aspirin use in an unselected IVF population. A third study including donor egg recipients found a positive effect of aspirin on implantation rates among those women whose endometrium was thinner than 8 mm. Heparin was found to improve pregnancy rates among women with thrombophilia and recurrent abortions. Currently the literature does not support the routine use of these medications among infertile women.
Nitric oxide relaxes vascular smooth muscle, an effect that is mediated by cyclic guanosine monophosphate (cGMP). Guanylate cyclase and cGMP have been detected in human myometrium obtained from both nonpregnant and pregnant women. Sildenafil is a selective inhibitor of the type V cGMP-specific phosphodiesterase. With the use of sildenafil, cGMP levels remain elevated, which leads to vascular relaxation and increased blood flow. Sher and colleagues evaluated the effect of sildenafil (viagra), administered in the form of a vaginal suppository, on endometrial development in 4 women who had had thin endometria during previous ART treatment (< 8 mm). Doppler studies revealed a decreased pulsatility index with sildenafil use, and in 3 of the 4 women a significantly thicker endometrium was achieved with the addition of sildenafil. All 3 of these women became pregnant. In a second study from the same group using a larger cohort of women (n = 105), improved endometrial development was achieved among 70% of women selected similarly to that in the initial study. Among these women, a 29% ongoing pregnancy rate was achieved. The pregnancy rate was significantly lower -- only 2% -- among those whose endometrium remained thin despite sildenafil(viagra) use.
The safety of sildenafil among infertile women has not been established, although no increased incidence of adverse events has been observed based on limited information. Most of the reported adverse events with sildenafil involved men with underlying cardiovascular disease or were possibly due to an interaction with other drugs. Animal studies have not revealed any adverse reproductive effects, but there are no human data evaluating sildenafil effects during pregnancy.
The exact mechanism by which vaginally administered sildenafil could improve pregnancy rates is not clear. One possible mechanism is that it may improve the uterine blood supply. Alternatively, sildenafil may have an effect on any of the cytokines that regulate endometrial development or implantation. Further, improved pelvic blood flow can have a beneficial effect on ovarian function. The effects of sildenafil among infertile women need to be evaluated in well-designed studies. The safety has to be established as well. At this point, sildenafil use should be considered experimental.
