Cilostazol and Its Effects on Human Oocyte Maturation in Vivo: A Pilot Study

Combined oral contraceptive pills (COCs) are the most commonly used hormonal form of birth control in the United States with at least 87% of women of reproductive age reporting oral contraceptive use at some point in their lives (9). Despite their frequent use, the six and twelve month discontinuation rates for oral contraceptive pills are 31 and 47 % respectively (17), with common reasons for discontinuation attributed to the side effects of abnormal bleeding, headache, and weight gain.

Additionally, COCs are contraindicated in certain groups of women as outlined by The Centers for Disease Control Medical Eligibility Criteria (11). Given the high prevalence of oral contraceptive users who commonly discontinue use secondary to side effects or who are not eligible for use as a result of underlying health conditions, the development of novel oral non-hormonal methods that are equally effective at pregnancy prevention are warranted.

The potential for the development of non-hormonal contraception has been present in the scientific literature since the 1980s at which point the critical components of gametogenesis of the mammalian oocyte were being classified. Bornslaeger and colleagues discovered that high concentrations of intracellular cAMP, an important second messenger for many biological processes, inhibited resumption of meiosis I in mouse oocytes (3). Later studies demonstrated that phosphodiesterase 3 inhibitors, capable of preventing the breakdown of cAMP, were able to prevent resumption of meiosis in mouse oocytes cultured in vitro (6).

Since the 1980s, additional studies have examined phosphodiesterase inhibitors and their role in prevention of oocyte maturation. Tsafriri and colleagues showed that phosphodiesterase inhibitors were able to exert their effects selectively via type specific isoforms. This study revealed that granulosa cells exert effects via type 4 phosphodiesterase inhibitors and oocytes respond to signals via type 3 phosphodiesterase inhibitors such that oocyte maturation was prevented in the presence of PDE3 inhibitors yet ovulation was unaffected (15). Most recently, Jensen and colleagues examined both in vitro and in vivo effects of a phosphodiesterase 3 inhibitor ORG 9935 on oocyte maturation in rhesus monkeys. In these animal studies, it was found that in vitro, ORG 9935 at a concentration of 1.0umol/l was able to completely inhibit oocyte maturation (7).

In vivo models demonstrated a similar reduction in oocyte maturation, with the most dramatic reduction in monkeys treated with an extended dose regimen of ORG 9935 (200mg/kg/d) prior to ovulation (8). Additionally, pregnancy rates in macaques treated with ORG 9935 was studied and compared to controls. Overall, there was not a statistically significant decrease in pregnancy rates in those macaques treated with PDE3 inhibitor; however, there did appear to be evidence of a dose response as no animal became pregnant who had serum ORG 9935 levels above 300nM/L (9). Despite a clear dose response, authors of this study acknowledge that PDE3-Is have systemic effects that are also dose-limiting. At higher doses, adverse effects such as tachycardia and hypotension were observed.