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The effects of superovulation on ovarian function and embryo development in rats Yun, Young Won


This study examined primary defects and related mechanisms leading to impaired fertility following superovulation with exogenous gonadotropin. Experiments were designed to address the ovulatory response, oocyte quality (gross morphology and nuclear maturation) and embryo development with reference to ovarian steroid and circulating LH levels in immature rats treated with 4, 20 or 40 IU pregnant mare's serum gonadotropin (PMSG). Superovulatory doses (20 and 40 IU) of PMSG induced the first ovulation as early as 24 hr and prolonged multiple ovulations with two increases: one before 36 hr and the other after 48 hr, while a low dose (4 IU) of PMSG induced a burst of ovulation between 60 and 72 hr. The biphasic superovulatory response was paralleled with two distinct luteinizing hormone (LH) peaks in circulating blood. Early ovulation could be, in part, due to the exogenous LH activity derived from high doses of PMSG. The initial prolonged elevation of serum LH before 54 hr resulted from actual cross-reaction of the injected PMSG with LH antibody in the assay and was dose-dependent, while a precipitous second elevation between 54 and 60 hr resulted primarily from an endogenous LH surge. Additionally, the observation of a marked ovulation inhibition by using a progesterone antagonist (RU 486) and an estrogen antagonist (tamoxifen) indicated the active participation of progesterone as well as estrogen in the PMSG-induced ovulation. A dose-dependent increase in the percentage of degenerate oocytes following superovulation was noticed from 36 hr onwards and positively correlated with the timing of increased levels of ovarian and serum androgens. Furthermore, superovulated oocytes with even normal appearance displayed substantially different stages of nuclear maturation varying from prophase I to metaphase II, while a majority of control oocytes (4 IU PMSG) was synchronized at metaphase II. The incidence of meiotically aberrant oocytes in superovulated rats was closely associated with abnormal follicular steroidogenesis, i.e. a marked alteration of follicular contents of progesterone and particularly androgens and/or a consistent disruption of sequential changes in overall ratios of androgens/17β-estradiol, progesterone/17β-estradiol and progesterone/androgens. Administration of an androgen antagonist (flutamide) in superovulated rats significantly reduced the proportion of degenerate oocytes and cellular degeneration of preimplantation embryos, and improved the developmental potential (embryo cleavage), at least in part, via decreased production of ovarian androgens. These results reflect a significant role of augmented ovarian androgen secretion in the perturbation of oocyte quality and subsequent embryo development following superovulation. However, the pharmacological effects of flutamide were restricted to early stage (Day 2) of pregnancy. Therefore, the actual improvement of the quality or development of early embryos by flutamide was ascribed to a substantial reduction of abnormal oocytes before fertilization. The results of an experiment using the RU486 and tamoxifen indicated that estrogen, but not progesterone, influenced oocyte quality in superovulated rats. RU486 treatment did not affect the oocyte morphology, but tamoxifen treatment was associated with a marked increase in the percentage of degenerate oocytes. The results of this research provide direct evidence of atypical ovulations of superovulated oocytes with premature or asynchronous nuclear maturation as a primary defect leading to impaired fertility including abnormal embryo development, and demonstrate a close relationship between meiotically aberrant oocytes and abnormal follicular steroidogenesis in superovulated rats. Increased levels of ovarian and circulating androgens preceding fertilization were particularly implicated in the perturbation of oocyte quality and embryo development following superovulation. Finally, the process of multiple ovulations induced by superovulatory doses of PMSG appears to involve the exogenous LH activity of PMSG as well as active participation of progesterone and estrogen.

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