Effects of Estradiol and Progesterone on Early Embryonic Development in Aging Rats1

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Abstract
Regularly cyclic, middle-aged female rats exhibit a decreased incidence of fertility, and those females that are fertile produce small litters. These decreases in fertility and litter size are associated with reduced numbers of normal blastocytes formed and implanted, suggesting that pre- and/or peri-implantation failures may be the causes for these aging-related reproductive declines. The present study examined the relationships and influence of circulating estradiol (E2) and progesterone (P) levels on early embryonic development and implantation in middle-aged rats. Serial blood samples obtained from cannulated, middle-aged pregnant rats revealed minor decreases in plasma P and increases in E2 levels during Days 2-4 of pregnancy, compared to young pregnant rats, resulting in significantly (p < 0.001) decreased plasma P/E2 ratios. These alterations in endogenous hormone secretion in middle-aged pregnant rats were associated with fewer normal blastocysts on Day 5 of pregnancy and reduced numbers of normally implanting embryos. Correlation analysis further revealed a significant (p < 0.05) inverse relationship between mean circulating E2 levels and numbers of normal conceptuses on Day 12 of gestation. Moreover, s.c. administration of P implants (in Silastic) to middle-aged pregnant rats increased serum P levels by about 34-40 ng/ml, and significantly (p < 0.05) reduced the incidence of abnormal embryos before implantation. In contrast, treatment with E2 minipumps produced a sustained rise in serum E2 (by about 7-15 pg/ml) and resulted in the complete absence of embryos in the reproductive tracts by Day 5 of pregnancy. However, concomitant treatment with P implants did not reverse the adverse effects of E2 minipumps on early embryos. These findings demonstrate that alterations in the hormonal patterns of early gestation, specifically increased E2 levels and/or decreased P/E2 ratios, influence the pattern of early embryonic development and implantation in middle-aged female rats. Therefore, the observed changes in ovarian steroidogenesis in middle-aged pregnant rats may underlie in part the declines in fertility and fecundity.