Chronological changes in fertility, fecundity and steroid hormone secretion during consecutive pregnancies in aging rats

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Abstract
During aging in female rats the incidence of regular estrous cyclicity decreases progressively. Concomitant with this decrease are declines in both fertility and fecundity in aged females. The causes of these age-related losses in reproductive function are currently unknown. To reveal the biology and endocrinology of pregnancy in aging females, we performed a longitudinal study in a group of multiparous rats bred once every 2 mo. Beginning at 4 mo and continuing through 12 mo of age in the same individual females, we determined the chronological changes in estrous cyclicity and fertility; examined the number of implantation scars; estimated the fetal resorption rate; and assessed the patterns of progestin, androgen, and estrogen secretion during 5 consecutive gestations. During each pregnancy, blood samples were obtained from the mothers on Days 2, 5, 8, 11, 14, 16, and 19 for measurement of steroid hormone concentrations. Laparotomies were performed after parturition to count the number of implantation scars. To estimate the number of fetal resorptions, the difference between the number of implantation scars and the total number of pups delivered was calculated for each animal. Fertility during aging followed a similar but more dramatic pattern of decline than did the incidence of regular cyclicity. While almost all females became infertile when their regular ovulatory cycles ceases, an increasing proportion of middle-aged (10-12 mo of age) regularly cyclic rats also failed to reproduce successfully. These observations indicate that the loss of fertility in aging female rats is due largely, but not exclusively, to the cessation of regular ovulatory cycles. Beginning at 8 mo and continuing to 12 mo of age, a significant (p < 0.01) decline in litter size was observed in these multiparous rats. This decline was associated with a similar decrease in the number of implantation scars. Neither the estimated number of fetal resorptions nor the number of dead pups delivered per pregnant rat changed significantly during 5 consecutive gestations. There were, however, age-related gradual increases in the percentage of fetal resorptions/implantation scars and of dead pups/total number of pups delivered. These data indicate that the age-related decline in fecundity is due mainly to reproductive failures early in gestation. The patterns of decreases in both fertility and fecundity found in repeatedly sampled and laparotomized females were similar to those seen in untreated multiparous rats. No discernible differences in serum levels of progestins, androgens or estrogens during Days 2-14 of pregnancy were observed between 5 consecutive gestations, despite marked decreases in litter size and number of implantation scars at middle age. However, serum concentrations of estradiol, estrone, testosterone and androstenedione on Days 16 and 19 were lower in 10- and 12-mo-old pregnant rats, which bore fewer conceptuses. These results suggest that middle-aged pregnant rats secrete adequate amounts of steroid hormones to maintain fertile gestations, and that decreases in fecundity may not be the result of deficient corpora luteal support. A decrease in the number of implantation scars indicates that pre-implantation failures and/or early postimplantation losses are directly responsible for a decline in the litter size of middle-aged pregnant rats. The reduced number of feto-placental units found in middle-aged pregnant rats appear to secrete lesser amounts of androgens, resulting in lower circulating estrogens during the latter third of gestation.