Estrogen-induced impairments as a mechanism in reproductive senescence of female C57BL/6J mice.

Reproductive senescence in female C57BL/6J mice is characterized by ovarian, neuroendocrine, and other nonovarian impairments. The studies reported here examined the role of the ovarian hormone estradiol in the development of nonovarian impairments during aging. In Study I, intact or ovariectomized 6-month-old mice were given estradiol valerate (EV; 10 micrograms/gm body wt.) or oil. When these mice were 12 months old (MA), their ovaries were exchanged by grafting with ovaries from 6-month-old mice. In mice not given EV, MA ovaries in young hosts and MA hosts with young ovaries both exhibited about 50% fewer cycles than young hosts with young ovaries. In contrast, MA hosts ovariectomized when young exhibited as many cycles as young hosts, suggesting that the presence of the ovaries contributed to the development of neuroendocrine impairments. Intact MA hosts given EV when young were unable to support any estrous cycles when given young ovarian grafts, whereas MA hosts ovariectomized and given EV when young exhibited impairments similar to intact MA hosts not given EV. In Study II, effects of estradiol implants were examined in cycling 6-month-old (Y) and 9-month-old (MA) mice given small (6 mm) or large (18 mm) implants for 6 weeks. The implants caused a monotonically dose-related decrease in the number of cycles mice exhibited while implants were in place as well as after implants were removed. These studies confirm our previous findings that reproductive senescence entails both ovarian and nonovarian impairments. They furthermore suggest that age-correlated reproductive nonovarian impairments are due in part to the cumulative exposure to ovarian estradiol.