Early Treatment of Young Female Rats with Progesterone Delays the Aging-Associated Reproductive Decline: A Counteraction by Estradiol1

We have recently reported that successive treatments of young virgin rats with progesterone (P) implants produce elevated circulating P and consistently low estradiol (E2) concentrations, and subsequently delay the aging-associated reproductive decline. Inasmuch as E2 has been implicated in causing the loss of regular estrous cyclicity in aging rats, the present study examined if the concomitant presence of moderately increased circulating E2 levels could counteract the effects of P implants on reproductive aging. Starting at 3½ mo and continuing to 8 mo of age, regularly cyclic, virgin rats received either s.c. Silastic implants of P (P-implanted), blank Silastic implants (virgin controls), or P + E2 implants (P + E2-implanted) for 3 wk, followed by implant removal for 1 wk. Each of these implant treatments was repeated in the same female rats 5 times. Blood samples were obtained on different days of the estrous cycle from the control group and on Day 11 of successive treatments with P or P + E2 implants for measurements of serum P and E2 values. At 8½ and 10 mo of age, estrous cyclicity of these same virgin rats was again monitored, and 10-mo-old regularly cyclic females from each treatment group were mated with young fertile males to complete term pregnancies. While virgin controls showed cyclic increases in E2 and P secretion during the estrous cycle, P-implanted virgins exhibited consistently low serum E2 and moderately increased P levels during 5 successive treatments. The latter indicates a potent inhibition of ovarian E2 secretion by P implants. In young females receiving P + E2 implants, both serum P and E2 levels were consistently higher than those in virgin rats receiving P implants alone. During 8½-l0 mo of age, the incidences of regular estrous cyclicity in female rats of all 3 groups appeared to be inversely related to the overall amounts of circulating E2 during the entire period of implant treatments. Thus, at 8½ mo of age, 76% and 55% of virgins that previously received P and P + E2 implants maintained regular cyclicity, respectively, whereas only 26% of the virgin controls remained as regularly cyclic. Among the 10-mo-old virgins displaying regular estrous cyclicity, only 20% of the controls became pregnant after mating, whereas 73% and 44% of mated females previously treated with P or P + E2, respectively, were fertile. The litter sizes produced by pregnant rats previously treated with P or P + E2 appeared to be greater than those by the control group. These results demonstrate that the effects of P implants to delay reproductive aging in the female rat are partially counteracted, but not abolished, by the concomitant presence of elevated circulating E2. These findings indicate that the amounts of circulating E2 rather than P are more influential on the agingassociated reproductive decline.