CONTROLLED NEONATAL EXPOSURE TO ESTROGEN - A SUITABLE TOOL FOR REPRODUCTIVE AGING STUDIES IN THE FEMALE RAT

The present study was designed to determine whether the modification of exposure time to large doses of estrogens provided a reliable model for early changes in reproductive aging. Silastic implants containing estradiol benzoate (EB) in solution were placed into 5-day-old female Wistar rats and removed 1 day (Ei1 group) or 5 days (Ei5) later. In addition, 10 mug EB dissolved in 100 mul com oil was administered s.c. to another group (EI). Control rats received either vehicle implants or 100 mul com oil. Premature occurrence of vaginal opening was observed in all three estrogenized groups independently of EB exposure. However, females bearing implants for 24 h had first estrus at the same age as their controls and cycled regularly, and neither histological nor gonadal alterations could be observed at 75 days. Interestingly, they failed to cycle regularly at 5 mo whereas controls continued to cycle. On the other hand, the increase of EB exposure (Ei5, EI) resulted in a gradual and significant delay in the onset of first estrus and in a high number of estrous phases, as frequently observed during reproductive decline. At 75 days, the ovaries of these last two groups showed a reduced number of corpora lutea and an increased number of large follicles. According to this histological pattern, ovarian weight and progesterone (P) content gradually decreased whereas both groups showed higher estradiol (E2) content than controls. This resulted in a higher E2:P ratio, comparable to that observed in normal aging rats. The results allow us to conclude that the exposure time to large doses of estrogens is critical to the gradual enhancement of reproductive decline. Furthermore, exposures as brief as 24 h led to a potential early model for aging studies that will be useful to verify whether neuroendocrine changes precede gonadal impairment.