Effect of Androgen Treatment During Fetal and/or Neonatal Life on Ovarian Function and Metabolic Factors in Rats.

Abstract

Up to 20% of women have polycystic ovaries (PCO), but only around 5% develop the syndrome (PCOS), associated with increased androgenisation and infertility. Studies in sheep and rhesus monkeys support the concept that PCO(S) develops as a consequence of overexposure during fetal life to androgens or potentially, estrogens. We have investigated the effects on ovarian development and aspects of metabolism of different windows of androgen treatment during fetal and neonatal life in rats to determine if the alterations in ovarian, pituitary and metabolic function that are a feature of PCO(S) in women could occur independently at different times during fetal and/or neonatal life. This study extends our previous investigations which identified distinct programming windows for reproductive tract masculinisation in male rats. Different treatment windows (control oil or testosterone proprionate 20mg/kg s.c. every third day) were given as follows: e14.5 to birth (e21.5); e14.5 through birth to postnatal day (pnd) 25; pnd 1-pnd 25; pnd15- pnd25. Any effects of these treatments were assessed in adult animals at pnd 90. Treatment during fetal life only (e14.5-e21.5), or from pnd15 to 25 did not result in any ovarian phenotype and adult animals exhibited normal estrous cycles, ovulated with normal numbers of corpora lutea, and had enlarged uteri as expected in proestrous. Treatment both during fetal life from e14.5 to birth and then of the neonates for a further 25 days resulted in streak ovaries with activated follicles containing oocytes, which only progressed to a small antral stage and inactive uteri confirming lack of estrogenic activity of these follicles. However, adults treated from birth to pnd 25, resulted in an absence of ovulations, and significantly (P<0.001) reduced ovarian and uterine weights compared to controls. In this group, analysis of follicle populations showed no change in total follicle numbers, but a significant (P<0.001) increase in both the number of primordial follicles and the size of the large antral follicles. This ovarian phenotype is similar to that seen PCOS ovaries. In addition, all animals treated with tp postnatally were significantly (P<0.05) heavier in adulthood (controls 217±10g versus pnd1-25 treated 318±6g; mean±sem). In contrast, tp treatment during fetal life did not affect adult weight. In further studies, the neonatal tp induced weight gain was related to a highly significant (P<0.001) increase in body fat, and liver weight without any differences in food intake. Current studies are refining the dose and timing of tp required to induce this phenotype. The present studies suggest that there are different windows in which androgens can affect the various phenotypes of PCOS in females. (poster)