Mechanism of ovarian disruption by neonatal DES exposure: A further investigation into ovarian function in the hamster cheek pouch
Treatment of hamsters on the day of birth with the synthetic estrogen and prototypical endocrine disruptor, diethylstilbestrol (DES), induces severe anomalies throughout the female reproductive tract. The disruption phenomenon seen in the ovaries must be the result of either: 1) A direct mechanism that involves primary lesions in the neonatal ovary; and/or 2) An indirect mechanism that involves primary lesions in the hypothalamus and/or pituitary that then secondarily result in altered gonadotropin-regulated function of the mature hamster ovary. To test those alternative hypotheses, we used the convenient hamster cheek pouch system to perform homo-transplantation and cross-transplantation of ovaries among postnatal/prepubertal (day 21) control (CON) and neonatally DES-treated donor and host animals. Thereafter, host animals were monitored for estrous cycle activity and finally sacrificed at two months of age when blood was collected to determine endocrine status and both ectopic ovarian masses and in situ uteri were collected and fixed for histological and immunohistochemical analysis. Evidence consistent with the indirect mechanism emerged early in the study from the monitoring of estrous cycle activity in hosts with viable ovarian transplants. Regardless of transplant treatment, all CON hosts exhibited regular, 4-day estrous cycles while all neonatally DES-treated hosts were non-cyclic. RIA analysis of sex steroids and gonadotropins in the serum of all treatment groups indicated maintenance of pituitary-ovarian axis function in terms of hormonal synthesis and secretion. Histological analysis revealed that the viable, ectopic ovarian masses, either as homotransplants or as cross-transplants, did not replicate either the normal morphology seen in intact, CON animals or the characteristic disrupted morphology seen in intact, DES-exposed animals. However, consistent with the equivalent serum estradiol levels measured in all four transplant groups, ovarian masses from all treatment groups were steroidogenically active as evidenced by immunohistochemical detection of aromatase. Despite the equivalent serum estradiol levels in all four transplant groups, severe endometrial dysplasia including evidence of inflammation was confined to the two neonatally DES-exposed host groups. We interpret the full spectrum of data reported here as being consistent with the alternative hypothesis that neonatal DES treatment disrupts morphogenesis and function of the adult hamster ovary via an indirect mechanism.
Thesis (M.S.)--Wichita State University, College of Liberal Arts and Sciences, Dept. of Biological Sciences