Permanent Effects of Neonatal Estrogen Exposure in Rats on Reproductive Hormone Levels, Sertoli Cell Number, and the Efficiency of Spermatogenesis in Adulthood1

Abstract

This study aimed to identify the mechanism(s) for impairment of spermatogenesis in adulthood in rats treated neonatally with estrogens. Rats were treated (days 2-12) with 10, 1, or 0.1 microg diethylstilbestrol (DES), 10 microg ethinyl estradiol (EE), 10 mg/kg of a GnRH antagonist (GnRHa), or vehicle and killed in adulthood. DES/EE caused dose-dependent reductions in testis weight, total germ cell volume per testis, and Sertoli cell volume per testis. Sertoli cell number at 18 days of age in DES-treated rats was reduced dose dependently. GnRHa treatment caused changes in these parameters similar to those in rats treated with 10 microg DES. Plasma FSH levels were elevated (P < 0.001) to similar levels in all treatment groups regardless of differences in Sertoli cell number and levels of inhibin B; the latter reflected Sertoli cell number, but levels were disproportionately reduced in animals treated with high doses of DES/EE. Neonatal estrogen treatment, but not GnRHa, caused dose-dependent reductions (40-80%) in plasma testosterone levels in adulthood, but did not alter LH levels. Preliminary evidence suggests that the decrease in testosterone levels in estrogen-treated rats is not due to reduced Leydig cell volume per testis. GnRHa-treated rats exhibited a significant increase in germ cell volume per Sertoli cell and a reduction in germ cell apoptosis, probably because of the raised FSH levels. Despite similar raised FSH levels, rats treated with DES (10 or 1 microg) or EE (10 microg) had reduced germ cell volume/Sertoli cell and increased germ cell apoptosis, especially when compared with GnRHa-treated animals. The latter changes were associated with an increase in lumen size per testis, indicative of impaired fluid resorption from the efferent ducts, resulting in fluid accumulation in the testis. Rats treated neonatally with 0.1 microg DES showed reduced germ cell apoptosis comparable to that in GnRHa-treated animals. The changes in apoptotic rate among treatment groups occurred across all stages of the spermatogenic cycle. It is concluded that 1) neonatal estrogen treatment results in dose-dependent alterations in Sertoli cell numbers, germ cell volume, efficiency of spermatogenesis, and germ cell apoptosis in adulthood; 2) the relatively poor spermatogenesis in estrogen-treated animals is most likely due to altered testis fluid dynamics and/or altered Sertoli cell function; 3) as indicated by FSH (LH) and testosterone levels, the hypothalamic-pituitary axis and Leydig cells are probably more sensitive than the Sertoli cells to reprogramming by estrogens neonatally; and 4) elevated FSH levels in adulthood may improve the efficiency of spermatogenesis.

Gestational Exposure to Synthetic Steroid Hormones Impaired Sperm Quantity and Quality in Wistar Rats

“…Compared to controls, a significant reduction in the serum testosterone level as well as a significant increase in the serum FSH and LH level were observed in the test group. Similar findings were reported in rats following prenatal exposure to hydroxyprogesterone [11,12] as well as neonatal exposure to estrogen [24,25]. e reduction in serum testosterone levels in the test group might be explained by a reduction in the Leydig cell count, diminished responsiveness of Leydig cells to LH, or direct inhibition of testicular steroidogenesis [5,25].…”

Estradiol Induction of Spermatogenesis Is Mediated via an Estrogen Receptor-α Mechanism Involving Neuroendocrine Activation of Follicle-Stimulating Hormone Secretion

“…mechanisms requiring the pituitary ER␣ receptor (49). The neuroendocrine mechanism underlying the ovulatory LH surge (with a concomitant FSH surge) characteristic of the mature female reproductive system is usually extinguished in males by neonatal androgen imprinting (50), although such a latent mechanism may still be evoked by toxicological doses of synthetic estrogens (51). Beyond establishing the existence of this pathway, whether it is a physiological mechanism or vestigial pharmacological reflex cannot be resolved by the present study.…”

Molecular Mechanisms and Signaling Pathways Involved in Sertoli Cell Proliferation

“…One of the first approaches employed to assess the effect of estrogens on Sertoli cell proliferation consisted of the in vivo administration of estrogens to rats. In this regard, estrogen treatment reduced Sertoli cell number when administered during proliferative periods (218). Similarly, results obtained in studies carried out in vivo using an aromatase inhibitor and a non-specific ER antagonist (ICI 182,780) suggested that Sertoli cell proliferation diminishes by activation of estrogen receptors (219, 220).…”