Abstract
Diethylstilbestrol (DES), a strong estrogenic compound, is well-known to affect the reproductive system. In this study, we investigated the effects of DES administration on gonadotropin levels and ovarian steroidogenesis in prepubertal rats. DES treatment acutely reduced serum LH levels, followed by a reduction in the expression of various steroidogenesis-related genes in theca cells. Serum FSH levels were almost unaffected by DES-treatment, even though Cyp19a1 expression was markedly reduced. Serum progesterone, testosterone and estradiol levels were also declined at this time. LH levels recovered from 12 h after DES-treatment and gradually increased until 96 h with a reduction of ERα expression observed in the pituitary. Steroidogenesis-related genes were also up-regulated during this time, except for Cyp17a1 and Cyp19a1. Consistent with observed gene expression pattern, serum testosterone and estradiol concentrations were maintained at lower levels, even though progesterone levels recovered. DES-treatment induced the inducible nitric oxide synthase (iNOS) in granulosa cells, and a nitric oxide generator markedly repressed Cyp19a1 expression in cultured granulosa cells. These results indicate that DES inhibits thecal androgen production via suppression of pituitary LH secretion and ovarian Cyp17a1 expression. In addition, DES represses Cyp19a1 expression by inducing iNOS gene expression for continuous inhibition of estrogen production in granulosa cells.
Highlights
Diethylstilbestrol (DES), a strong estrogenic compound, is well-known to affect the reproductive system
To investigate various phenomena occurring during granulosa cell differentiation, many researchers have used granulosa cells from immature rodents primed with E2 or DES
These granulosa cells are known to be highly responsive to Follicle stimulating hormone (FSH) and differentiate into the cells showing a preovulatory stage phenotype
Summary
Diethylstilbestrol (DES), a strong estrogenic compound, is well-known to affect the reproductive system. DES treatment acutely reduced serum LH levels, followed by a reduction in the expression of various steroidogenesis-related genes in theca cells. DES represses Cyp19a1 expression by inducing iNOS gene expression for continuous inhibition of estrogen production in granulosa cells. Upon binding to cognate receptors (LHR and FSHR, respectively), LH and FSH increase androgen and estrogen production by up-regulating gene expression of previously described steroidogenesis-related factors. This occurs mainly via transcriptional factors, such as steroidogenic factor-1 (SF-1, known as adrenal 4 binding protein) and liver receptor homolog-1 (LRH-1)[6]. These organs are potential targets of endocrine disrupting chemicals (EDCs) that mimic endogenous estrogen signals
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