Altered gene activity of epidermal growth factor receptor (ErbB-1) in the hypothalamus of aging female rat is linked to abnormal estrous cycles.

Abstract

Activation of the ErbB-1 receptor is necessary for initiating mammalian female puberty by stimulating the release of LH-releasing hormone. It remains unclear whether ErbB-1 is also required in governing reproduction during adulthood and whether altered ErbB-1 signaling is linked to changes in gonadotropin secretion in aging females. The present study examined these issues. RT-PCR was employed to determine changes in ErbB-1 mRNA levels during proestrus in both young adult (YA) and middle-aged (MA) female rats. Before the LH surge, expression levels in the preoptic area of YA rats increased to a maximal value. No such increase in ErbB-1 mRNA was found in MA rats. This difference was confirmed by the analysis of in situ hybridization histochemistry, where a stronger mRNA signal was observed in the preoptic area of YA rats compared with MA females. ErbB-1 protein levels measured by Western blot reflected this difference. A peak level of ErbB-1 mRNA in the median eminence-arcuate nucleus was detected at 0800 h in YA rats, but it was delayed in MA animals. There were intense ErbB-1 mRNA-positive cells in the arcuate nucleus. Pharmacological blockade of ErbB-1 receptor-mediated signal transduction resulted in the disruption of estrous cyclicity in YA rats. These results indicate that ErbB-1 receptors are necessary for maintaining normal estrous cycles. Consequently, age-related alterations in hypothalamic ErbB-1 gene activity may contribute to a delayed preovulatory LH secretion in aging females. Thus, the ErbB-1 signaling system plays an important role in the control of female reproduction during adulthood.