Abstract

 Mammalian ovulation is induced by a luteinizing hormone (LH) surge, which is triggered by elevated plasma estrogen levels; however, chronic exposure to high levels of estradiol (E2) is known to inhibit LH secretion. In the present study, we hypothesized that the inhibition of the LH surge by chronic E2 exposure is due to the downregulation of the estrogen receptor α (ERα) in kisspeptin neurons at the hypothalamic anteroventral periventricular nucleus (AVPV), which is known as the gonadotropin-releasing hormone (GnRH)/LH surge generator. Animals exposed to E2 for 2 days showed an LH surge, whereas those exposed for 14 days showed a significant suppression of LH. Chronic E2 exposure did not affect the number of AVPV kisspeptin neurons and the percentage of kisspeptin neurons with ERα or c-Fos, but did affect the number of kisspeptin neurons in the arcuate nucleus (ARC). Furthermore, chronic E2 exposure did not affect GnRH neurons. In the pituitary, 14-day E2 exposure significantly reduced the expression of Lhb mRNA and LHβ-immunoreactive areas. GnRH-induced LH release was also reduced significantly by 14-day E2 exposure. We revealed that the suppression of an LH surge by chronic E2 exposure was induced in association with the significant reduction in kisspeptin neurons in the ARC, LH expression in the pituitary, and pituitary responsiveness to GnRH, and was not caused by changes in the ERα-expressing kisspeptin neurons in the AVPV and GnRH neurons, which are responsible for E2 positive feedback.