Opposite Roles of Estrogen Receptor (ER)-α and ERβ in the Modulation of Luteinizing Hormone Responses to Kisspeptin in the Female Rat: Implications for the Generation of the Preovulatory Surge

Abstract

Ovulation is triggered by the preovulatory rise of gonadotropins, which is in turn elicited by the preceding increase in circulating estrogen. Kisspeptins, ligands of G protein-coupled receptor 54 encoded by the KiSS-1 gene, have emerged as potent stimulators of GnRH/LH secretion, and KiSS-1 neurons at the anteroventral periventricular nucleus have been shown to be involved in the generation of preovulatory LH surge, estrogen being a potent elicitor of KiSS-1 gene expression selectively at the anteroventral periventricular nucleus. Whether, in addition to transcriptional effects, estrogen influences other aspects of kisspeptin-induced GnRH/LH release in the female remains unexplored. We provide herein evidence for the specific roles of estrogen receptor (ER)-alpha and ERbeta in the modulation of LH responses to kisspeptin and the generation of the preovulatory surge. Selective blockade of ERalpha in cyclic females blunted LH responses to kisspeptin, eliminated the endogenous preovulatory rise of LH, and blocked ovulation. In contrast, antagonism of ERbeta failed to cause major changes in terms of LH surge and ovulatory rate but significantly augmented acute LH responses to kisspeptin. Notably, defective LH secretion and ovulation after ERalpha blockade were not observed after GnRH stimulation, which elicited maximal acute (<2 h) LH responses regardless of ERalpha/ERbeta signaling. In addition, net LH secretion in response to kisspeptin was decreased by ovariectomy and increased after selective activation of ERalpha but not ERbeta. Altogether, our data document the prominent positive role of ERalpha in the regulation of GnRH/LH responsiveness to kisspeptin and, thereby, ovulation. In addition, our results disclose the putative function of ERbeta as negative modifier of GnRH/LH response to kisspeptin, a phenomenon that might contribute to partially restraining LH secretion at certain physiological states.

Interactions between kisspeptin and neurokinin B in the control of GnRH secretion in the female rat

“…On the morning of the day of the experiment, the phase of the estrous cycle was confirmed, and only animals in proestrus or diestrus 1 were selected (n ϭ 10 per group). Then senktide or vehicle alone (physiological saline, 0.9% NaCl) was injected intracerebroventricularly into each animal, and blood samples (300 l) were obtained by jugular venipuncture, while the animals were maintained under fluorourethane anesthesia [following a process described elsewhere (28)]. Blood was collected before (0 min) and 20, 60, and 120 min after the injection and stored as described above.…”

Rola sygnalizacji kisspeptyny w osi podwzgórze–przysadka–nadnercza — aktualna perspektywa

“…In addition, injection of kisspeptin-10 in ovariectomised rats resulted in maximal gonadotrophin response only after oestrogen and progesterone replacement [89]. Further exploration revealed that selective blockade of ERα in rats resulted in significant suppression of LH response and reduced preovulatory LH surge to exogenous administration of Kp-10 (but no effects were observed on preovulatory LH surge after selective ERβ blockade) and enhanced the magnitude of acute response to 96]. It suggested that oestrogen moulds gonadotrophin response to kisspeptins during the preovulatory period by maintaining a balance between ERα and ERβ signalling [96].…”

“…Further exploration revealed that selective blockade of ERα in rats resulted in significant suppression of LH response and reduced preovulatory LH surge to exogenous administration of Kp-10 (but no effects were observed on preovulatory LH surge after selective ERβ blockade) and enhanced the magnitude of acute response to 96]. It suggested that oestrogen moulds gonadotrophin response to kisspeptins during the preovulatory period by maintaining a balance between ERα and ERβ signalling [96]. These studies also observed maximal response of gonadotrophin secretion when ovariectomised rats were supplemented with progesterone and selective ERα agonists favouring their potential role in inducing preovulatory gonadotrophins surge [7].…”

Kisspeptin and fertility

“…Adult female rodents pre-administered with an ERa antagonist fail to ovulate or undergo a pre-ovulatory LH surge and have blunted LH response following administration of kisspeptin-10 ( Roa et al 2008). Furthermore, ovariectomised, oestrogen-replaced, neuron-specific ERa null mice are infertile.…”