Neonatal Aromatase Inhibition Blocked Defeminization of AVPV Kiss1 Neurons and LH Surge-Generating System in Male Rats.

ABSTRACT

The neuroendocrine system that controls the preovulatory surge of gonadotropin-releasing hormone (GnRH)/luteinizing hormone (LH), which triggers ovulation in female mammals, is sexually differentiated in rodents. A transient increase in circulating testosterone levels in male rats within a few hours of birth is primarily responsible for the defeminization of anteroventral periventricular nucleus (AVPV) kisspeptin neurons, which are critical regulators of the GnRH/LH surge. The present study aimed to determine whether neonatal estradiol-17ß (E2) converted from testosterone by aromatase primarily causes the defeminization of AVPV kisspeptin neurons and the surge of GnRH/LH in male rodents. The results of the present study showed that the neonatal administration of letrozole (LET), a nonsteroidal aromatase inhibitor, within 2 hours of birth rescued AVPV Kiss1 expression and the LH surge in adult male rats, while the neonatal administration of testosterone propionate (TP) irreversibly attenuated AVPV Kiss1 expression and the LH surge in adult female rats. Furthermore, the neonatal LET-treated Kiss1-Cre-activated tdTomato reporter males exhibited a comparable number of AVPV Kiss1-Cre-activated tdTomato-expressing cells to that of vehicle-treated female rats, while neonatal TP-treated females showed fewer AVPV Kiss1-Cre-activated tdTomato-expressing cells than vehicle-treated females. Moreover, neonatal TP administration significantly decreased the number of arcuate Kiss1-expressing and Kiss1-Cre-activated tdTomato-positive cells and suppressed LH pulses in adult gonadectomized female rats; however, neonatal LET administration failed to affect them. These results suggest that E2 converted from neonatal testosterone is primarily responsible for the defeminization of AVPV kisspeptin neurons and the subsequent GnRH/LH surge generation in male rats.