The Effects of Chronic Subcutaneous Administration of an Investigational Kisspeptin Analog, TAK-683, on Gonadotropin-Releasing Hormone Pulse Generator Activity in Goats

Abstract

The continuous activation of the kisspeptin receptor by its agonists causes the abrogation of kisspeptin signaling, leading to decreased pulsatile luteinizing hormone (LH) secretion. Employing this phenomenon as a tool for probing kisspeptin action, this study aimed to clarify the role of kisspeptin in gonadotropin-releasing hormone (GnRH) pulse generation in goats. We examined the effects of chronic administration of TAK-683, an investigational kisspeptin analog, on LH secretion, GnRH immunostaining, pituitary responses to exogenous GnRH, and GnRH pulse generator activity, reflected by a characteristic increase in multiple-unit activity (MUA volley). An osmotic pump containing TAK-683 was subcutaneously implanted on day 0. TAK-683 treatment dose-dependently suppressed pulsatile LH secretion on day 1. Higher doses of chronic TAK-683 profoundly suppressed pulsatile LH secretion but had little effect on GnRH immunostaining patterns and pituitary responses to GnRH on day 5. In ovariectomized goats, MUA volleys occurred at approximately every 30 min on day -1. On day 5 of chronic TAK-683 administration, pulsatile LH secretion was markedly suppressed, whereas MUA volleys were similar to those observed on day -1. Male pheromones and senktide (neurokinin B receptor agonist) induced an MUA volley but had no effect on LH secretion during chronic TAK-683 administration. The results indicate that the chronic administration of a kisspeptin analog profoundly suppresses pulsatile LH secretion without affecting GnRH content, pituitary function or GnRH pulse generator activity, and they suggest an indispensable role for kisspeptin signaling in the cascade driving GnRH/LH pulses by the GnRH pulse generator.