OR13-06 Effects of pulsatile kisspeptin infusion on the puberty onset in female rhesus monkeys

Abstract Disclosure: M.L. Gloo: None. R.J. Adam: None. E.M. Wolf: None. S.G. Schott: None. G.L. Del Frate: None. C.J. Geraci: None. J.M. Timbeross: None. E. Terasawa: None. Effects of pulsatile kisspeptin infusion on the puberty onset in female rhesus monkeys The kisspeptin neuron in the hypothalamus is critical for puberty, as mutations of the KISS-1 gene result in absence or abnormal timing of puberty onset (Seminara et al., N Engl J Med. 349:1614, 2003; De Roux et al., PNAS, 100: 10972, 2003). A series of studies in this lab further indicate that in both male and female rhesus monkeys the pubertal increases in GnRH release are accompanied with the pubertal increase in kispeptin release. However, it is unknown whether pulsatile kisspeptin infusion into prepubertal monkeys leads to precocious puberty, similar to that shown with pulsatile infusions of GnRH (Wildt et al., Science 207:1373, 1980). Therefore, in the present study, we examined the effect of the kisspeptin agonist kisspeptin 10 (KP10) on puberty onset in 8 prepubertal female monkeys at 15.3±0.2 months of age. Four females received hourly bolus KP10 infusion through a small subcutaneously implanted infusion pump for 8-15 months, whereas 4 control females did not receive any treatment. We initially tested several different doses, and decided to examine two doses of KP10 (2 µg/5 µl/h in 3 of the 4 females and 0.1 µg /5 µl/h in the remaining female). Pubertal markers, including development of the nipple size, sex-skin color, body size (height and weight), and circulating hormone levels were monitored weekly. Preliminary results indicated that the kisspeptin treatment resulted in a cascade of pubertal changes in all treated female monkeys, including increased nipple volume and swelling of the sex-skin at younger ages than the control. In fact, the age of menarche in the kisspeptin group (23.8±0.2 mo., n=4) was significantly (P<0.01) younger than that (27.1±0.2 mo., n=4) in the control animals. Nevertheless, the kisspeptin effect on the mean age of the first ovulation were overridden by individual variations such as seasonal influence on reproduction and puberty, which are unique in this species. To date (∼30 months after the initiation of the study), 3 of the 4 in the kisspeptin group ovulated, whereas 2 of the 4 in the control group also ovulated. These results indicate that although the kisspeptin treatment leads to puberty onset, the role of kisspeptin is rather permissive, when compared to the classical report showing that a similar treatment with GnRH peptide in prepubertal females results in menarche and the first ovulation within several weeks (Wildt et al., 1980). Collectively, our observations are interpreted to mean that, although an increase in kisspeptin release in the hypothalamus leads to puberty onset, additional maturational changes in the GnRH neurosecretory circuit are required for a fully matured hypothalamo-pituitary gonadal axis. (Supported by HD043341 and HD089495.) Presentation: Sunday, July 13, 2025