Kisspeptin and Neurokinin B Signaling Network Underlies the Pubertal Increase in GnRH Release in Female Rhesus Monkeys

Abstract

Loss-of-function or inactivating mutations in the genes coding for kisspeptin and its receptor (KISS1R) or neurokinin B (NKB) and the NKB receptor (NK3R) in humans result in a delay in or the absence of puberty. However, precise mechanisms of kisspeptin and NKB signaling in the regulation of the pubertal increase in gonadotropin-releasing hormone (GnRH) release in primates are unknown. In this study, we conducted a series of experiments infusing agonists and antagonists of kisspeptin and NKB into the stalk-median eminence, where GnRH, kisspeptin, and NKB neuroterminal fibers are concentrated, and measuring GnRH release in prepubertal and pubertal female rhesus monkeys. Results indicate that (1) similar to those previously reported for GnRH stimulation by the KISS1R agonist (i.e., human kisspeptin-10), the NK3R agonist senktide stimulated GnRH release in a dose-responsive manner in both prepubertal and pubertal monkeys; (2) the senktide-induced GnRH release was blocked in the presence of the KISS1R antagonist peptide 234 in pubertal but not prepubertal monkeys; and (3) the kisspeptin-induced GnRH release was blocked in the presence of the NK3R antagonist SB222200 in the pubertal but not prepubertal monkeys. These results are interpreted to mean that although, in prepubertal female monkeys, kisspeptin and NKB signaling to GnRH release is independent, in pubertal female monkeys, a reciprocal signaling mechanism between kisspeptin and NKB neurons is established. We speculate that this cooperative mechanism by the kisspeptin and NKB network underlies the pubertal increase in GnRH release in female monkeys.

Regulation of prepubertal dynorphin secretion in the medial basal hypothalamus of the female rat

“…Earlier studies in rats have produced varied results showing that NKB can either stimulate or inhibit GnRH/LH secretion, often depending on species, sex and age. The present study clearly shows a stimulatory action of senktide/NKB to release GnRH which supports previous studies showing increased GnRH/LH release in prepubertal female rats sheep and rhesus monkeys, as well as in adult sheep and mice …”

“…Therefore, the inability of senktide to stimulate Kp release in the present study could be the result of a species difference or to the low levels of oestradiol in late juvenile female rats. Interestingly, this previous study also showed that NKB and Kp take independent signalling paths to affect the release of GnRH in prepubertal female monkeys . Another report using tissue slices from adult male transgenic mice also indicated that NK3R activated GnRH release was Kp‐independent .…”

“…In this regard, we did not observe any senktide‐induced changes in Kp synthesis or release from the same late juvenile female rats that were used for the above mentioned DYN/GnRH assessments, hence indicating that Kp was not involved in the senktide‐induced release of GnRH. A previous report, however, demonstrated that senktide infused into the stalk median eminence stimulated Kp release in prepubertal female monkeys, although the release was markedly less than that produced in pubertal monkeys, an effect considered to be a result of differences in circulating oestradiol levels. Therefore, the inability of senktide to stimulate Kp release in the present study could be the result of a species difference or to the low levels of oestradiol in late juvenile female rats.…”

“…Although the above examples demonstrate that DYN is an inhibitor of prepubertal GnRH, additional information is required to determine what upstream substance(s) are involved in controlling its synthesis and release. We considered neurokinin B (NKB) a likely candidate for such a role because it is synthesised by neurones within the ARC, it is known to increase in the hypothalamus as puberty approaches and it contributes to the rise in prepubertal GnRH/LH secretion . Therefore, the present study utilised both in vivo and in vitro approaches to first investigate whether the prepubertal administration of senktide, an NKB agonist, could concomitantly suppress DYN and elevate GnRH secretion and, if so, to determine the specificity and reversibility of the actions.…”

Accelerated Episodic Luteinizing Hormone Release Accompanies Blunted Progesterone Regulation in PCOS-like Female Rhesus Monkeys (Macaca Mulatta) Exposed to Testosterone during Early-to-Mid Gestation

“…In PA female sheep, fetal T exposure reduces synaptic input to GnRH neurons [96], including diminished synaptic connections from hypothalamic AR-expressing kisspeptin/neurokinin B/dynorphin (KNDy) neurons [97] and diminished synaptic inter-connections between hypothalamic KNDy neurons accompanying lower post-synaptic expression for the neurokinin B receptor [97,98]. Since the kisspeptin and neurokinin B network plays a key role in neuronal stimulation for GnRH release in rhesus monkeys [99,100] and, together with dynorphin, is functionally implicated in regulating GnRH release in men [101], fetal T exposure may either enhance kisspeptin and neurokinin B stimulation of episodic GnRH release or impair dynorphin-mediated GnRH inhibition. A KNDy neuronal site for PCOS reproductive pathogenesis is consistent with therapeutic results obtained from neurokinin B NK3-receptor antagonist treatment of women with PCOS.…”