Involvement of Central Metastin in the Regulation of Preovulatory Luteinizing Hormone Surge and Estrous Cyclicity in Female Rats

TLDR

Ovulation is triggered by estrogen‑induced GnRH and LH surges, but the central positive‑feedback mechanism remains incompletely understood. This study tested whether the KiSS‑1 product metastin acts centrally to regulate the GnRH/LH surge and estrous cyclicity in female rats. Metastin stimulated LH release when injected into the third ventricle or preoptic area of estrogen‑primed ovariectomized rats, and immunohistochemistry showed KiSS‑1 neurons in the arcuate nucleus co‑express estrogen receptors and project to GnRH neurons in the preoptic area. Expression of KiSS‑1 and its receptor GPR54 in the arcuate nucleus and preoptic area, combined with the abolition of the LH surge and estrous cycle by a metastin‑blocking antibody and increased ARC metastin neuron activity during proestrus, demonstrates that metastin released in the preoptic area induces the preovulatory LH surge and regulates estrous cyclicity.

Abstract

Ovulation is caused by a sequence of neuroendocrine events: GnRH and LH surges that are induced by positive feedback action of estrogen secreted by the mature ovarian follicles. The central mechanism of positive feedback action of estrogen on GnRH/LH secretion, however, is not fully understood yet. The present study examined whether metastin, the product of metastasis suppressor gene KiSS-1, is a central neuropeptide regulating GnRH/LH surge and then estrous cyclicity in the female rat. Metastin had a profound stimulation on LH secretion by acting on the preoptic area (POA), where most GnRH neurons projecting to the median eminence are located, because injection of metastin into the third ventricle or POA increased plasma LH concentrations in estrogen-primed ovariectomized rats. Metastin neurons were immunohistochemically found in the arcuate nucleus (ARC) to be colocalized with estrogen receptors with some fibers in the preoptic area (POA) in close apposition with GnRH neuronal cell bodies or fibers. Quantitative RT-PCR has revealed that KiSS-1 and GPR54 mRNAs were expressed in the ARC and POA, respectively. The blockade of local metastin action in the POA with a specific monoclonal antibody to rat metastin completely abolished proestrous LH surge and inhibited estrous cyclicity. Metastin-immunoreactive cell bodies in the ARC showed a marked increase and c-Fos expression in the early proestrus afternoon compared with the day of diestrus. Thus, metastin released in the POA is involved in inducing the preovulatory LH surge and regulating estrous cyclicity.