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Endocrinology, doi:10.1210/en.2005-0195
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Endocrinology Vol. 146, No. 10 4431-4436
Copyright © 2005 by The Endocrine Society

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

Mika Kinoshita, Hiroko Tsukamura, Sachika Adachi, Hisanori Matsui, Yoshihisa Uenoyama, Kinuyo Iwata, Shunji Yamada, Kinji Inoue, Tetsuya Ohtaki, Hirokazu Matsumoto and Kei-Ichiro Maeda

Graduate School of Bioagricultural Sciences (M.K., H.T., Y.U., K.Iw., S.Y., K.-I.M.), Nagoya University, Nagoya 464-8601; Faculty of Science (S.A., K.In.), Saitama University, Saitama 338-8570; and Frontier Research Laboratories, Pharmaceutical Research Division, Takeda Pharmaceutical Co., Ltd. (H.M., T.O., H.M.), Ibaraki 300-4293, Japan

Address all correspondence and requests for reprints to: Kei-Ichiro Maeda, Graduate School of Bioagricultural Sciences, Nagoya University, Nagoya 464-8601, Japan. E-mail: keimaeda{at}agr.nagoya-u.ac.jp.

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.




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