title: Reduced responsiveness of kisspeptin neurons to estrogenic positive feedback associated with age-related disappearance of LH surge in middle-age female rats.
abstract: Age-related disappearance of the LH surge is one of major biomarkers of reproductive aging in female rats. Kisspeptin neurons in the hypothalamic anteroventral periventricular nucleus (AVPV) are proposed as the critical regulator of the preovulatory LH surge in response to estrogenic positive feedback. Here we investigated the possible involvement of the AVPV kisspeptin neurons in the disappearance of the LH surge in middle-age rats. Middle-age rats exhibiting persistent estrus (M-PE) did not show an LH surge although neither Kiss1 mRNA nor peptide in the AVPV was differentially expressed when compared to young rats exhibiting normal estrous cycles (YN). M-PE released LH in response to exogenous kisspeptin in a similar dose-dependent manner as YN, suggesting that their GnRH neurons still maintained responsiveness to kisspeptin. To investigate the estrogenic positive feedback effect on kisspeptin neurons in the AVPV, rats were ovariectomized and supplemented with estradiol (OVX+E2). We performed in situ hybridization and immunohistochemistry for Kiss1 mRNA and cFos, respectively, and found that M-PE exhibited a significantly lower percentage of Kiss1 mRNA positive neurons with cFos immunoreactivity, although the total number of kisspeptin neurons was not different from that in cyclic rats. Furthermore, OVX+E2 M-PE did not show the surge-like LH release under high estradiol administration while YN did. Thus our current study suggests that the reduced responsiveness of the AVPV kisspeptin neurons to estrogenic positive feedback presumably results in the decrease in kisspeptin secretion from neurons and eventually causes the age-related disappearance of the LH surge in middle age female rats.
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Kanagawa 251-8555, Japan; Department of Basic Veterinary Science, United Graduated School of Veterinary Sciences, Gifu University, Gifu 501-1193, Japan; Laboratory of Veterinary Physiology, Department of Veterinary Medicine, Faculty of Agriculture, Tokyo University of Agriculture and Technology, Tokyo 183-8509, Japan. Electronic address: Ishii_Misawa@takeda.co.jp.
authors.forename: Misawa Niki
authors.initials: MN
authors.lastname: Ishii
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Matsumoto
authors.forename: Hisanori
authors.initials: H
authors.lastname: Matsui
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Seki
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Matsumoto
authors.forename: Kaori
authors.initials: K
authors.lastname: Ishikawa
authors.forename: Fumio
authors.initials: F
authors.lastname: Chatani
authors.forename: Gen
authors.initials: G
authors.lastname: Watanabe
authors.forename: Kazuyoshi
authors.initials: K
authors.lastname: Taya
mesh_terms: D000818:Animals; D004958:Estradiol / Q000494:pharmacology; D005260:Female; D007031:Hypothalamus / Q000187:drug effects / Q000378:metabolism; D059648:Kisspeptins / Q000378:metabolism*; D007986:Luteinizing Hormone / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D059648:Kisspeptins; D004958:Estradiol; D007986:Luteinizing Hormone
keywords: 3V; AUC; AVPV; Aging; Arc; EIA; ERα; Estrous cycle; G-protein coupled receptor 54; GPR54; GnRH; Gonadotropin releasing hormone; Kisspeptin; Kp-54; LH; Luteinizing hormone; OVX; POA; RIA; Rats; SD rat; Sprague–Dawley rat; VMPO; ac; anterior commissure; anteroventral periventricular nucleus; arcuate nucleus; area under the curve; enzyme immunoassay; estrogen receptor alpha; kisspeptin-54; luteinizing hormone; och; optic chiasma; ovariectomized; preoptic area; radioimmunoassay; third ventricle; ventromedial preoptic nucleus