Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Oxford University Press (OUP)  

Abstract

Mammalian ovulation is induced by a luteinizing hormone (LH) surge, which is triggered by elevated plasma estrogen levels; however, chronic exposure to high levels of estradiol (E2) is known to inhibit LH secretion. In the present study, we hypothesized that the inhibition of the LH surge by chronic E2 exposure is due to the downregulation of the estrogen receptor α (ERα) in kisspeptin neurons at the hypothalamic anteroventral periventricular nucleus (AVPV), which is known as the gonadotropin-releasing hormone (GnRH)/LH surge generator. Animals exposed to E2 for 2 days showed an LH surge, whereas those exposed for 14 days showed a significant suppression of LH. Chronic E2 exposure did not affect the number of AVPV kisspeptin neurons and the percentage of kisspeptin neurons with ERα or c-Fos, but did affect the number of kisspeptin neurons in the arcuate nucleus (ARC). Furthermore, chronic E2 exposure did not affect GnRH neurons. In the pituitary, 14-day E2 exposure significantly reduced the expression of Lhb mRNA and LHβ-immunoreactive areas. GnRH-induced LH release was also reduced significantly by 14-day E2 exposure. We revealed that the suppression of an LH surge by chronic E2 exposure was induced in association with the significant reduction in kisspeptin neurons in the ARC, LH expression in the pituitary, and pituitary responsiveness to GnRH, and was not caused by changes in the ERα-expressing kisspeptin neurons in the AVPV and GnRH neurons, which are responsible for E2 positive feedback.

DOI： 10.1093/biolre/ioad129

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Japan Society of Histochemistry & Cytochemistry  

Hypothalamic kisspeptin neurons stimulate gonadotropin-releasing hormone (GnRH) and luteinizing hormone (LH) release. Kisspeptin neurons in the anteroventral periventricular nucleus (AVPV) of rats induce an LH surge for ovulation, and those in the arcuate nucleus (ARC) regulate pulsatile LH secretion for follicle development and spermatogenesis. Dysfunction of kisspeptin neurons thus reduces the reproductive function. This review focuses on the effect of androgen or aging on kisspeptin expression in rats. Although androgen directly suppresses ARC kisspeptin neurons in female rats, the AVPV kisspeptin neurons are hardly affected. In rats, plasma LH concentrations decrease in both sexes with aging, and ARC kisspeptin expression also decreases in old rats compared with young rats. In addition, kisspeptin neurons may be associated with hyperprolactinemia in old female rats because they are known to release prolactin through hypothalamic tuberoinfundibular dopaminergic (TIDA) neurons. Hypothalamic kisspeptin neurons are thus the main regulator to secrete LH, and inhibition of kisspeptin expression leads to various kinds of reproductive dysfunction.

DOI： 10.1267/ahc.19013

PubMed

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：BIOSCIENTIFICA LTD  

Hyperandrogenic women have various grades of ovulatory dysfunction, which lead to infertility. The purpose of this study was to determine whether chronic exposure to androgen affects the expression of kisspeptin (ovulation and follicle development regulator) or release of luteinizing hormone (LH) in female rats. Weaned females were subcutaneously implanted with 90-day continuous-release pellets of 5 alpha-dihydrotestosterone (DHT) and studied after 10 weeks of age. Number of Kiss1-expressing cells in both the anteroventral periventricular nucleus (AVPV) and arcuate nucleus (ARC) was significantly decreased in ovary-intact DHT rats. Further, an estradiol-induced LH surge was not detected in DHT rats, even though significant differences were not observed between DHT and non-DHT rats with regard to number of AVPV Kiss1-expressing cells or gonadotrophin-releasing hormone (GnRH)-immunoreactive (ir) cells in the presence of high estradiol. Kiss1-expressing and neurokinin B-ir cells were significantly decreased in the ARC of ovariectomized (OVX) DHT rats compared with OVX non-DHT rats; pulsatile LH secretion was also suppressed in these animals. Central injection of kisspeptin-10 or intravenous injection of a GnRH agonist did not affect the LH release in DHT rats. Notably, ARC Kiss1-expressing cells expressed androgen receptors (ARs) in female rats, whereas only a few Kiss1-expressing cells expressed ARs in the AVPV. Collectively, our results suggest excessive androgen suppresses LH surge and pulsatile LH secretion by inhibiting kisspeptin expression in the ARC and disruption at the pituitary level, whereas AVPV kisspeptin neurons appear to be directly unaffected by androgen. Hence, hyperandrogenemia may adversely affect ARC kisspeptin neurons, resulting in anovulation and menstrual irregularities.

DOI： 10.1530/JOE-16-0568

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Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE INC  

Pulsatile secretion of gonadotropin-releasing hormone (GnRH)/luteinizing hormone (LH) decreases during aging. Kisspeptin (encoded by Kiss1) neurons in the arcuate nucleus coexpress neurokinin B (Tac3) and dynorphin (Pdyn) and are critical for regulating the GnRH/LH pulse. We therefore examined kisspeptin neurons by histochemistry and pulsatile LH release in rats aged 2-3 (Young), 12-13 (YoungMiddle), 19-22 (Late-Middle), and 24-26 (Old) months. Total LH concentrations, sampled for 3 hours, decreased in both sexes with aging. In females, numbers of Tac3 and Pdyn neurons were significantly reduced in all aging rats, and numbers of Kiss1 neurons were significantly reduced in Late-Middle and Old rats. In males, numbers of all 3 neuron-types were significantly decreased in all aging rats. GnRH agonist induced LH release in all animals; however, the increased LH concentration in all aging rats was less than that in Young rats. These results suggest that expression of each gene in kisspeptin neurons may be controlled individually during aging, and that reduction of their expression or change in pituitary responsiveness may cause attenuated pulsatile LH secretion. (C) 2016 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.neurobiolaging.2016.10.018

Web of Science

PubMed

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：JAPAN SOC HISTOCHEMISTRY & CYTOCHEMISTRY  

Kisspeptin neurons in the arcuate nucleus (ARC) regulate prolactin secretion, and are in physical contact with tuberoinfundibular dopaminergic (TIDA) neurons, which inhibit prolactin secretion. Prolactin levels in the blood are increased with advancing age in rats; therefore, we investigated the interactions with TIDA neurons and kisspeptin neurons in aged female rats (24 months of age), relative to those of young adult female rats (9-10 weeks of age). Plasma prolactin levels in the aged rats were significantly higher than those of young adult rats. Tyrosine hydroxylase (TH)-immunoreactive (ir) cell bodies and kisspeptin-ir nerve fibers were found in the dorsomedial ARC of both groups. The number of TH-ir cell bodies in the dorsomedial ARC did not differ significantly between groups. Additionally, no significant differences in the number of TH-ir cells in contact with kisspeptin-ir fibers was observed between groups. However, the number of kisspeptin-ir or Kiss1 mRNA-expressing cells in the ARC was significantly reduced in the aged rats compared with that of the young rats. These results suggest that the contacts between TIDA neurons and kisspeptin neurons are maintained after reproductive senescence, while production of kisspeptin in the ARC decreases significantly during aging.

DOI： 10.1267/ahc.16027

Web of Science

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Language：Japanese   Publisher：日本組織細胞化学会  

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J-GLOBAL

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J-GLOBAL

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J-GLOBAL

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Language：Japanese  

J-GLOBAL

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Event date： 2024.3

Presentation type：Poster presentation  

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Event date： 2022.10

Language：Japanese   Presentation type：Oral presentation (general)  

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Event date： 2022.10

Presentation type：Oral presentation (general)  

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Event date： 2019.9

Presentation type：Poster presentation  

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Language：English   Presentation type：Poster presentation  

Venue：Australia  

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