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      Hyperactive LH Pulses and Elevated Kisspeptin and NKB Gene Expression in the Arcuate Nucleus of a PCOS Mouse Model

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          Abstract

          Polycystic ovary syndrome (PCOS), a common reproductive disorder in women, is characterized by hyperandrogenemia, chronic anovulation, cystic ovarian follicles, and luteinizing hormone (LH) hyper-pulsatility, but the pathophysiology isn’t completely understood. We recently reported a novel mouse model of PCOS using chronic letrozole (LET; aromatase inhibitor). Letrozole-treated females demonstrate multiple PCOS-like phenotypes, including polycystic ovaries, anovulation, and elevated circulating testosterone and LH, assayed in “one-off” measures. However, due to technical limitations, in vivo LH pulsatile secretion, which is elevated in PCOS women, was not previously studied, nor were the possible changes in reproductive neurons. Here, we used recent technical advances to examine in vivo LH pulse dynamics of freely moving LET female mice versus control and ovariectomized (OVX) mice. We also determined whether neural gene expression of important reproductive regulators such as kisspeptin, neurokinin B (NKB), and dynorphin, is altered in LET females. Compared to controls, LET females exhibited very rapid, elevated in vivo LH pulsatility, with increased pulse frequency, amplitude, and basal levels, similar to PCOS women. Letrozole-treated mice also had markedly elevated Kiss1, Tac2, and Pdyn expression and increased Kiss1 neuronal activation in the hypothalamic arcuate nucleus. Notably, the hyperactive LH pulses and increased kisspeptin neuron measures of LET mice were not as elevated as OVX females. Our findings indicate that LET mice, like PCOS women, have markedly elevated LH pulsatility, which likely drives increased androgen secretion. Increased hypothalamic kisspeptin and NKB levels may be fundamental contributors to the hyperactive LH pulse secretion in the LET PCOS-like condition and, perhaps, in PCOS women.

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          Author and article information

          Journal
          Endocrinology
          Endocrinology
          endo
          Endocrinology
          Oxford University Press (US )
          0013-7227
          1945-7170
          April 2020
          07 February 2020
          07 February 2021
          : 161
          : 4
          : bqaa018
          Affiliations
          Department of OBGYN and Reproductive Sciences, University of California San Diego , La Jolla, California
          Author notes
          Correspondence:  Dr. Alexander S. Kauffman, Department of Reproductive Medicine, Leichtag Building, Room 3A-15, University of California San Diego, 9500 Gilman Drive #0674, La Jolla, California 92093. E-mail: akauffman@ 123456ucsd.edu .
          Author information
          http://orcid.org/0000-0001-8631-6097
          Article
          PMC7341557 PMC7341557 7341557 bqaa018
          10.1210/endocr/bqaa018
          7341557
          32031594
          1c0214bf-8017-4a15-b76c-a258cc6055ae
          © Endocrine Society 2020. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com

          This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model ( https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model)

          History
          : 25 November 2019
          : 05 February 2020
          : 13 March 2020
          Page count
          Pages: 15
          Funding
          Funded by: National Institutes of Health, DOI 10.13039/100000002;
          Funded by: UCSD, DOI 10.13039/100007911;
          Award ID: NIH P50 HD012303
          Award ID: R01 HD090161
          Award ID: R01 HD082567
          Funded by: University of Virginia, DOI 10.13039/100008457;
          Award ID: NIH P50-HD28934
          Categories
          Research Article
          AcademicSubjects/MED00250

          dynorphin,reproduction,infertility,neurokinin B,androgen,aromatase,Tac2,Kiss1,kisspeptin,GnRH,PCOS

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