title: A Novel Letrozole Model Recapitulates Both the Reproductive and Metabolic Phenotypes of Polycystic Ovary Syndrome in Female Mice.
abstract: Polycystic ovary syndrome (PCOS) pathophysiology is poorly understood, due partly to lack of PCOS animal models fully recapitulating this complex disorder. Recently, a PCOS rat model using letrozole (LET), a nonsteroidal aromatase inhibitor, mimicked multiple PCOS phenotypes, including metabolic features absent in other models. Given the advantages of using genetic and transgenic mouse models, we investigated whether LET produces a similar PCOS phenotype in mice. Pubertal female C57BL/6N mice were treated for 5 wk with LET, which resulted in increased serum testosterone and normal diestrus levels of estradiol, similar to the hyperandrogenemia and follicular phase estrogen levels of PCOS women. As in PCOS, ovaries from LET mice were larger, polycystic, and lacked corpora lutea versus controls. Most LET females were acyclic, and all were infertile. LET females displayed elevated serum LH levels and higher Lhb mRNA in the pituitary. In contrast, serum FSH and Fshb were significantly reduced in LET females, demonstrating differential effects on gonadotropins, as in PCOS. Within the ovary, LET females had higher Cyp17, Cyp19, and Fsh receptor mRNA expression. In the hypothalamus, LET females had higher kisspeptin receptor mRNA expression but lower progesterone receptor mRNA levels. LET females also gained more weight than controls, had increased abdominal adiposity and adipocyte size, elevated adipose inflammatory mRNA levels, and impaired glucose tolerance, mirroring the metabolic phenotype in PCOS women. This is the first report of a LET paradigm in mice that recapitulates both reproductive and metabolic PCOS phenotypes and will be useful to genetically probe the PCOS condition.
authors.affiliation: Department of Reproductive Medicine and Center for Reproductive Science and Medicine, University of California San Diego, La Jolla, California akauffman@ucsd.edu.
authors.forename: Alexander S
authors.initials: AS
authors.lastname: Kauffman
authors.affiliation: Department of Reproductive Medicine and Center for Reproductive Science and Medicine, University of California San Diego, La Jolla, California.
authors.forename: Varykina G
authors.initials: VG
authors.lastname: Thackray
authors.affiliation: Department of Reproductive Medicine and Center for Reproductive Science and Medicine, University of California San Diego, La Jolla, California.
authors.forename: Genevieve E
authors.initials: GE
authors.lastname: Ryan
authors.affiliation: Department of Reproductive Medicine and Center for Reproductive Science and Medicine, University of California San Diego, La Jolla, California.
authors.forename: Kristen P
authors.initials: KP
authors.lastname: Tolson
authors.affiliation: Department of Reproductive Medicine and Center for Reproductive Science and Medicine, University of California San Diego, La Jolla, California.
authors.forename: Christine A
authors.initials: CA
authors.lastname: Glidewell-Kenney
authors.affiliation: Department of Reproductive Medicine and Center for Reproductive Science and Medicine, University of California San Diego, La Jolla, California.
authors.forename: Sheila J
authors.initials: SJ
authors.lastname: Semaan
authors.affiliation: Department of Reproductive Medicine and Center for Reproductive Science and Medicine, University of California San Diego, La Jolla, California.
authors.forename: Matthew C
authors.initials: MC
authors.lastname: Poling
authors.affiliation: Department of Reproductive Medicine and Center for Reproductive Science and Medicine, University of California San Diego, La Jolla, California.
authors.forename: Nahoko
authors.initials: N
authors.lastname: Iwata
authors.affiliation: Department of Reproductive Medicine and Center for Reproductive Science and Medicine, University of California San Diego, La Jolla, California.
authors.forename: Kellie M
authors.initials: KM
authors.lastname: Breen
authors.affiliation: Department of Reproductive Medicine and Center for Reproductive Science and Medicine, University of California San Diego, La Jolla, California.
authors.forename: Antoni J
authors.initials: AJ
authors.lastname: Duleba
authors.affiliation: Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Elisabet
authors.initials: E
authors.lastname: Stener-Victorin
authors.affiliation: Department of Reproductive Medicine and Center for Reproductive Science and Medicine, University of California San Diego, La Jolla, California.
authors.forename: Shunichi
authors.initials: S
authors.lastname: Shimasaki
authors.affiliation: Department of Medicine, University of California San Diego, La Jolla, California.
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Webster
authors.affiliation: Department of Reproductive Medicine and Center for Reproductive Science and Medicine, University of California San Diego, La Jolla, California.
authors.forename: Pamela L
authors.initials: PL
authors.lastname: Mellon
mesh_terms: D000818:Animals; D003338:Corpus Luteum / Q000378:metabolism; D004031:Diestrus / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000633:toxicity*; D030762:Estrous Cycle / Q000187:drug effects; D005260:Female; D017588:Hyperandrogenism / Q000097:blood / Q000139:chemically induced; D007031:Hypothalamus / Q000187:drug effects / Q000378:metabolism; D059648:Kisspeptins / Q000096:biosynthesis / Q000235:genetics; D000077289:Letrozole; D051379:Mice; D008810:Mice, Inbred C57BL; D009570:Nitriles / Q000633:toxicity*; D010641:Phenotype; D010902:Pituitary Gland / Q000187:drug effects / Q000378:metabolism; D011085:Polycystic Ovary Syndrome / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology*; D011247:Pregnancy; D012098:Reproduction / Q000187:drug effects*; D013739:Testosterone / Q000097:blood; D014230:Triazoles / Q000633:toxicity*
chemical_list: D004791:Enzyme Inhibitors; D059648:Kisspeptins; D009570:Nitriles; D014230:Triazoles; D013739:Testosterone; D000077289:Letrozole
keywords: GnRH; PCOS; androgen; aromatase; female; infertility; metabolism; obesity; ovary; pituitary; reproduction