A Novel Letrozole Model Recapitulates Both the Reproductive and Metabolic Phenotypes of Polycystic Ovary Syndrome in Female Mice

Biol Reprod. 2015 Sep;93(3):69. doi: 10.1095/biolreprod.115.131631. Epub 2015 Jul 22.


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.

Keywords: GnRH; PCOS; androgen; aromatase; female; infertility; metabolism; obesity; ovary; pituitary; reproduction.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Corpus Luteum / metabolism
  • Diestrus / metabolism
  • Enzyme Inhibitors / toxicity*
  • Estrous Cycle / drug effects
  • Female
  • Hyperandrogenism / blood
  • Hyperandrogenism / chemically induced
  • Hypothalamus / drug effects
  • Hypothalamus / metabolism
  • Kisspeptins / biosynthesis
  • Kisspeptins / genetics
  • Letrozole
  • Mice
  • Mice, Inbred C57BL
  • Nitriles / toxicity*
  • Phenotype
  • Pituitary Gland / drug effects
  • Pituitary Gland / metabolism
  • Polycystic Ovary Syndrome / chemically induced*
  • Polycystic Ovary Syndrome / metabolism
  • Polycystic Ovary Syndrome / pathology*
  • Pregnancy
  • Reproduction / drug effects*
  • Testosterone / blood
  • Triazoles / toxicity*


  • Enzyme Inhibitors
  • Kisspeptins
  • Nitriles
  • Triazoles
  • Testosterone
  • Letrozole