Antiandrogen Treatment Ameliorates Reproductive and Metabolic Phenotypes in the Letrozole-Induced Mouse Model of PCOS

• Published in: Endocrinology (Philadelphia) 2018-04, Vol.159 (4), p.1734-1747
• Main Authors: Ryan, Genevieve E, Malik, Shaddy, Mellon, Pamela L
• Format: Article
• Language: English
• Subjects: Adipocytes - drug effects; Adipocytes - metabolism; Androgen Antagonists - pharmacology; Androgen Antagonists - therapeutic use; Androgen receptors; Androgens; Animals; Aromatase; Aromatase Inhibitors; Body size; Body weight; Body Weight - drug effects; Disease Models, Animal; Endocrine disorders; Endocrinology; Estrous Cycle - drug effects; Estrous Cycle - metabolism; Estrus; Etiology; Female; Females; Flutamide; Flutamide - pharmacology; Flutamide - therapeutic use; Follicle Stimulating Hormone - metabolism; Follicle-stimulating hormone; Follicles; Fuel consumption; Letrozole; Luteinizing hormone; Luteinizing Hormone - metabolism; Menopause; Metabolism; Mice; Nitriles; Ovaries; Ovary - drug effects; Ovary - metabolism; Phenotype; Phenotypes; Pituitary; Pituitary Gland - drug effects; Pituitary Gland - metabolism; Polycystic ovary syndrome; Polycystic Ovary Syndrome - chemically induced; Polycystic Ovary Syndrome - drug therapy; Polycystic Ovary Syndrome - metabolism; Receptors, LHRH - metabolism; Reproduction - drug effects; Steroid 17-alpha-Hydroxylase - metabolism; Testosterone; Testosterone - blood; Triazoles
• ISSN: 1945-7170; 0013-7227; 1945-7170
• DOI: 10.1210/en.2017-03218

Abstract Polycystic ovary syndrome (PCOS), the most common endocrinopathy in women of reproductive age, is characterized by hyperandrogenism, anovulation, and polycystic ovaries. Although its etiology is unknown, excess androgens are thought to be a critical factor driving the pathology of PCOS. We previously demonstrated that continuous exposure to the aromatase inhibitor letrozole (LET) in mice produces many hallmarks of PCOS, including elevated testosterone (T) and luteinizing hormone, anovulation, and obesity. In the current study, we sought to determine whether androgen receptor (AR) actions are responsible for any of the phenotypes observed in LET mice. C57BL/6 female mice were subcutaneously implanted with LET or placebo control and subsequently treated with the nonsteroidal AR antagonist flutamide or vehicle control. Flutamide treatment in LET females reversed elevated T levels and restored ovarian expression of Cyp17a1 (critical for androgen synthesis) to normal levels. Pituitary expression of Lhb was decreased in LET females that received flutamide treatment, with no changes in expression of Fshb or Gnrhr. Flutamide treatment also restored estrous cycling and reduced the number of ovarian cyst-like follicles in LET females. Furthermore, body weight and adipocyte size were decreased in flutamide-treated LET females. Altogether, our findings provide strong evidence that AR signaling is responsible for many key reproductive and metabolic PCOS phenotypes and further establish the LET mouse model as an important tool for the study of androgen excess. Female mice were treated with letrozole or placebo and then exposed to 2.5 weeks of flutamide or control. We found that flutamide treatment reversed many PCOS phenotypes induced by letrozole.