Androgen receptor (AR) signaling is responsible for key reproductive and metabolic polycystic ovary syndrome (PCOS) phenotypes, according to animal study, the results of which were published recently in Endocrinology.
Researchers led by Pamela L. Mellon, PhD, of the University of California, San Diego, point out that animal models have proven to be a valuable resource in studying PCOS mechanisms and pathways, which is important since PCOS is the most common reproductive disorder in women. Mellon’s team had previously shown that continuous exposure to aromatase inhibitor letrozole (LET) in mice produces many hallmarks of PCOS, including elevated testosterone (T) and luteinizing hormone (LH), anovulation, and obesity. “In the present study,” the authors write, “we sought to determine whether [AR] actions are responsible for any of the phenotypes observed in LET mice.” They go on to write that understanding specific contributions to androgens to LET PCOS phenotypes will allow insight into the mechanisms underlying reproductive and metabolic dysfunction in this model, and lay the groundwork for combining transgenic mouse models with LET treatment to study the pathogenesis of PCOS.
The researchers implanted female mice with LET or placebo control (CON), and then treated the mice with an AR antagonist 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,” the authors write. “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.”
Based on these results, Mellon and her team demonstrated that blocking AR with the AR antagonist flutamide ameliorates or reverses PCOS phenotypes in the LET mouse after only a couple of weeks. Furthermore, the authors note that PCOS phenotypes similar to ones they found to be reversed with flutamide treatment in LET females have been improved with antiandrogen treatment in animal and human models. “Altogether,” the authors conclude, “we have shown that many reproductive and metabolic aspects of the LET PCOS phenotype can be attributed to AR signaling, establishing the relevance and importance of this model for the study of mechanisms underlying PCOS.”