Mouse Study Hints at Specific Brain Receptor behind PCOS Symptoms

Deletion of androgen receptors (ARs) in leptin receptor (LepRb) neurons improves estrous cycles, providing a possible therapeutic target for the symptoms of polycystic ovarian syndrome (PCOS), according to a mouse study recently published in Endocrinology.

Researchers led by Carol F. Elias, PhD, of the University of Michigan Medical School’s Department of Molecular and Integrative Physiology, point out that mice with neuronal deletion of ARs are protected from development of anovulation, polycystic ovaries, and metabolic abnormalities on exposure to androgen excess. “However, the population of AR neurons that are adversely affected is still unknown,” the authors write.

Elias and her team, as well as others, have previously shown that AR is highly expressed in LepRb neurons, particularly in the arcuate (ARH) and the ventral premammillary nuclei (PMv). For this study, researchers hypothesized that leptin could be a link between metabolism and reproduction, since a subpopulation of people with PCOS are more likely to have diabetes and obesity. “Owing to the role of leptin in reproductive and metabolic regulation, we hypothesized that LepRb neurons have a role in the reproductive dysfunction caused by hyperandrogenism in female mice,” the authors write. “In this study, we examined if LepRb-specific deletion of AR protects against the development of reproductive dysfunction in a prenatal model of female androgen excess.”

The researchers exposed mice that had androgen receptors deleted from leptin receptor neurons to excess androgens prenatally. These mice had improvement in some PCOS symptoms including regulation of their estrous cycles.

“In summary, our findings demonstrate that androgen action via AR in LepRb cells has an important role in the hyperandrogenism-induced anestrus of mice,” the authors conclude. “They also strongly suggest a dissociation between the brain sites acting on the control of pubertal maturation and female cyclicity in mice.”

First author Alexandra Cara, PhD, a former graduate student in the U-M Medical School’s Department of Molecular and Integrative Physiology and current postdoctoral research fellow at the University of California, Los Angeles says she hopes follow up studies will explore androgen exposure around puberty, as this type of model tends to mimic the weight gain found in some people with PCOS.

“I hope these mouse studies can find better therapeutic targets for people with PCOS,” Cara says. “The first intervention offered is lifestyle modification, like diet and exercise, but as anyone with the condition would tell you, that doesn’t help everything.”