Abstract
Hyperandrogenism is the most common diagnostic criterion of polycystic ovary syndrome (PCOS), and androgen signalling through the androgen receptor (AR) is implicated in promoting reproductive and metabolic dysfunction. However, the specific physiological targets of female androgen excess in driving PCOS-associated pathology remain poorly understood. Studies in animal models of PCOS suggest liver and adipose tissue may be critical sites of androgen-induced metabolic dysfunction in mouse models of PCOS. We therefore aimed to investigate the therapeutic potential of tissue-specific AR silencing RNA (siRNA) for alleviating PCOS-like metabolic dysfunction. Two preclinical mouse models of PCOS, exposing female mice to androgens (or vehicle controls) either during the prenatal period (gestation day 16-18; prenatal androgenisation, PNA) or chronically from postnatal day 21 (peripubertal androgenisation, PPA), were treated with PBS or with proprietary, tissue-specific AR siRNA to induce AR-knockdown (ARKD). Delivery of AR siRNA, initiated at 3 weeks of age, was directed to either the liver (liver-ARKD), adipose tissue (adipose-ARKD), or both (combination-ARKD). Male and female PNA mice demonstrated mild metabolic impairments (significantly increased weight gain, impaired glucose homeostasis) compared to controls, while PPA females were significantly heavier and showed robust impairments in glucose and insulin homeostasis compared to control females. However, ARKD was unable to alleviate these effects regardless of target tissue, despite inducing a 5-fold reduction in AR gene expression as measured by qPCR. While tissue-level analysis is ongoing to investigate AR protein knockdown, lipid accumulation and metabolic gene expression, evidence to date does not support liver or adipose tissue-specific silencing of AR as a therapeutic treatment for PCOS-associated metabolic dysfunction. These data suggest that other tissues such as the brain may be responsible for androgen-induced metabolic disturbances in PCOS. Alternatively, hyperandrogenism during key developmental windows may program future androgen-independent alterations in metabolic tissue function. Further understanding of how androgens drive reproductive and metabolic programming in females will be critical for the future development of targeted treatments for PCOS.