Reduced CAG Repeats in the Androgen Receptor Gene May Independently Cause Polycystic Ovarian Syndrome

Polycystic ovarian syndrome (PCOS) affects over 116 million women globally and is typically linked with excess androgens such as testosterone. Many patients, however, display classic PCOS symptoms despite normal serum androgen. One proposed mechanism for these cases involves a shortened CAG (i.e., encodes glutamine) repeat length in the androgen receptor (AR) gene, which increases AR activity without elevating testosterone. Fewer glutamine repeats alter the AR's N-terminal domain and may contribute to strengthened interactions with co-activators and enhanced transcription of androgen-regulated genes. Heightened AR activity in hypothalamus neurons stimulates increased pulsatile release of gonadotropin-releasing hormone (GnRH), which disrupts pituitary secretion dynamics and favors luteinizing hormone (LH) over follicle-stimulating hormone (FSH). This altered LH/FSH ratio leads to impaired folliculogenesis, anovulation and other hallmark PCOS symptoms. Targeting AR activity directly, for example by using compounds that covalently modify the AR N-terminal domain to suppress activity, may therefore offer a more precise treatment strategy for PCOS.