Polycystic Ovary Syndrome (PCOS) is the most common endocrine-metabolic disorder in women (Wolf et al., 2018), and it is characterized primarily by elevated circulating androgen levels. Hyperandrogenism impacts multiple systems, contributing to cardiovascular, metabolic and immune dysfunctions (Teede et al., 2023). Notably, PCOS is also associated with various psychiatric disorders including anxiety, depression, Autism Spectrum Disorders (ASD), Attention-Deficit/Hyperactivity Disorder (ADHD), and eating disorders, among others (Rotem et al., 2021, Katsigianni et al., 2019, Månsson et al., 2008, Cesta et al., 2016).

Several factors may explain this association: stigma and self-image distortions due to the phenotypical characteristics of the condition (Sari et al., 2020), reduced quality of life (Begum et al., 2024), and the potential effects of hyperandrogenism on the development of the Central Nervous System (CNS). Regarding the latter, women with PCOS experience hyperandrogenism during two critical periods of CNS development: intrauterine life (Sir-Petermann et al., 2002)and adolescence (Sir-Petermann et al., 2009). As androgens exert organizational and activational effects on the brain, this exposure could alter normal developmental trajectories.

The impact of being exposed to a pathological hormonal environment during these two periods can be better understood through the dual-hit hypothesis. This hypothesis proposes that an early-life genetic or environmental insult establishes a neural predisposition to psychopathology, which may manifest later when a “second hit” occurs. Initially developed in cancer research (Knudson, 2001), the dual-hit hypothesis has proven valuable for studying multifactorial neuropsychiatric disorders such as epilepsy (Love, 2005), depression (McNaughton and Glue, 2020), anxiety (Catuzzi and Beck, 2014), autism (Picci and Scherf, 2014) and schizophrenia (Maynard et al., 2001). This perspective aligns with Baker’s developmental origins of health and disease hypothesis, which links adverse intrauterine conditions to health issues in adulthood (Wadhwa et al., 2009). Evidence suggests that PCOS exemplifies these principles, indicating that early insults that increase susceptibility to the metabolic and reproductive aspects of PCOS may also influence neurodevelopment in affected women.

In this review, we will discuss the pathophysiology and etiology of PCOS, focusing on the alterations in steroidogenesis that result in hyperandrogenism during intrauterine life and adolescence. We will then explore how hyperandrogenism exposure during these sensitive periods of brain development may lead to neurodevelopmental alterations and an increased risk of neuropsychiatric disorders. Finally, we will frame the literature within the double-hit hypothesis, highlighting how this approach could guide the development of therapies targeting PCOS hormonal abnormalities during sensitive brain developmental periods to improve mental health outcomes in this population.