Polycystic ovary syndrome (PCOS), a prevalent endocrine disorder characterized by hyperandrogenism, has been increasingly associated with a high risk of autism spectrum disorder (ASD) in offspring. The emerging interaction between reproductive endocrinology and neurodevelopmental biology suggests that excessive androgen exposure during gestation may perturb neurotrophic signaling and impair neural circuit formation. Brain-derived neurotrophic factor (BDNF) acts through tropomyosin receptor kinase B receptor to activate downstream phosphoinositide 3-kinase/protein kinase B and extracellular signal-regulated kinase/mitogen-activated protein kinase pathways, both of which are fundamental to neuronal survival and synaptogenesis. Disruption of these signaling cascades under hyperandrogenic conditions may lead to altered neuroarchitecture, impaired synaptic connectivity, and ASD-like behavioral phenotypes. Clinical and experimental studies also implicate aberrant BDNF expression in ovarian dysfunction, oocyte maturation deficits, and placental steroidogenic imbalance, highlighting a shared endocrine-neurodevelopmental axis in PCOS. Moreover, androgen excess may induce epigenetic modifications and post translational alterations of BDNF or tropomyosin receptor kinases B receptors, further compromising downstream signaling. These molecular events can dysregulate the transcriptional control of multiple synaptic and neurodevelopmental genes, thereby promoting atypical neuronal circuit formation. Understanding the interaction between BDNF signaling and androgen excess provides a mechanistic framework to explain how maternal endocrine imbalance influences neurodevelopment of offspring. This review integrates multidisciplinary findings spanning clinical cohorts, animal models, and molecular studies to delineate how androgen-BDNF interactions amplified by epigenetic, transcriptional, and post translational dysregulation underpin key neurodevelopmental disruptions observed in ASD. Furthermore, it emphasizes the translational potential of targeting BDNF-related pathways as early biomarkers or therapeutic entry points to mitigate the intergenerational neurodevelopmental consequences of PCOS.
Nautiyal et al. (Thu,) studied this question.