Microglia as candidate links between hormonal signals and neuronal circuits in polycystic ovary syndrome: evidence gaps and a research agenda.

Abstract

Polycystic ovary syndrome (PCOS) combines reproductive endocrine dysfunction with metabolic, autonomic, and neurobehavioral phenotypes, yet the contribution of brain microglia remains uncertain. We conducted a structured narrative review that separates human PCOS evidence, PCOS-like animal findings, PCOS-related cellular observations, and non-PCOS mechanistic bridges. Only three heterogeneous PCOS-like studies directly assessed microglial outcomes, and none established a conserved microglial state, microglial necessity, a complete hormone-microglia-neuron causal chain, or human relevance. We therefore propose the PCOS Neuroimmune-Endocrine Triangular Network (PNETN), a falsifiable framework linking endocrine and metabolic signals, context-dependent microglial states, and neuronal circuits regulating GnRH/KNDy activity, luteinizing-hormone dynamics, ovulation, metabolism, autonomic function, and behavior. The framework defines criteria for causal promotion, including cell identity, regional specificity, temporal precedence, selective perturbation, rescue, orthogonal functional readouts, and independent replication. Microglia should currently be regarded as candidate contributors, not established clinical targets.