From follicular monoamines to the neuro-immuno-endocrine ovary: three decades of progress in ovarian neuroendocrinology

For much of the twentieth century, ovarian physiology was interpreted primarily through the classical hypothalamic-pituitary-ovarian axis. During the early 1990s, however, clinical and experimental studies demonstrated the presence of catecholamines and serotonin in human follicular fluid and showed that cultured human granulosa cells respond directly to neurotransmitters, including noradrenaline, dopamine, acetylcholine and histamine, by altering steroid hormone secretion. These observations challenged the traditional endocrine paradigm and suggested that neurotransmitters participate in the local regulation of follicular maturation and steroidogenesis. Over the following three decades, these early findings evolved into the broader field of ovarian neuroendocrinology. Experimental and clinical studies established that autonomic innervation actively contributes to follicular development, ovulation, luteinization and endocrine activity. Particular attention has focused on sympathetic noradrenergic pathways, whose dysregulation has been implicated in reproductive disorders, especially polycystic ovary syndrome. The subsequent discovery of locally produced acetylcholine in granulosa cells further demonstrated that neurotransmitter signalling within the ovary is not restricted to neural inputs but also involves intrinsic intraovarian regulatory mechanisms. More recent research has revealed extensive interactions among neural pathways, endocrine regulators, metabolic signals and immune mediators. These integrated networks link ovarian function to systemic physiological processes including energy homeostasis, stress adaptation and reproductive aging. This historical review traces the development of ovarian neuroendocrinology from the first demonstration of intrafollicular monoamines to contemporary concepts of integrated ovarian regulation. Collectively, the available evidence supports the view that the ovary functions as a neuro-immuno-endocrine organ whose activity emerges from continuous interactions among neural, hormonal, immune and metabolic signalling systems.