New Perspectives on the Pathogenesis of PCOS: Neuroendocrine Origins

Excess prenatal anti-Müllerian hormone and excess prenatal and postnatal androgen exposure lead to specific hypothalamic circuit changes in the female brain that are associated with impaired fertility. Programmed enhancement of GABAergic innervation and transmission to GnRH neurons may underpin hyperactive GnRH/LH secretion in PCOS. Strong evidence now supports hyperandrogenism as a causative factor in the pathogenesis of PCOS. Silencing of androgen receptor actions specifically in the brain protects against the development of numerous reproductive and metabolic PCOS features in a mouse PCOS model. Therapeutic targeting to suppress androgen excess or modulation of GnRH activity are logical approaches for the treatment of PCOS symptoms. Polycystic ovary syndrome (PCOS) is the most common endocrine condition in reproductive-aged women. It is characterized by reproductive, endocrine, metabolic, and psychological features. The cause of PCOS is unknown, thus there is no cure and its management remains suboptimal because it relies on the ad hoc empirical management of symptoms only. We review here the strong support for PCOS having a neuroendocrine origin. In particular, we focus on the role of aberrant hypothalamic–pituitary function and associated hyperandrogenism, and their role as major drivers of the mechanisms underpinning the development of PCOS. This important information now provides a target site and a potential mechanism for the future development of novel, targeted, and mechanism-based effective therapies for the treatment of PCOS. Polycystic ovary syndrome (PCOS) is the most common endocrine condition in reproductive-aged women. It is characterized by reproductive, endocrine, metabolic, and psychological features. The cause of PCOS is unknown, thus there is no cure and its management remains suboptimal because it relies on the ad hoc empirical management of symptoms only. We review here the strong support for PCOS having a neuroendocrine origin. In particular, we focus on the role of aberrant hypothalamic–pituitary function and associated hyperandrogenism, and their role as major drivers of the mechanisms underpinning the development of PCOS. This important information now provides a target site and a potential mechanism for the future development of novel, targeted, and mechanism-based effective therapies for the treatment of PCOS.