Central Regulation of PCOS: Abnormal Neuronal-Reproductive-Metabolic Circuits in PCOS Pathophysiology

Abstract

Polycystic ovary syndrome (PCOS) is a common reproductive endocrine disease. PCOS patients are characterized by hyperandrogenemia, anovulation, and metabolic dysfunction. Hypothalamus–pituitary–ovary axis imbalance is considered as an important pathophysiology underlying PCOS, indicating that central modulation, especially the abnormal activation of hypothalamic GnRH neurons plays a vital role in PCOS development. Increased GnRH pulse frequency can promote LH secretion, leading to ovarian dysfunction and abnormal sex steroids synthesis. By contrast, peripheral sex steroids can modulate the action of GnRH neurons through a feedback effect, which is impaired in PCOS, thus forming a vicious cycle. Additionally, hypothalamic GnRH neurons not only serve as the final output pathway of central control of reproductive axis, but also as the central connection point where reproductive function and metabolic state inter-regulate with each other. Metabolic factors, such as insulin resistance and obesity in PCOS patients can regulate GnRH neurons activity, and ultimately regulate reproductive function. Besides, gut hormones act on both brain and peripheral organs to modify metabolic state. Gut microbiota disturbance is also related to many metabolic diseases and has been reported to play an essential part in PCOS development. This review concludes with the mechanism of central modulation and the interaction between neuroendocrine factors and reproductive or metabolic disorders in PCOS development. Furthermore, the role of the gut microenvironment as an important part involved in the abnormal neuronal–reproductive–metabolic circuits that contribute to PCOS is discussed, thus offering possible central and peripheral therapeutic targets for PCOS patients.

The Prevalence of Polycystic Ovary Syndrome, Its Phenotypes and Cardio-Metabolic Features in a Community Sample of Iranian Population: Tehran Lipid and Glucose Study

“…We defined MetS according to the Joint Interim Statement criteria (36) as the presence of any three or more of the following five risk factors: [1] fasting triglycerides (TG) level of ≥150 mg/dl or specific treatment; [2] fasting high-density lipoprotein (HDL) ≤50 mg/dl or specific treatment; [3] raised systolic blood pressure (SBP) ≥130 mmHg, or raised diastolic blood pressure (DBP) ≥85 mm Hg, or receiving treatment; [4] fasting plasma glucose of ≥100 mg/dl or treatment, and [5] high waist circumference using waist-circumference cutoff points of >90 cm according to the population and the country-specific cutoff point for Iranians (37).…”

“…The syndrome is a complex and heterogeneous disorder that may have various clinical manifestations, mainly including hyperandrogenism and/or hyperandrogenemia (HA), oligo/anovulation (OA) and polycystic ovaries morphology (PCOM) (2,3). Although the exact underlying etiology of PCOS remains unclear, emerging evidence suggests that insulin resistance (IR) appears to be implicated in its pathogenesis (4)(5)(6).…”

Therapeutic effect and safety of curcumin in women with PCOS: A systematic review and meta-analysis

“…The pathogenesis may include abnormal gonadotropin secretion and hyperinsulinism caused by IR. Abnormally increased LH pulse frequency and amplitude further enhance androgen synthesis in ovarian theca cell and promote hyperandrogenemia in patients with PCOS ( 62 ). Hyperinsulinemia may cause an augmented androgen production in the adrenal cortex and follicles via stimulation of LH secretion and a decreased SHBG production, resulting elevated androgen levels that may lead to the characteristic clinical manifestations like acne and hirsutism ( 63 ).…”

Present and Future: Crosstalks Between Polycystic Ovary Syndrome and Gut Metabolites Relating to Gut Microbiota

“…Polycystic ovary syndrome (PCOS), characterized by oligo-ovulation or anovulation, hyperandrogenemia, and polycystic ovarian morphology, is a common disorder of the reproductive endocrine system, affecting 8%–13% of the women of reproductive age as well as impairing their fertility and long-term health ( 1 , 2 ). Women with PCOS have a higher risk of infertility and pregnancy complications, accompanied by subsequent complications, such as obesity, type 2 diabetes, non-alcoholic fatty liver disease (NAFLD) ( 3 ), cardiovascular disease ( 4 ), endometrial cancer, and osteoporosis ( 5 ).…”