Pathophysiology of Polycystic Ovary Syndrome (PCOS)
The pathophysiology of PCOS fundamentally involves the interaction of altered hypothalamic-pituitary-ovarian function and concomitant hyperinsulinemia/insulin resistance with promotion of androgen excess, creating a complex endocrine disorder with reproductive, metabolic, and psychological manifestations. 1
Core Neuroendocrine Mechanisms
- Acceleration of pulsatile gonadotropin-releasing hormone (GnRH) secretion leads to disruption of the normal hypothalamic-pituitary-ovarian axis 1
- Hypersecretion of luteinizing hormone (LH) relative to follicle-stimulating hormone (FSH), often resulting in an elevated LH/FSH ratio >2 1
- Dysregulated kisspeptin, dynorphin, and neurokinin B signaling in KNDy neurons contributes to altered GnRH pulsatility 2
- Modified GABAergic input and increased anti-Müllerian hormone (AMH) further disrupt normal neuroendocrine function 2, 3
Ovarian Dysfunction
- Ovarian theca stromal cell hyperactivity results in excessive androgen production 1
- Hypofunction of the FSH-granulosa cell axis impairs follicular development 1
- Follicular arrest leads to multiple small antral follicles and polycystic ovarian morphology 1
- Chronic anovulation manifests as oligomenorrhea or amenorrhea 1, 4
- Bone morphogenetic proteins (BMPs) expression alterations in oocytes and granulosa cells contribute to abnormal folliculogenesis 3
Insulin Resistance and Metabolic Dysregulation
- Insulin resistance is a central feature in PCOS pathophysiology, present in both lean and obese women with PCOS 5, 1
- Hyperinsulinemia directly stimulates ovarian androgen production and decreases sex hormone binding globulin (SHBG) production, leading to increased free androgens 5, 1
- Insulin resistance creates downstream metabolic dysregulation including dyslipidemia and glucose intolerance 1
- Fasting glucose/insulin ratio >4 is suggestive of reduced insulin sensitivity 1
- Mitochondrial dysfunction contributes to oxidative stress and worsens insulin resistance 2
Hyperandrogenism Mechanisms
- Increased androgen production from ovarian theca cells due to hyperinsulinemia 5, 1
- Decreased SHBG levels lead to higher free testosterone levels 1
- Hyperandrogenism further exacerbates insulin resistance, creating a vicious cycle 2, 3
- Post-translational modifications affect androgen receptor signaling and contribute to hyperandrogenism 2
Inflammatory and Oxidative Stress Pathways
- Chronic low-grade inflammation is present in PCOS 3
- Advanced glycation end-products (AGEs) exaggerate PCOS symptoms and contribute to ovarian dysfunction 3
- Reactive oxygen species (ROS) formation and oxidative stress worsen insulin resistance and hyperandrogenemia 3
- Abdominal adiposity increases inflammation, creating another self-perpetuating cycle 1, 3
Genetic and Environmental Factors
- Complex genetic predisposition involving multiple genes 3, 4
- Prenatal androgen exposure may program fetal tissues for PCOS development later in life 3
- Exposure to endocrine-disrupting chemicals (EDCs) and toxins like bisphenol-A can contribute to PCOS development 2, 3
- Epigenetic modifications affect gene expression related to ovarian function and metabolism 2, 4
Clinical Implications of Pathophysiology
- PCOS affects 8-13% of reproductive-age women according to Rotterdam criteria 5
- Diagnosis requires two of three Rotterdam criteria: oligo/anovulation, hyperandrogenism, and polycystic ovaries 6, 4
- Metabolic consequences include increased risk for type 2 diabetes (4x higher), metabolic syndrome (2x higher), and cardiovascular disease 1, 6
- Reproductive consequences include infertility and increased risk of endometrial cancer (at least 2x higher) 6
- Early identification and management is essential to prevent long-term complications 1
- Weight management is crucial as weight reduction improves both reproductive and metabolic manifestations of PCOS 1, 6
Pathophysiological Basis for Treatment
- Lifestyle modifications target insulin resistance and weight management 5, 6
- Metformin improves insulin sensitivity and metabolic parameters 6, 3
- Oral contraceptives regulate menstrual cycles and reduce androgen levels 6
- Letrozole and clomiphene address ovulatory dysfunction for women seeking pregnancy 6
- Anti-androgens like spironolactone target dermatologic manifestations of hyperandrogenism 6