What is the etiology and pathophysiology of Polycystic Ovary Syndrome (PCOS)?

Etiology and Pathophysiology of Polycystic Ovary Syndrome (PCOS)

PCOS is a complex polygenic disorder where altered hypothalamic-pituitary-ovarian function interacts with insulin resistance and hyperinsulinemia to drive androgen excess, creating a self-perpetuating cycle of reproductive, metabolic, and endocrine dysfunction. 1, 2

Etiology

Genetic Basis

• PCOS demonstrates autosomal dominant inheritance patterns but is fundamentally a multigene disorder with no single fully penetrant variant identified across families 3, 4
• Multiple genetic loci contribute to disease susceptibility, affecting pathways controlling androgen production, insulin signaling, folliculogenesis, and metabolic regulation 3, 5
• Genome-wide association studies have identified specific genes linked to hyperandrogenism, ovulatory dysfunction, and metabolic features, though the physical and genetic interactions between these elements remain incompletely understood 3, 4

Environmental and Lifestyle Triggers

• Weight gain serves as a major trigger for PCOS development in genetically susceptible women, with obesity and PCOS demonstrating a complex bidirectional relationship 2
• Physical inactivity and unhealthy dietary patterns (lower diet quality, higher cholesterol intake, lower magnesium and zinc intake) actively contribute to disease progression 1, 5
• Prenatal exposure to excess anti-Müllerian hormone (AMH), androgens, or environmental toxins (bisphenol-A, endocrine-disrupting chemicals) may represent etiologic mechanisms 5, 6
• Advanced glycation end-products (AGEs), whether endogenously produced or consumed through diet, exaggerate PCOS symptoms and impair ovarian function 5, 6

Drug-Induced PCOS

• Certain medications, particularly valproate (antiepileptic drug), can trigger or exacerbate PCOS 2
• Antiepileptic and psychiatric medications have been implicated in PCOS development 5

Pathophysiology

Neuroendocrine Dysfunction

The core neuroendocrine abnormality involves accelerated gonadotropin-releasing hormone (GnRH) pulsatility, which drives the entire hormonal cascade. 1, 2

• Dysregulated kisspeptin, dynorphin, and neurokinin B signaling in KNDy neurons initiates increased GnRH pulsatility 6
• Modified GABAergic input further disrupts normal hypothalamic signaling 6
• Hypersecretion of luteinizing hormone (LH) relative to follicle-stimulating hormone (FSH) results, typically producing an LH/FSH ratio >2 1, 2
• Elevated LH directly stimulates ovarian theca stromal cells to overproduce androgens, particularly testosterone 2
• FSH levels remain relatively low or normal, creating hypofunction of the FSH-granulosa cell axis 2

Ovarian-Level Consequences

• Theca stromal cell hyperactivity produces excessive androgens in response to elevated LH 1, 2
• Granulosa cells fail to mature properly due to inadequate FSH stimulation and toxic effects of excess androgens 2
• Follicles arrest at 2-8mm diameter rather than progressing to dominant follicle selection, creating the characteristic polycystic appearance on ultrasound 2
• Chronic anovulation manifests as oligomenorrhea or amenorrhea 1
• Low mid-luteal phase progesterone levels confirm anovulation 2

Insulin Resistance and Metabolic Dysfunction

Insulin resistance and hyperinsulinemia are not merely consequences but active drivers of anovulation in PCOS, present in both lean and obese women. 1, 2

• Hyperinsulinemia directly stimulates ovarian androgen production by theca cells, independent of LH 1, 2
• Insulin suppresses hepatic production of sex hormone-binding globulin (SHBG), increasing free testosterone levels 2
• Fasting glucose/insulin ratio >4 suggests reduced insulin sensitivity 1
• Mitochondrial dysfunction and chronic inflammation create oxidative stress, forming a self-perpetuating cycle that compromises oocyte quality and worsens metabolic imbalance 6
• Abdominal obesity exacerbates both insulin resistance and hyperandrogenism 1

Inflammatory Component

• Chronic low-grade inflammation characterizes PCOS, with alterations in the follicular microenvironment contributing to infertility 5
• Hyperandrogenism drives reactive oxygen species (ROS) formation, oxidative stress, and abdominal adiposity, which in turn increase inflammation, ROS production, insulin resistance, and hyperandrogenemia 5
• Women demonstrate greater occurrence of inflammatory disorders associated with hypertension and cardiovascular disease 7

Post-Translational Modifications

• Phosphorylation, methylation, acetylation, and ubiquitination play essential roles in granulosa cell function, androgen receptor signaling, insulin sensitivity, and oocyte maturation 6
• These modifications represent emerging therapeutic targets for future interventions 6

Long-Term Metabolic and Cardiovascular Consequences

• Women with PCOS face increased risk for type 2 diabetes, metabolic syndrome, dyslipidemia, and hypertension 7, 1
• Endothelial dysfunction serves as a marker of cardiovascular disease risk, with multiple studies demonstrating endothelial function abnormalities and subclinical atherosclerosis in PCOS 7
• Metabolic-associated fatty liver disease, gestational hypertension, and pregnancy complications occur with higher frequency 7
• Whether PCOS itself confers high cardiovascular disease risk or whether associated cardiometabolic features drive this risk remains debated 7

Clinical Diagnostic Markers

• Elevated LH and LH/FSH ratio >2 2
• Elevated testosterone (biochemical hyperandrogenism) 2
• Ultrasound showing >10 peripheral follicles 2-8mm in diameter (polycystic ovarian morphology) 2
• Low mid-luteal phase progesterone confirming anovulation 2

Important Clinical Caveat

PCOS should not be confused with isolated polycystic ovaries, which occurs in 17-22% of the general population without the syndrome's metabolic and reproductive consequences. 2