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

Pathophysiology of Polycystic Ovary Syndrome (PCOS)

PCOS pathophysiology fundamentally involves the interaction of disrupted hypothalamic-pituitary-ovarian axis function with insulin resistance and hyperinsulinemia, creating a self-perpetuating cycle of androgen excess that drives both reproductive and metabolic dysfunction. 1

Core Neuroendocrine Dysfunction

The hypothalamic-pituitary-ovarian axis disruption begins at the hypothalamic level and cascades through the entire reproductive system:

• Accelerated GnRH pulsatility drives the primary hormonal imbalance, initiated by dysregulated kisspeptin, dynorphin, and neurokinin B signaling in KNDy neurons, along with modified GABAergic input 1, 2
• Hypersecretion of LH relative to FSH results in an elevated LH/FSH ratio often >2, which directly stimulates ovarian theca cells 1
• Ovarian theca stromal cell hyperactivity produces excessive androgens in response to elevated LH 1
• FSH-granulosa cell axis hypofunction impairs normal follicular development and maturation 1
• Follicular arrest at the small antral stage creates the characteristic polycystic ovarian morphology with multiple 2-9mm follicles 1
• Chronic anovulation manifests clinically as oligomenorrhea or amenorrhea, with low mid-luteal phase progesterone levels confirming absent ovulation 1

Insulin Resistance and Metabolic Dysfunction

Insulin resistance represents a central pathophysiological mechanism present in both lean and obese women with PCOS, creating a vicious cycle with hyperandrogenism:

• Hyperinsulinemia directly stimulates ovarian androgen production through insulin receptors on theca cells, independent of LH stimulation 1
• Decreased sex hormone binding globulin (SHBG) production occurs due to hyperinsulinemia, increasing free (bioavailable) androgen levels 1
• Fasting glucose/insulin ratio <4 indicates reduced insulin sensitivity and can be used as a clinical marker 1
• Mitochondrial dysfunction and chronic inflammation drive oxidative stress, creating a self-perpetuating cycle that worsens both insulin resistance and metabolic imbalance 2
• Downstream metabolic dysregulation includes dyslipidemia, glucose intolerance, and increased risk for type 2 diabetes and metabolic syndrome 1

The Hyperandrogenism-Insulin Resistance Cycle

These two core mechanisms exacerbate each other in a bidirectional manner:

• Hyperandrogenism worsens insulin resistance by promoting abdominal adiposity and altering glucose metabolism 2, 3
• Insulin resistance amplifies hyperandrogenism through direct ovarian stimulation and reduced SHBG 1
• Abdominal obesity further exacerbates both insulin resistance and hyperandrogenism, creating a third amplifying factor 1
• Chronic low-grade inflammation with elevated inflammatory markers perpetuates both metabolic and reproductive dysfunction 2, 3

Genetic and Environmental Contributions

PCOS is highly heritable with autosomal dominant patterns, though recent evidence indicates multigene origins:

• Environmental factors contribute more than genetic factors to disease development, including intrauterine environment, follicular microenvironment, and postnatal lifestyle 4
• Prenatal exposure to excess androgens, AMH, or endocrine-disrupting chemicals (bisphenols, EDCs) may program the neuroendocrine dysfunction seen in PCOS 2, 3
• Advanced glycation end-products (AGEs) from diet or endogenous production exaggerate PCOS symptoms and ovarian dysfunction 3
• Physical inactivity and unhealthy dietary patterns play vital roles in disease progression, with women with PCOS showing lower overall diet quality, higher cholesterol intake, lower magnesium and zinc intake, and lower total physical activity 5

Post-Translational Modifications

Emerging evidence identifies specific molecular mechanisms at the cellular level:

• Phosphorylation, methylation, acetylation, and ubiquitination play essential roles in granulosa cell function, androgen receptor signaling, insulin sensitivity, and oocyte maturation 2
• Altered follicular microenvironment with disrupted signaling contributes to infertility in PCOS patients 3

Clinical Implications for Long-Term Health

The pathophysiological mechanisms create multiple downstream health risks:

• Increased cardiovascular disease risk from dyslipidemia, insulin resistance, and chronic inflammation 1, 6
• At least twofold increased risk of endometrial cancer from unopposed estrogen exposure due to chronic anovulation 6
• Elevated risk of depression and obstructive sleep apnea requiring routine screening 6
• Pregnancy complications when conception occurs 5

Early identification and intervention targeting both insulin resistance and hyperandrogenism are essential to interrupt the self-perpetuating pathophysiological cycle and prevent long-term metabolic and reproductive complications. 1