What is the pathophysiology of polycystic ovary syndrome (PCOS)?

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 Pathophysiological Mechanisms

Neuroendocrine Dysfunction

• Acceleration of pulsatile gonadotropin-releasing hormone (GnRH) secretion leads to disruption of the normal hypothalamic-pituitary-ovarian axis 1
• Hypersecretion of luteinising hormone (LH) relative to follicle-stimulating hormone (FSH), often resulting in an elevated LH/FSH ratio >2 1
• Altered hypothalamic signaling contributes to ovulatory dysfunction and hormonal imbalance 1

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 (2-8mm) and polycystic ovarian morphology 1
• Chronic anovulation manifests as oligomenorrhea or amenorrhea 1

Insulin Resistance and Hyperinsulinemia

• Insulin resistance is a central feature in PCOS pathophysiology, present in both lean and obese women with PCOS 1
• Hyperinsulinemia directly stimulates ovarian androgen production and decreases sex hormone binding globulin (SHBG) production 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

Hyperandrogenism

• Excess androgen production primarily from ovarian theca cells, with some contribution from adrenal glands 1
• Elevated testosterone (>2.5 nmol/L) and other androgens disrupt follicular development 1
• Clinical manifestations include hirsutism, acne, and male-pattern hair loss 1, 2
• Hyperandrogenism further exacerbates insulin resistance, creating a self-perpetuating cycle 3

Genetic and Environmental Factors

• PCOS has a strong genetic component with autosomal dominant inheritance patterns, though it is increasingly recognized as a multigene disorder 4, 5
• Obesity genes are noted in genetic studies of PCOS, highlighting the bidirectional relationship between PCOS and obesity 1
• Prenatal androgen exposure may program fetal tissues for PCOS development later in life 4, 3
• Environmental factors make larger contributions than genetic factors in PCOS development, including intrauterine environment, follicular microenvironment, and lifestyle factors 3

Metabolic Consequences

• Abdominal obesity is common and exacerbates both insulin resistance and hyperandrogenism 1
• Increased risk for type 2 diabetes, metabolic syndrome, and cardiovascular disease 1, 2
• Chronic low-grade inflammation contributes to insulin resistance and reproductive dysfunction 4
• Altered lipid metabolism with tendency toward dyslipidemia 2

Reproductive Consequences

• Chronic anovulation leads to infertility in many women with PCOS 6
• Low mid-luteal phase progesterone levels (<6 nmol/L) indicate anovulation 1
• Endometrial dysfunction increases risk for endometrial hyperplasia and cancer 2
• Altered follicular microenvironment affects oocyte quality 4, 3

Clinical Phenotypes

• The Rotterdam criteria (requiring two of three features: hyperandrogenism, oligo/anovulation, and polycystic ovaries) generates four distinct phenotypes 6
• Phenotypic expression varies based on genetic predisposition, environmental factors, and metabolic status 5
• The 2023 International Evidence-based Guideline PCOS criteria has updated diagnostic approaches, differentiating between adolescent and adult criteria 1

Comorbidities and Complications

• Increased risk for obesity, diabetes, metabolic pregnancy complications, cardiovascular disease, and sleep apnea 1
• At least twofold increased risk of endometrial cancer due to unopposed estrogen exposure 2
• Higher prevalence of psychological disorders including depression and anxiety 6, 2
• Potential for long-term health consequences across the lifespan 6

Clinical Implications

• Early identification and management of PCOS is essential to prevent long-term metabolic and reproductive complications 1, 2
• Weight management is crucial as weight reduction improves both reproductive and metabolic consequences of PCOS 1
• Insulin-sensitizing agents like metformin can address the underlying insulin resistance 2
• Hormonal therapy with combined oral contraceptives helps regulate menstrual cycles and reduce hyperandrogenism 2