What causes insulin resistance in Polycystic Ovary Syndrome (PCOS)?

Why PCOS Causes Insulin Resistance

PCOS causes insulin resistance through an intrinsic post-receptor signaling defect in insulin pathways that exists independently of obesity, affecting both lean and overweight women equally. 1, 2

Core Pathophysiologic Mechanism

The fundamental defect in PCOS involves abnormal serine phosphorylation of the insulin receptor and insulin receptor substrate-1 (IRS-1), which selectively impairs metabolic insulin signaling while paradoxically preserving mitogenic (growth-promoting) pathways. 2 This creates a unique situation where:

• Metabolic actions of insulin are blocked (glucose uptake, lipid metabolism) in skeletal muscle and adipose tissue 2
• Mitogenic and steroidogenic actions remain intact in the ovary, allowing insulin to continue stimulating androgen production 2
• This selective resistance explains why women with PCOS have both metabolic dysfunction AND hyperandrogenism simultaneously 3

The Bidirectional Androgen-Insulin Cycle

High androgen levels themselves augment both hyperinsulinemia and insulin resistance, creating a self-perpetuating vicious cycle. 4 This means:

• Androgens worsen insulin resistance 4, 2
• Insulin resistance leads to compensatory hyperinsulinemia 5
• Hyperinsulinemia directly stimulates ovarian theca cells to produce more androgens, independent of LH 3
• Insulin also suppresses hepatic sex hormone-binding globulin (SHBG) production, increasing free testosterone levels 3
• More androgens further worsen insulin resistance, perpetuating the cycle 4, 2

Genetic and Molecular Basis

The insulin resistance in PCOS appears to involve multiple gene polymorphisms rather than single gene mutations, including: 6

• Insulin receptor substrate (IRS)-1 and IRS-2 variants 6
• Calpain-10 polymorphisms 6
• Peroxisome proliferator-activated receptor gamma (PPARγ) variants 6
• Constitutive activation of serine kinases in the MAPK-ERK pathway in skeletal muscle 2

These genetic variants are common in the general population but alone cannot cause PCOS—they require additional factors (obesity, androgens, environmental triggers) to manifest clinically. 6

The Intrinsic Nature of Insulin Resistance in PCOS

Approximately 50-70% of all women with PCOS have insulin resistance, and this occurs independently of body weight. 7 Critical points:

• Lean women with PCOS can have the same degree of insulin resistance as obese women with PCOS 1, 2
• The insulin resistance is intrinsic to the syndrome itself, not simply a consequence of obesity 1
• However, obesity significantly exacerbates the underlying insulin resistance 5, 7
• Visceral adiposity is particularly problematic, with visceral fat directly correlated with hyperinsulinemia and inversely correlated with insulin sensitivity 5

Beta Cell Dysfunction Component

Women with PCOS also have abnormalities in pancreatic beta cell function, not just peripheral insulin resistance. 1 Specifically:

• Adolescents with PCOS and impaired glucose tolerance show a 50% reduction in first-phase insulin secretion 5, 1
• This beta cell dysfunction means that even the compensatory hyperinsulinemia may eventually fail 5
• The combination of insulin resistance plus beta cell dysfunction explains the high progression rate to type 2 diabetes in PCOS 5

Clinical Implications

All women with PCOS require diabetes screening regardless of BMI or body weight, using a 2-hour oral glucose tolerance test with 75g glucose load. 1 This is because:

• Insulin resistance exists even in lean women with PCOS 1, 2
• The American Academy of Family Physicians recommends screening at diagnosis and repeating every 2 years 1
• The OGTT is the best office-based method because it assesses both insulin resistance and glucose intolerance simultaneously 7

Important Mechanistic Nuance

Recent evidence suggests hyperinsulinemia may sometimes precede insulin resistance rather than always being compensatory. 4 This challenges the traditional model and suggests:

• In some women, primary hyperinsulinemia (from beta cell dysfunction or other causes) may drive insulin resistance 4
• High insulin levels can directly cause insulin receptor downregulation and desensitization 4
• The heterogeneous nature of PCOS means the sequence of events likely varies between individuals 4

Common Pitfall to Avoid

Do not assume insulin resistance in PCOS is solely due to obesity—this leads to inadequate screening in lean women and misses the intrinsic metabolic defect that defines the syndrome. 1, 2 Even lean women with PCOS have marked insulin resistance independent of body composition and require metabolic screening and management. 1, 2