What is the role of insulin in Polycystic Ovary Syndrome (PCOS)?

The Role of Insulin in Polycystic Ovary Syndrome (PCOS)

Insulin resistance is a central pathophysiologic driver in PCOS, present regardless of body weight, causing compensatory hyperinsulinemia that directly worsens hyperandrogenism through effects on the pituitary, liver, and ovaries, while simultaneously increasing risks for type 2 diabetes, cardiovascular disease, and reproductive dysfunction. 1

Core Pathophysiologic Mechanisms

Insulin Resistance and Hyperinsulinemia

• Insulin resistance occurs in both lean and obese women with PCOS, affecting the majority of patients independent of BMI 1
• The hyperinsulinemia resulting from insulin resistance is not purely compensatory—it also reflects decreased insulin clearance, which is a distinct metabolic defect in PCOS separate from peripheral insulin sensitivity 2
• Women with PCOS demonstrate metabolic clearance rates of insulin (MCRI) approximately 40% lower than matched controls (420 vs. 743 ml/m²/min), directly correlating with their elevated insulin levels 2

Direct Effects on Reproductive Function

• Hyperinsulinemia directly stimulates ovarian androgen production by acting on theca cells, independent of luteinizing hormone (LH) 3
• Insulin amplifies LH-stimulated androgen synthesis while simultaneously suppressing hepatic sex hormone-binding globulin (SHBG) production, increasing free testosterone levels 3
• At the pituitary level, insulin enhances GnRH-stimulated LH secretion, perpetuating the neuroendocrine dysfunction characteristic of PCOS 4

Metabolic Consequences

• Insulin resistance predisposes to impaired glucose tolerance and type 2 diabetes, with 38% of PCOS women demonstrating abnormal glucose tolerance (14% impaired fasting glucose, 17% impaired glucose tolerance, 7% diabetes) 5
• The insulin resistance pattern includes elevated triglycerides, increased small dense LDL cholesterol, and decreased HDL cholesterol, creating a cardiovascular risk profile 1
• Chronic hyperinsulinemia drives mitochondrial dysfunction and oxidative stress, creating a self-perpetuating cycle that compromises oocyte quality and worsens metabolic imbalance 4

Clinical Screening and Assessment

Recommended Testing

• All women with PCOS should undergo screening for type 2 diabetes using fasting glucose followed by a 2-hour glucose level after a 75-gram oral glucose load 1
• Fasting lipoprotein profiles (total cholesterol, LDL, HDL, triglycerides) should be obtained in all PCOS patients due to insulin resistance-associated dyslipidemia 1
• Calculate BMI and waist-hip ratio as markers of metabolic risk 1

Practical Insulin Resistance Screening

• A fasting glucose-to-insulin ratio (G:I) below 4.5 serves as an effective screening test for insulin resistance in PCOS, with 95% sensitivity and 84% specificity 6
• This simple ratio correlates better with gold-standard insulin sensitivity testing than fasting insulin alone or oral glucose tolerance test parameters 6
• Physical examination should specifically assess for acanthosis nigricans, a cutaneous marker of severe insulin resistance 1

Therapeutic Implications

First-Line Management

• Lifestyle modification targeting 5-10% weight loss through diet and exercise is first-line therapy, as it directly improves insulin sensitivity and reduces hyperinsulinemia 1, 7
• Even modest weight loss of 5% improves both metabolic and reproductive abnormalities by reducing insulin resistance 7

Pharmacologic Insulin Sensitization

• Metformin improves insulin sensitivity and is associated with decreased circulating androgens, better glucose tolerance, and improved metabolic outcomes 1
• Metformin has a favorable weight profile (tends to decrease weight) compared to thiazolidinediones (which increase weight) 1
• For ovulation induction, interventions improving insulin sensitivity increase ovulation frequency based on good and consistent scientific evidence 1
• Metformin appears safe in pregnancy according to ACOG, though it lacks FDA approval specifically for PCOS treatment 1, 7

Treatment Hierarchy

• Begin with regular exercise and weight control before initiating drug therapy for metabolic management 1
• For women attempting conception: start with lifestyle modification, then clomiphene citrate (80% ovulation rate, 50% conception rate among ovulators) 1, 7
• For women not attempting conception: combination oral contraceptives suppress ovarian androgen secretion and increase SHBG, though they may worsen triglycerides 1

Critical Clinical Pitfalls

• Do not assume insulin resistance only affects obese PCOS patients—lean women with PCOS also demonstrate significant insulin resistance requiring screening and management 1
• Obesity exacerbates but does not cause the insulin resistance in PCOS—the metabolic defect is intrinsic to the syndrome 1
• While oral contraceptives effectively manage hyperandrogenism, they may worsen the lipid profile through increased triglycerides, requiring ongoing metabolic monitoring 1
• The role of insulin-sensitizing agents in preventing long-term cardiovascular disease remains unknown, though they improve intermediate risk factors 1