The impact of weight reduction on metabolic, endocrine, and anthropometric variables was studied in 13 obese, insulin-resistant women with the polycystic ovary syndrome (PCOS). Insulin sensitivity (euglycemic insulin clamp), insulin secretion and glucose tolerance (iv glucose tolerance test), basal sex steroid hormones, gonadotropins and free fatty acids (FFA), skin folds and waist hip ratio (WHR) were evaluated before (PCO-BD) and after (PCO-AD) diet-induced weight reduction to a weight stable level [mean (SD) diet duration 14.9 (6.2) months]. Mean weight loss was 12.4 kg (4.7; P < 0.0001), equalling a reduction from a body mass index (BMI) of 32.2 (3.7) kg/m2 to 27.6 (3.7; P < 0.0001) kg/m2. The results were compared with those of two groups of weight stable (no diet) women, 21 with PCOS (PCO-ND) and 23 normal control subjects (C), who were matched to the BMI the diet group reached after weight loss. Insulin sensitivity index (M/I) improved on average 132% (P < 0.001) and plasma FFA by 32% (P < 0.01), serum sex hormone binding globulin levels increased by 35% (P < 0.01), and the sum of truncal-abdominal skin-folds (subscapular, umbilical, and suprailiacal) were reduced by 28% (P < 0.0001), whereas the early insulin response to iv glucose, the levels of gonadotropins and androstenedione, and the femoral sc fat did not change significantly with weight loss. M/I, levels of SHBG and FFA and truncal-abdominal fat reached levels similar to the controls, whereas PCO-ND had lower M/I (P < 0.01) and SHBG levels (P < 0.0001), greater concentrations of FFA (P < 0.01) and truncal-abdominal fat (P < 0.05) than C. Among women with normal glucose tolerance, the insulin increment was higher in both PCO-AD (P < 0.05) and PCO-ND (P < 0.01) than in C. There was a strong correlation between M/I and sum of truncal-abdominal skinfolds in all groups (PCO-BD: r = 0.82; P < 0.001, PCO-AD: r = 0.68; P < 0.05, PCO-ND: r = 0.81; P < 0.0001, C: r = 0.44; P < 0.05). The variation in M/I in PCO-AD and PCO-ND (pooled) was best explained by FFA and truncal-adbominal fat (model R2 = 0.67). In conclusion, insulin resistance in obese women with PCOS was reduced by weight loss to similar levels as BMI-matched control subjects, suggesting that insulin resistance in PCOS is not a feature of PCOS per se.(ABSTRACT TRUNCATED AT 400 WORDS)