Objective: We sought to investigate the effect of oral progestins on estrogen-mediated changes in the insulin-like growth factor axis in the peripheral circulation. Study Design: Oral conjugated equine estrogen alone or in combination with medroxyprogesterone acetate, desogestrel, or norethindrone was given in a randomized triple-crossover fashion to 10 healthy postmenopausal women, and the effects on the insulin-like growth factor axis were determined. Results: Baseline circulating insulin-like growth factor I levels were significantly reduced by conjugated equine estrogen (359 ± 54 vs 225 ± 44 ng/mL; P =.0001). This effect was reversed by progestins (medroxyprogesterone acetate, 254 ± 44 ng/mL; desogestrel, 266 ± 50 ng/mL; norethindrone, 286 ± 48 ng/mL; F = 12.2; P =.0015). Free insulin-like growth factor I was reduced by conjugated equine estrogen (1.00 ± 0.15 ng/mL vs 2.10 ± 0.39 ng/mL; P =.004), but addition of progestogens had no further effect. Insulin-like growth factor II and insulin levels were unaffected by conjugated equine estrogen or progestins. Plasma insulin-like growth factor binding protein 1 concentration increased significantly from baseline with conjugated equine estrogen alone (44.1 ± 6.0 vs 154 ± 30 μg/L; P =.003). This rise was opposed by progestins of increasing androgenicity (medroxyprogesterone acetate, 130 ± 26 μg/L; desogestrel, 100 ± 16 μg/L; norethindrone, 78.0 ± 12 μg/L; F = 12.5; P =.0015). Insulin-like growth factor binding protein 3 levels fell with conjugated equine estrogen, and this was reversed by progestins (conjugated equine estrogen, 2.17 ± 0.13 mg/L; vs norethindrone and conjugated equine estrogen, 2.41 ± 0.12 mg/L; F = 7.6; P =.01). Insulin-like growth factor binding protein 4 levels increased with conjugated equine estrogen with or without progestins, whereas insulin-like growth factor binding protein 2 levels were unchanged. Conclusions: Coadministration of androgenic progestins abrogates estrogen-related changes in circulating insulin-like growth factor I, insulin-like growth factor binding protein 1, and insulin-like growth factor binding protein 3. Such hormone replacement therapy–induced changes may have significant consequences for the development of cardiovascular disease and osteoporosis and implications for the use of insulin-like growth factor I in monitoring growth hormone replacement. (Am J Obstet Gynecol 2000;183:593-600.)