Osteocalcin (OC), the major noncollagenous bone protein, is a vitamin K-dependent protein which is synthesized in osteoblasts. Serum OC is increased in patients with certain metabolic bone diseases, but little is known about the effects of menopause, castration, and the estrogen-replacement therapy on serum OC. In this study, we attempted to determine the serum OC level before and after menopause and castration, and the effects of estrogen on serum OC were also studied. Mean serum OC in women who underwent menopause or castration within 5 years was 4.56 +/- 1.74 ng/ml (mean +/- SD) and the concentration was significantly higher than that of premenopausal women. Serum OC was then, transiently reduced but increased again when estrogen deprived conditions lasted for more than 10 years. Estrogen replacement therapy (conjugated estrogen 0.625 mg/day for 6 months) could decrease not only serum Ca. P and ALP but also the serum OC from 4.45 +/- 1.40 to 2.97 +/- 1.43 ng/ml (p less than 0.001). There was a significant correlation between the percent changes in serum OC and ALP before and after estrogen administration (r = 0.60, p less than 0.05).