Although age-related decrease in melatonin secretion in humans and animals is well documented, there is a paucity of data on the precise changes in melatonin secretion that occur during the perimenopausal period. The present study was designed to measure changes in nocturnal melatonin and to characterize the role played by estrogen in controlling nocturnal melatonin secretion in perimenopausal women. Nocturnal serum melatonin concentrations were determined every 2 hr in 46 premenopausal women, 44 postmenopausal women, and 11 premenopausal women with uterine leiomyoma scheduled for hysterectomy and bilateral salpingo-oophorectomy. Nocturnal serum melatonin secretion in premenopausal women declined moderately from 17 to 45 years of age, and increased during the period from 46 to 50 years of age. Among postmenopausal women, a steep, age-related decline in nocturnal melatonin secretion was found for up to 15 years postmenopause, followed by an extremely gradual decline thereafter. A significant negative correlation was observed between the peak serum melatonin concentration and the serum 17 beta-estradiol concentration in premenopausal women aged 40-50 years (r = -0.661, P<0.0005). Daily oral administration of conjugated estrogen (0.625 mg) to postmenopausal women suppressed nocturnal melatonin secretion (P<0.005). A low estrogen state, induced by oophorectomy of premenopausal women with uterine leiomyoma led to an increase in nocturnal melatonin secretion (P<0.0001). Our findings suggest that transient elevated nocturnal melatonin secretion during menopause may be related to the existence of a low estrogen environment. The age-related decrease in melatonin secretion observed in other conditions is most likely attributable to other age-related factors.