An extensive body of literature indicates that estrogen, progesterone, and testosterone play important regulatory roles in the circadian rhythms of hamsters and rats. However, this area has received little systematic attention in humans. This experiment is designed to study the circadian rhythms of male and female volunteers under pharmacologically controlled hormonal conditions. Normal volunteers are treated with Leuprolide acetate (Lupron), a gonadotropin releasing hormone (GnRH) agonist for two (men) or three (women) months. The treatment temporarily suppresses the endogenous secretion of gonadotropins and gonadal steroids. In the course of Lupron treatment, hormone replacement is prescribed so that female subjects can be studied in three hormonal conditions (hypogonadal, estrogen, progesterone), while men can be studied in two (hypogonadal, testosterone). In each of these hormonal conditions, the subjects' circadian rhythms are studied through the use of sleep logs, wrist activity monitors, and rectal temperature monitors. In addition, during a 48-hour period in each of the conditions, subjects are admitted for intensive evaluation that includes a night of EEG-monitored sleep and a 24-hour constant routine procedure. The constant routine procedure is designed to minimize the masking effects of sleep, light, and caloric loading on circadian rhythms. During this procedure, blood samples are drawn for the measurement of TSH and melatonin. Two women and five men have completed the study, with another woman and six men currently enrolled. Melatonin data are available for two women and two men. These preliminary data support the hypothesis that gonadal steroids do regulate circadian rhythms in humans. In the two women, the hypogonadal state is associated with an increase in the amplitude and duration of melatonin secretion, while estrogen appears to phase-advance (shift earlier) the time of onset of nocturnal melatonin secretion. In the two men, the time of onset of nocturnal melatonin secretion is later in the testosterone condition, compared to the hypomgonadal condition. This line of research is important because of possible etiologic links between sleep and affective illness, and between gonadal steroids and affective illness. For example, results from project ZO1 MH 02614-01 CPB indicate that changes in the timing of circadian phase, such as those caused by gonadal steroids in animals, may have etiologic significance in rapid cycling bipolar disorder. If gonadal steroids have phase- shifting effects in humans, this may explain the increased prevalence of rapid cycling bipolar disorder (RCBD) in women, compared to bipolar men. In addition, the protocol may elucidate some of the effects of hormone replacement therapy on sleep and circadian rhythms in peri- and post- menopausal women.
