Sex difference in the near-24-hour intrinsic period of the human circadian timing system

Abstract

The circadian rhythms of melatonin and body temperature are set to an earlier hour in women than in men, even when the women and men maintain nearly identical and consistent bedtimes and wake times. Moreover, women tend to wake up earlier than men and exhibit a greater preference for morning activities than men. Although the neurobiological mechanism underlying this sex difference in circadian alignment is unknown, multiple studies in nonhuman animals have demonstrated a sex difference in circadian period that could account for such a difference in circadian alignment between women and men. Whether a sex difference in intrinsic circadian period in humans underlies the difference in circadian alignment between men and women is unknown. We analyzed precise estimates of intrinsic circadian period collected from 157 individuals (52 women, 105 men; aged 18-74 y) studied in a month-long inpatient protocol designed to minimize confounding influences on circadian period estimation. Overall, the average intrinsic period of the melatonin and temperature rhythms in this population was very close to 24 h [24.15 ± 0.2 h (24 h 9 min ± 12 min)]. We further found that the intrinsic circadian period was significantly shorter in women [24.09 ± 0.2 h (24 h 5 min ± 12 min)] than in men [24.19 ± 0.2 h (24 h 11 min ± 12 min); P < 0.01] and that a significantly greater proportion of women have intrinsic circadian periods shorter than 24.0 h (35% vs. 14%; P < 0.01). The shorter average intrinsic circadian period observed in women may have implications for understanding sex differences in habitual sleep duration and insomnia prevalence.biological rhythm | gender | phase angle O n average, women go to bed earlier and wake up earlier than men, and they are more likely to rate themselves as morning types than men on standardized questionnaires (1). We recently reported a substantial sex difference in the entrainment of human circadian rhythms, such that the circadian rhythms of melatonin and temperature were entrained to an earlier time relative to the nightly sleep/darkness episode in women compared with men (2). The neurobiological mechanism underlying this sex difference in entrained circadian phase, which may have important implications for sleep quality and daytime alertness in women, remains unknown. Animal studies suggest that such differences in entrainment, technically called a phase angle difference between an endogenous rhythm (e.g., nightly secretion of melatonin) and the 24-h environmental light-dark (and wakesleep cycle) to which the rhythm is synchronized, may be attributable to underlying differences in either the resetting sensitivity to environmental synchronizers or the intrinsic period of the circadian pacemaker(s) driving circadian rhythmicity (3-5). Little is known about sex differences in the sensitivity to photic resetting in humans, and no sex difference in the sensitivity to melatonin suppression by light has been reported in most studies (6)(7)(8). Findings from multiple studies in nonhuman animals have demonstra...

Diurnal and circadian variation of sleep and alertness in men vs. naturally cycling women

“…Nevertheless, it should be noted that our sample size is smaller than in these studies, which could have prevented us from detecting between-sex differences. Similar to current findings, a subsequent study using a forced desynchrony protocol also failed to detect a statistically significant sex difference in the circadian phase of melatonin secretion (12). Our prior controlled study found no menstrual phase difference in the circadian melatonin profile (13), although there have been other reports of decreases (30), increases (31), phase delays (32), or no change (29) in melatonin secretion during the luteal vs. follicular phase.…”

“…Duffy et al also reported that women have a shorter intrinsic circadian period of CBT and melatonin vs. men (12), which might contribute to these observations. Unfortunately, many prior studies that documented sex differences in circadian physiology have not done so while controlling for menstrual cycle and hormonal contraceptive use in female participants.…”

Sex differences in sleep: impact of biological sex and sex steroids

“…Sex differences exist in the circadian timing of sleep; women tend to go to bed earlier and wake up earlier than men [32,49,50]. Retrospective analyses of the circadian timing system in men and women with similar sleep times and durations find that women have an early timing of circadian rhythms, particularly for endogenous temperature and melatonin [51], partly as a consequence of a significantly shorter circadian period [52]. Together, these studies suggest that circadian timing in women is even earlier than the sex difference in sleep timing would predict.…”

Male-female differences in 6-sulfatoxymelatonin excretion in hypopituitary patients

“…Such finding of a sex difference in intrinsic circadian period are consistent with studies conducted in a number of nonhuman animals that have demonstrated that circadian period is shorter in females than in males. The shorter intrinsic circadian period described in women may be attributable, partly, to the higher circulating levels of estrogen in women (29). In addition, exposure to high estrogen at some point during development could alter the hypothalamic circadian pacemaker, leading to the sexual dimorphism that has been reported in suprachiasmatic nucleus structure (30).…”