Sexual dimorphism in body clocks: The repeated pattern of dimorphic rhythmicity observed in humans & animal models suggest that these differences are not attributable simply to societal pressures on either sex

Sexual dimorphism in body clocks. Seán T. Anderson, Garret A. FitzGerald. Science  Sep 4 2020, Vol. 369, Issue 6508, pp. 1164-1165, DOI: 10.1126/science.abd4964

Abstract: Circadian rhythms, or the body clock, confer temporal structure on human behavior and physiology to align homeostatic processes with anticipated changes in the environment. Disruption of these rhythms can influence health and well-being. Chronobiological research has often failed to consider how this temporal organization may be affected by sex. The few studies that do consider how these rhythms differ between sexes suggest a dimorphism that warrants further investigation. Recent findings from both humans and animal models illustrate how the systems that generate circadian rhythms diverge between the sexes, which has potential consequences for health and resilience to changes in sleep pattern.

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The repeated pattern of dimorphic rhythmicity observed in humans and animal models suggest that these differences are not attributable simply to societal pressures on either sex. Consistent with the findings that female mice show enhanced entrainment to phase shifts, studies in rodents have shown that females tend to be more resistant to genetic and environmental circadian disruption. In ClockΔ19/Δ19 mutant mice, in which mutation of the Clock protein interferes with transcriptional regulation by the BMAL1-CLOCK heterodimer and leads to lengthening of the circadian period, females do not develop any detectable cardiac dysfunction until 21 months of age, despite male ClockΔ19/Δ19 mice showing cardiac hypertrophy and dysfunction after 12 months (14). However, in ovariectomized ClockΔ19/Δ19 mice, cardiometabolic function was impaired relative to ovariectomized controls by 8 months of age, highlighting the protective effect of estrogen.

One possible reason for the resilience to circadian disruption in females relates to their biological imperative. Resistance to the negative consequences of circadian disruption coupled with improved sleep, even when experiencing nocturnal disturbances, may facilitate their adaptation to frequent nocturnal awakenings over a sustained period, given their predominant role in nurturing offspring. The early-activity chronotypes seen in women before menopause also align with those in children.

Circadian rhythms are influenced by sex, and this interaction is remolded throughout life. In the healthy state, females often show higher-amplitude oscillations with an earlier peak in gene expression. Dimorphism can also shape the response to circadian misalignment and the downstream consequences of disruptions to normal rhythms. A chronic disruption to human circadian rhythms is shiftwork, which is associated with cardiometabolic disease and cancer. Studies have sought to clarify whether this risk is affected by sex (15), but the results are constrained by a lack of longitudinal data. There are large differences in the rhythmic regulation of the liver transcriptome between males and females, but it is unknown whether other organs show similar differences or how faithfully this translates to protein expression and function. In humans, well-controlled, longitudinal analyses of the impact of misalignment will be necessary to address the hypothesis that females are more resilient than males to the disruption of circadian function caused by shiftwork and repeated long-distance travel.