INS IGHTS | P E R S P E C T I V E S
PHYSIOLOGY
Sexual dimorphism in body clocks
Sexual dimorphism in chronobiology has implications for the health of our 24-hour society
By Seán T. Anderson and Garret A. FitzGerald
C
ircadian rhythms, or the body clock,
confer temporal structure on hu-
man behavior and physiology to
align homeostatic processes with an-
ticipated changes in the environment.
Disruption of these rhythms can influ-
ence 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 investiga-
tion. Recent findings from both humans and
animal models illustrate how the systems
that generate circadian rhythms diverge be-
tween the sexes, which has potential conse-
quences for health and resilience to changes
in sleep pattern.
Circadian rhythms are generated centrally
by a transcription-translation feedback loop
in the suprachiasmatic nucleus (SCN) of the
hypothalamus. The proteins brain and mus-
cle ARNT-like 1 (BMAL1) and circadian loco-
motor output cycles kaput (CLOCK) form the
positive arm of the molecular clock. This het-
erodimer promotes the expression of its own
repressors period 1 (PER1) and PER2 and
cryptochrome 1 (CRY1) and CRY2. Inhibition
of the BMAL1-CLOCK heterodimer in turn
suppresses PER1/2 and CRY1/2, allowing
BMAL1 and CLOCK expression levels to rise
once again. This cycle takes roughly 24 hours,
forming the core molecular clock. Photic
(light) input to the SCN can also induce the
expression of PER1/2 and CRY1/2 and repre-
sents the main stimulus that entrains the cir-
cadian rhythm to the day-night cycle.
Estrogen and androgen receptors are
expressed in a sexually dimorphic pattern
along the central neuronal circuitry regulat-
ing circadian rhythms and show rhythmic
expression in peripheral tissues (1) (see the
figure). Early studies of hamsters placed into
constant darkness observed shorter free-run-
ning periods among females, indicating that
their core molecular clock machinery oscil-
lates faster than that of males (2). Females
also showed significantly earlier onset of
activity and responded differently to stimuli
that shift the intrinsic timing of the circa-
Institute for Translational Medicine and Therapeutics,
Perelman School of Medicine, University of Pennsylvania,
Philadelphia, PA, USA. Email: garret@upenn.edu
1164 4 SEP TEMBER 2020 • VOL 369 ISSUE 6508
dian clock. It was subsequently reported that
in female mice, behavioral rhythms were
more consolidated, had higher amplitudes
(difference between the peak and the mean
24-hour activity level), and peaked earlier in
the day than in males.
Recently, large-scale collections of remote
sensing data have enabled the observation of
natural activity patterns in humans. A study
of 91,105 participants in the UK Biobank re-
vealed that males were more likely to have
low-amplitude behavioral rhythms than fe-
males (3). This can be due to increased ac-
tivity at night or decreased activity in the
daytime, reflecting the conservation of more
robust oscillations in activity rhythms among
females. Females also spend more time
asleep, spend more of their time in slow-wave
(deep) sleep, and are more resilient to noctur-
nal disturbances than males (4).
A study of chronotype, or day-night pref-
erence, in more than 53,000 individuals
highlighted how age and sex both substan-
tially affect the timing of circadian rhythms
(5). Whereas children are typically morn-
ing types regardless of sex, after puberty
males tend to be more evening oriented
than females, mirroring the findings in
animal models. The hormonal changes as-
sociated with menopause add extra com-
plexity to the aging process for females;
chronotypes converge during middle age as
both sexes become more morning oriented.
New efforts to study rhythmic changes out-
side the laboratory are characterizing the
“chronobiome”—a phenotype incorporating
the in-depth assessment of thousands of
time-of-day signals across diverse physio-
logical readouts that will clarify the array of
sexually dimorphic rhythms in humans (6).
Forced desynchrony protocols, in which
the sleep-wake cycle is desynchronized from
endogenous circadian rhythms, have also
been used to examine how key parameters
of circadian rhythmicity differ between the
sexes. One such study found that females had
higher-amplitude rhythms in their perfor-
mance on cognitive tests that assess working
memory, attention, effort, mood, and sleepi-
ness (7). Together with a higher-amplitude
rhythm in the sleep-promoting hormone
melatonin, this increased amplitude in cog-
nitive processing resulted in females experi-
encing a greater deficit during the biological
night compared with their peak functioning
time. Although higher amplitudes (peaks-to-
Published by AAAS
trough ratio) are typically beneficial because
they allow for greater compartmentalization
of different homeostatic processes, in this ex-
ample a higher amplitude may be detrimen-
tal when females must be awake at night.
The expansion of sequencing efforts has
revealed how sexual dimorphism in chrono-
biology extends into oscillations of the tran-
scriptome, metabolome, and microbiome.
In a study of transcriptional and metabolic
rhythmicity in mice, 71% of liver transcripts
showed conserved rhythmicity between
Downloaded from http://science.sciencemag.org/ on September 4, 2020
males and females, 9% of genes showed
rhythmicity only in males, and 16% of genes
showed rhythmicity only in females (8). A
further 4% were rhythmically expressed in
both sexes but differed in their phase or am-
plitude, including several core clock genes
that showed higher-amplitude oscillations in
females. Only 55% of liver metabolites and
29% of serum metabolites had conserved
oscillations between sexes. Germ-free mice,
which have no gut microbiota, had dimin-
ished sexual dimorphism in their gene ex-
pression and circadian rhythms. Female mice
have greater diurnal oscillations in their total
bacterial load, and genetic disruption of the
host clock machinery affects gut microbiota
differentially in male and female mice (9).
Thus, the gut microbiota can contribute to
the orchestration of circadian rhythms dur-
ing development and adulthood; this contri-
bution is likely to differ between the sexes.
A clinical study comparing the metabolic
response to misalignment between sexes
tracked energy consumption and expendi-
ture during 8 days on a normal schedule
and then for 8 days featuring a 12-hour
phase shift, achieved through an 8-hour
wake opportunity followed by a 4-hour
sleep opportunity on the fourth day (10).
Circadian misalignment increased the hun-
ger hormone ghrelin and decreased the sa-
tiety hormone leptin in females, which was
accompanied by decreased feelings of full-
ness. Female participants’ carbohydrate oxi-
dation rate and respiratory quotients also
dropped after misalignment, whereas their
energy expenditure and lipid oxidation rate
increased. Conversely, males showed an in-
crease in leptin and no change in ghrelin af-
ter the phase shift. They reported increased
cravings for energy-dense foods, which is
inconsistent with their hormone changes,
and showed no difference in energy utiliza-
tion. This switch in energy utilization may
sciencemag.org SCIENCE
 reflect an adaptive response to misalign- whereas males took 10 days to adapt (13). until 21 months of age, despite male ClockD19/D19
ment in females. This difference disappeared in the absence of mice showing cardiac hypertrophy and dys-
Studies in animal models have shown that Liver X Receptor a (Lxra), with male mice in function after 12 months (14). However, in
sex hormones are not required to maintain which Lxra is deleted showing significantly ovariectomized ClockD19/D19 mice, cardiometa-
circadian rhythms but can affect their ampli- faster entrainment than that of wild types. bolic function was impaired relative to ovari-
tude and response to photic stimuli. Female This may be due to the impact of Lxra dele- ectomized controls by 8 months of age, high-
mice in which the estrogen receptor 1 (Esr1) tion on corticosterone rhythms, which affect lighting the protective effect of estrogen.
gene is deleted show fractured behavioral reentrainment. It is not well understood how One possible reason for the resilience to
rhythms and blunted phase delays produced sex hormones influence rhythmicity directly circadian disruption in females relates to
by light pulses given in the early active phase in the SCN because whole-body deletion of their biological imperative. Resistance to the
of the day. By contrast, light pulses given the receptors or removal of sex organs oblit- negative consequences of circadian disrup-
late in the active phase increase phase ad- erates signaling across the entire organism. tion coupled with improved sleep, even when
experiencing nocturnal disturbances, may
facilitate their adaptation to frequent noc-
Sex hormone receptors in the circadian network turnal awakenings over a sustained period,
The patterning of estrogen receptors (purple) and androgen receptors (green) throughout the circadian given their predominant role in nurturing
network varies between males and females. The suprachiasmatic nucleus (SCN) signals to peripheral organs, offspring. The early-activity chronotypes seen
many of which also have circadian oscillations in sex hormone receptors. Circulating estrogen and testosterone in women before menopause also align with
are also likely to affect the SCN in a sexually dimorphic, rhythmic fashion. This dimorphism is manifested at the those in children.
behavioral level through higher-amplitude rhythms in female activity patterns compared with that of males. Circadian rhythms are influenced by sex,

Downloaded from http://science.sciencemag.org/ on September 4, 2020

and this interaction is remolded throughout
life. In the healthy state, females often show
Female Male
Dorsal Dorsal higher-amplitude oscillations with an ear-
raphe raphe lier peak in gene expression. Dimorphism
nuclei Intergeniculate Intergeniculate nuclei can also shape the response to circadian
leafet leafet
Median Median
misalignment and the downstream conse-
raphe raphe quences of disruptions to normal rhythms.
nuclei nuclei A chronic disruption to human circadian
Retinohypothalamic
Shell tract Shell rhythms is shiftwork, which is associated
Core Core
with cardiometabolic disease and cancer.
Studies have sought to clarify whether this
SCN SCN risk is affected by sex (15), but the results are
constrained by a lack of longitudinal data.
Estrogen Estrogen There are large differences in the rhythmic
regulation of the liver transcriptome be-
Circulation Circulation Testosterone tween males and females, but it is unknown
Testosterone
whether other organs show similar differ-
Peripheral ences or how faithfully this translates to
High amplitude Moderate amplitude
tissue protein expression and function. In humans,
clocks well-controlled, longitudinal analyses of the
Behavior

Behavior

impact of misalignment will be necessary to

Time
vances compared with that of controls (11).
This suggests that estrogen consolidates be-
havioral rhythms in female mice and could
facilitate the faster entrainment to phase
shifts observed in female mice. The same
study showed that Esr1 deletion did not af-
fect phase shifting in males, but that wild-
type males showed smaller phase shifts than
those of females when exposed to light early
in the active phase.
Gonadectomy in male mice deconsolidates
behavioral rhythms and enhances the phase
GRAPHIC: A. KITTERMAN/SCIENCE
address the hypothesis that females are more
resilient than males to the disruption of cir-
cadian function caused by shiftwork and re-
Time
peated long-distance travel. j
Sexual dimorphism in the SCN should be RE FERENCES AND NOTES
revisited by using single-cell transcriptomics 1. K. M. Hatcher et al., Eur. J. Neurosci. 51, 217 (2020).
and SCN-targeted deletions of estrogen and 2. F. C. Davis et al., Am. J. Physiol. 244, R93 (1983).
3. L. M. Lyall et al., Lancet Psych. 5, 507 (2018).
androgen receptors. 4. E. O. Bixler et al., J. Sleep Res. 18, 221 (2009).
The repeated pattern of dimorphic rhyth- 5. D. Fischer et al., PLOS ONE 12, e0178782 (2017).
micity observed in humans and animal mod- 6. C. Skarke et al., Sci. Rep. 7, 17141 (2017).
7. N. Santhi et al., Proc. Natl. Acad. Sci. U.S.A. 113, E2730
els suggest that these differences are not (2016).
attributable simply to societal pressures on 8. B. D. Weger et al., Cell Metab. 29, 362 (2019).
9. X. Liang et al., Proc. Natl. Acad. Sci. U.S.A. 112, 10479
either sex. Consistent with the findings that (2015).
female mice show enhanced entrainment to 10. J. Qian et al., Proc. Natl. Acad. Sci. U.S.A. 116, 23806 (2019).
phase shifts, studies in rodents have shown 11. M. S. Blattner, M. M. Mahoney, J. Biol. Rhythms 28, 291
(2013).
that females tend to be more resistant to

12. I. N. Karatsoreos et al., Endocrinology 152, 1970 (2011).

shift produced by light in the early active but
not the late active phase. Thus, testosterone
may restrain the phase-shifting effect of light
(12). Nonreproductive factors are also perti-
nent to the sexual dimorphism in circadian
rhythmicity. For example, female mice en-
trained to an 8-hour phase shift in 6 days,
genetic and environmental circadian disrup- 13. C. Feillet et al., PLOS ONE 11, e0150665 (2016).
14. F. J. Alibhai et al., Cardiovasc. Res. 114, 259 (2018).
tion. In ClockD19/D19 mutant mice, in which 15. W. Liu et al., Dis. Markers 2018, 7925219 (2018).
mutation of the Clock protein interferes with
ACKNOWL EDGMENTS
transcriptional regulation by the BMAL1-
We gratefully acknowledge funding from the Volkswagen
CLOCK heterodimer and leads to lengthen-
Stiftung. G.A.F. is a senior adviser to Calico Laboratories.
ing of the circadian period, females do not
develop any detectable cardiac dysfunction 10.1126/science.abd4964

SCIENCE sciencemag.org 4 SEP TEMBER 2020 • VOL 369 ISSUE 6508 1165
Published by AAAS
Sexual dimorphism in body clocks
Seán T. Anderson and Garret A. FitzGerald

Science 369 (6508), 1164-1165.

DOI: 10.1126/science.abd4964

Downloaded from http://science.sciencemag.org/ on September 4, 2020

ARTICLE TOOLS http://science.sciencemag.org/content/369/6508/1164

REFERENCES This article cites 15 articles, 3 of which you can access for free
http://science.sciencemag.org/content/369/6508/1164#BIBL

PERMISSIONS http://www.sciencemag.org/help/reprints-and-permissions

Use of this article is subject to the Terms of Service

Science (print ISSN 0036-8075; online ISSN 1095-9203) is published by the American Association for the Advancement of
Science, 1200 New York Avenue NW, Washington, DC 20005. The title Science is a registered trademark of AAAS.
Copyright © 2020, American Association for the Advancement of Science