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Review
. 2014 Jan;35(1):111-39.
doi: 10.1016/j.yfrne.2013.11.003. Epub 2013 Nov 25.

Sex differences in circadian timing systems: implications for disease

Matthew Bailey  1 , Rae Silver  2
Affiliations
Review

Sex differences in circadian timing systems: implications for disease

Matthew Bailey et al. Front Neuroendocrinol. 2014 Jan.

Abstract

Virtually every eukaryotic cell has an endogenous circadian clock and a biological sex. These cell-based clocks have been conceptualized as oscillators whose phase can be reset by internal signals such as hormones, and external cues such as light. The present review highlights the inter-relationship between circadian clocks and sex differences. In mammals, the suprachiasmatic nucleus (SCN) serves as a master clock synchronizing the phase of clocks throughout the body. Gonadal steroid receptors are expressed in almost every site that receives direct SCN input. Here we review sex differences in the circadian timing system in the hypothalamic-pituitary-gonadal axis (HPG), the hypothalamic-adrenal-pituitary (HPA) axis, and sleep-arousal systems. We also point to ways in which disruption of circadian rhythms within these systems differs in the sexes and is associated with dysfunction and disease. Understanding sex differentiated circadian timing systems can lead to improved treatment strategies for these conditions.

Keywords: 17β-estradiol; 5-FU; 5-HT; 5-fluorouracil; ACTH; AMY; ANS; AP; AR; ARC; AVP; AVPV; BMAL1; BNST; C-FOS; CRH; Circadian; DD; DHT; DMH; DR; DSPS; Delayed Sleep Phase Syndrome; E(2); EEG; EP; ER; ERα; FASPS; Familial Advanced Sleep Phase Syndrome; GC; GDX; GHT; GR; GRP; GnIH; GnRH; HA; HB; HPA; HPG; Hormones; IGL; IML; KO; Kiss1; Kiss1 R; Kiss1 receptor; LC; LD; LH; LHA; LS; MR; MUA; MnPO; NA; Neuronal PAS domain-containing protein 2; Npas2; OVX; P; PER1; PER2; POA; PVA; PVN; Per1; Per2; Period1 gene or mRNA; Period1 protein; Period2 gene or mRNA; Period2 protein; RHT; Rch; Reproduction; SCN; SD; Sex differences; Sleep; Stress; Suprachiasmatic nucleus; T; TH; TMN; VIP; VLPO; VMH; VNTR; WT; action potential; adrenocorticotropic hormone; amygdala; androgen receptors; anterior paraventricular thalamic nuclei; anterolateral paraventricular nucleus; arcuate nucleus; arginine vasopressin; autonomic nervous system; bed nucleus of the stria terminalis; brain and muscle ARNT-like protein1; c-fos; constant darkness; corticotropin releasing hormone; denoting the gene or mRNA; denoting the protein; dihydrotestosterone; dorsal raphe; dorsomedial hypothalamus; electroencephalography; estradiol plus progesterone; estrogen receptor alpha; estrogen receptors; gastrin-releasing peptide; geniculo-hypothalamic tract; glucocortocoid receptor; glucocortocoids; gonadectomy; gonadotropin inhibiting hormone; gonadotropin releasing hormone; habenula; histamine; hypothalamic–adrenal; hypothalamic–pituitary–gonadal; intergeniculate leaflet; intermediolateral column; kisspeptin; knock out; lateral hypothalamic area; lateral septum; light-dark; locus coeruleus; luteinizing hormone; mPOA; medial parvocellular PVN; medial preoptic area; medial raphe; median preoptic area; mpPVN; multi-unit neural activity; norandrenergic; ovariectomized; paraventricular nucleus of the hypothalamus; preoptic area; progesterone; retinohypothalamic tract; retrochiasmatic area; sPVZ; serotonergic; sleep deprivation; sub paraventricular zone SWA, slow wave activity; suprachiasmatic nuclei; testosterone; tuberomammillary nucleus; tyrosine hydroxylase; variable nucleotide tandem repeat; vasoactive intestinal polypeptide; ventrolateral preoptic area; ventromedial nucleus of the hypothalamus; wild type.

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Figures

Figure 1
Figure 1. Representation of circadian timing system
The circadian clock has been represented as having three components: input pathways, a central oscillator (or pacemaker), and output pathways. Input pathways such as photic signals from the retina, or temperature, can influence the master oscillator in the suprachiasmatic nucleui (SCN) of the hypothalamus which produces the endogenous biological rhythm that synchronize the rest of the body. Output pathways to target sites entail both neural connections and diffusible signals, and these regulate clock-controlled biological processes. Additional pathways (shown as dotted lines) include multiple interlocking positive or negative feedback from clock controlled activities. One prominent feedback mechanism are the systemically secreted hormones which can then influence the circadian system at all levels, including input pathways, the central oscillator, and output pathways. Adapted from Kriegsfeld et al. (2002).
Figure 2
Figure 2. Experimental Paradigms in circadian rhythms research
(A). Shows the parameters used to measurea circadian rhythms, including the lowest point (nadir), the highest point (peak), the distance from peak to trough (amplitude), the time taken to complete one full cycle (period). (B). Top half of the figure shows the activity record of a representative individual animal. The vertical black bars represent when the animal is active, occurring primarily during the night or subjective night. When a light pulse is given in the middle of the subjective day occurring (white region of behavioral profile), there is no effect on the timing of the daily locomotor behavior. When a light pulse is given early in the subjective night is a small phase delay in activity onset and when a light pulse is given slightly later in the subjective night, there ensues a larger phase delay. When a light pulse is given in the latter half of the subjective night there is a large phase advance in the daily rhythm, and when a light pulse is given at the end of the subjective night there is smaller phase advance. Bottom Half, shows the phase response curve corresponding to the animal receiving a light pulse at one of the previously mentioned times. Red dots correspond to the phase shift corresponding to the light pulse condition. Adapted from Moore-Ede and Czeisler (1982). (C). Top panel Shows an entrainment paradigm of a diurnal animal exposed to either constant darkness (DD) or a light-dark (LD) cycle of 14 hours light, 10 hours darkness (indicated by black and white bars at the top). This double plotted actogram has two consecutive days plotted side by side and consecutive days on each subsequent row (dark bars indicate activity output). To visually inspect an actogram for entrainment, a line is draw at the start of activity each day, and if the line fits the activity after the constant environmental conditions resume (after LD), masking has occurred. Here, the line does not overlap (two red lines) so the light condition entrained the animal. Bottom panel Shows a masking paradigm of same animal in either constant warm (WW) conditions of 200C, or hot-cold (HC) conditions of 250C or 150C for 10:14 hours; respectively. Here, because the line drawn at the start of each day’s activity perfectly fits with the activity after the return to constant conditions (single red line), masking is said to have occurred.
Figure 3
Figure 3. Circadian clock genes: Historical perspective
(A). Represents our understanding of the circadian pacemaker around a decade ago. This understanding was limited to a single ‘core loop’ in which clock genes and their protein products are regulated by negative and positive feedback loops. Briefly, CLOCK and BMAL1 hetero-dimerize and activate the expression of period genes (Per1, 2, and 3) and Cry1 and 2. PER and CRY proteins enter the nucleus and repress CLOCK-BMAL1-driven transcription (Reviewed in Antle and Silver, 2005). (B). Represents the understanding in the past half-decade, where a more complex model has been developed based on triple interlocking loops, which include the PER–CRY loop, which is the primary loop, and the retinoid-related orphan receptor (ROR)–REV–ERB- and DBP–E4 promoter-binding protein 4 (E4BP4)-associated loops. In addition to the primary loop, which was previously recognized as the core loop (A), transcriptional regulation of CLOCK and BMAL1 is controlled by ROR transcriptional activators and the dimeric REV–ERB repressors (by binding to REV response element (RRE)), the expression of which is governed by CLOCK–BMAL1 activity (through binding to E-box-containing DNA elements). Furthermore, the transcriptional activator DBP (the expression of which is controlled by an E-box) and E4BP4 (the expression of which is controlled by RRE) synergistically regulate the expression of D-box containing genes, including PER. Reprinted from Zhang et al. (2010).
Figure 4
Figure 4. Sex difference in AR expression in the SCN
(A) Sex difference in androgen receptor (AR) expression in the SCN ventromedial core. Top panel showed AVP-ir cells (green) which defines the core of the SCN, middle shows AR-ir cell expression (red), and lower panel shows overlay of AVP and AR. Males have higher expression of AR-ir cells than females. (B) Photomicrographs show AR-ir in GDX/OVX (upper panel) and GDX/OVX+TP (lower panel). AR expression is regulated by TP in both males and females. Reprinted from Iwahana et al. (2008).
Figure 5
Figure 5. Gonadal hormone receptor expression in SCN afferents and efferents
(A) The main afferent pathways of the SCN, with nuclei expressing estrogen receptors (ER), red, or androgen receptors (AR), blue, or both ER and AR, red/blue. Light information from the Retina is sent to the SCN core via the retinothypothalamic tract (RHT). Non-photic information is sent to the SCN core from the intergenculate leaflet (IGL) via the geniculohypothalamic tract (GHT), and the dorsal and medial raphe nuclei (DR and MR). (B) Main efferent pathways of the SCN to hypothalamic nuclei (black arrows) and extra hypothalamic sites (grey arrowss), which express ER, red, AR, blue, or both, red/blue Nuclei receiving inputs from the SCN core and shell include: the pre optic area (POA) - specifically the medial preoptic area (mPOA), the median preoptic area (MnPO), and the anteroventral periventricular nucleus (AVPA); as well as sparse connections with the ventrolateral peroptic area (VLPO). Projections extending dorsally heavily innervate the sub paraventricular zone (sPVZ) - including ventral sPVZ; as well as the paraventricular nucleus of the hypothalamus (PVN). Caudal projections innervate the the retrochiasmatic area (Rch), the arcuate nucleus (ARC), ventromedial nucleus of the hypothalamus (VMH), the dorsomedial hypothalamus (DMH). Extra hypothalamic regions receiving direct SCN input include: the lateral septum (LS), the bed nucleus of the stria terminalis (BNST), the anterior paraventricular thalamic nuclei (PVA), the amygdala (AMY), the habenula (HB), and the intergeniculate leaflet (IGL). (Simerly et al., 1990; Simerly, 2002; Zhang et al., 2002; Shughrue et al., 1992; Shughrue et al., 1997; Shughrue et al., 2001; Orikasa and Sakuma, 2004). (Kriegsfeld et al., 2004; Abrahamson et al., 2001; Leak el al., 2001; Morin, 2013; Dibner et al., 2010).
Figure 6
Figure 6. Sex differences in SCN efferent sites
Sex difference have been demonstrated in the medial pre optic area (mPOA) as AR expression is greater in males (A) than females (B). AR expression in the BNST is also greater in males (C) than females (D). The fiber tracts of AR expressing neurons projecting from the BNST are denser in males (E) than females (F). Reprinted from Shah et al. (2004). The number of Kisspetin- (Kiss1) expressing neurons in the AVPV is greater in females (H) than in males (G). Image in (B) provided by (L. Kriegsfeld, L., and A. Geserich).
Figure 7
Figure 7. Sex steroids and hypothalamic control of the HPG-axis
Hypothalamic nuclei involved in regulation of gonadotropin release at the level of the hypothalamus. Neurons expressing estrogen receptors (ER), red, with ER subtype (α or β) indicated. Axons depicted in green represent neuronal inputs promoting the release of gonadotropins and axons depicted in red represent neuronal inputs inhibiting their release. The gonadotropin releasing hormone (GnRH) neurons, green, of the medial pre optic area (mPOA), light green, release gonadotropins into the medial eminence. Excitatory inputs upstream of the GnRH neurons include Kisspeptin (Kiss1) producing neurons in the anteroventral paraventricular nucleus (AVPV), grey, which project onto the somas of GnRH neurons, as well as Kisspeptin neurons of the arcuate nucleus (ARC), silver, which project onto the axons of GnRH neurons. The major inhibitory signals come from gonadotropin inhibiting hormone (GnIH) releasing neurons of the dorsomedial hypothalamus (DMH), light orange. The SCN influences multiple sites involved in control of gonadotropin release throughout the hypothalamus. Black arrows indicate monosynaptic projections from the shell of the SCN, to the positive (kisspeptin, and GnRH) as well as the negative signal of the GnIH. Adapted from Williams and Kriegsfeld (2012).
Figure 8
Figure 8. Sex differences in GDX effects on free-runs
Actograms depicting the free running locomotor activity of male (left) and female (right) mice housed under conditions of constant darkness (horizontal axis show 48 consecutive hours; vertical axis show consecutive days). Each box shows an individual animal before (top) and after (bottom) an experimental manipulation. Top two boxes shows behavior of intact male and female at the top, and following gonadectomized (GDX) and overectomized (OVX); respectively, at the bottom. The bottom boxes show GDX/OVX animals at the top that are then treated with either testosterone propionate (TP) and dihydrotestosterone propionate (DHT); respectively, at the bottom. Reprinted from Iwahana et al. (2008).
Figure 9
Figure 9. Sex difference in HPA-axis steroid secretion rhythms
(A) (A) The SCN controls the phase of the circadian rhythms in the hypothalamicpituitary- adrenal axis (HPA) secretion of glucocorticoids through both neural and humoral output signals. Adapted from Chung et al. (2011). (B) Depicts the sex difference in circadian rhythms of stress related hormones. Female rodents have a circadian rhythm in plasma levels of stress related hormones as observed by the higher peak of both corticosterone (top) and immunoreactive ACTH (I-ACTH), (bottom) than males. Reprinted from Atkinson (1997) with permission from Endocrinology.
Figure 10
Figure 10. Sex differences in sleep onset with age
Assessment of chronotype (N≈25,000 people). (A) Shows the distribution of chronotypes based on midpoint to sleep on free days (MSF) with 0 corresponding to earliest and 12 corresponding to the latest. (B) Shows the age-dependent changes in average chronotype (±SD) shift to later chronotypes around the time of puberty. (C) Shows sex difference in the age-dependent changes in chronotype (filled circles and black line: females; open circles and gray line: males). Gray areas indicate significant male–female differences (t-test, p < 0.001). Reprinted from Roenneberg et al. (2004).
Figure 11
Figure 11. Sex difference in Insomnia: Prevalence and cortical activity
(A) Shows the sex difference in the prevalence of insomnia complaints at different ages in a general population between women (grey) and men (black). The sex difference begins around puberty, implicating gonadal hormones. Figure adapted and data re-plotted from Mong et al. (2011). (B) Shows the sex difference in cortical activity between primary insomnia patients and controls. Plot depicts the F ratio of differences in EEG activity from F tests conducted between healthy females and females with primary insomnia (grey) and healthy males and males with primary insomnia (black) at each 1-Hz frequency bin for all-night NREM data (dashed grey (female) and black (male) line = p<.05, dotted grey (female) and black (male) line = p<.01) (see Buysse et al., 2008 for data across all NREM stages). A sex difference exists as cortical brain activity during sleep is significantly different between healthy females and female insomnia patients, but the same is not true for males. This may be related to the sex difference in prevalence of insomnia, see (A), observed between males and females. Figure adapted and data replotted from Buysse et al. (2008).
Figure 12
Figure 12. Circadian timing and anticancer drugs
(A) The circadian timing system determines the optimal circadian timing of anticancer medications through actions on drug transport, bioactivation, detoxification, metabolism, targets, and elimination. All of these are important determinants of the chronopharmacology of anticancer agents at various levels (cellular, tissue, and whole organism levels) (left). Various cell-cycle-related events that gate G1/S or G2/M transitions as well as DNA repair and apoptosis are regulated by the circadian clock. This influences the chronopharmacodynamics of anticancer drugs (right). The relationship between chronopharmacokinetics and chronopharmacodynamics influence the optimal chronomodulated drug delivery schedules (middle). (B) Circadian timing determines the tolerability of anticancer drugs. Circadian timing (in ZT) associated with optimal tolerability, and relative magnitude of survival benefit from optimal to worst timing, ranging from 0 to 200%. The diagram illustrates chronotolerance for 16 anticancer drugs in male mice, synchronized with LD12:12. The average circadian rhythm in body temperature is shown in the internal circle and provides a CTS biomarker, an endogenous reference for optimal drug timing. Reprinted from Levi et al. (2010).
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