Sex differences in circadian timing systems: implications for disease

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.