Sleep, rhythms, and the endocrine brain: influence of sex and gonadal hormones

Abstract

While much is known about the mechanisms that underlie sleep and circadian rhythms, the investigation into sex differences and gonadal steroid modulation of sleep and biological rhythms is in its infancy. There is a growing recognition of sex disparities in sleep and rhythm disorders. Understanding how neuroendocrine mediators and sex differences influence sleep and biological rhythms is central to advancing our understanding of sleep-related disorders. While it is known that ovarian steroids affect circadian rhythms in rodents, the role of androgen is less understood. Surprising findings that androgens, acting via androgen receptors in the master "circadian clock" within the suprachiasmatic nucleus, modulate photic effects on activity in males point to novel mechanisms of circadian control. Work in aromatase-deficient mice suggests that some sex differences in photic responsiveness are independent of gonadal hormone effects during development. In parallel, aspects of sex differences in sleep are also reported to be independent of gonadal steroids and may involve sex chromosome complement. This a summary of recent work illustrating how sex differences and gonadal hormones influence sleep and circadian rhythms that was presented at a Mini-Symposium at the 2011 annual meeting of the Society for Neuroscience.

Figure 1.

Prevalence of insomnia complaints by sex and age in a general population. Sleep disorders among women are a significant public health issue: sleep complaints such as insufficient sleep and insomnia are more prevalent in women. This sex difference in insomnia emerges after puberty, suggesting that hormonal events underlying puberty may be involved. Data are redrawn from Zhang et al. (2009) and Ohayon (1997).

Figure 2.

Schematic representation of differences between the site of action of estrogenic and androgenic hormones on the SCN. ER-rich nuclei (red), including the retina, the intergeniculate leaflet (IGL), and the dorsal raphe (DR), via the median raphe (MR), project to the SCN (top). The DR also contains androgen receptors and projects to the SCN. However, unlike the ER, ARs are densely located in the core SCN (bottom). Testosterone can be aromatized into estradiol and thus may have dual androgenic/estrogenic impacts on the system. The SCN regulates circadian timing in physiology and behavior by sending outputs to the neuroendocrine systems.

Figure 3.

Schematic of four core genotype mouse model. This mouse line was initiated by a spontaneous deletion of the testis-determining gene “Sry” from the Y chromosome and the subsequent insertion of the Sry transgene onto an autosome (Mahadevaiah et al., 1998). In the absence of the Sry gene, testis development fails to occur. Thus, XY⁻ mice develop ovaries and are phenotypically female. When XY⁻ mice have an Sry autosomal transgene (XY^−Sry), they develop normal-functioning testes. The four genotypes are derived by from the crossing of XY^−Sry fathers and XX (wild-type) mothers: XX (genetic and phenotypic female), XY⁻ (genetic male, phenotypic female), XX^Sry (phenotypic male, genetic female) and XY^−Sry (genetic and phenotypic male). This allows a 2 × 2 comparison of genes versus hormones. Differences seen in mice with the same environmental milieu (such as XX and XY⁻) may be attributed to possible chromosomal effects. Redrawn from Arnold and Chen (2009).