General discussion 267 the hypothalamic-pituitary-adrenal (HPA) axis, which respectively release melatonin and cortisol in a diurnal pattern, regulating wakefulness and sleepiness. Sleep-wake rhythms are also regulated by the sleep-wake homeostasis, in a process which is called the S-process, which is dependent on how much time has passed since one last slept. The sleep-wake homeostasis is regulated by the accumulation of the neurotransmitter adenosine during the day, which increases sleep drive the longer one is awake (Borbély, 2022; Borbély, 1982). Circadian rhythms could be affected by sex hormones via multiple pathways. Firstly, there are estrogen and androgen receptors present in the SCN, which could increase or decrease the sensitivity of the SCN. Via this route, estradiol and testosterone could therefore influence melatonin release (Kruijver & Swaab, 2002). Researchers have also hypothesized that there is a bidirectional relationship between melatonin production and sex hormone regulation (Cipolla-Neto et al., 2022). Secondly, studies show that sex hormones can directly affect the HPA axis, as shown in section 2.2 of this chapter, resulting in higher morning cortisol levels in cisgender women compared to men (Juster et al., 2016). Sleep-wake homeostasis is regulated by the ventrolateral preoptic area (VLPO), which is inhibited by adenosine and asserts somnogenic effects via the release of galanin and GABA (Saper et al., 2005). The VLPO shows sex differences, which could be caused by exposure to sex hormones: Cusmano et al. (2014) found that male mice have fewer sleep-active cells in the VLPO than female mice, and that testosterone administration in female mice during development reduced the number of sleep-active cells in the VLPO. The VLPO could also be affected by allopregnanolone, a metabolite from progesterone. In rodents, allopregnanolone administration shortened latency to non REM-sleep and affected pre-REM sleep, indicating that allopregnanolone could have effects similar to benzodiazepines. Thus far, this mechanism was only studied in male rats (Lancel et al., 1997). Wakefulness and sleep stages are also affected by serotonin, which is primarily produced in the raphe nucleus, norepinephrine, which is primarily produced in the locus coeruleus, dopamine, which is partially produced in the ventral tegmental area, and orexin, which is primarily produced in the hypothalamus. Rodent studies show that sex hormones could affect these
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