Associations between sex hormones, sleep problems and depression 219 In men, lowered testosterone levels have been associated with sleep problems such as nocturnal awakenings and lower sleep efficiency and symptoms of depression (Barrett-Connor et al., 2008; Westley et al., 2015). For example, ageing men whose testosterone levels drop have an increased risk for depressive symptoms (Seidman, 2003) and testosterone administration in depressed patients may lead to a reduction in depressive symptoms (Zarrouf et al., 2009). Testosterone levels can, conversely, also decline as a result of shortened or fragmented sleep, possibly due to altered nocturnal testosterone secretion (Leproult & Van Cauter, 2011; Schmid et al., 2012). Testosterone therapy is known to possibly increase the risk of OSAS and sleep breathing disorders. Its effect on sleep has only been tested once in older men, where testosterone was found to reduce sleep duration (Liu et al., 2003). Preclinical studies in rodents offer insight into mechanistic effects of sex hormones. Sudden estrogen withdrawal in rodents can increase “depressive-like” behavior (Galea et al., 2001; Schiller et al., 2013) and subsequent administration of estradiol can reduce these behaviors. Administration of estradiol in sleep-deprived rats has shown varying results on sleep, indicating it could either worsen (Schwartz & Mong, 2011) or facilitate recovery after sleep deprivation (Deurveilher et al., 2009). High doses of exogenous progesterone seem to have an anxiolytic and sedative effect in humans (Söderpalm et al., 2004; van Broekhoven et al., 2006). Progesterone administration seems to shorten non-REM sleep and prolong REM sleep duration in a similar fashion to agonistic GABA-A receptor modulators (Lancel et al., 1996). This sedative effect might be driven by metabolite products from progesterone, which can affect GABA receptors (van Broekhoven et al., 2006). A progesterone withdrawal paradigm in rats (Li et al., 2012) showed increased anhedonia and social withdrawal after a sudden reduction of progesterone in rats, which was seen as a robust model for premenstrual dysphoric disorder. Here, a possible underlying role of serotonin was explored, but progesterone withdrawal did not seem to affect brain serotonin levels and serotonin metabolite levels. Testosterone administration has also shown to reduce depression-like symptoms in young male mice (Buddenberg et al., 2009) as well as ageing mice (Frye & Walf, 2009), and it also increased sleep duration and NREM
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