Sleep regulation and sex hormones exposure in men and women across adulthood.

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Available online at

ScienceDirect www.sciencedirect.com

Review

Sleep regulation and sex hormones exposure in men and women across adulthood Re´gulation du sommeil et hormones sexuelles chez les hommes et les femmes au cours de la vie adulte C. Lord a, Z. Sekerovic a, J. Carrier a,*,b,c a

De´partement de psychologie, universite´ de Montreál, Pavillon Marie-Victorin, 90, avenue Vincent-d’Indy, H2V 2S9 Montreál, Que´bec, Canada Center for advanced research in sleep medicine, hoˆpital du Sacre´-Cœur de Montreál, 5400, boulevard Gouin-Ouest, H4J 1C5 Montreál, Que´bec, Canada c Institut universitaire de ge´riatrie de Montreál, universite´ de Montreál, Pavillon Coˆte des neiges, 4565, chemin Queen-Mary, H3W1W5 Montreál, Que´bec, Canada b

A R T I C L E I N F O

A B S T R A C T

Article history: Received 1 March 2014 Accepted 11 July 2014 Available online xxx

This review aims to discuss how endogenous and exogenous testosterone exposures in men and estrogens/progesterone exposures in women interact with sleep regulation. In young men, testosterone secretion peaks during sleep and is linked to sleep architecture. Animal and human studies support the notion that sleep loss suppresses testosterone secretion. Testosterone levels decline slowly throughout the aging process, but relatively few studies investigate its impact on age-related sleep modifications. Results suggest that poorer sleep quality is associated with lower testosterone concentrations and that sleep loss may have a more prominent effect on testosterone levels in older individuals. In women, sex steroid levels are characterized by a marked monthly cycle and reproductive milestones such as pregnancy and menopause. Animal models indicate that estrogens and progesterone influence sleep. Most studies do not show any clear effects of the menstrual cycle on sleep, but sample sizes are too low, and research designs often inhibit definitive conclusions. The effects of hormonal contraceptives on sleep are currently unknown. Pregnancy and the postpartum period are associated with increased sleep disturbances, but their relation to the hormonal milieu still needs to be determined. Finally, studies suggest that menopausal transition and the hormonal changes associated with it are linked to lower subjective sleep quality, but results concerning objective sleep measures are less conclusive. More research is necessary to unravel the effects of vasomotor symptoms on sleep. Hormone therapy seems to induce positive effects on sleep, but key concerns are still unresolved, including the long-term effects and efficacy of different hormonal regimens. ß 2014 Published by Elsevier Masson SAS.

Keywords: Sleep Testosterone Estrogens Progesterone Menopause Pregnancy Menstrual cycle

R E´ S U M E´

Mots cle´s : Sommeil Testoste´rone Estroge`nes Meńopause Grossesse Cycle menstruel

L’objectif de cette revue est d’e´valuer les effets de l’exposition exoge`ne et endoge`ne a` la testoste´rone chez l’homme et aux estroge`nes et a` la progeste´rone chez la femme sur le sommeil. Les niveaux de testoste´rone sont maximaux lors du sommeil et la privation de sommeil supprime la testoste´rone. Peu d’e´tudes ont e´value´ les effets de la diminution de la testoste´rone avec l’aˆge sur les modifications de sommeil associeés au vieillissement. Lors du vieillissement, les niveaux plus bas de testoste´rone seraient associe´s a` une qualite´ moindre de sommeil et les effets de la privation de sommeil sur la testoste´rone seraient plus prononce´s. Chez les femmes, les niveaux d’hormones sexuelles fluctuent lors du cycle menstruel et des e´tapes de la vie reproductive. Les mode`les animaux indiquent que les estroge`nes et la

* Corresponding author. E-mail address: [email protected] (J. Carrier). http://dx.doi.org/10.1016/j.patbio.2014.07.005 0369-8114/ß 2014 Published by Elsevier Masson SAS.

Please cite this article in press as: Lord C, et al. Sleep regulation and sex hormones exposure in men and women across adulthood. Pathol Biol (Paris) (2014), http://dx.doi.org/10.1016/j.patbio.2014.07.005

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progeste´rone influencent le sommeil. La plupart des e´tudes ne montrent pas d’effet marque´ du cycle menstruel sur le sommeil mais souvent avec un ećhantillon tre`s petit ou un design expe´rimental non optimal. La grossesse et la pe´riode postpartum sont associeés a` des difficulte´s de sommeil mais leurs liens avec le milieu hormonal reste a` de´terminer. Finalement, la transition vers la meńopause s’accompagne d’une diminution de la qualite´ subjective du sommeil mais les e´tudes sur les variables objectives restent non concluantes. Le roˆle des symptoˆmes vasomoteurs dans la de´te´rioration du sommeil lors de la meńopause devra e´galement eˆtre de´termine´. L’hormonothe´rapie semble ame´liorer le sommeil mais des questions cruciales restent a` ećlaircir, notamment les effets a` long terme et l’efficacite´ des types offerts. ß 2014 Publie´ par Elsevier Masson SAS.

1. Introduction Although sex hormones have received considerable attention in research, our knowledge of their relation to sleep is still limited. The objective of this review is to bring together results that demonstrate the link between sleep and the regulation of sex hormones over the lifespan of men and women. The review will focus mainly on the major sex hormones, namely testosterone in men and estrogens and progesterone in women, and describe how endogenous and exogenous exposures to these hormones interacts with sleep regulation throughout adulthood. 2. Factors contributing to endogenous sex steroid exposure In women, biosynthesis in the gonads is stimulated by a cascade of hormonal events initiated in the brain at puberty and terminated at menopause, whereas in men, it is a lifelong process following puberty. In brief, the series of events begins in the hypothalamus, which releases gonadotropin-releasing hormones (GnRH) in a pulsatile fashion and stimulates the anterior pituitary to secrete two gonadotropins, luteinizing hormone (LH) and follicle-stimulating hormone (FSH), which in turn stimulate the secretion of gonadal hormones (estrogens and progesterone in women and testosterone in men). In women, sex steroids have positive and negative feedback effects on the secretion of LH and FSH. These closed-loop feedback systems create the cyclical process of the menstrual cycle with varying sex steroid levels depending on the phase of the cycle [1–3]. In men, sex steroids levels decline slowly and in a linear fashion with aging across adulthood [4,5]. On the other hand, female sex steroid levels are characterized during adulthood by a marked monthly cycle in addition to reproductive milestones such as menarche, pregnancy, breast-feeding, and menopause, all of which have a profound influence on endogenous sex steroid exposure. 3. Sleep and testosterone exposure in males 3.1. Sleep and testosterone in young men It is widely accepted that testosterone secretion fluctuates throughout the day with blood concentrations peaking around wake time and falling during the day [6–8]. This circadian rhythm is accompanied by a shorter ultradian rhythm in which blood testosterone concentration oscillates every 90 minutes, reflecting its pulsatile secretory pattern [9]. However, results from one study suggest that the diurnal testosterone rhythm might be a sleeprelated rather than a circadian-driven phenomenon [10]. Research from this study reported that in healthy young men, testosterone levels increased and reached peak concentrations during sleep, regardless of whether subjects slept during the day or night. In addition, testosterone levels decreased after waking from both

daytime and nighttime sleep. In a series of studies, Luboshitzky et al. evaluated whether the rise of testosterone levels across the night was correlated with sleep architecture. The authors found that in young men, nocturnal testosterone rise begins at sleep onset, peaks around the time of the first REM-sleep episode, and remains heightened throughout the rest of the night [11,12]. They also showed that REM latency correlates with the slope of this testosterone rise (i.e. the rise was smoother when the REM latency was longer) [11]. Sleep restriction studies in animals and humans indicate that sleep disturbances induce changes in the gonadal endocrine axis, resulting in reduced levels of circulating testosterone. Recently, Wu et al. evaluated serum testosterone levels in adult male rats after 24 or 48 hours of total sleep deprivation (SD). Compared to control and sham groups, the sleep-deprived rats secreted significantly less testosterone regardless of the duration of SD [13]. These results also support findings from studies using selective REM-sleep deprivation in male rats, in which testosterone levels show a linear time-dependent decrease during a period of up to 7 days of REM-sleep deprivation [14,15]. Interestingly, an equivalent period of recovery sleep following REM-sleep deprivation does not necessarily restore testosterone to its baseline levels, which suggests that long periods of SD may lead to lasting adverse effects on sexual hormone regulation [14]. However, it is welldocumented that SD induces stress response by increasing hypothalamus-pituitary-adrenal (HPA) axis activity, which has been shown to reduce testosterone production [16]. Therefore, the possibility that the testosterone reduction following SD might be related to an increase of HPA axis-related hormones, especially corticosterone in rodents, cannot be dismissed [14]. In humans, results from SD studies are, to some extent, in line with animal studies. In a recent study, the sleep of 10 healthy young men was restricted to 5 hours during 8 consecutive days, a condition experienced by at least 15% of the U.S. working population [17]. One week of sleep restriction led to a 10 to 15% decrease in daytime testosterone levels when compared with the levels found after a normal night of sleep [17]. A recent study also reported that compared with a normal sleep episode, daytime testosterone levels were lower after one night of total SD or after a 4.5-hour sleep episode restricted to the first half of the night [18]. However, the results also showed that daytime testosterone levels were not affected by two consecutive 4-hour sleep episodes restricted to the second half of the night, which is heavier in REMsleep [18]. These data are supported by another study that observed no change in daytime testosterone levels after 5 nights of sleep restricted to the latter part of the night [19]. Taken together, research suggests that the timing, rather than the severity of sleep restriction, plays a pivotal role in daytime testosterone concentrations [18]. Nevertheless, extending sleep duration and avoiding SD should be further explored as behavioural modifications that may prevent sex hormone alterations in men. It is worth noting, however, that even though it is believed that testosterone


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secretion peaks during the night, none of the previously described studies measured the effects on nighttime testosterone levels. Studies with nighttime hormonal assessment are needed to better understand the impact of partial or total SD on testosterone dynamics. 3.2. Sleep and testosterone in aging men Beginning between the ages of 30 and 40, testosterone production progressively decreases at an average rate of 1 to 2% per year [20,21]. Often referred to as ‘‘andropause,’’ this testosterone decline is more moderate and gradual than that of estrogens during menopause in women [22,23]. At the same time, starting in the midlife years, sleep shortens and sleep patterns become more disturbed with multiple and longer awakenings across the night [24–26]. Compared to REM-sleep, non-REM-sleep (NREM) changes considerably with aging, undergoing a substantial reduction in slow-wave sleep (SWS) and a rise in lighter NREMsleep stages [25,26]. As a result, one may expect certain consequences of age-related sleep alterations to have an effect on hormone levels or vice versa. However, to date, relatively few studies have investigated this relationship in older populations. In one clinical trial, 10 young men and 8 older men underwent multisite intensive monitoring, which included simultaneous overnight EEG recordings and frequent blood testosterone sampling (every 2.5 minutes) [27]. The study indicated a clear relationship between increasing testosterone secretion and deepening of sleep in young men. This positive correlation between testosterone release and sleep stage transitions, however, was not present in older men. Another study investigated the relationship between mean overnight blood testosterone concentrations and sleep architecture in 67 men between the ages of 45 and 74. When adjusted for age, lower levels of circulating testosterone were associated with reduced sleep efficiency, increased time awake after sleep onset, decreased number of REM-sleep episodes, and greater latency of the first REM-sleep period [28]. Moreover, in a group of 12 subjects between the ages of 64 and 74, a lower amount of nighttime sleep was a strong and independent predictor of lower morning blood testosterone levels [29]. Results from these studies suggest that in middle-aged and older men, poorer sleep quality is associated with lower testosterone concentrations, regardless of age-related effects on both endocrine regulation and sleep. In animals, one study analyzed hormonal changes following different durations of REM-sleep deprivation (3, 5, or 7 days) in young and old male rats [15]. Serum testosterone concentrations decreased after REM-sleep deprivation in a time-dependent manner for both groups. However, this decrease was more prominent in the older rats. Most importantly, testosterone levels failed to recover after 5 days following REM-sleep deprivation in older rats, whereas testosterone levels in the younger group showed a progressive linear recovery over three days [15]. These results indicate that REM-sleep deprivation has more detrimental effects on testosterone levels in older animals. Since testosterone already decreases with age, ongoing sleep disturbances in older males could have important health implications given the role of testosterone in a number of physiological conditions [19]. Conversely, supraphysiological doses of testosterone might actually be associated with sleep disturbances in older men. Liu et al. (2003) examined the effects of short-term high-dose testosterone treatment on the sleep of 17 men over the age of 60 in a randomized double-blind placebo-controlled crossover study. Each subject received three injections in intervals of oneweek each (500 mg dose of testosterone esters or oil based placebo in the first injection and 250 mg in each of the subsequent two injections) before crossing over to the other treatment. Compared

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to the placebo, testosterone treatments shortened sleep duration by about an hour with a reduction in both NREM and REM-sleep, as well as in sleep efficiency [30]. Even though testosterone doses in this study were not comparable to those administered during longterm androgen therapy in older men, the authors concluded that high-quality studies examining both the efficiency and safety of long-term androgen therapy are needed before its use in the healthy aging male population can be recommended.

4. Sleep and estrogens/progesterone exposure in females It has been less than two decades since sleep researchers began to extend their findings to include women in their study designs along with men. However, it came to scientific attention that factors unique to women, such as the menstrual and reproductive phases during which women are tested, may influence sleep results and, in turn, may have resulted in inconsistent findings and/ or incorrect conclusions in the past. Moreover, studies demonstrating the effects of sex differences on sleep patterns contributed to this change in thinking by encouraging the study of women as a separate entity. Thus, few studies are available on women’s sleep over an entire lifespan, and less information is available on the relationship between sex hormone levels and sleep regulation. It is important to consider the methodological challenges associated with studies that evaluate the role of sex steroids on sleep regulation in women. Researchers face a challenge with several crucial variables that are difficult to operationalize. For instance, the different phases of the menstrual cycle are not easy to control for in a group setting because individual differences — such as the length of the phases and overall cycle — exist between and within subjects. Ovulation timing, anovulatory cycle, and/or use of hormonal contraception can also affect the dynamics of estrogens. The challenge becomes even greater during the perimenopausal years, characterized by erratic cycles and sex steroids regulation, which leaves premenopausal women between the ages of 35 and 50 greatly understudied. Furthermore, symptoms related to the menopausal transition, such as hot flashes, are often defined differently in various studies, which complicate the process of distinguishing the direct and indirect effects of changes in exposure to estrogens on sleep. Finally, a large proportion of women are exposed to synthetic hormonal contraceptives and hormone therapy — some for the majority of their lives starting at puberty. These exogenous hormonal treatments are diverse and difficult to control for in studies. All of these methodological factors leave researchers with, among other things, significant issues in regards to statistical power. Study designs need to include several testing phases with a single individual and/or a large number of women in order to compensate for the multiple subdivisions that are necessary for the assessment of fluctuations in the lifelong female reproductive event. These studies, therefore, prove very costly in time, effort, and finance, as well as very difficult to replicate. 4.1. Animal models to estimate the effects of female sex hormones on sleep Rodent studies (for review see [31]) support the notion that estradiol consistently suppresses NREM and/or REM-sleep in ovariectomized rodents [32–44]. Proestrus (spontaneous estradiol and progesterone peaks) in intact female rodents is also associated with an arousal-promoting effect as measured by increased awakenings and more time spent awake [45–47]. This arousalpromoting effect of estradiol is more prominent during the dark active phase of the sleep-wake cycle [42–48]. Recent studies also show that in adult ovariectomized rats, treatment with estradiol


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alone or in combination with progesterone enhances wake time and decreases NREM and REM-sleep during baseline sleep [42–44]. Findings are less consistent when evaluating the effects of female hormones on the ability to recover after sleep loss. Whereas at baseline, estradiol reduced sleep in the dark phase, during recovery in the dark phase, estradiol alone or in combination with progesterone seemed to promote REM-sleep and contributed to greater NREM-sleep consolidation [43]. Indeed, after 6 hours of total sleep deprivation during the last part of the light phase, one research group reported that estradiol-treated as well as estradioland progesterone-treated ovariectomized rats showed a greater relative rebound (increase) in NREM and REM-sleep, reaching the same levels of NREM and REM-sleep as the placebo-treated group [46,47]. However, NREM-sleep EEG delta power was attenuated in hormone-treated groups during recovery, despite the relative increase in NREM-sleep duration [42]. On the other hand, in middle-aged ovariectomized rats, combined treatment with estradiol and progesterone enhanced the intensity of recovery sleep, as measured by EEG delta power, compared to estradiol treatment alone [44]. Other studies observed a reduction in NREMsleep or REM-sleep in the dark phase following SD in estradioltreated versus placebo-treated ovariectomized animals [37– 39]. However, one of these studies showed that when rats recovered during the light phase after 6 hours of sleep deprivation, estradiol-facilitated REM-sleep recovery matched that of the placebo group [38]. These results suggest that estradiol modulation of sleep architecture in female rodents is to some degree under circadian control [31]. The impact of progesterone and its metabolites on sleep EEG in female animal models is somewhat less documented (for review see [49]). Studies generally report a hypnotic, benzodiazepine-like effect of progesterone on sleep EEG in rodents. Hence, some studies have shown that progesterone and allopregnanolone, a neuroactive progesterone metabolite, decrease wakefulness, NREM latency, and NREM EEG activity at lower frequencies (< 7 Hz), whereas they enhance NREM EEG activity at a higher frequency range (> 13 Hz) [50,51]. Progesterone lengthened REM-sleep latency and reduced the amount of REM-sleep, and both progesterone and allopregnanolole enhanced REM EEG activity in the beta frequency range [50,51]. Another study reported that compared to a placebo, pregnanolone, another neuroactive progesterone metabolite, decreased wakefulness and increased NREM-sleep [52]. However, it is noteworthy that all the studies stated above were conducted with intact adult male rats, making it difficult to generalize the results to include females. Still, one recent study observed REM-suppressing effects of progesterone in adult ovariectomized rats. During the dark phase, progesteronetreated females spent less time in REM-sleep compared to their placebo counterparts [42]. The mechanisms by which ovarian hormones exert their influence on sleep regulation in animals are still unclear. The presence of estrogens and progesterone receptors in many sleepwake regulatory nuclei is likely part of the answer (for reviews see [31,49]). 4.2. Sleep and estrogens/progesterone during female adulthood: influence of the menstrual cycle

Estrogen levels peak late in the follicular phase and plunge to a nadir at ovulation. During the luteal phase, estrogen levels remain low, whereas progesterone rises and drops immediately before menses, allowing another cycle to start. The timing of the LH surge, ovulation, and peaks and nadirs of the gonadal hormones varies at each cycle both within and across individual women [1–3]. Within the past few decades, a few attempts have been made to draw a clearer portrait of the impact of gonadal steroids on sleep across the menstrual cycle. In an early study, Parry et al. (1989) noticed that in 8 women with premenstrual depressive symptoms and 8 matched controls, stage 3 sleep and the number of intermittent awakenings varied with phases of the menstrual cycle [53]. In 1999, the same group published the results of a study that included 14 women suffering from premenstrual dysphoric disorder (PMDD) and 9 normal controls with a mean age of 37 (range 24–45). Their results showed that compared to the follicular phase, REM latency was longer, REM and SWS were higher, and stage 1 was lower in the luteal phase in both groups of women [54]. Lee et al. (1990) conducted a sleep study with 13 women between the ages of 25 and 35 that monitored regular and ovulatory menstrual cycles with salivary progesterone measurements. The only significant within-subject comparison was shorter REM latency during the luteal phase compared with the follicular phase. However, 7 women reported negative affect symptomatology that was not controlled for [55]. Another small sample study showed less REM-sleep, more SWS, and slightly less time spent awake in stage 1 sleep during the luteal phase as opposed to the follicular phase [56]. In an elegant study design, Driver et al. (1996) recorded the sleep of 9 women every other night throughout an ovulatory cycle for a total of 138 PSG recordings. Measures of gonadal hormones, however, were taken only once, at midluteal phase, to confirm cycle stage. Researchers observed no significant changes across the menstrual cycle for subjective ratings and objective sleep measures (total sleep time, sleep efficiency, sleep latency, REM-sleep latency, and slow-wave sleep). However, EEG power density in the 14.25–15.0 hertz band, associated with sleep spindles, varied across the menstrual cycle, with higher power density in the luteal phase [57]. In line with these results, Chuong et al. (1997) and Baker et al. (2001) also did not find any significant changes in sleep architecture across the menstrual cycle [58,59]. Reviews on the subject are very cautious in their conclusions, taking into account the very small sample sizes of their studies and their differences in design. However, researchers noticed that the premenstrual phase might be more linked to enhanced sleep disturbances [49,60,61]. The heterogeneity in the sleep architecture findings can potentially be explained by individual differences in sex steroids levels, metabolism, and rate of change. Moline et al. (2003) concluded that results point towards a non-significant effect of gonadal hormone fluctuations on sleep in young cycling women, but too few studies are available to disregard their possible relation to sleep in young women. Moreover, to date, women between the ages of 30 and 45 have been understudied. They thus concluded that until groups of regularly cycling women of varying age groups are studied, the gonadal impact on sleep cannot be ruled out [60]. 4.3. Sleep and hormonal contraceptives

The menstrual cycle lasts 28 days on average and consists of 3 regular phases: follicular (including menses), ovulatory, and luteal. The first days correspond to the menstruation in which both estrogens and progesterone are low. During the early follicular phase, estrogen levels remain low, only to subsequently increase at a steady rate as a consequence of follicular production. At the midfollicular phase, there is a transition from suppression to stimulation of LH secretion following a sustained rise in estrogens.

Women using hormonal contraception are often excluded from study designs. The variety of compounds available makes it difficult to compare them to one another and to group women according to different types. Moreover, most hormonal contraceptives are composed of both estrogens and progesterone, making it impossible to differentiate the effects of each. Of note, only two studies of a very small sample size have attempted to investigate


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the effect of the menstrual cycle and use of oral contraceptives on sleep architecture. These studies demonstrated that women using oral contraceptives showed less SWS than non-users in the luteal phase [59,62]. With a significant proportion of women using hormonal contraception during their reproductive life, more research is needed in order to better investigate both the shortand long-term effects of exogenous hormones on sleep regulation during these years. 4.4. Sleep and estrogens during the perinatal period In comparison to non-pregnant concentrations, during the prenatal period, there is a significant increase of maternal gonadal hormone excretion [1,3,63]. The estrogens and progesterone concentrations increase with gestational age, culminating prior to delivery and followed by a rapid decline and return to normal levels following parturition [1,3,63–65]. This quick decline in estrogens and progesterone allows lactogenesis to occur, most likely by releasing its antagonistic effect on prolactin [64]. Following delivery, most women go through a period of infertility associated with anovulatory amenorrhea, during which gonadal hormones are near postmenopausal levels [66], eventually returning to normal levels in 2 to 3 months postpartum for non-breast-feeding mothers [64]. In nursing mothers, however, the length of this suppressed ovarian period is believed to depend on both the central actions (hypothalamic GnRH level) of the suckling stimulus and its frequency [64]. It is well-know that pregnancy and the arrival of a newborn are external factors that contribute to sleep disruption. Sleep deregulation happens for obvious reasons such as physical discomfort associated with pregnancy in the late stages, the soporific effect of certain rising hormones during pregnancy, and/ or the rapid-feeding cycle and sleep pattern of a newborn. These variables come into play and further confuse the impact of gonadal hormones on sleep. Methodologically speaking, design and data collection in these contexts are even more difficult. In their review, Moline et al. (2003) report that sleep complaints significantly increase as pregnancy advances and that sleep difficulties are mostly evidenced by physical symptoms associated with pregnancy. Importantly, an increase in specific sleep disorders, including obstructive sleep apnea and restless leg movement disorder, is also observed during pregnancy [67,68]. During the postpartum period, complaints about sleep disturbances are also very high and are linked to various challenges, including the baby’s needs, the feeding method, and the mother’s anxiety and depression levels. Interestingly, Kennedy et al. (2007) conducted a qualitative study on sleep during pregnancy and up to early postpartum to discover that mothers did not expect the level of sleep disturbance that all twenty of them experienced. In the article, the authors presented a model conceptualizing how women described sleep changes, the factors that contributed to sleep disturbances, and how they learned to manage sleep, taking into account both the infant’s needs and their own. In addition to stressing the value of educating women about sleep changes during and after pregnancy as well as the restorative function of sleep, the authors also highlighted the importance of providing suggestions on how to improve sleep quality [69]. There are very few studies using objective measures of sleep during pregnancy. A study performed with PSG at home on 33 women demonstrated that as pregnancy progressed, significant decreases in SWS were observed, which did not recover until after delivery. An increase in wake time and a decrease in sleep efficiency throughout the perinatal period were also noticeable, with the 3 months postpartum period exhibiting significantly lower sleep efficiency than that of pre-pregnancy [70]. Another longitudinal study during the perinatal period on 9 women showed

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that nighttime wake increased from the second to the third trimester, whereas the amount of REM-sleep decreased from the first to the second semester. Spectral analysis of the EEG in NREMsleep revealed a significant reduction in delta, theta, and sigma frequencies in the third semester, suggesting decreased sleep depth [71]. Finally, one study performed on 5 women during the perinatal period corroborated the increase in time awake after sleep onset but did not report a reduction in SWS. Conversely, the results showed an increase in SWS during the last trimester. The authors also observed lower time spent in REM-sleep after the second trimester until the postpartum period [72]. Relatively new data and hypotheses on the impact of maternal sleep disturbances during pregnancy on maternal and fetal outcomes are of great concern. Limited evidence exists so far, but sleep deprivation during pregnancy may be associated with longer and more painful labor, higher rates of preterm labor, preeclampsia, caesarean section, and greater risk of depression (for reviews on the subject see [73,74]). These results are in line with what is known about the impact of sleep deprivation on several biological pathways associated with cardiovascular morbidity, including the neuroendocrine, metabolic, and inflammatory systems. This should prompt more research on this issue during the perinatal period and urge clinicians not to disregard significant lack of sleep and associated complaints. 4.5. Sleep and gonadal hormones in the menopausal years 4.5.1. Before and after menopause Menstrual irregularities mark the beginning of perimenopause, occurring at 46 years of age on average and lasting from 2 to 8 years with an average duration of 5 years [75,76]. During this period, gonadal hormone levels vary unpredictably. Eventually, the gonads begin to secrete fewer hormones, and ovulation and menstruation become sparse, ultimately ceasing spontaneously between the ages of 50 and 52 on average. Menopause marks the permanent cessation of menstruation. To be considered menopausal, most definitions of the term require that women do not experience menstruation for at least twelve consecutive months with no other obvious cause. The postmenopausal years are characterized by very low estrogen levels arising from peripheral conversion of testosterone into estrogens, as there is no longer any ovarian production [1,3,4,77]. Sleep complaints are one of the most common symptoms related to the menopausal transition, affecting 40–60% of women [78]. It has been observed that sleep problems (e.g. obstructive sleep apnea, restless sleep problems) are more common during the menopausal transition [79,80]. Women also report more trouble falling asleep, fragmented sleep, nighttime wakefulness, and the inability to resume sleep during the menopausal years [81– 88]. Aging and other menopausal symptoms, such as hot flashes, mood alterations, and stress related to the menopausal transition, may also contribute to sleep problems (reviewed in [88]), making it difficult to determine whether menopausal sleep difficulties are mediated by direct changes in hormonal milieu or by other indirect effects. Woods and Mitchell have developed and tested a model to account for the plethora of contributors to specific sleep complaints (e.g. early morning awakening, nighttime awakenings) observed during this period in women’s lives. They concluded that whereas menopausal transition and hot flashes were linked to some specific sleep variables, other factors contributed significantly and should be taken into account to help alleviate sleep difficulties in middle-aged women. [89,90]. Vasomotor symptoms (e.g. hot flashes, night sweats) are one of the major controversial contributors to sleep disturbances during the menopausal transition. Some have shown very clear adverse effects of vasomotor symptoms on sleep disturbances without


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being their sole determinant, whereas others do not report significant relationships between vasomotor symptoms and sleep quality at all [91–95]. An editorial written by Regestein in 2012 exposed the challenge posed by the discrepancies between subjective and objective measures of hot flashes. One of the problems resides in the different criteria used by women and the scientific community to define hot flashes and the significant magnitude (frequency and intensity) necessary to interfere with sleep. Several methodologies have been proposed to measure hot flashes both objectively and subjectively, which creates disparate results. Moreover, it has recently been demonstrated that participant characteristics, such as negative affect, sleep, and race and ethnicity, influence the recall of vasomotor symptoms [96]. Importantly, there seems to be a discrepancy between postmenopausal subjective and objective sleep data. Studies assessing sleep architecture have failed to uncover a mechanism explaining why women frequently report long-lasting sleep disruptions despite the fact that objective sleep quality indicators often do not decrease during the menopausal years. Few studies investigated the longitudinal dynamics of sex steroids changes during the menopause transition with objective sleep characteristics. However, comparisons between these studies are difficult because of their diverse methodological designs, definitions of menopause transition, and hormonal measures, among other things (for reviews see [49,60]). Recently, large sample population-based longitudinal studies assessing sleep architecture helped to resolve issues of statistical power, control of confounding factors, and sample bias. In 2003, a study using the PSG data from the Wisconsin Sleep Cohort Study reported objective sleep parameters in 589 middle-aged women. It confirmed that women are less satisfied with their sleep quality during the menopausal transition. However, contrary to the hypothesis that sleep would be worse after menopause, as the subjective reports suggested, it demonstrated that postmenopausal women had the best overall sleep architecture, whereas premenopausal women had the worst, and perimenopausal women were in between. Compared to premenopausal women, postmenopausal women had more SWS and longer sleep durations, and perimenopausal women had less light sleep (stage 1) and more SWS [97]. Two other reports also emerged from the Study of Women’s Health Across the Nation (SWAN) cohort that evaluated the association between gonadal hormones and sleep in a large multi-ethnic community sample [98,99] (for review see [93]). Kravitz et al. showed an increase in difficulty falling asleep and more complaints of waking up several times at night during the menopausal transition in a sample of 3045 women studied over a period of 7 years. They also observed that decreasing estrogen levels were associated with more frequent awakenings and trouble falling asleep, while increasing FSH levels were associated with more awakenings [98]. Sowers et al. (2008) demonstrated that FSH, estrogens, and testosterone influenced PSG sleep during the menopausal transition in 365 women. Their results indicated that women transitioning faster, as observed by more rapid change over time in FSH levels, slept longer and had more deep sleep (SWS). On the other hand, women transitioning faster reported poorer subjective sleep quality. Estrogen levels and rate of change were not associated with sleep measures, aside from a significant relation between higher estrogen levels at baseline and slightly poorer selfreported sleep 5 to 7 years later. They also observed that women with the highest testosterone levels had fewer awakenings after falling asleep compared with women with the lowest levels. Interestingly, when data were analysed using menopausal status instead of hormonal changes over time, associations between sleep and menopausal status were not significant [99].

In light of these findings, further research is needed to better understand the complex associations between sex steroids and subjective and objective sleep during the menopausal transition. Sleep complaints significantly increase as the transition to menopause advances, but the link with objective sleep variables is less obvious. The notion that subjective and objective sleep may differ between menopausal women with and without hot flashes warrants studying them separately or controlling for menopausal symptoms. More longitudinal objective and subjective sleep studies in large community samples are thus needed to take into account the temporal dynamics of hormonal changes (FSH, estrogens, progestogen) and confounding factors such as age and menopausal symptoms. 4.6. The effects of hormone therapy (HT) on sleep Studies on exogenous use of gonadal hormones and sleep are scarce, inconsistent between subjective versus objective data, and consist mostly of small, randomized-controlled trials using various designs and HT preparations. Most studies have shown that both estrogen therapy alone and estrogen/progestogen therapy improve subjective sleep quality and vigilance during the day [100– 107]. Enhancement of subjective sleep quality is associated with a reduction of vasomotor symptoms and with an improvement of mood [103]. There are still very few studies on the effects of hormone therapy on PSG measures of sleep. Most studies have indicated only small improvements of PSG sleep on a number of different parameters. Both estrogens alone and estrogen/progestogen therapy may reduce sleep latency [108,109], enhance sleep consolidation [102,110–112], and increase REM-sleep [108– 110,112]. One study suggested that progesterone alone may prevent sleep disturbances in stressful situations [113]. Only a few studies have shown no effect of hormonal therapy on PSG sleep parameters [104]. Importantly, data from blind, randomized trials seem to show that the HT-mediated improvement of subjective sleep can also be independent of objective sleep patterns [114– 116]. Differences in selection criteria (sleep complaints, severity of vasomotor symptoms, associated sleep disorders, etc.) and methodology (duration of treatment, evaluation of sleep during estrogen phase treatment or estrogen/progesterone phase treatment) may explain the divergence in results between studies. These parameters need to be controlled in future studies to better identify factors related to the efficacy of hormone therapy in alleviating sleep difficulties in middle-aged women. Furthermore, very few studies have compared the effects of different regimens of hormone therapy on sleep. One report suggested that micronized progesterone may work better than medroxyprogesterone to improve the quality of sleep in postmenopausal women taking estrogen [102]. Schu¨ssler et al. (2008) extended these findings on the specific effect of micronized progesterone in a randomized blind crossover design. Progesterone treatment alone led to decreased time spent awake, increased REM-sleep in the first third of the night, and no difference in spectral analysis [117]. Another study comparing two HT preparations demonstrated that sleep efficiency and wake duration improved significantly in a combined estrogens and micronized progesterone group but not in a medroxyprogesterone acetate group, while menopause symptoms and subjective sleep measures improved after treatment in both groups [102]. Finally, long-term effects (more than 6 months) of hormone therapy on sleep should also be addressed. While hormone therapy is used to alleviate menopausal symptoms, including sleep complaints and vasomotor symptoms [118], the observations in the general population are often biased since HT users may be different from non-users to start with; women with poor sleep quality for instance, may be more likely to seek HT. For example, Young et al. (2003) did not find HT use to be


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related to better objective sleep measures. Postmenopausal women not using HT had less light sleep and more deep sleep, were falling asleep faster, and had better sleep efficiency as well as longer sleep [97]. However, Kravitz et al. (2008) noted that HT users reported less trouble falling asleep and less frequent awakenings [100]. The data on HT’s effect on sleep need further investigation but seem to point towards a positive effect of HT on sleep complaints and architecture. Whereas these effects are independent of menopausal symptoms, alleviation requires more in depth research with designs that assess, for example, the conjunct effect of HT on vasomotor symptoms and sleep regulation. 5. Conclusion The accumulation of data reviewed here strongly suggests that both endogenous and exogenous steroid hormones can have an impact on the sleep of women and men, but due to methodological issues and lack of data, no clear conclusions can be derived from many hypotheses. The results currently available are just the beginning of a growing field of study and indicate that the association between sleep and sex steroids is complex and needs further attention. Disclosure of interest The authors declare that they have no conflicts of interest concerning this article. References [1] Speroff L, Glass RH, Kase NG. Clinical gynecologic endocrinology and infertility. Philadelphia: Lippincott Williams & Wilkins; 1999. [2] Knochenhauer E, Azziz R. Ovarian hormones and adrenal androgens during a woman’s life span. J Am Acad Dermatol 2001;45:S105–15. [3] Speroff L, Fritz MA. Clinical gynecologic endocrinology and infertility. Philadelphia: Lippincott Williams & Wilkins; 2005. [4] Lamberts SW, van den Beld AW, van der Lely AJ. The endocrinology of aging. Science 1997;278:419–24. [5] Vermeulen A, Kaufman JM, Goemaere S, van Pottelberg I. Estradiol in elderly men. Aging Male 2002;5:98–102. [6] Marrama P, Carani C, Baraghini GF, Volpe A, Zini D, Celani MF, et al. Circadian rhythm of testosterone and prolactin in the ageing. Maturitas 1982;4:131–8. [7] Plymate SR, Tenover JS, Bremner WJ. Circadian variation in testosterone, sex hormone-binding globulin, and calculated non-sex hormone-binding globulin bound testosterone in healthy young and elderly men. J Androl 1989;10: 366–71. [8] Albertsson-Wikland K, Rosberg S, Lannering B, Dunkel L, Selstam G, Norjavaara E. Twenty-four-hour profiles of luteinizing hormone, follicle-stimulating hormone, testosterone, and estradiol levels: a semilongitudinal study throughout puberty in healthy boys. J Clin Endocrinol Metab 1997;82:541–9. [9] Borst SE, Mulligan T. Testosterone replacement therapy for older men. Clin Interv Aging 2007;2:561–6. [10] Axelsson J, Ingre M, Akerstedt T, Holmba¨ck U. Effects of acutely displaced sleep on testosterone. J Clin Endocrinol Metab 2005;90:4530–5. [11] Luboshitzky R, Herer P, Levi M, Shen-Orr Z, Lavie P. Relationship between rapid eye movement sleep and testosterone secretion in normal men. J Androl 1999;20:731–7. [12] Luboshitzky R, Shen-Orr Z, Herer P. Middle-aged men secrete less testosterone at night than young healthy men. J Clin Endocrinol Metab 2003;88: 3160–6. [13] Wu J-L, Wu RS-C, Yang J-G, Huang C-C, Chen K-B, Fang K-H, et al. Effects of sleep deprivation on serum testosterone concentrations in the rat. Neurosci Lett 2011;494:124–9. [14] Andersen ML, Martins PJF, D’Almeida V, Bignotto M, Tufik S. Endocrinological and catecholaminergic alterations during sleep deprivation and recovery in male rats. J Sleep Res 2005;14:83–90. [15] Oh MM, Kim JW, Jin MH, Kim JJ, Moon DG. Influence of paradoxical sleep deprivation and sleep recovery on testosterone level in rats of different ages. Asian J Androl 2012;14:330–4. [16] Gao H-B, Tong M-H, Hu Y-Q, Guo Q-S, Ge R, Hardy MP. Glucocorticoid induces apoptosis in rat leydig cells. Endocrinology 2002;143:130–8. [17] Leproult R, Van Cauter E. Effect of 1 week of sleep restriction on testosterone levels in young healthy men. JAMA 2011;305:2173–4. [18] Schmid SM, Hallschmid M, Jauch-Chara K, Lehnert H, Schultes B. Sleep timing may modulate the effect of sleep loss on testosterone. Clin Endocrinol (Oxf) 2012;77:749–54.

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Predictors of HIV Sexual Risk Behavior among Men Who Have Sex with Men, Men Who Have Sex with Men and Women, and Transgender Women.

Effects of norgestrel and ethinyloestradiol ingestion on serum levels of sex hormones and gonadotrophins in men.

Relationship between serum sex hormones and glucose, insulin and lipid abnormalities in men with myocardial infarction.

STI Prevalence and Intervention Exposure Among Men Who Have Sex with Men and Women (MSMW) and Men Who Have Sex with Men Only (MSMO) in India: Implications for HIV Prevention.

Sex, sex hormones and chronic liver diseases.