SECTION 4 - SLEEP AND HEALTH

Sleep, Sex Differences, and Women's Health

Background

Women from adolescence to post-menopause are underrepresented in studies of sleep and its disorders. Although sleep complaints are twice as prevalent in women, 75% of sleep research has been conducted in men. More sleep studies in the past five years have included women, but small sample sizes prohibit meaningful sex comparisons. Thus, sex differences in sleep and sleep disorder characteristics, in responses to sleep deprivation, and in sleep-related physiology remain unappreciated. Furthermore, findings from studies based primarily in men are often considered to be representative of 'normal' even when it is recognized that there are important sleep-related physiological differences in women, including timing of nocturnal growth hormone secretion and differential time course of delta activity across the night.

Sexual dimorphism in the central nervous system has been well documented but the functional implications of sex differences in the neurotransmitter and peptide systems that modulate sleep and wake are unknown. There is a need to study sex differences in sleep and homeostatic regulation across species to more fully understand the role that sleep plays in normal development, maturation, adaptation, aging, and disease propensity. Sex hormones influence sleep and circadian rhythms, and sleep affects neuroendocrine functioning, in particular the episodic secretion of gonadatropin hormones. There are potentially different effects of endogenous sex hormone cycling on neuronal groups involved in regulating behavioral states and circadian rhythms. Of importance is understanding how sex-related differences in sleep and its regulation influence the risk for and mechanisms of sleep disorders and other diseases.

Evidence from animal studies supports the presence of sex-related differences throughout the lifespan in susceptibility to disease in general and to sleep disorders in particular. As classic examples of sexual dimorphism, both the long-term neurobehavioral consequences of sleep-associated intermittent hypoxia as occurs in Sleep-Disordered Breathing (SDB) and the consequences induced by early life maternal separation stress exposures are reduced in female animals when compared to male littermates. The mechanistic roles of sex-related hormones and their receptors and signaling pathways in mediating the emerging sex-dependent differences in susceptibility to specific neural insults are only now beginning to be explored, and the new insights achieved should have major implications for the development of novel therapeutic interventions.

Physiologic changes in neuroendocrine hormones, body temperature, mood, and emotional state during puberty, the menstrual cycle, pregnancy, and menopause have profound effects on sleep quality, daytime functioning, and well-being in adolescent girls and adult women. It generally has been assumed that sleep prior to puberty is similar in girls and boys, and that sex differences first emerge during this developmental transition. The validity of this assumption, however, and the extent of sex differences in sleep and sleep disorders in children and adolescents are not known. There have been no cross-sectional or longitudinal studies of subjective and objective measures of sleep coupled with measures of neuroendocrine functioning during and after puberty. Despite the propensity for mood disorders to emerge during adolescence and the greater prevalence in girls compared to boys, little is known about how changes in sleep, sex hormones, and sleep deprivation affect mood and emotional problems in this age group.

Although female sex is a risk factor for Insomnia, and Insomnia is a risk factor for depression, little is known about how changes in sex hormones during the menstrual cycle impact sleep physiology and mood in adolescent girls and women. In fact, most of what is known about sex hormones and sleep is derived from studies of exogenous hormones in adult rodents and humans. Little is known about endogenous sex hormones, changes in sleep physiology, and the development of dysphoric mood and dysmenorrhea during the menstrual cycle. There have been only a few sleep laboratory studies in small samples of adult women during all phases of the menstrual cycle. Findings show wide individual variation with no consistent relationships between menstrual phase and changes in sleep physiology.

There are considerable methodological challenges in studying sleep across phases of the menstrual cycle. Without normative data based on ovulating and non-ovulating women, however, neither the researcher nor the clinician have reference points to aid in the interpretation of menstrual cycle effects on sleep or its disorders. Although not all women of childbearing age experience premenstrual symptoms and secondary Insomnia, Insomnia and related symptoms may occur associated with onset of menses. Insomnia related to menses may be related to a fall in endogenous progesterone or a differential sensitivity to endogenous hormone fluctuations, but these hypotheses require further testing. Potential health consequences or disease risk that are engendered by this repetitive 'incident' insomnia that can occur every month for 40 years of a woman's life are not known. However, menstrual cycle symptoms and premenstrual dysphoria correlate with. Women with significant dysmenorrhea may be at higher risk for developing insomnia and depression.

Hormonal changes and physical discomfort are common during pregnancy and both can affect sleep. Although nearly all pregnant women will experience disturbed sleep by the third trimester, there have been only two longitudinal sleep studies of subjective and objective sleep measures during pregnancy. There have been no reports of intervention studies to improve sleep quality during pregnancy. Some have assumed that disturbed sleep is a 'natural' consequence of pregnancy, labor, delivery, and post-partum that resolves over time since few women seek assistance to improve sleep. Research has not shown a relationship between sleep quality and quantity and any perinatal adverse outcome, length of labor, or type of delivery. More studies are needed, however, to clarify the extent to which sleep-related problems during pregnancy may have adverse fetal, perinatal, or infant-related consequences.

Very little is known about the effects of late stage pregnancy sleep disturbances on labor and delivery, emotional distress, or post-partum depression. However, nighttime labor and a history of sleep disruption in late stage pregnancy are related to a higher incidence of post-partum 'blues.' Certain sleep disorders such as Restless Legs Syndrome (RLS), Periodic Limb Movement Disorder (PLMS), SDB, or Insomnia may emerge during pregnancy and the extent to which these disorders resolve or place women at higher risk for sleep disorders later in life is not clear. Pregnancy induces changes in the upper airway and in functional residual capacity that predispose women to snoring, SDB, and reduced oxygen stores. Pregnant women who snore may be at risk for pre-eclampsia and/or SDB. The number of pregnant women with SDB may be substantial, but the prevalence has not been defined in either uncomplicated or complicated pregnancy. Women with pre-eclampsia and excessive weight gain during pregnancy are at greater risk for the development of SDB and pregnancy-induced hypertension, which have been associated with adverse perinatal outcomes, but few polysomnographic studies have been done in these women.

Many women during the menopausal transition (perimenopause, menopause, post-menopause) complain of sleep disturbances that are attributed to vasomotor symptoms (e.g., hot flushes and night sweats) rather than to menopausal status. Estimates of self-reported menopausal-related Insomnia range from 33 to 51%, but the actual prevalence of sleep disturbances in midlife women, particularly as a function of race, ethnicity, and body size is not well defined. Although there have been only a few sleep studies with both subjective and objective measures, a majority of midlife women with self-reported poor sleep quality report high psychological distress without objective evidence of poor sleep efficiency. Whether these women are physiologically hyperaroused (e.g., increased hypothalamic-pituitary-adrenal axis or sympathetic activity) without significant impact on standard indices of laboratory sleep remains to be clarified.

Data on changes in sleep physiology in women during the menopausal transition are sparse and no longitudinal sleep studies have been conducted. Compared to placebo, short-term hormone replacement therapy (HRT) has shown beneficial effects on improving subjective and objective sleep quality in women with menopausal symptoms, but not all studies show the same effects. Menopause may be a significant risk factor for SDB. It has been suggested that menopause-induced sex hormone deficiency might explain the increased prevalence of SDB in post-menopausal women and that women on HRT might be at lower risk. Given concerns about disease risk such as related to thromboembolic events, cardiovascular disease, and breast cancer) associated with hormone replacement therapy for the treatment of menopausal symptoms, fewer women in the future may receive HRT and hence more women may experience menopause-related insomnia or HRT withdrawal symptoms that could exacerbate insomnia. Alternative and established therapies for insomnia need to be systematically evaluated in women during and after menopause.

In addition to perimenopausal and menopausal effects on sleep in women, surveys show that more than 80% of working women report fatigue and exhaustion, and half of them obtain inadequate sleep. Women shift workers with altered sleep and circadian rhythms are at increased risk for menstrual irregularities, infertility, miscarriage, and low birth weight infants. Women remain the main caregivers for children and elderly family members. These responsibilities may add a significant stress burden and increased vulnerability for sleep disturbances with negative impact on health and quality of life. In addition, significant life events such as spontaneous abortions, stillbirth, or death of a child or spouse have been associated with development of posttraumatic symptoms, including sleep disturbances. Women who consume alcohol as a method of coping with work, family, and social demands are at increased risk for alcohol-induced sleep disturbances.

Progress In The Last 5 Years

Sleep and the Menstrual Cycle/Premenstrual Syndrome:

- Sleep architecture is unaffected by menstrual cycle phase. But body temperature is elevated and circadian rhythm amplitude is reduced during sleep, however, in the high progesterone phase (luteal) of the menstrual cycle, but the underlying mechanism is not known. Compared to men, women have a blunted drop in body temperature and an earlier nadir of the circadian body temperature rhythm.

- Women on oral contraceptives have reduced slow wave sleep and REM latency. Body temperature throughout the menstrual cycle is similar to that of normal cycling women in the luteal phase.

- Dysmenorrhea is associated with significantly disturbed sleep quality prior to menses. Compared to control women, women with dysmenorrhea had altered sex hormones, body temperature, and sleep throughout the menstrual cycle.

Sleep in Pregnancy and Post-Partum:

- Longitudinal studies indicate that age combined with anemia is related to first trimester fatigue and that reduced sleep time is related to fatigue during the third trimester. Both reduced sleep time and anemia are related to fatigue post-partum. Significant changes in sleep are evident in the first trimester of pregnancy with increased total sleep time coupled with more awakenings, but post-partum sleep efficiency is lower than pre-pregnancy. Slow wave sleep percentage is reduced throughout pregnancy compared to pre-pregnancy and post-partum. REM sleep was s reduced during pregnancy in one study, but was reduced in another longitudinal study, most notably during the third trimester.

- Restless Legs Syndrome (RLS) occurs in about 20% of pregnant women and may be associated with reduced levels of folate.

- Thirty percent of pregnant women begin snoring for the first time during the second trimester.

- Pre-eclamptic women show evidence of SDB associated with increased blood pressure. Pregnant women who snore have a twofold greater incidence of hypertension, pre-eclampsia, and fetal growth restriction compared to nonsnorers.

- Self-reported sleep quality derived from sleep diaries shows considerable sleep disturbances in the early post-partum period. Sleep efficiency improves during the first year post-partum, but it is unclear whether sleep quantity and quality return to pre-pregnancy levels.

- There is a relationship between sleep and mood during pregnancy and through the first three to four months post-partum. Increased disturbances in self-reported sleep and decreased reported total sleep time are associated with depressed mood post-partum.

Sleep and Menopausal Transition:

- Longitudinal studies of midlife women showed increased self-reported insomnia, night sweats, and hot flushes across the menopausal transition from late peri-menopause to post-menopause. Self-reported sleep disturbance in middle-aged women also has been associated with worse mood, higher blood pressure, higher waist/hip ratios, and chronic dissatisfaction with sleep.

- The prevalence of self-reported insomnia is 17% in a community-based cohort of racially mixed peri-menopausal menstruating women. Reduced estradiol, increased hot flashes, and psychosocial factors are all associated with poor sleep quality after controlling for current sleep medication use.

- Sleep quality as measured by polysomnography (PSG) does not appear to be different in peri- or post-menopausal women compared to premenopausal women. Also, there do not appear to be any differences in PSG sleep quality in women who use HRT versus those who do not. These observations imply that sleep disturbances in midlife women are not a 'normal' part of the menopausal transition.

- Hormone replacement therapy (estrogen preparations) is effective in reducing menopausal symptoms and self-reported sleep disturbances (insomnia and daytime sleepiness), and in increasing REM sleep and the amount of slow wave sleep in the first third of the night. In one randomized trial comparing two different forms of progesterone in combination with estrogen therapy, PSG sleep efficiency improved with reduced wake after sleep onset in the group receiving micronized progesterone.

- The prevalence of SDB in postmenopausal women on HRT is significantly lower than in postmenopausal women not on HRT, indicating that menopause may be a significant risk factor for SDB in women and HRT may reduce that risk. The hypothesis that healthy postmenopausal women not on HRT have more SDB compared to women on HRT has also been confirmed in a large population-based study.

Research Recommendations

- Establish how sex-related differences in sleep and its regulation influence the mechanisms and risks of developing disease and sleep disorders. We need to study sex differences in sleep and homeostatic regulation across species to more fully understand the role that sleep plays in normal development, maturation, adaptation, aging, and disease propensity. Animal models of sleep disorders need to be developed and incorporate careful delineation of sex-related differences in susceptibility to development of these disorders and their consequences. The specific cellular and molecular mechanisms underlying sex differences in sleep disorders throughout the lifespan should be pursued.

- Conduct longitudinal studies of sleep during pregnancy and through the post-partum period that include both subjective and objective sleep indicators and include baseline measurements. We need to describe more fully the extent of sleep disorders developing during pregnancy and post-partum so that novel and existing therapies can be instituted to reduce health risks to the mother and the fetus. The relationship between extent of disturbed sleep during the late stages of pregnancy and delivery and the development of post-partum depression warrants study as a basis for designing novel interventions. Effects of sleep disturbance post-partum on maternal-infant interactions also require further study.

- Determine the extent to which the prevalence of insomnia and sleep disorders increases during the menopausal transition, identify factors that predict which premenopausal women are at high risk for developing insomnia, and evaluate alternative and traditional therapies for improving sleep in menopausal women.

- Obtain normative sleep data from girls before, during, and after puberty, as well as from women of child-bearing age, to assess changes associated with different phases of the menstrual cycle, changes in endogenous sex hormones, and in response to exogenous hormones.

- Determine the extent to which adolescent girls and young women with significant dysmenorrhea are at risk for insomnia and depression.

- Study how sleep disturbance in pregnancy affects fetal development and health as well as the maturation of fetal physiology related to sleep, and the extent to which fetal effects may be associated with long-term pediatric consequences.