Insomnia in Women: Menopause and Melatonin
Part I of II-Part Series
By Susan T. Marcolina, MD, FACP and Beth Rosenshein, BSEE. Dr. Marcolina is a board-certified internist and geriatrician in Issaquah, WA; Beth has her BA in Electrical Engineering; both report no financial relationships relevant to this field of study.
Insomnia, particularly disturbances of sleep initiation and maintenance, significantly impacts the lives of adult women at various stages of their reproductive life cycles, most notably during the menopausal transition and the subsequent postmenopausal period.1 This dramatic physiologic transition is experienced by all women between the ages of 48-55 years, and can occur over several years, or be more abrupt in onset, with symptoms such as irregular, often anovulatory, bleeding, hot flashes, vaginal dryness, sexual dysfunction, mood lability, and sleep disruption; all symptoms are attributed to the withdrawal of the ovarian sex steroid hormones estrogen, progesterone, and androgens (testosterone, androstenedione, and dehydroepiandrosterone (DHEA). Overall, women have a 1.3-1.8 greater risk of developing insomnia than men from menarche to menopause.2
This increased prevalence of insomnia during a woman's life suggests this symptom is influenced by changes in blood levels of hormones of the Hypothalamic-Pituitary-Gonadal (HPG) axis. Large fluctuations in reproductive hormone blood levels occur during the climacteric due to the tight coupling of egg follicular development in the ovary and its elaboration of sex steroid hormones. Once a woman's finite egg supply is depleted, ovarian sex hormone production and secretion sharply declines.3
Another hormone, melatonin, elaborated by the pineal gland, plays an important role, along with the suprachiasmatic nucleus (SCN) of the hypothalamus, in the control of circadian rhythms in the body, such as temperature and the sleep-wake cycle. Fluctuations in melatonin levels and changes in sleep patterns with aging and the complex interactions between melatonin, the SCN and the HPG hormones can significantly impact sleep quality in older women and increase the predilection for sleep disorders. Additional comorbid problems that may present during midlife and contribute to sleep problems include sleep disordered breathing, mood disorders, medical illness, and medication effects.4
Since sleep comprises approximately one-third of a woman's life, and most women in industrialized countries can expect to live one-third of their lives after ovarian failure, it is important to address sleep problems comprehensively because the sequelae are increased susceptibility to accidents and diminished productivity due to poor concentration, fatigue, and cognitive dysfunction, all of which decrease the quality of life.5
Central Circadian Pacemaker
The suprachiasmatic nucleus (SCN) is a part of the hypothalamus that regulates endogenous circadian rhythms in mammals via the sympathetic and parasympathetic nervous systems. It imposes a 24-hour time table to many biological functions, including temperature, production of the hormone melatonin in the pineal gland, and the sleep-wake cycle. Generally, humans tend to be diurnal (day active) creatures, programmed to be active during the daylight hours and asleep at night. As the body's biological "clock," the SCN synchronizes with the outside world via afferent input of light signals from the optic nerves. When light from the sun or another bright light source shines in the eyes, the nerve pathways to the SCN switch the clock to the "off" phase. This turns off melatonin production by the pineal gland. As the ocular light input decreases, the SCN turns "on" and the melatonin production and secretion resumes and is released into the bloodstream and to all body cells.6
Estrogen (ERs) and progesterone receptors (PRs) are located throughout the SCN and periaqueductal gray matter.7,8
Gender Differences in Insomnia
Foley and colleagues, in an epidemiologic study of 9000 male and females aged 65 and older, found that women, compared with men, had significantly more trouble falling asleep (36% vs 29%), awakening early (31% vs 21%), or falling back to sleep after early awakening (25 vs 20%) despite adjustments for smoking history, age, and psychological status.9 Table 1 identifies clinical characteristics of women, which can be risk factors for insomnia.
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Insomnia: Finding the Cause
In the clinical evaluation of insomnia, it is important to discern whether it is a primary problem or it is secondary to a problematic sleep environment, the use of medications or other substances that interfere with sleep, or an underlying medical or psychiatric illness. Table 2 summarizes common medical and psychiatric causes of secondary insomnia. Restless Legs Syndrome (RLS) can be secondary to iron or folate deficiency anemia or renal insufficiency, and patients who present with this complaint should undergo the appropriate evaluation and treatment.12 Sleep Apnea Syndrome is a double-edged sword because it is associated with increased morbidity due to impaired daytime functioning, as well as cardiovascular morbidity with increased risk for nocturnal arrhythmias, hypertension, and myocardial infarction.13
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Sleep Architecture and Menopause
Sleep is a restorative, recuperative brain process essential to overall physical and mental health. Estrogen and progesterone influence the quality or architecture of sleep, which is divided clinically into two major states: rapid eye movement (REM) sleep and non-rapid eye movement (NREM) sleep based on characteristic electroencephalographic (EEG) (brain wave) patterns discerned during a polysomnographic study (overnight sleep study), generally done in a sleep lab. These stages alternate throughout the duration of sleep.
The average time it takes to fall asleep (sleep latency) is approximately 10 minutes. The initial part of sleep is usually the NREM phase, which is subdivided into stages 1-4 depending upon the degree of wakefulness. The first rapid eye movement (REM) phase occurs about 90 minutes after sleep onset and reappears at approximately 90 minute intervals. There are usually 4-6 cycles of REM sleep alternating with NREM each night. As night progresses, REM sleep episodes last longer and NREM sleep is shorter and lighter. During intervals of REM sleep, information obtained during wakefulness appears to be reprocessed, integrated, and consolidated within the brain. Overall REM sleep constitutes 20-25% of total sleep time and generally comprises a more constant percentage of sleep time from age 30 to extreme old age versus NREM sleep with decreases progressively after the third decade. Interestingly, REM sleep is characterized by an absence of thermoregulatory responsiveness which is offset by the inhibition of REM sleep with extreme variations in environmental temperatures.14
Postmenopausal women have a lower sleep efficiency, longer sleep latency (time it takes to fall asleep), and increased difficulty maintaining sleep than premenopausal women.15
Effects of Hot Flashes
One of the most common early symptoms of menopause, and a primary reason for seeking medical care, are hot flashes, or vasomotor episodes (VMEs). Approximately 45-75% of women in the menopausal transition experience these recurrent, transient sensations of intense heat that may be accompanied by nausea, headache, dizziness, and insomnia. The physiology responsible for the hot flash is widespread cutaneous vasodilation with sweating, tachycardia, and an increase in metabolic rate. Increased central sympathetic output occurs during hot flashes, which may have negative cardiovascular health implications for middle aged women.16,17 The explanatory hypothesis for hot flashes is a downward alteration in the set point of the hypothalamic thermoregulatory center, with an increase in the threshold for shivering and a decrease in the threshold for sweating. Thus, small elevations in core body temperature trigger these thermoregulatory effector responses as levels of sex hormones, particularly estrogen, decline with loss of ovarian function. Not all hot flashes, however, occur as a result of sex hormone deficiency. Symptoms of flushing and sweating can also occur with thyroid disease states (hyperthyroidism), pheochromocytoma, carcinoid, pancreatic tumors, and leukemias. If the clinical situation is unclear, an appropriate work-up should ensue and estrogen deficiency should be documented by elevated levels of follicle stimulating hormone (FSH).18
According to the Study of Women's Health Across the Nation (SWAN), African-American and Caucasian women have a greater incidence of vasomotor symptoms compared to Asian women.19 Although VMEs may only last three to five years for many women, they are more long-term for others, and are intense, disruptive, and indicate the presence of uncompensated, clinically important estrogen deficiency.16
Association of Hot Flashes with Sleep Disruptions
There has been conflicting information in the literature as to whether hot flashes are responsible for sleep disruptions. Several epidemiologic studies20-22 describe a clear association between hot flashes and sleep fragmentation, whereas a laboratory study evaluating sleep quality did not confirm that hot flashes cause sleep disturbances.23 Freedman and Roehrs, in a later study, helped to clarify the relationship by assessing the occurrence of hot flashes and sleep disruptions in a polysomnographic study on 36 healthy, medication-free women (24 postmenopausal [18 symptomatic, 6 asymptomatic] and 12 premenopausal). They measured sleep parameters during two halves of the night, recognizing that NREM sleep is predominant during the first half of the night, whereas REM sleep, during which thermoregulatory effector responses are abolished or reduced, dominates for the second half of the night. Interestingly, they found that, during the first (NREM dominant) half of the night, women with hot flashes had significantly more arousals (P less than .001) than the other two groups; the two post menopausal groups had significantly more awakenings than did the premenopausal group (P less than .05). Additionally, during the NREM dominant portion of the night, the majority of hot flashes preceded the arousals, whereas, for the second half of the night (REM dominant), the order was reversed.24
REM latency (time to onset of REM sleep) is increased and sleep efficiency (time asleep/overall time in bed) decreased in menopausal women who experience VMEs compared to those who do not experience VMEs.25 (Avid NE, et al. Psychosocial, behavioral, and health factors related to menopause symptomatology. Womens Health. 1997;3:103-120.
Sex Hormones and Sleep
The sex steroids elaborated by the ovary have diverse effects on a wide range of central nervous system (CNS) psychopharmacologic systems related to sleep, particularly the serotonin and GABA neurotransmitters.
The serotonin neurotransmitter system is widely distributed in the central nervous system (CNS) and is involved in the modulation of sleep and other activities.
Bethea and colleagues showed that the 5-HT2A receptor is regulated by estrogen and progesterone and plays an important role in the VMEs that can disrupt sleep. In addition, these 5-HT 2A receptors also primarily mediate the excitatory effects of serotonin on upper-airway motor neurons. This is important in modulating upper-airway tone during sleep; loss of this tone with ovarian failure increases the resistance to breathing during sleep, which causes arousals that diminish sleep quality and contribute to the development of sleep disordered breathing in conjunction with other risk factors such as obesity and increased neck circumference.26,27
Gonadal hormones also influence gamma aminobutyric acid (GABA), the primary inhibitory neurotransmitter that serves an important function in the initiation and maintenance of sleep. Progesterone, and several of its metabolites, increase the number of GABA A receptor sites in the brain and modulate these receptor sites in a similar way to benzodiazepines. Progesterone and one of its metabolites, allopregnanolone, shorten the latency to NREM sleep in a dose-dependent manner. Estrogen enhances the progesterone effect by up-regulation of progesterone receptors.28
The multiple locations of progesterone, estrogen, androgen, prolactin, and LH hormone receptors in various tissues such as the trachea, lungs, brain, and brainstem suggests that these hormones act locally and centrally in the regulation of breathing during sleep.7
Although Polo-Kantola and colleagues found that transdermal estrogen therapy did not have an effect on sleep architecture in a randomized dB crossover trial in 62 postmenopausal women treated for 7 months, they did find that estrogen treatment improved objective sleep quality by attenuating the frequency of nocturnal movement arousals and decreasing vasomotor symptoms.29
Montplaisir and colleagues, in a study comparing two types of progestogen on sleep quality, found that Prometrium significantly improved sleep efficacy (P = .014) compared to medroxyprogesterone (MPA) (Provera) after a six-month trial.30
Sleep Disordered Breathing After Ovarian Failure
Although more prevalent in men, obstructive sleep apnea (OSAS) is underrecognized and, therefore, untreated in women because it presents differently and tends to be much less common until after ovarian failure. Whereas men tend to have more severe apneic episodes and oxygen desaturations, women are more likely to have sleep fragmentation, daytime sleepiness, and less likely to manifest complete airflow cessation or oxygen desaturation. Although sleep-disordered breathing syndromes can occur in premenopausal women, they are generally less common until post ovarian failure.4
Diminution of progesterone levels with ovarian failure may be a cause of sleep-disordered breathing since progesterone is a known respiratory stimulant, upper airway dilator, and modulates the GABA A receptor complexes to promote sleep.31 Netzer and colleagues performed a small clinical cohort study of 53 women (ages 24-72) undergoing evaluation for daytime sleepiness at a University Hospital Sleep Laboratory. After controlling for age and postmenopausal status, patients with an AHI (apnea no airflow for 10 or more seconds) /hypopnea (notable reduction in respiratory effort for 10 or more seconds resulting in oxyhemoglobin desaturation of 4% or more index) greater than 10 had significantly lower levels of progesterone, estradiol, and 17-hydroxy progesterone levels compared with those with AHIs less than 10.32 While this study does not prove a cause and effect mechanism, it certainly suggests an important clinical correlation between symptoms of daytime sleepiness, sleep disordered breathing, and diminished progesterone and estradiol levels in peri-and postmenopausal women.
Guilleminault and colleagues noted that both obesity and the AHI increase after the onset of ovarian failure.33 Increased BMI, particularly increased neck circumference and central adiposity, have been identified as risk factors for obstructive sleep apnea.34
Skeletal muscles contain receptors for estrogens, progesterone, and testosterone, and the presence of these hormones is required for optimal muscle function. As levels of ovarian sex hormones, particularly testosterone, decline with progressive ovarian failure, lean muscle mass declines with concomitant decreases in strength, stability, and basal metabolic rate, which results in an increase and central redistribution of adipose.35
Resta and colleagues studied a population of 230 (148 female) obese patients aged 16-75 and found that among subjects older than 55, the dominance of males, with respect to the prevalence and severity of OSA, was markedly attenuated compared to that observed in the under 55 age group with a male/female ratio of 2:1-3:1, compared to early epidemiological studies, which suggested a male/ female ratio of 10:1 or greater. They also found that body mass index (BMI), neck circumference, waist-to-hip (WHR) ratio, and the presence of obstructive sleep apnea (OSA) were statistically significantly higher in postmenopausal compared with premenopausal women (all with P less than .01).36 Young and colleagues, in The Wisconsin Cohort Study of 589 women ages 30-60 evaluated in a sleep laboratory, found a statistically significant trend (P = .01) toward increasing odds ratio of an AHI of 5 or more episodes/hr of sleep, with increasing duration of years since last menstrual period. For almost every age in the range of 32-53 years, and at every BMI level, the prevalence of SDB was higher in postmenopausal women compared to premenopausal women, after controlling for smoking, hypertension, exercise, and overall health.37
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Marcolina ST, Rosenhein B. Insomnia in women: Menopause and melatonin. 2008;10:33-38.You have reached your article limit for the month. Subscribe now to access this article plus other member-only content.
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