When choosing therapy, consider patient factors and insomnia severity. For example, mirtazapine is typically associated with weight gain, so consider other options for overweight patients. Those with severe insomnia may prefer not to wait 3 to 4 weeks for improved sleep. With hypnotics, consider cost, any coexisting chemical dependency, and potential for morning hangover.
Psychotherapy can help perimenopausal patients accept aging, evaluate relationships, and examine their roles in the lives of more-dependent parents and less-dependent children.
HOT FLASHES AND INSOMNIA
Persistent hot flashes that disturb sleep may cause depression.12 They can wake a perimenopausal woman repeatedly (Figure 1). The awakenings may be brief—90% last <3 minutes—but a severely affected woman can lose an hour of sleep in a night.13 Even after a hot flash resolves, other factors such as anxiety may keep her awake.
Up to 85% of perimenopausal women experience hot flashes, especially during the first year after menses cease. Hot flashes persist for 5 years after menopause in 25% of women and indefinitely in a minority (Box ).14
Hot flashes: Thermoregulatory changes may set scene for noradrenergic spark
Estrogen deficiency is thought to cause hot flashes via decreased serotonin synthesis and up-regulated 5HT2A receptors—the mediators of heat loss. As a result, a woman’s thermoregulatory zone narrows during perimenopause, reducing her tolerance for core body temperature changes. The thermoregulatory nucleus resides in the medial preoptic area of the anterior hypothalamus.
A hot flash begins with facial warmth when core temperatures exceed the thermoregulatory line. Heat spreads to the chest, often accompanied by flushing, diaphoresis, and headache. A woman may feel agitated, irritable, and distressed.
CNS noradrenergic activity may initiate hot flashes. Freedman et al13 compared the effects of IV clonidine (an alpha2 adrenergic agonist) plus yohimbine (an alpha2 adrenergic antagonist) or placebo in menopausal women with or without vasomotor symptoms. Among 9 symptomatic women, 6 experienced hot flashes when given yohimbine, and none did with placebo. No hot flashes occurred in asymptomatic women. Clonidine increased the duration of peripheral heating needed to trigger a hot flash and reduced the number of hot flashes in symptomatic women, compared with baseline.
Risk factors for nocturnal hot flashes include surgical menopause, Caucasian versus Asian ethnicity, lack of exercise, and nicotine use.8 Women suffering anxiety and stress also are at increased risk.15
HOT-FLASH THERAPIES
Placebo-controlled trials of hot flash therapies have found efficacies from 85% for HRT to 25% for placebo, vitamin E, black cohosh, soy, and behavioral therapy (Figure 2).16 Most trials were not designed to test the link between hot flashes and sleep, and many enrolled cancer patients not experiencing natural menopause. With the 25% placeboresponse rate, some therapies’ efficacy is unclear.
HRT can reduce nocturnal hot flash frequency. In a polysomnographic study,17 21 postmenopausal women received 6 months of conjugated estrogens, 0.625 mg/d, with medroxyprogesterone, 5 mg/d, or micronized progesterone, 200 mg/d. Sleep efficiency improved by 8% in women receiving micronized progesterone but was unchanged with medroxyprogesterone. Even so, both groups reported improved sleep quality and duration, with decreased awakenings.
The Wisconsin Sleep Cohort Study9 found that HRT was not associated with improved sleep, as measured by polysomnography. Even so, the women in that study noted subjective sleep improvement with HRT.
Antidepressants. Venlafaxine, 75 mg/d, and fluoxetine, 20 mg/d, have shown benefit in reducing hot flashes,18 presumably by increasing CNS serotonin. As mentioned, however, many antidepressants can cause insomnia, and few studies have examined this problem.
Gabapentin has been effective for patients with hot flashes.19 This agent, which increases GABA levels and may modestly increase slow-wave sleep—can improve conditions that disrupt sleep, including restless legs syndrome and chronic pain. It is well-tolerated, even at 900 mg/d, and is more-sedating than most serotonergic antidepressants.
Hypnotics. Surprisingly little evidence addresses hypnotics’ role in managing insomnia caused by hot flashes. No data have been published on the role of benzodiazepines or the benzodiazepine receptor agonists (zolpidem, zaleplon, and eszopiclone). In my experience, benzodiazepine receptor agonists improve sleep quality compromised by multiple factors, including hot flashes.
Soy and black cohosh. Isoflavones in soy may be estrogen receptor modulators. Twelve randomized, controlled trials of soy or soy extracts have shown a modest benefit for hot flashes.20
Black cohosh extracts, 8 mg/d, were given to 80 postmenopausal women in a randomized, double-blind, placebo-controlled trial (RCT). Hot flashes in those receiving black cohosh decreased from 4.9 to 0.7 daily, compared with reductions of 5.2 to 3.2 in women receiving estrogen and 5.1 to 3.1 in those receiving placebo.21 As a result, the National Institutes of Health is funding a 12-month, RCT to determine whether black cohosh reduces hot flash frequency and intensity.