August 2008
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Menopausal Symptoms and Treatment: An Update
Current evidence inadequately addresses important issues concerning the menopausal transition and its care.
By Heidi D. Nelson, MD, MPH
Menopause is a complex physiological process resulting from reduced secretion of the ovarian hormones estrogen and progesterone. Menopause occurring naturally is recognized after 12 months of amenorrhea that is not associated with a pathologic cause. Menopause can also induced by surgery, chemotherapy, or radiation. Although menopause is determined by a discrete event—the final menstrual cycle, the menopausal transition may span several years and provide a range of personal experiences.
The mean age of onset of the menopausal transition is 47.5 years, often lasting 4 to 5 years.1 The mean age of the last menstrual cycle is 51 years, and can vary normally between age 40 and 58 years.1 Menopause before 40 years of age is considered premature. Initially, menstrual cycle lengths become irregular, and follicle-stimulating hormone (FSH) concentrations rise in response to decreased concentrations of ovarian hormones. As the menopausal transition progresses, menstrual cycles are missed and ultimately stop and ovulation ceases. Three consecutive months of amenorrhea, or mean cycle lengths longer than 42 days, are predictors of impending menopause for some women.2,3
Several terms have been used to describe the menopausal transition, and various models have been proposed. A model developed at the STRAW (Stages of Reproductive Aging Workshop)4 describes stages of the reproductive aging continuum including reproductive stages, characterized by regular menstrual cycles; menopausal transition stages, with variable menstrual cycles and high follicle-stimulating hormone (FSH) values; and postmenopause stages, beginning with the final menstrual period and lasting until the end of life. Most women do not progress precisely through each stage, and studies indicate much individual variation including skipping stages and moving back and forth between stages.5
SYMPTOMS ASSOCIATED WITH THE MENOPAUSAL TRANSITION
Many symptoms have been attributed to the menopausal transition, however, only vasomotor dysfunction, vaginal symptoms, and sleep disturbances are consistently supported by epidemiologic evidence (Table 1).6 Mood symptoms7 and sexual function are inconsistently associated.6 Studies of these symptoms are confounded by other factors, and outcomes are measured using various methods. Urinary symptoms, such as incontinence and leakage, and somatic symptoms, such as joint and body pain, are inconsistently associated with the menopausal transition in only a few studies.6 Associations with quality-of-life measures and cognitive changes are not supported.6 Studies of menopausal symptoms need to be carefully interpreted because of their methodological limitations, inconsistencies in terminology and outcome measures, and confounding by conditions attributed to aging. Factor analysis studies show that menopausal status is more consistently associated with vasomotor than with psychological or physical symptoms, arguing against a universal menopausal syndrome that includes all of them.8
Vasomotor dysfunction refers to the spontaneous, transient sensation of warmth, often associated with perspiration, palpitations, and anxiety, resulting from a vasomotor response to declining estrogen levels. It is hypothesized that endorphin concentrations in the hypothalamus decrease with falling estrogen production enhancing release of norepinephrine and serotonin. This lowers the set point in the thermoregulatory nucleus and leads to inappropriate heat-loss mechanisms.9-11 Vasomotor symptoms are described as hot flashes or flushes and nightsweats, and are the most common symptom related to the menopausal transition, experienced by more than 50% of menopausal women.6 Symptoms can persist for several years after menopause, and for some women, can interfere with activities or sleep to such a degree that treatment is requested. A study of older postmenopausal women with vasomotor symptoms persisting for ≥3 years indicated associations with lower education level, more recent menopause, prior estrogen use, hysterectomy, higher body mass index, higher FSH levels, lower HDL cholesterol levels, vaginal dryness, and trouble sleeping, but not with estradiol levels.12
Vaginal symptoms, such as vaginal dryness, itching, and dyspareunia, are experienced by up to 30% of women during the menopausal transition and postmenopause.6 These symptoms reflect physiological responses to low estrogen states resulting in reduced blood flow and vaginal secretions, tissue changes, and alterations in vaginal pH. Sleep disturbances are experienced by approximately 40% to 60% of women during the menopausal transition and postmenopause.6 Vasomotor symptoms often accompany sleep disturbances, but may not be the primary cause.13
THERAPIES FOR TREATING MENOPAUSAL SYMPTOMS
Several therapies have been used to treat menopausal symptoms. Most placebo-controlled trials focus on vasomotor outcomes, and few trials of these therapies demonstrate efficacy (Table 1). Estrogen has been used as a hormone supplement for many years to treat menopausal symptoms and is also US Food and Drug Administration-approved for osteoporosis prevention. Estrogen is provided in several formulations, and is most commonly administered by oral, transdermal, or vaginal routes. Estrogen is used with a progestogen to avoid endometrial hyperplasia and endometrial cancer (opposed regimen); women with hysterectomies can use estrogen alone (unopposed regimen). All formulations and regimens of estrogen evaluated in placebo-controlled trials reduced hot flash severity and frequency by approximately two to three per day,14,15 and improved vaginal symptoms.16
Results of the WHI (Women's Health Initiative) trial indicated that long-term use of estrogen is not effective in preventing chronic conditions other than osteoporosis, and can cause important adverse outcomes such as thromboembolic events, coronary heart disease, stroke, and breast cancer in women using estrogen and progestin.17 Women using estrogen without progestin in the WHI had increased risks for thromboembolic events and stroke.18 Recent analysis indicates that women starting estrogen within 10 years of menopause in the WHI had reduced rates of coronary disease compared to those who started later.19
Few trials of progestin or progesterone agents describe their effectiveness as single therapies in treating hot flashes, and these report conflicting or inconclusive results.6 Trials comparing tibolone, a synthetic steroid with progestogenic, androgenic, and estrogenic effects, against placebo suggest improved severity of hot flashes and improved sleep.6
Gabapentin, a gama-aminobutyric acid analogue for treatment of seizures, reduced hot flash frequency and severity compared with placebo in three trials.20 Hot flashes were reduced by approximately two per day.21 This effect may be due to increased activity of neurotransmitters in the hypothalamus as a consequence of up regulation of the gabapentin binding site from estrogen withdrawal.22
Two trials of paroxetine, a selective serotonin reuptake inhibitor (SSRI), showed significant reductions in hot flash frequency of at least one per day.21 Trials of sertraline, an SSRI, and venlafaxine, a serotonin norepinephrine reuptake inhibitor (SNRI), show mixed results,20,21 and effects were not statistically significant in other trials of SSRIs/SNRIs.21 Hot flashes may be linked to an overloading of serotonin receptor sites in the hypothalamus that could be mediated by SSRIs/SNRIs.23 Trials of veralipride suggest improvement in severity, but are inconclusive because of methodologic limitations.21
Clonidine, a centrally active alpha-adrenergic agonist antihypertensive, significantly reduced hot flash frequency or severity in some, but not all trials. Hot flashes were reduced by 1 to 1.5 per day.21 Clonidine may relieve vasomotor symptoms by reducing peripheral vascular reactivity. Trials comparing methyldopa, an alpha-adrenergic agonist antihypertensive, with placebo found no significant differences in hot flash frequency.21
Phytoestrogens are plant-based substances with weak estrogenic and antiestrogenic activities that bind to estrogen receptors and potentially mediate hot flashes triggered by estrogen deficiency. Trials of soy isoflavone extracts, containing predominantly daidzein, genistein, and their glucoconjugates, suggest reduction in hot flash frequency or severity in some, but not all trials.21 Estimates of reductions in hot flash frequency are either not significant or of borderline statistical significance, depending on the analysis.21,24,25 Trials of dietary forms of soy are more difficult to interpret because of the variability of components and doses. Few trials of these forms reported any improvement in frequency or other measure.20,26
Red clover isoflavones, containing genistein, daidzein, formononetin, and biochanin, did not improve frequency or severity of hot flashes in placebo controlled trials.21 Phytoestrogens from hop extract, flax, or in topical forms also did not show benefit in treating hot flashes.20
Black cohosh (Cimicifuga racemosa) is an herbal therapy believed to have estrogenic properties. Black cohosh does not reduce the frequency of hot flashes, and while some trials indicate improvement of other hot flash measures, others do not.20,26
Several other therapies have been evaluated in trials and show no differences compared to placebo, or studies are too limited to support use. These include Chinese herbs, evening primrose oil, phospholipids liposome, pollen extract, other supplements, osteopathic manipulations, reflexology, magnets, aerobic exercise, and acupuncture.20,26
APPROACH TO PATIENTS
Current evidence inadequately addresses important issues concerning the menopausal transition and its care. In order to respond appropriately to the needs of patients, clinicians must use available information on menopausal symptoms and therapies, but not over generalize findings of a limited evidence base. Existing studies, while valuable, may not translate to women who differ markedly from the study populations and have specific medical, psychological, and cultural contexts. The optimal approach to managing menopausal symptoms, if requested, is to address each woman's unique needs.
Most women have transient symptoms during the menopausal transition that are manageable with self-care approaches, such as avoiding triggers for vasomotor responses and using over-the-counter vaginal moisturizers for vaginal dryness, for example. Some women experience symptoms that interfere with function, such as frequent and severe hot flashes that disturb activities and sleep. These women may benefit from proven therapies, such as limited courses of systemic estrogen. Adverse effects can be reduced by using the smallest dose for the shortest time necessary to control symptoms. Symptoms should be closely monitored and attempts to discontinue estrogen therapy should be made periodically. Alternatives to estrogen, including SSRI/SNRI antidepressants, clonidine, or gabapentin, could be considered for women with severe vasomotor symptoms who need to avoid estrogen. The potential adverse effects of these medications, however, must also be considered.
Use of unproven therapies, such as dietary supplements, herbs, and acupuncture is currently popular. Women should be informed of their lack of evidence of efficacy before considering them. They could be encouraged to adopt practices known to improve health such as smoking cessation, weight control, exercise, and improvement in diet. Coexistent health concerns, such as mood changes, incontinence, or joint pain, for example, may complicate the presentation. These conditions require separate evaluation and management approaches, and should not be attributed primarily to the menopausal transition and treated solely with estrogen.
Heidi D. Nelson, MD, MPH, is from the Oregon Evidence-based Practice Center, Department of Medical Informatics and Clinical Epidemiology and Department of Medicine, Oregon Health & Science University, and the Women and Children's Health Research Center, Providence Health & Services, Portland, Oregon. Dr. Nelson may be reached at nelsonh@ohsu.edu; phone: 503-494-1566; or fax: 503-494-4551.
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