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This Journal feature begins with a case vignette highlighting a common clinical problem. Evidence supporting various strategies is then presented, followed by a review of formal guidelines, when they exist. The article ends with the author's clinical recommendations.
A 51-year-old woman has frequent and distressing hot flushes that interfere with her work and sleep, and vaginal dryness that makes sexual intercourse with her husband uncomfortable. She is otherwise healthy. How should her case be managed?
The Clinical Problem
Menopausal Transition
All healthy women transition from a reproductive, or premenopausal, period, marked by regular ovulation and cyclic menstrual bleeding, to a postmenopausal period, marked by amenorrhea (Table 1). The onset of the menopausal transition is marked by changes in the menstrual cycle and in the duration or amount of menstrual flow.1 Subsequently, cycles are missed, but the pattern is often erratic early in the menopausal transition. Menopause is defined retrospectively after 12 months of amenorrhea.
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Women in the menopausal transition commonly report a variety of symptoms, including vasomotor symptoms (hot flushes and night sweats), vaginal symptoms, urinary incontinence, trouble sleeping, sexual dysfunction, depression, anxiety, labile mood, memory loss, fatigue, headache, joint pains, and weight gain. However, in longitudinal studies, after adjusting for age and other confounders, only vasomotor symptoms, vaginal symptoms, and trouble sleeping are consistently associated with the menopausal transition.3,4 Symptoms such as memory loss and fatigue may be due to frequent hot flushes or trouble sleeping.
Vasomotor Symptoms
A hot flush is a sudden feeling of warmth that is generally most intense over the face, neck, and chest. The duration is variable but averages about 4 minutes. It is often accompanied by sweating that can be profuse and followed by a chill. The prevalence of hot flushes is maximal in the late menopausal transition, occurring in about 65% of women5 (Table 1), but the prevalence varies markedly, depending on the definition of flushing and the population studied. In the United States, flushes are more common in black and Latina women and less common in Chinese and Japanese women than in white women.6 Cigarette smoking increases the likelihood of flushing5; other factors — including surgical menopause, physical activity, body-mass index, alcohol consumption, and socioeconomic status — have been inconsistently associated with hot flushes.4 It is not possible to predict whether a particular woman will have hot flushes.
In most women, hot flushes are transient. The condition improves within a few months in about 30 to 50% of women and resolves in 85 to 90% of women within 4 to 5 years.7 However, for unclear reasons, about 10 to 15% of women continue to have hot flushes many years after menopause.
Hot flushes resemble heat-dissipation responses and may represent abnormal thermoregulation by the anterior hypothalamus. The precise role of estrogen in the pathogenesis of this symptom is not clear. Endogenous estrogen levels do not differ substantially between postmenopausal women who have hot flushes and those who do not have them.2 Flushes do not occur in women with gonadal dysgenesis unless estrogen therapy is used and then discontinued,8 which suggests that estrogen withdrawal is important. In the Study of Women's Health Across the Nation, a large U.S. multicenter cohort study, higher levels of follicle-stimulating hormone were the only hormonal measure independently associated with flushing after adjustment for levels of estradiol and other hormones.2 A possible role for androgens is suggested by the observation that flushing is common among men treated with androgen-deprivation therapy for prostate cancer.
Vaginal Symptoms
Vaginal symptoms (including dryness, discomfort, itching, and dyspareunia) are reported by about 30% of women during the early postmenopausal period4 and up to 47% of women during the later postmenopausal period.3 Urologic symptoms (including urgency, frequency, dysuria, and incontinence) are not clearly correlated with the menopausal transition.3 Unlike hot flushes, vaginal symptoms generally persist or worsen with aging.
As compared with premenopausal women, postmenopausal women with vaginal symptoms generally have decreased vaginal blood flow and secretions, hyalinization of collagen, fragmentation of elastin, and proliferation of vaginal connective tissue. Vaginal fluid, which is acidic before menopause, becomes more neutral, facilitating the proliferation of enteric organisms associated with urinary tract infection.
The responsiveness of many of these physiologic changes to estrogen therapy suggests that estrogen deficiency may contribute to the pathogenesis. However, vaginal symptoms have been associated with lower serum levels of androgens but not of estrogens.9
Strategies and Evidence
Evaluation
Vasomotor Symptoms
Classic vasomotor symptoms in a woman in her late 40s to mid-50s do not require laboratory evaluation unless there is reason to suspect another cause. Careful history taking can generally rule out other causes, such as alcohol consumption, carcinoid, the dumping syndrome, hyperthyroidism, narcotic withdrawal, pheochromocytoma, and medications including nitrates, niacin, gonadotropin-releasing hormone agonists, and antiestrogens. Levels of follicle-stimulating hormone and luteinizing hormone may be within the normal premenopausal range during the menopausal transition; measurement of these hormones is not routinely recommended (Table 1).
Vaginal Atrophy
Postmenopausal vaginal atrophy is generally identified when there are vaginal symptoms and findings of pallor, dryness, and decreased rugosity of the vaginal mucosa. A pelvic examination should be performed to look for these signs and to rule out other potential causes of symptoms, including trauma and infection. History taking that includes age and menopausal status and pelvic examination are generally sufficient for diagnosis. Findings of an elevated pH level in vaginal fluid (above 6.0) and cytologic analysis of exfoliated cells from the vaginal wall containing more than 20% parabasal cells are correlated with menopause, but their use in the diagnosis of symptomatic vaginal atrophy has not been established.
Treatment of Vasomotor Symptoms
Because the self-reported frequency and severity of hot flushes improve markedly with placebo, conclusive evidence of efficacy of treatments requires findings from randomized, controlled trials. Such evidence is the only type that was used to support treatment recommendations in this review. Clinical trials of treatments for hot flushes have typically been small and brief, and provide little information about longer-term efficacy and risks.
Behavioral and Alternative Therapies
Many women have mild flushes and obtain adequate relief with simple measures, such as lowering the ambient temperature.10 A randomized trial among overweight postmenopausal women found that moderate exercise did not improve flushing, as compared with stretching.11 In another small trial, practicing slow breathing (paced respiration), which may reduce overall sympathetic tone, reduced the frequency of flushing 35% more than did muscle relaxation.12
There is no convincing evidence that acupuncture, yoga, Chinese herbs, dong quai, evening primrose oil, ginseng, kava, or red clover extract improve hot flushes.4,13 One trial of vitamin E found a statistically significant effect, but the benefit was only one hot flush per day less with treatment, as compared with placebo.14 Evidence regarding black cohosh is mixed but primarily negative with regard to an improvement in the frequency or severity of flushing.15
Many trials have evaluated dietary soy and various phytoestrogen preparations. Although some of these studies have reported benefit, the weight of evidence, especially from good-quality trials with blinded comparisons, suggests that soy is not effective in the treatment of hot flushes.4 Many women prefer alternative medications in the belief that these treatments are safe, but phytoestrogens and possibly black cohosh bind estrogen receptors and could cause adverse outcomes similar to those seen with estrogen. No studies of these preparations have been of adequate size or duration to document safety.
Estrogens
Multiple randomized trials have demonstrated that estrogen markedly improves the frequency and severity of hot flushes, generally reducing the frequency by 80 to 95%.16 All types and routes of administration of estrogen are effective. The benefit is dose-related, but even low doses of estrogen are often effective (Table 2).17,18,19 Relief is usually substantial within 4 weeks after starting standard doses of estrogens (1 mg per day of oral estradiol or its equivalent). Lower doses may not have maximal effects for 8 to 12 weeks but are associated with lower rates of side effects, such as uterine bleeding and breast tenderness.20
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The finding of the Women's Health Initiative that the rate of adverse events with estrogen plus progestin is higher than that with estrogen alone21,22 suggests that progestins may exacerbate risks. However, treatment with unopposed estrogen in women with a uterus markedly increases the risk of uterine hyperplasia and cancer, as well as that of gynecologic procedures and hysterectomy.27,28 The lowest dose of progestin that protects the endometrium depends on the dose of estrogen, the progestin preparation, and the dose and frequency of administration. Table 4 provides a selected list of combination hormone products with documented endometrial safety approved by the Food and Drug Administration (FDA) for the treatment of menopausal hot flushes. To minimize exposure, progestins are sometimes given every third or fourth month for 14 days, rather than monthly, but the safety of these regimens for the endometrium is uncertain.29
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At high doses, the progestins medroxyprogesterone acetate30 and megestrol31 are effective for the treatment of hot flushes, but side effects are common4,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46 (Table 5), and data from the Women's Health Initiative suggest that progestins may increase the risk of adverse events. Tibolone, a steroid hormone not marketed in the United States but available elsewhere, is effective for the treatment of hot flushes, but long-term risks have not been adequately investigated.4,32
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Several selective serotonin-reuptake inhibitors (SSRIs) and serotonin–norepinephrine reuptake inhibitors (SNRIs) have been studied in randomized trials for the treatment of vasomotor symptoms, with mixed results (Table 5). Results have varied among agents (with negative results reported for citalopram and sertraline, inconsistent results for fluoxetine and venlafaxine, and a modest benefit in two trials of paroxetine) and with trial populations (with mostly positive results in studies involving breast cancer survivors,34,35,39 as compared with the negative results reported more often in women without this history33,40). It is not clear why the efficacy of SSRIs might be associated with a history of breast cancer, but the use of antiestrogens and a higher prevalence of depression among breast cancer survivors might play a role.
Gabapentin has shown modest efficacy in the treatment of hot flushes, both in women with a history of breast cancer42 and those without,43 but is also associated with side effects42,43,46 (Table 5). The 
-adrenergic agonist clonidine has been suggested as a treatment for vasomotor symptoms, but trials have suggested little or no benefit, and side effects (including dry mouth, drowsiness, and dizziness) are common.4,46
Clinical trials of the effects of nonestrogenic prescription drugs in women with hot flushes have been too small or too brief to detect uncommon adverse events.
Treatment of Vaginal Symptoms
For vaginal symptoms, vaginal estrogens (administered as creams, tablets, or an estradiol-releasing ring) are highly effective, with improvement or relief reported by 80 to 100% of treated women47,48(Table 6). Vaginal preparations are preferred over systemic estrogens for this indication, since they are similarly or more effective49 and generally raise serum estrogen levels very little. When they are used at the recommended dose and frequency, the addition of a progestin to protect the uterus is not necessary.50,51 However, higher doses or more frequent use of vaginal estrogens can increase systemic levels of estrogen48 and potentially cause estrogenic side effects.
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Areas of Uncertainty
The causes and predictors of hot flushes and vaginal atrophy remain uncertain. Although many treatments have been evaluated for hot flushes, none have been proved to be both highly effective and safe.
Guidelines
The FDA and the American College of Obstetricians and Gynecologists recommend that postmenopausal hormone therapy be used at the lowest dose and for the shortest possible time for the treatment of menopausal symptoms.54,55 The North American Menopause Society recommends that women with mild vasomotor symptoms first consider lifestyle changes, either alone or combined with a nonprescription remedy. For moderate to severe hot flushes, hormone therapy is recommended as the therapeutic standard. Therapy with progestins, SSRIs, or gabapentin is suggested as an alternative for women who wish to avoid estrogens.56
The FDA,54 the North American Menopause Society,56 and the Society of Obstetricians and Gynaecologists of Canada51 recommend the use of vaginal estrogen preparations when menopausal symptoms are limited to the vagina.
Conclusions and Recommendations
The patient in the vignette is having hot flushes and symptoms of vaginal atrophy, both common in the menopausal transition. She should be told that vasomotor symptoms generally improve or resolve within a few years but that vaginal symptoms may not improve spontaneously.
Although it is reasonable to discuss behavioral changes (e.g., dressing in layers and lowering room temperature), such strategies are unlikely to be adequate in women with severe hot flushes. Women with moderate hot flushes, especially those with contraindications to or concerns about hormone therapy, may choose to try nonhormonal therapies, such as an SSRI or gabapentin, recognizing that there are limited data to support their use and that these medications are not approved by the FDA for this indication. Hormone therapy is the most effective treatment for severe hot flushes and is a reasonable choice in the absence of contraindications. If the patient has not had a hysterectomy, estrogen with an added progestin is recommended. She should be informed about potential side effects and risks but also told that the increase in the absolute risk of serious adverse events is low. The lowest dose of estrogen that adequately controls symptoms should be used. Given the natural history of vasomotor symptoms, it is reasonable to try discontinuing hormone therapy every 6 to 12 months. If symptoms recur, restarting and then gradually tapering the dose or the number of days per week that hormones are used may be helpful.57 Infrequently, vasomotor symptoms persist and require long-term treatment.
For vaginal symptoms alone, systemic estrogen therapy is not indicated. A vaginal moisturizer may provide adequate relief; if not, topical estrogen therapy should be used.
Dr. Grady reports receiving consulting fees for serving on data and safety monitoring boards from Organon and Intarcia Therapeutics and grant funding from Berlex, Bionovo, Eli Lilly, and Pfizer. No other potential conflict of interest relevant to this article was reported.
I thank Margaret Kristof, R.N., and George Sawaya, M.D., for their advice and editorial assistance.
Source Information
From the Women's Health Clinical Research Center, University of California, San Francisco, and the San Francisco Veterans Affairs Medical Center — both in San Francisco.
Address reprint requests to Dr. Grady at the Women's Health Clinical Research Center, 1635 Divisadero St., Suite 600, San Francisco, CA 94115.
References
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Related Letters:
Menopausal Symptoms
Bouts B. A., Koratamaddi L. P., Prasad M., Grady D.
Extract |
Full Text |
PDF
N Engl J Med 2007;
356:1176-1178, Mar 15, 2007.
Correspondence
This article has been cited by other articles:
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