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MD Consult: Books: Goldman: Cecil Medicine: MENOPAUSAL SYMPTOMS

Goldman: Cecil Medicine, 23rd ed.

Copyright © 2007 Saunders, An Imprint of Elsevier

MENOPAUSAL SYMPTOMS

Menopause is a very positive occurrence in the life of many women. It marks the end of cyclic bleeding and the need for birth control. It occurs at an age when children generally have become independent adults, thereby reducing family and child-care responsibilities. Conversely, menopause is a notable sign of aging in a culture that values youth. In addition, it often occurs with other stresses such as caring for elderly or ill parents. Women in the menopausal transition commonly report a wide variety of symptoms, including hot flushes, night sweats, vaginal dryness, trouble sleeping, sexual dysfunction, depression, anxiety, labile mood, memory loss, fatigue, headache, joint pains, weight gain, and urinary incontinence. However, in longitudinal studies, the prevalence of most of these symptoms does not differ across the menopausal transition after adjusting for age and other confounding variables. Only vasomotor symptoms, vaginal dryness, and sleep disturbance are consistently associated with the menopausal transition.[1] Other reported symptoms may result from aging or stress associated with menopause. Some symptoms, such as depression, anxiety, memory loss, and fatigue, may be the consequence of frequent hot flushes or poor sleep.

   VASOMOTOR SYMPTOMS

Definition

Vasomotor symptoms include hot flushes, chills, and sweats. A hot flush is a sudden feeling of warmth, generally most intense over the face, neck, and chest. The duration is variable, but it averages approximately 4 minutes. It is often accompanied by sweating that can be profuse and followed by a chill.

Epidemiology

The prevalence of hot flushes is maximal in the late menopausal transition, occurring in approximately 50% of women ( Fig. 262-2 ). However, prevalence varies markedly, depending on the definition of flushing (any flushing, daily flushing, troublesome flushing) and the population studied. Lower prevalence is reported among women in China, Japan, and other Asian countries. The reason for this variation is not clear, but investigators have suggested that it may result from differences in biology, cultural influences on experiencing or reporting flushes, or diet and lifestyle. In the United States, flushes are more common in African American and Latina women and less common in Chinese and Japanese women compared with white women. Approximately 15% of women with menopausal symptoms consult a physician.

FIGURE 262-2  Prevalence of hot flushes during the menopause (MP) transition.

Cigarette smoking increases the likelihood of flushing, but other potential risk factors, including surgical menopause, physical activity, body mass index, alcohol consumption, and socioeconomic status, have been inconsistently associated with hot flushes.[1] Currently, there is no way to predict whether an individual woman will suffer from hot flushes.

Natural History

In most women, hot flushes are transient. Approximately 30 to 50% of women note an improvement within a few months, and symptoms resolve in 85 to 90% within 4 to 5 years. However, some women continue to have frequent and severe flushes many years after menopause. Approximately 10 to 15% of women in their middle to late 60s report significant flushing. It is not clear why flushes persist for many years in some women and resolve in others.

Pathobiology

In humans, body temperature is regulated by inducing vasodila-tion and sweating to release heat and vasoconstriction and shivering to conserve heat ( Fig. 262-3 ). Thermoregulation is complex and depends on central stimuli from the anterior hypothalamus and local changes in cutaneous vasoconstriction or dilation. A hot flush is very similar to a heat dissipation response, because both result in vasodilation, sweating, and reduction in core body temperature. The core body temperature at which postmenopausal women with hot flushes vasodilate and sweat is lower than in premenopausal women or in postmenopausal women without hot flushes. Variability in core body temperature does not appear to be greater in postmenopausal women with hot flushes than in premenopausal women or in postmenopausal women without hot flushes, but normal small fluctuations in core body temperature may exceed the lowered threshold for vasodilation and result in hot flushes.

FIGURE 262-3  Menopausal hot flushes resemble normal heat dissipating responses with a narrowed thermoregulatory null zone.

The cause of altered thermoregulation in postmenopausal women with hot flushes is not clear. One theory suggests that changes in estrogen levels associated with menopause alter central nervous system adrenergic neurotransmission. This theory is supported by studies showing that metabolites of norepinephrine increase during spontaneous and experimentally induced hot flushes, and that systemic administration of yohimbine, an α2-adrenergic antagonist that increases norepinephrine release, provokes hot flushes, whereas administration of clonidine, an α2-adrenergic agonist that decreases norepinephrine release, reduces the frequency of hot flushes. Alternatively, some evidence indicates that declining estrogen levels during the menopause transition result in changes in serotonergic neurotransmission that could cause hot flushes. Lower estrogen levels are associated with lower levels of serotonin (5-hydroxytryptamine) in blood, resulting in increased sensitivity of 5-hydroxytryptamine-2A receptors in the hypothalamus. Stimulation of these receptors can alter the thermoregulatory set point in animals. Mild stressors, such as heat or anxiety, cause a brief release of 5-hydroxytryptamine that may stimulate central 5-hydroxytryptamine-2A receptors, lower the thermoregulatory set point, and cause flushing. This hypothesis is supported by the finding that several drugs that increase central serotonin levels may be effective in the treatment of hot flushes.

Estrogen treatment effectively relieves hot flushes, but the exact role of estrogen in flushing is not clear. Fluctuations in estrogen levels in an individual woman do not correlate with the onset of flushes. Prepubertal girls with very low levels of endogenous estrogen, premenopausal women with marked fluctuations in estrogen during the menstrual cycle, and most postmenopausal women with low, constant levels of estradiol do not experience flushing. However, women with gonadal dysgenesis who are treated with estrogen for several months experience flushing when treatment is discontinued. Thus, withdrawal of estrogen, rather than the absolute estrogen level, seems to play a key role in the etiology of hot flushes.

In addition to changes in estradiol, menopause is associated with multiple other hormonal changes. In the Study of Women’s Health Across the Nation (SWAN), a large cohort study in the United States, lower estradiol was associated with flushing in middle-aged women in univariate models. However, higher FSH was the only measure independently associated with flushing after adjustment for other hormone levels. Hot flushes correlate with pulsatile increases in LH, but suppression of LH with gonadotropin-releasing hormone agonists does not eliminate flushing. Androgens may also play a role, because men who are treated with androgen deprivation therapy for prostate cancer frequently report severe flushing.

Diagnosis

Vasomotor symptoms are classic manifestations of the menopause transition, and the diagnosis is generally obvious from a woman’s age and description of the symptoms. No abnormal physical findings are associated with hot flushes. Estradiol, FSH, and LH levels may be in the normal premenopausal range during the menopausal transition (see Fig. 262-1 ). A woman in her middle 40s to middle 50s who complains of classic hot flushes does not require any specific physical or laboratory evaluation unless there is good reason to suspect another cause of flushing ( Table 262-1 ). However, an FSH determination may be helpful in assessing the risk of pregnancy. A woman in her middle 40s to middle 50s with an FSH level obtained on the third day after menses that is higher than 20 IU/L is not at risk of becoming pregnant.


TABLE 262-1   — 
DIFFERENTIAL DIAGNOSIS OF HOT FLUSHES

   Alcohol consumption
   Carcinoid syndrome
   Dumping syndrome
   Hyperthyroidism
   Narcotic withdrawal
   Pheochromocytoma
   Medications

   Aromatase inhibitors
   Gonadotropin-releasing hormone agonists or antagonists
   Nicotinic acid
   Nitrates
   Selective estrogen receptor modulators (tamoxifen and raloxifene)
Treatment

Because self-reported frequency and severity of hot flushes improve markedly with placebo, conclusive evidence of efficacy of treatments requires randomized, blinded trials. Clinical trials of treatments for hot flushes have typically been small and of short duration, limiting information about potential adverse effects.

General Measures

Behavioral and Alternative Therapies

Many women have mild flushes and obtain adequate relief with simple measures such as lowering ambient temperature and wearing lighter clothing. Moderate exercise does not improve flushing ( Table 262-2 ).

There is no convincing evidence that acupuncture, Chinese herbs, dong quai, evening primrose oil, ginseng, kava, or red clover extract improve hot flushes (see Table 262-2 ).

Evidence regarding black cohosh is mixed but primarily negative.[1] Multiple trials have been performed using different phytoestrogen preparations. Although some of these studies have reported benefit, the weight of evidence, especially from good quality trials with blinded comparisons, suggests little benefit.[1] One trial of vitamin E supplementation found an improvement in flushes, but the decrease was only one hot flush per day. Many women prefer alternative medications because they believe that these treatments are harmless, but phytoestrogens and, possibly, black cohosh bind estrogen receptors and theoretically could cause adverse outcomes similar to those observed with estrogen. No studies of these preparations have been of adequate size or duration to document safety.

Medical Therapy

 

Estrogens

Multiple randomized trials have demonstrated that estrogen markedly improves the frequency and severity of hot flushes.[2] All types, preparations, and routes of administration of estrogen are effective. The benefit is dose related, but even low doses are often effective ( Table 262-3 ). Higher doses of estrogen may control symptoms more rapidly, but they are also associated with a higher rate of side effects including uterine bleeding, breast tenderness, and headache. [3] [4] [5]

At similar biologically active doses, oral and transdermal estrogens are approximately equally effective for treatment of vasomotor symptoms. Oral estrogens undergo “first pass” metabolism in the liver that results in changes in hepatic proteins and enzymes. Hepatic effects are responsible for the beneficial effects of estrogen on lipoproteins (reduced low-density lipoprotein cholesterol and increased high-density lipoprotein cholesterol) but also for potentially adverse effects such as increases in clotting factors. The transdermal route may be safer because it minimizes these changes.

Many estrogen preparations are approved for treatment of vasomotor symptoms ( Table 262-4 ). To individualize treatment, physicians should become familiar with several of these preparations, including at least one oral and one transdermal preparation.

Treatment with estrogen alone generally increases the risk of uterine hyperplasia and cancer. The risk of endometrial abnormalities appears not to be increased with the use of vaginal estrogens that deliver low systemic doses, especially if they are used only a few times per week, as is generally suggested for long-term use ( Table 262-5 ).

Adding a progestin to the estrogen regimen prevents the increased risk of uterine cancer. For this reason, a woman with a uterus who takes estrogen should also be given a progestin. There is no reason to add progestins to the hormone regimen in women who have had a hysterectomy. Several progestins are approved by the U.S. Food and Drug Administration for this purpose and are available either to add to estrogen or in preparations combined with estrogen (see Table 262-4 ). Two general approaches are used to prescribing progestins to protect the endometrium. Sequential therapy (estrogen given daily with a progestin added on the last 14 days of a 28-day cycle) results in endometrial shedding and cyclic bleeding resembling a menstrual period in approximately 80% of women. Alternatively, the progestin can be added to the estrogen every day. This continuous regimen results in endometrial atrophy and unpredictable uterine spotting or bleeding that can be difficult for the woman to anticipate and manage. Bleeding occurs in approximately 80% of women in the first 6 months of continuous treatment. Amenorrhea becomes more common with prolonged use, but some women continue to bleed or spot for many years.

The most commonly used progestins in sequential regimens in women using standard doses of estrogens (0.625 mg oral conjugated estrogens, 1 mg oral estradiol, or 0.05 mg transdermal estradiol) are medroxyprogesterone acetate, 5 mg, norethindrone, 0.5 mg, and micronized progesterone, 200 mg, for 10 to 14 days per month. Continuous regimens generally include half these progestin doses given daily. In some situations, it may be slightly less costly to prescribe estrogen and progestins separately, but the convenience of taking a single pill and the assurance that the estrogen is adequately opposed by progestin indicate that combination preparations are preferred.

Side Effects and Risks of Postmenopausal Hormone Therapy.

Estrogen is generally well tolerated, but it may cause headache (especially in women with a history of migraine) and breast tenderness. Added progestins tend to make these side effects more severe and also cause uterine bleeding.

Based on the results of multiple observational studies, postmenopausal hormone therapy was formerly thought to reduce the risk of coronary events, fracture, and dementia and to increase risk of breast cancer (see Table 262-6 ). Effects on disease outcomes have now been evaluated among generally healthy postmenopausal women in the Women’s Health Initiative (WHI) randomized trials ( Table 262-6 ). [6] [7] [8] [9] The results of these trials support observational findings with regard to fracture risk: both estrogen and estrogen in combination with progestin reduced the risk of hip fracture 35 to 40%. In contrast to the findings of observational studies, neither estrogen alone nor estrogen with a progestin reduced the risk for coronary events, and both increased the risk for stroke approximately 40%.

Compared with estrogen alone, added progestin appears to increase the risk for coronary events, pulmonary embolism, breast cancer, and dementia (see Table 262-6 ). This finding suggests that adding a progestin should be avoided, but treatment with unopposed estrogen in women with a uterus markedly increases the risk of uterine hyperplasia and cancer, as well as the rate of gynecologic procedures and hysterectomy.

The excess risk of any one of the adverse events listed in Table 262-6 in the WHI trials was 2 per 1000 women treated for 1 year with estrogen in combination with progestin (4.3 per 1000/year in women more than 65 years old if dementia is included), and 0.6 strokes per 1000 women treated with unopposed estrogen. These risks are relatively small, but they cumulate such that treatment for 5 years is associated with an excess risk of 1 event per 100 women treated with estrogen in combination with progestin and 3 strokes per 1000 women treated with unopposed estrogen. Based on the findings of the WHI trials and the availability of other effective and safe drugs (e.g., bisphosphonates) for prevention of osteoporotic fractures, postmenopausal hormone therapy currently has a very limited role for prevention of disease (i.e., bisphosphonate failures).

The mean age of the women included in the WHI trials was 63 years, whereas the average age of women treated for menopausal vasomotor symptoms is approximately a decade younger. Because the risk for most diseases approximately doubles with each decade of age, the absolute risk for the outcomes listed in Table 262-6 is less for younger than for older women, and the absolute risk increase is proportionately smaller. However, hormone therapy is relatively contraindicated in women with a history of stroke, breast cancer, and venous thromboembolic events and should be avoided in women at high risk of these conditions.

Stopping Hormone Therapy.

Given the possible adverse effects of hormone therapy, current guidelines recommend that women use the lowest effective dose for the shortest time necessary. Vasomotor symptoms improve or resolve spontaneously within a few months to a few years of onset in the majority of women, a finding suggesting that most women should be able to discontinue hormone therapy within a few years of starting. Women using hormone therapy for treatment of symptoms should stop every 6 to 12 months to determine whether symptoms have improved to the point that treatment is no longer needed. Most women are able to stop hormone therapy after a few years of treatment, but some women are unable to stop, mainly because vasomotor symptoms recur.

Women experiencing intolerable symptoms after stopping hormone treatment can be told to resume therapy and either to begin a slow taper or to wait 6 months before trying again to stop. Tapering can be accomplished by decreasing the dose of hormone therapy, but it may be easier to slowly decrease the number of days per week that hormone therapy is used. The dose taper involves progressively reducing the dose of hormone therapy, for example by reducing the dose of conjugated estrogens from 0.625 mg/day to 0.45 to 0.3 mg/day and then discontinuing therapy. If changing to a lower dose is associated with symptoms, the next reduction in dose should not occur until symptoms improve and are easily tolerable, which may require 3 to 6 months in some women. The day taper involves decreasing the number of days per week of hormone therapy use and effectively decreasing the weekly dose. For example, therapy with the same dose of hormone therapy may be continued, but only Monday through Friday. If this reduced weekly dose is tolerated, therapy may be discontinued on Thursday, and so on. As with the dose taper, if symptoms develop, the weekly dose should be maintained until symptoms improve. Both these approaches to tapering can require many months or even years until therapy is discontinued. The day taper has the advantages of allowing smaller reductions in weekly dose, ensuring that the estrogen dose is appropriately opposed by a progestin in women using combined continuous therapy and does not require multiple new prescriptions for different doses of hormone therapy. For women who cannot tolerate even a slow taper, the value of symptom relief likely outweighs the risks of hormone therapy.

Other Prescription Drugs.

A drug that appears to be as effective as estrogens for treatment of hot flushes is tibolone, a steroid hormone that is not marketed in the United States but is widely available elsewhere ( Table 262-7 ). Tibolone also preserves bone density, but its effects on fracture, cardiovascular disease, and uterine and breast cancer risk have not been adequately investigated. The progestins megestrol and medroxyprogesterone acetate are effective for the treatment of hot flushes, but they have frequent side effects, and progestin use was associated with increased risk of adverse effects in the WHI trials. Several selective serotonin/norepinephrine reuptake inhibitors and gabapentin have been studied.[10] Paroxetine and gabapentin seem to have modest efficacy in relieving hot flushes (see Table 262-7 ). Although these therapies are thought to be safe, clinical trials have not been adequately large or prolonged to detect uncommon adverse effects.

Summary of Approach to Treatment of Vasomotor Symptoms

Women with mild vasomotor symptoms may find adequate relief by wearing layered clothing and keeping the home and bedroom cool. Women with moderate symptoms may choose a low dose of estrogen or a nonestrogen therapy. Paroxetine is modestly effective and probably has the best side effect profile of the nonhormonal drugs. For women with severe symptoms, hormone therapy is the most effective treatment.


TABLE 262-2   — 
EVIDENCE FROM RANDOMIZED, CONTROLLED CLINICAL TRIALS OF THE EFFICACY OF BEHAVIORAL AND ALTERNATIVE THERAPIES FOR TREATMENT OF MENOPAUSAL HOT FLUSHES

Therapy Evidence of Benefit References
BEHAVIORAL
Exercise No Aiello EJ, Yasui Y, Tworoger SS, et al: Effect of a yearlong, moderate-intensity exercise intervention on the occurrence and and severity of menopause symptoms in postmenopausal women. Menopause 2004;11:382–388.
    Lindh-Astrand L, Nedstrand E, Wyon Y, et al: Vasomotor symptoms and quality of life in previously sedentary postmenopausal women randomised to physical activity or estrogen therapy. Maturitas 2004;48:97–105.
ALTERNATIVE
Acupuncture No Nelson HD, Haney E, Humphrey L, et al: Management of Menopause-Related Symptoms. AHRQ Publication No. 05-E016-2. Rockville, MD, Agency for Healthcare Research and Quality, 2005.
Black cohosh No[*] Kronenberg F, Fugh-Berman A: Complementary and alternative medicine for menopausal symptoms: A review of randomized, controlled trials. Ann Intern Med 2002;137:805–813.
    Nelson HD, Haney E, Humphrey L, et al: Management of Menopause-Related Symptoms. AHRQ Publication No. 05-E016-2. Rockville, MD, Agency for Healthcare Research and Quality, 2005.
Chinese herbal compounds No Kronenberg F, Fugh-Berman A: Complementary and alternative medicine for menopausal symptoms: A review of randomized, controlled trials. Ann Intern Med 2002;137:805–813.
    Nelson HD, Haney E, Humphrey L, et al: Management of Menopause-Related Symptoms. AHRQ Publication No. 05-E016-2. Rockville, MD, Agency for Healthcare Research and Quality, 2005.
Dong quai No Kronenberg F, Fugh-Berman A: Complementary and alternative medicine for menopausal symptoms: A review of randomized, controlled trials. Ann Intern Med 2002;137:805–813.
    Nelson HD, Haney E, Humphrey L, et al: Management of Menopause-Related Symptoms. AHRQ Publication No. 05-E016-2. Rockville, MD, Agency for Healthcare Research and Quality, 2005.
Evening primrose oil No Kronenberg F, Fugh-Berman A: Complementary and alternative medicine for menopausal symptoms: A review of randomized, controlled trials. Ann Intern Med 2002;137:805–813.
    Nelson HD, Haney E, Humphrey L, et al: Management of Menopause-Related Symptoms. AHRQ Publication No. 05-E016-2. Rockville, MD, Agency for Healthcare Research and Quality, 2005.
Ginseng No Kronenberg F, Fugh-Berman A: Complementary and alternative medicine for menopausal symptoms: A review of randomized, controlled trials. Ann Intern Med 2002;137:805–813.
    Nelson HD, Haney E, Humphrey L, et al: Management of Menopause-Related Symptoms. AHRQ Publication No. 05-E016-2. Rockville, MD, Agency for Healthcare Research and Quality, 2005.
Kava No Nelson HD, Haney E, Humphrey L, et al: Management of Menopause-Related Symptoms. AHRQ Publication No. 05-E016-2. Rockville, MD, Agency for Healthcare Research and Quality, 2005.
Phytoestrogens No[*] Kronenberg F, Fugh-Berman A: Complementary and alternative medicine for menopausal symptoms: A review of randomized, controlled trials. Ann Intern Med 2002;137:805–813.
    Nelson HD, Haney E, Humphrey L, et al: Management of Menopause-Related Symptoms. AHRQ Publication No. 05-E016-2. Rockville, MD, Agency for Healthcare Research and Quality, 2005.
    Krebs EE, Ensrud KE, MacDonald R, et al: Phytoestrogens for treatment of menopausal symptoms: A systematic review. Obstet Gynecol 2004;104:824–836.
Red clover No Nelson HD, Haney E, Humphrey L, et al: Management of Menopause-Related Symptoms. AHRQ Publication No. 05-E016-2. Rockville, MD, Agency for Healthcare Research and Quality, 2005.
    Krebs EE, Ensrud KE, MacDonald R, et al: Phytoestrogens for treatment of menopausal symptoms: A systematic review. Obstet Gynecol 2004;104:824–836.
Vitamin E Yes[] Barton DL, Loprinzi CL, Quella SK, et al: Prospective evaluation of vitamin E for hot flashes in breast cancer survivors. J Clin Oncol 1998;16:495–500.

* Some studies had positive findings, but the weight of evidence is not convincing.
One trial in survivors of breast cancer found a 17% greater reduction in frequency of hot flushes with vitamin E 800 IU compared with placebo.


TABLE 262-3   — 
EFFICACY OF TREATMENT WITH VARIOUS DOSES OF ESTROGEN FOR HOT FLUSHES

Estrogen Daily Dose (mg) Percentage of Reduction in Frequency of Hot Flushes with Treatment[*] Percentage of Reduction in Frequency of Hot Flushes with Placebo[*]
Oral conjugated equine estrogens[5] 0.625 94% 44%
  0.45 78%  
  0.3 78%  
Oral 17β-estradiol[3] 2.0 96% 55%
  1.0 89%  
  0.5 79%  
  0.25 59%  
Transdermal 17β-estradiol[4] 0.1 96% 45%
  0.05 96%  
  0.025 86%  

* Estimated from figures provided in each reference.


TABLE 262-4   — 
ESTROGEN AND PROGESTIN PREPARATIONS FOR TREATMENT OF MENOPAUSAL VASOMOTOR SYMPTOMS

Hormones Generic Name Brand Name Dose (mg/day)
Estrogens[*]
  Oral Conjugated estrogens Premarin 0.3, 0.45, 0.625, 0.9, 1.25
    17β-Estradiol Estrace/generics 0.5, 1.0, 2.0
  Transdermal 17β-Estradiol Alora[] 0.025, 0.05, 0.075, 0.1
      Climara[] 0.025, 0.0375, 0.05, 0.075, 0.1
  Vaginal Estradiol acetate Femring Vaginal Ring[§] 0.05, 0.1
Progestins
  Oral Medroxyprogesterone acetate Provera/generics 2.5, 5.0, 10.0
    Micronized progesterone Prometrium 100, 200 (in peanut oil)
  Vaginal Progesterone Prochieve 4% 45 every other day
Combination Preparations
  Oral sequential    Conjugated estrogens and medroxyprogesterone acetate Premphase 0.625 + 5.0
  Oral continuous[] Conjugated estrogens and medroxyprogesterone acetate Prempro 0.625 + 5.0
        0.45 + 2.5 or 1.5
    17β-Estradiol and norethindrone acetate Activella 0.3 + 1.5
        1.0 + 0.5
Transdermal continuous[] 17β-Estradiol and levonorgestrel ClimaraPro[] 0.045 + 0.015
    17β-Estradiol and norethindrone acetate CombiPatch[] 0.05 + 0.14 or 0.25

* Approximately equivalent doses of estrogens are shown in bold.
Patch applied twice per week.
Patch applied once per week.
§ Vaginal ring inserted every 90 days: note that Femring, as opposed to the vaginal preparations listed in Table 262-5 , delivers systemic levels of estrogen and should be opposed by a progestin in women with a uterus.
Each pill contains estrogen days 1 to 14 and estrogen with progestin days 15 to 28.
Each pill or patch contains estrogen and progestin.


TABLE 262-5   — 
ESTROGEN VAGINAL PREPARATIONS FOR TREATMENT OF VAGINAL DRYNESS[*]

Preparation Generic Name Brand Name Dose
Vaginal cream Conjugated estrogens Premarin 0.625 mg/2 g cream: 2 g/day for 2 weeks, then 1–2 g 2 to 3 times/wk
  17β-Estradiol Estrace 0.1 mg/2 g cream: 2 g/day for 2 wk, then 1–2 g 2 to 3 times/wk
Vaginal tablet Estradiol hemihydrate Vagifem 0.025 mg tablet: 1 tablet/day for 2 wk, then 1 tablet twice/wk
Vaginal ring 17β-Estradiol Estring[] 0.0075 mg/day

* Most oral, transdermal, and vaginal products listed in Table 262-4 for treatment of vasomotor symptoms are also approved for treatment of vaginal dryness.
Vaginal ring is inserted every 90 days.


TABLE 262-6   — 
RESULTS OF OBSERVATIONAL STUDIES AND THE WOMEN’S HEALTH INITIATIVE RANDOMIZED TRIALS OF THE EFFECTS OF POSTMENOPAUSAL HORMONE THERAPY ON DISEASE OUTCOMES

Outcomes Relative Risk (95% Confidence Interval) Observational Studies[*] Women’s Health Initiative[] [6] [7] Estrogen and Progestin Women’s Health Initiative[] [8] [9] Estrogen
Coronary heart disease events 0.66 (0.53–0.84)[a] 1.29 (1.02–1.63) 0.91 (0.75–1.12)
Stroke 1.12 (1.01–1.23)[b] 1.41 (1.07–1.85) 1.39 (1.10–1.77)
Pulmonary embolism 2.14[§] (0.89–8.75)[b] 2.13 (1.39–3.25) 1.34 (0.87–2.06)
Breast cancer 1.35[] (1.21–1.45)[c] 1.26 (1.00–1.59) 0.77 (0.59–1.01)
Colon cancer 0.80 (0.74–0.86)[d] 0.63 (0.43–0.92) 1.08 (0.75–1.55)
Hip fracture 0.75 (0.68–0.84)[e] 0.66 (0.45–0.98) 0.61 (0.41–0.91)
Dementia 0.71 (0.53–0.96)[f] 2.05 (1.21–3.48) 1.49 (0.83–2.66)
Death 0.81 (0.71–0.92)[b] 0.98 (0.82–1.18) 1.04 (0.88–1.22)

Sources:

* Results of multiple observational studies among postmenopausal hormone users and non-users summarized in systematic reviews as listed in the sources below.
Results of the Women’s Health Initiative estrogen plus progestin randomized trial: 16,608 postmenopausal women without hysterectomy randomized to 0.625 mg conjugated estrogen plus 2.5 mg medroxyprogesterone acetate per day or identical placebo and followed for 5.2 years.
Results of the Women’s Health Initiative estrogen only randomized trial: 10,739 postmenopausal women with hysterectomy randomized to 0.625 mg conjugated estrogen per day or identical placebo and followed for 6.8 years.
§ Relative risk is for all venous thromboembolic events.
Relative risk for 5 or more years of estrogen use.
a Barrett-Connor E, Grady D: Hormone replacement therapy, heart disease, and other considerations. Ann Rev Public Health 1998;19:55–72.
b Nelson HD, Humphrey LL, Nygren P, et al: Postmenopausal hormone replacement therapy: Scientific review. JAMA 2002;288:872–881.
c Collaborative Group on Hormonal Factors in Breast Cancer: Breast cancer and hormone replacement therapy: Collaborative reanalysis of data from 51 epidemiological studies of 52,705 women with breast cancer and 108,411 women without breast cancer. Lancet 1997;350:1047–1059.
d Grodstein F, Newcomb PA, Stampfer MJ: Postmenopausal hormone therapy and the risk of colorectal cancer: A review and meta-analysis. Am J Med 1999;106:574–582.
e Torgerson DJ, Bell-Syer SEM: Hormone replacement therapy and prevention of nonvertebral fractures: A meta-analysis of randomized trials. JAMA 2001;285:2891–2897.
f Yaffe K, Sawaya G, Lieberburg I, et al: Estrogen therapy in postmenopausal women: Effects on cognitive function and dementia. JAMA 1998;279:688–695.


TABLE 262-7   — 
EVIDENCE FROM RANDOMIZED, CONTROLLED CLINICAL TRIALS OF THE EFFICACY OF NON-ESTROGEN DRUGS FOR TREATMENT OF MENOPAUSAL HOT FLUSHES

Treatment Evidence of Benefit Comments References Side Effects[*]
ANTIDEPRESSANTS
Citalopram No No benefit of 30 mg citalopram compared with placebo Suvanto-Luukkonen E, Koivunen R, Sundstrom H, et al: Citalopram and fluoxetine in the treatment of postmenopausal symptoms: A prospective, randomized, 9-month, placebo-controlled, double-blind study. Menopause 2005;12:18–26. Selective serotonin reuptake inhibitors fluoxetine, paroxetine, and citalopram: nausea, vomiting, diarrhea, insomnia or somnolence, anxiety, decreased libido, dry mouth, worsening depression, mania, suicidality, serotonin syndrome, withdrawal syndrome, and possible decreased tamoxifen effectiveness
Fluoxetine Mixed One trial among breast cancer survivors found the frequency of hot flushes was reduced 50% with fluoxetine 20 mg/day compared to 36% with placebo, whereas another found no benefit among women without breast cancer who were treated with 30 mg fluoxetine compared with placebo Loprinzi CL, Sloan JA, Perez EA, et al: Phase III evaluation of fluoxetine for treatment of hot flashes. J Clin Oncol 2002;20:1578–1583.  
Suvanto-Luukkonen E, Koivunen R, Sundstrom H, et al: Citalopram and fluoxetine in the treatment of postmenopausal symptoms: A prospective, randomized, 9-month, placebo-controlled, double-blind study. Menopause 2005;12:18–26.
Paroxetine Yes One trial found the frequency of hot flushes was reduced 62% with 12.5 mg and 65% with 25 mg paroxetine CR compared with 38% in placebo; a crossover trial in which 81% of participants had a history of breast cancer found that paroxetine 10 mg reduced hot flush frequency by 41% compared to 14% with placebo and paroxetine 20 mg reduced hot flush frequency by 52% compared with 27% with placebo Stearns V, Beebe KL, Iyengar M, et al: Paroxetine controlled release in the treatment of menopausal hot flashes: A randomized controlled trial. JAMA 2003;289:2827–2834.  
Stearns V, Slack R, Greep N, et al: Paroxetine is an effective treatment for hot flashes: Results from a prospective clinical trial. J Clin Oncol 2005;23:6919–6930.
Sertraline No One trial among women with a history of breast cancer found no benefit of treatment with 50 mg of sertraline compared with placebo; another trial among generally healthy women found no benefit of 100 mg of sertraline compared with placebo. Kimmick GG, Lovato J, McQuellon R, et al: Randomized, double-blind, placebo-controlled crossover study of sertraline (Zoloft) for the treatment of hot flashes in women with early stage cancer taking tamoxifen. Breast J 2006;12:114–122.  
Grady D, Cohen B, Tice J, et al: Ineffectiveness of sertraline for treament of hot flushes. Obstet Gynecol 2007;109:823–830.
Venlafaxine Mixed One trial among survivors of breast cancer found the frequency of hot flushes to be reduced 61% with 75 or 150 mg venlafaxine compared with 27% with placebo; another trial among women without breast cancer found no effect on frequency of flushes with 75 mg venlafaxine, but women treated with venlafaxine were more likely to report that flushes improved compared with placebo Loprinzi CL, Kugler JW, Sloan JA, et al: Venlafaxine in management of hot flashes in survivors of breast cancer: A randomised controlled trial. Lancet 2000;356:2059–2063. In addition to the side effects noted above, the selective serotonin/norepinephrine reuptake inhibitor venlafaxine can also cause hypertension
Evans ML, Pritts E, Vittinghoff E, et al: Management of postmenopausal hot flushes with venlafaxine hydrochloride: A randomized, controlled trial. Obstet Gynecol 2005; 105:161–166.
ANTIHYPERTENSIVES
Clonidine Mixed Several small trials suggest little or no benefit Nelson HD, Haney E, Humphrey L, et al: Management of Menopause-Related Symptoms. AHRQ Publication No. 05-E016-2. Rockville, MD, Agency for Healthcare Research and Quality, 2005. α–Adrenergic antagonist: dry mouth, drowsiness, dizziness, hypotension, rebound hypertension
Goldberg RM, Loprinzi CL, O’Fallon JR, et al: Transdermal clonidine for ameliorating tamoxifen-induced hot flashes. J Clin Oncol 1994;12:155–158.
Pandya KJ, Raubertas RF, Flynn PJ, et al: Oral clonidine in postmenopausal patients with breast cancer experiencing tamoxifen-induced hot flashes: A University of Rochester Cancer Center Community Clinical Oncology Program Study. Ann Intern Med 2000;132:78–93.
Methyldopa No   Nelson HD, Haney E, Humphrey L, et al: Management of Menopause-Related Symptoms. AHRQ Publication No. 05-E016-2. Rockville, MD, Agency for Healthcare Research and Quality, 2005.  
HORMONES
Medroxyprogesterone acetate Yes One trial found the frequency of hot flushes was reduced 74% with 20 mg medroxyprogesterone acetate compared with 26% with placebo Schiff I, Tulchinsky D, Cramer D, et al: Oral medroxyprogesterone in the treatment of postmenopausal symptoms. JAMA 1980;244: 1443–1445. Progestins megestrol and medroxyprogesterone: nausea, vomiting, constipation, somnolence, depression, breast tenderness, uterine bleeding; possible increased risk of venous thromboembolism, cardiovascular events, and breast cancer
Megestrol Yes One trial in breast cancer survivors found the frequency of hot flushes was reduced 74% with 20 mg megestrol twice/day compared to 27% with placebo Loprinzi CL, Michalak JC, Quella SK, et al: Megestrol acetate for the prevention of hot flashes. N Engl J Med 1994;331:347–352.  
Tibolone[] Yes Several trials reported improved hot flushes compared with placebo and efficacy equivalent to standard doses of estrogens with 1.25–5.0 mg tibolone Modelska K, Cummings S: Tibolone for postmenopausal women: Systematic review of randomized trials. J Clin Endocrinol Metab 2002;87:16–23. Steroid hormone: headache, weight gain, uterine bleeding; effects on venous thromboembolism, cardiovascular disease, and breast and uterine cancer unclear
Nelson HD, Haney E, Humphrey L, et al: Management of Menopause-Related Symptoms. AHRQ Publication No.05-E016-2. Rockville, MD, Agency for Healthcare Research and Quality, 2005.
OTHER DRUGS
Gabapentin Yes One trial found the frequency of hot flushes was reduced 45% with gabapentin 300 mg three times/day compared with 29% with placebo; another found the frequency of hot flushes was reduced 31% more than placebo among breast cancer survivors Guttuso TJ, Kurlan R, McDermott MP, et al: Gabapentin’s effects on hot flashes in postmenopausal women: A randomized controlled trial. Obstet Gynecol 2003;101:337–345. Nausea, vomiting, somnolence, dizziness, rash, ataxia, fatigue, leukopenia
Pandya JK, Morrow GR, Rosco JA, et al: Gabapentin for hot flashes in 420 women with breast cancer: A randomized double-blind, placebo-controlled trial. Lancet 2005;366:818–824.

* Side effects were reported in clinical trials of the therapy or from Epocrates Rx drug reference (available at www.epocrates.com).
This drug had not been approved by the U.S. Food and Drug Administration at the time of publication

   Vaginal Dryness

Epidemiology

The prevalence of vaginal dryness, discomfort, itching, and dyspareunia increases as women transition through the menopause.

Up to 30% of perimenopausal and early postmenopausal women and a higher proportion of older menopausal women express these complaints. Urologic symptoms, including urgency, frequency, dysuria, incontinence, and increased risk of urinary tract infections, are not clearly correlated with the menopause transition.

Pathobiology

Vaginal symptoms generally correlate with findings (often called vaginal atrophy) including pallor, dryness, friability, and decreased rugosity of the vaginal mucosa. Vaginal fluid in premenopausal women is acidic, ranging from a pH of approximately 4.5 to 5.5 with mild alkalinization to approximately 6.0 before ovulation. Acidity is produced by proton excretion from the vaginal epithelial cells and by metabolism of glycogen stored in vaginal epithelial cells by Lactobacillus species, the normal vaginal flora. The acid environment of the vagina inhibits growth of Escherichia coli and other enteric gram-negative bacteria that are a potential cause of urinary tract infections. Vaginal pH can easily be measured from lateral vaginal wall fluid.

In postmenopausal women, vaginal pH is generally neutral, and the predominant flora is often E. coli and other gram-negative bacteria. This appears to occur because estrogen deficiency associated with menopause causes vaginal epithelial cell dysfunction, including decreased storage of glycogen, less ability to acidify the vaginal fluid, and lowered production of vaginal lubrication. Vaginal epithelial cells, which are primarily superficial and intermediate cells in premenopausal women, shift to predominately immature parabasal cells in postmenopausal women. Treatment with estrogen improves or relieves vaginal dryness, lowers vaginal pH, and increases the proportion of superficial cells in the vaginal epithelium.

Diagnosis

Diagnosis is primarily based on typical complaints of vaginal dryness, discomfort, itching, or dyspareunia in women undergoing the menopause transition or older postmenopausal women. Pelvic examination should exclude other causes of discomfort, including infections, lesions, and trauma. Physical findings of vaginal dryness, pallor, friability, and vaginal pH greater than 5.5 support the diagnosis. Cytologic examination of the proportion of superficial, intermediate, and parabasal cells from a scraping of the lateral vaginal wall (vaginal maturation index) showing primarily parabasal cells also supports the diagnosis, but the accuracy of this test is not clear.

Treatment

Many women with vaginal symptoms obtain adequate relief with use of over-the-counter vaginal moisturizers, such as Repleus. Estrogen therapy is highly effective. Topical therapy is efficacious[11] and is preferred because it generally results in smaller increases in systemic estrogen levels than oral or transdermal therapy. Estrogen vaginal creams, tablets, and rings approved for treatment of vaginal dryness are listed in Table 262-5 .

Most clinicians do not add a progestin to protect the uterus in women treated with vaginal estrogen, but evidence to support the uterine safety of vaginal estrogen is limited to very short-term studies. Low-dose, intermittent treatment (e.g., 1 to 2 g conjugated estrogen cream or 0.025 mg estradiol tablet twice/week) results in very small increases in systemic estrogen levels that appear not to cause endometrial stimulation. However, full-dose daily treatment has been shown to increase estradiol levels to 50 pg/mL or higher in approximately half of treated women and has been associated with uterine bleeding and hyperplasia.

   Sleep Disturbance

The prevalence of self-reported sleep disturbance increases from about 40% of premenopausal women to approximately 60% of postmenopausal women.[1] Sleep disturbances including trouble falling asleep and early awakening are reported by menopausal women, but awakening during the night appears to be most bothersome.

The etiology of sleep disturbance associated with menopause is unclear. Postmenopausal women with hot flushes are more likely to report sleep disturbance than are those without flushes, and women commonly report that they are awakened by hot flushes. However, studies using actigraphy and polysomnography find that nocturnal hot flushes do not consistently occur at the same time as sleep disturbance. Thus, disturbed sleep appears to be part of a menopausal syndrome, but it may not be caused by flushing.

Menopause-related sleep disturbance can be treated using standard approaches to sleep hygiene and prescription medications. Both oral and transdermal estrogen preparations improve sleep in perimenopausal and postmenopausal women with hot flushes.

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