For nearly 70 percent of women, the transition into menopause is smooth1; however, many women seek advice for management of associated symptoms such as hot flushes or vaginal dryness, or for assistance in the prevention of associated long-term health problems such as osteoporosis and coronary artery disease.
Women and physicians have questions and concerns about the use of hormone replacement therapy (HRT) during and after menopause. In addition, many alternative and nonhormonal treatments lack rigorous scientific study but are popular with patients. Family physicians need to know the available treatment options in order to address patients' questions and concerns.
Pharmacologic Therapy for Symptoms of Menopause
A hot flush is a flushed or blushed feeling of the face, neck and upper chest. Skin temperature can rise several degrees. The severity of hot flushes increases with fatigue and stress. The most severe hot flushes usually occur at night and may adversely affect sleep. About 75 percent of American women experience hot flushes during menopause, although not all are subjectively troublesome. Menopausal women living in Asian countries experience a much lower incidence of hot flushes and sleep disturbance, which may be related to dietary factors such as phytoestrogens that are contained in soy products.2 Hot flushes may persist for several years around the time of menopause.
Estrogen therapy can reduce hot flushes. Progesterone therapy alone may help women who choose not to take estrogen. Clonidine (Catapres), a centrally acting alpha-adrenergic agonist, has also been used with mixed success.3
Mood swings, depression and concentration difficulties are psychologic symptoms that are associated with menopause. Estrogen therapy improves mood and dysphoria, possibly by affecting the metabolism of serotonin in the central nervous system.4 However, depression has not been shown to be caused by menopause alone but is usually the result of additional factors that include previous history of depression, psychologic factors and life stressors that may accumulate around the time of menopause.3 While estrogen improves mood or dysphoria associated with menopause, HRT is not effective in the treatment of primary depression.
The urogenital tissues are estrogen sensitive. Declining estrogen levels lead to atrophy of the urogenital tissues and vaginal thinning and shortening, resulting in dyspareunia and urethral irritation. In addition, urinary tract infections and urinary incontinence may develop because of tissue thinning, laxity, decreased urethral apposition and alteration of the vaginal flora.
A meta-analysis of estrogen treatment (oral or intravaginal) for urinary incontinence revealed a significant improvement in subjective symptoms, but no improvement in objective measures such as urodynamic testing.5 Intravaginal estrogen administration has been shown to decrease the number of recurrent urinary tract infections.6 Doses of estriol 0.5 mg administered intravaginally did not cause a significant rise in plasma estrogen levels within 24 hours. The risk of endometrial cancer is low with this regimen.6
Pharmacologic Management of Long-Term Risks
CORONARY ARTERY DISEASE
Estrogen's physiologic effects, such as arterial vasodilatation, decreased fibrinogen levels, increased high-density lipoprotein (HDL) cholesterol levels and decreased low-density lipoprotein (LDL) cholesterol levels, are likely to reduce cardiovascular risk. Unopposed estrogen offers the most beneficial effect on HDL cholesterol levels; however, the addition of progestin agents does not negate improvement.7 Oral estrogen can increase the serum HDL level by 20 to 30 percent and reduce the serum LDL level by 10 to 15 percent. The effect is comparable to or better than that of a statin drug.8
Many observational studies have shown that estrogen is associated with a 40 to 50 percent reduction in the risk of heart disease.9–11 Meta-analyses of these nonrandomized trials9–11 demonstrated a pooled reduction in relative risk of heart disease of one third in women who had ever used estrogen.12,13
Conversely, the results of the Heart and Estrogen/Progestin Replacement Study (HERS),14 a recent randomized, controlled trial, found no benefit of HRT for secondary prevention of cardiovascular events in 2,763 postmenopausal women followed over four years.14 Although the conflicting results illustrate the shortcomings of nonrandomized trials and raise caution, it should be noted that the HERS participants had established coronary heart disease, and 25 percent of the women in the active treatment arm dropped out of this study. Perhaps HRT provides minimal to no benefit in women with established coronary heart disease but may provide primary prevention in otherwise healthy women.
The protective effect of estrogen against stroke is unclear. The National Health and Nutrition Examination Survey15 found an adjusted relative risk of 0.37 (95 percent confidence interval [CI]; range: 0.14 to 0.92) for fatal stroke in women who had ever used estrogen. In the Leisure World Study,9 the risk of death from stroke for women who were taking estrogen was reduced by 20 to 40 percent. Other studies have illustrated no protection against stroke.10,16
Critics of HRT studies state that women who take estrogen may be better informed and healthier than women who choose not to take estrogen. Most studies do not have the rigorous design of a randomized, controlled trial, which is necessary to ascertain whether the estrogen or the associated healthier attitudes and practices of the participants are the major causes of reduced disease. Until such information is available, HRT is considered important in the primary prevention of cardiovascular disease; however, questions remain about its role in secondary cardiovascular risk reduction.
In the United States, 4 to 6 million women have osteoporosis. One consequence of this situation is that more than 250,000 hip fractures occur annually, with a health care cost of approximately $14 billion per year. A hip fracture carries a 10 to 20 percent risk of death within a year and a 25 percent chance of institutionalization.17 Estrogen deficiency is the primary cause of osteoporosis, although many other secondary causes for osteoporosis exist (e.g., poor diet, glucocorticoid excess). Thus, women at risk for osteoporosis should be considered candidates for HRT.
The daily dosage required to prevent bone loss is 0.625 mg of conjugated estrogen or the equivalent (Table 1), but even 0.3 mg may suffice if taken with adequate calcium supplements. Resumption of bone loss following discontinuation of HRT has been reported.18 The maximal protective effect of estrogen on bone mineral density (BMD) occurs if HRT is initiated within three years of menopause. However, effectiveness has been documented with initiation of therapy in the later years of menopause.9
|Formulation*||Minimum effective dosage||Cost†|
|Conjugated estrogen||0.625 mg||$15|
|Premarin (0.3, 0.625, 0.9, 1.25, 2.5)|
|Micronized estradiol||1.0 mg||14|
|Estrace (0.5, 1.0, 2.0)|
|Esterified estrogen||0.625 mg|
|Estratab (0.3, 0.625, 2.5)||14|
|Menest (0.3, 0.625, 1.25, 2.5)||6|
|Ogen (0.625, 1.25, 2.5)||27|
|Ortho-Est (0.625, 1.25)||22|
|Transdermal estradiol||0.05 mg|
|Alora (0.05, 0.075, 0.1)||19|
|Climara (0.05, 0.1)||23|
|Estraderm (0.05, 0.1)||22|
|Vivelle (0.0375, 0.05, 0.75, 0.1)||23|
|Combipatch||0.05 mg estradiol/0.14 mg norethindrone||30|
|Estratest||1.25 mg esterified estrogen/2.5 mg methyltestosterone||31|
|Estratest HS||0.625 mg esterified estrogen/1.25 mg methyltestosterone||25|
|Premphase‡||0.625 mg conjugated estrogen (14 tablets) and 0.625 mg conjugated estrogen/5 mg medroxyprogesterone acetate (14 tablets in sequence)||20|
|Prempro||0.625 mg conjugated estrogen/2.5 mg or 5.0 mg medroxyprogesterone acetate||22 each|
|Micronized estradiol cream (Estrace)||0.01 % or 0.1 mg per g (42.5 g/tube)||36§|
|Estropipate cream (Ogen)||1.5 mg per g (42.5 g/tube)||48§|
|Conjugated estrogen cream (Premarin)||0.625 mg per g (42.5 g/tube)||42|
|Dienestrol cream (Ortho)||0.01 % or 0.1 mg per g (78 g/tube)||30§|
|Estradiol vaginal ring (Estring)||7.5 μg per 24 hours every 90 days||69|
Study results demonstrate the efficacy of estrogen in increasing BMD and decreasing the number of fractures of the forearm, vertebrae and hip.19,20 Thus, HRT is not only preventive but can also be used to treat established osteoporosis. Spinal BMD has been shown to increase by 10.6 percent12 and hip BMD by 5.5 percent over a two-year period with HRT. The relative risk of hip fracture was 0.65 (95 percent CI; range: 0.44 to 0.98) in women who had taken estrogen at any time and 0.32 (95 percent CI; range: 0.12 to 0.98) in those taking estrogen within the past two years.21 In one large study, the incidence of all osteoporotic fractures was estimated to be reduced by 30 to 50 percent with long-term HRT (three to 10 years' duration).22
Alternatives to HRT include bisphosphonates, which inhibit osteoclast activity and localize and bind to resorption sites on the bone. The current recommended therapeutic course is three years, to avoid the potential risk of osteomalacia. Long-term data are forthcoming. Alendronate (Fosamax) is labeled by the U.S. Food and Drug Administration for treatment of osteoporosis. Several large, randomized, controlled trials have demonstrated its efficacy in increasing BMD and reducing fractures by 40 percent.23,24 To prevent esophagitis, alendronate should be taken in an upright position with a full glass of water 30 minutes before eating; the upright position should be maintained for the 30 minutes. This agent may cause musculoskeletal pain and gastrointestinal upset. Contraindications include symptomatic upper gastrointestinal disease (esophageal stricture, achalasia, gastroesophageal reflux) and renal insufficiency.
Etidronate (Didronel) is another bisphosphonate. It is FDA-labeled for treatment of Paget's disease, but has had an unlabeled use as a treatment for osteoporosis in patients who cannot tolerate alendronate. In one study,25 it was documented in a sample of 66 women with postmenopausal osteoporosis that etidronate increased vertebral BMD 5.3 percent (95 percent CI; range: 2.0 to 8.6) and reduced fracture rate (six versus 54 fractures per 100 patient years) over three years. The patients in the intervention arm received etidronate in a dosage of 400 mg per day for two weeks every 15 weeks for three years. This agent has proved effective in increasing vertebral BMD and reducing fracture rates. It is more cost effective than alendronate.22
Intranasal calcitonin (Mialcalcin) is a polypeptide hormone that also inhibits osteoclastic activity. An injectable form has been available for about 15 years; however, a convenient intranasal form is now available for treatment of established osteoporosis. In a randomized, placebo-controlled trial, 76 percent of post-menopausal women receiving a dosage of 200 IU per day intranasally demonstrated a positive response, with a 2.0 to 3.6 percent increase in BMD, while participants receiving placebo lost bone mass.26,27 No data are available on change in fracture rate.
A new selective estrogen receptor modulator, raloxifene (Evista), has been FDA-labeled for prophylactic treatment of osteoporosis. For women whose main interest is prevention of osteoporosis, this agent offers an alternative to traditional HRT. The modulator does not stimulate endometrial or breast tissue but does increase BMD (although only approximately one half as effectively as estrogen) and reduce total and LDL cholesterol levels with no change in triglycerides or HDL cholesterol levels.28 Longitudinal studies are needed to determine the net effect on cardiovascular disease and breast cancer. Other selective estrogen receptor modulators pending FDA labeling include droloxifene and idoxifene.
The evidence concerning prevention of dementia with HRT is conflicting but promising. Observational studies have demonstrated a protective effect and no effect on the risk of Alzheimer's dementia. A meta-analysis of the observational studies of estrogen use and development of dementia have shown an odds ratio of 0.71 (95 percent CI; range: 0.52 to 0.98).29 Prospective randomized trials are needed. Proposed mechanisms of action include increased blood flow to the brain and enhanced neuronal dendritic growth to support neurotransmitter production.
The mortality rate among women who take estrogen has been shown to be lower than the rate in women who do not. The Nurses Health Study16 (data from 1976 to 1994) revealed decreased mortality in women who took estrogen; however, the benefit decreased with longer duration of use and was lower in women already considered at low risk for coronary artery disease. Other studies have shown lower all-cause mortality rates among women taking HRT.30
The issue of HRT among special populations of women (i.e., survivors of breast cancer) has not been adequately addressed. Trials are currently under way to address this issue.
HRT Administration and Regimens
The most common HRT regimen consists of estrogen with or without progestin. Transdermal estrogen preparations avoid the first-pass liver effect. This may be efficacious in the treatment of vasomotor symptoms but may also reduce the positive effect on cholesterol levels. Many women have a problem with skin sensitivity to the patches. Vaginal preparations are widely used, especially for treatment of atrophic vaginitis. Injectable and slow-release implant formulations of estrogen are available but are not preferred by many patients. Despite the availability of a variety of administration routes, the concern about coronary artery disease makes the oral route of administration preferable because of the hepatic effect on HDL cholesterol levels.
Estrogen-only regimens are appropriate in women who have undergone hysterectomy. The paucity of data showing that progestins protect against an increased risk of breast cancer and the concern regarding the adverse effect of progestins on lipoproteins make the estrogen-only regimen preferable to combined therapy in women without a uterus.
Progestin should be added to the estrogen-only regimen for at least 12 days per month in women with an intact uterus to avoid the five-to eightfold risk of endometrial adenocarcinoma resulting from unopposed estrogen use. If progestins are not tolerated, women who have not had a hysterectomy may be followed closely on an estrogen-only regimen with an annual endometrial biopsy, uterine ultrasonography or progesterone challenges,31 to screen for endometrial hyperplasia.
Postmenopausal women generally dislike cyclic regimens because they mean resumption of menses. Continuous regimens are the most widely accepted. Oral pill (singly or in combination) and combination skin patch (Combipatch) formulations are available. Vaginal bleeding may occur during the first six months of therapy; however, amenorrhea is usually achieved after the first year. Some authors recommend that patients undergo a pretreatment endometrial biopsy to exclude hyperplasia before initiating hormone therapy; others believe this is unnecessary in asymptomatic women and recommend biopsy only if bleeding persists past six months of therapy.32
THE ROLE OF ANDROGENS/TESTOSTERONE
Interest is growing in the use of androgens to enhance well-being during post-menopausal therapy.
Androgenic hormones are produced in the ovaries and the adrenal glands and act on musculoskeletal, nervous, hepatic and vascular tissues. Androgens are known to increase libido and protect bone mass.33,34 However, lipid profiles change when androgens are added to HRT. The HDL fraction decreases with androgen therapy; however, triglyceride concentrations decrease significantly in patients given estrogen-androgen combination therapy. HDL cholesterol and triglyceride levels may be important factors in determining cardiac risk.34
Adverse effects such as virilization are few and can be minimized with reduction of the dosage. Considering the subsequent lipid effect (although without information from long-term studies), it is probably prudent to avoid androgen therapy in women with known low HDL cholesterol levels and established cardiovascular disease.34
Forty percent of women discontinue HRT within eight months of initial therapy or never fill the prescription.35 Adverse effects attributed to HRT include breast tenderness, breakthrough bleeding, cancer (breast or endometrial) and thromboembolic disorders. In addition, there are relative and absolute contraindications to the use of HRT (Table 2). 35,36 The Nurses' Health Study38 reported that risk of breast cancer was highest among women who received HRT for five years or longer (relative risk: 1.45; 95 percent CI; range: 1.01 to 2.09). No elevated risk associated with past use was reported. A collaborative analysis of 51 studies showed an increased risk with duration of therapy (relative risk: 1.35; P = 0.0001), although the excess numbers of breast cancers were small.39 A definitive answer has not emerged from the large number of studies, suggesting that the risk of breast cancer is relatively low. Randomized, controlled trials are needed, and the Women's Health Initiative may provide more answers.
|Estrogen-responsive breast cancer|
|Undiagnosed abnormal vaginal bleeding|
|Active thromboembolic disease|
|History of malignant melanoma|
|Chronic liver disease|
|Previous thromboembolic disease|
Many herbal substances and similar products have been suggested as therapeutic agents in managing menopause, but most lack scientific proof of efficacy.
Natural progesterone, present in yam root, is touted as a remedy for premenstrual and menopausal symptoms. The natural ingredient, disogenin, is not well absorbed orally, and special compounding into a topical cream is necessary. The standard dosage is 40 to 1,000 mg per day of the 1.5 or 3.0 percent topical formulation, applied twice daily to areas with soft tissue (e.g., abdomen, inner thighs). It is also available in an oral micronized form, Prometrium, and considered to have no adverse side effects at standard doses.40,41
Soy products contain compounds known as isoflavones (natural phytoestrogens), which are 500 to 1,000 times weaker than endogenous estrogen. Soy protein appears to be effective in reducing hot flushes, bone loss and total and LDL cholesterol levels. It may also inhibit the growth of different cancer cell lines in vitro and in vivo.42 Food sources include soy nuts, soy milk and tofu.
Several other natural substances have been used to treat menopausal symptoms. These substances include vitamin E, which is thought to stabilize estrogen levels; black cohosh (Cimicifuga racemosa), marketed in the United States as Remifemin (standard dosage: 40 mg per day), thought to suppress luteinizing hormone; and Chasteberry (Vitex agnuscastus), which may decrease prolactin. None of these products has been examined or has proved effective in well-designed clinical trials. Other substances, such as dong quai (Angelica sinensis) and licorice root (Glycyrrhiza glabra) are not considered helpful. No herbal derivative has been shown to be effective in the prevention or treatment of osteoporosis.43
Adequate dietary calcium intake is essential, and supplementation is helpful if dietary sources are inadequate. Total calcium intake should approximate 1,500 mg per day, which usually requires supplementation.
Mounting evidence suggests that vitamin D deficiency may be more prevalent than previously believed. Vitamin D supplementation (400 to 800 IU per day), in addition to calcium supplementation, is recommended for women who cannot spend 30 minutes per day in the sun.44
Several lifestyle approaches may be recommended for the management of menopausal symptoms in general (Table 3). Most are common-sense recommendations that apply to a healthy lifestyle.
|High fiber||Decreases CAD risk|
|Low fat||Improves cholesterol profile|
|Rich in antioxidants||May decrease hot flushes and other menopausal symptoms|
|Increased intake of soy products|
|Cardiovascular||Decreases CAD risk|
|Weight-bearing||Improves cholesterol profile|
|Strengthening||Decreases osteoporosis risk, decreases risk of falls, may decrease hot flushes, may improve depressive symptoms, aids sleep, helps prevent weight gain|
|Smoking cessation||Decreases CAD risk, decreases osteoporosis risk, may decrease hot flushes|
|Decrease alcohol intake||May decrease hot flushes, decreases osteoporosis risk|
|Maintain regular sexual activity||May decrease vaginal dryness, may improve depressive symptoms|
|Daily sunlight||May improve depressive symptoms, decreases osteoporosis risk|
|Relaxation and stress reduction||Decreases CAD risk, may improve depressive symptoms|
A woman's current health status, personal health risks and beliefs should guide the management of symptoms and health risks related to menopause. The goals of therapy and the risks and benefits of the various treatment options should be presented and discussed. On average, the incidence of heart disease far outpaces the risk of breast cancer (a 1 in 2 versus 1 in 8 chance, respectively); but clearly, the fear of breast cancer emerges as a more powerful influence in the decision-making process for many women. Although breast cancer may claim 43,000 lives per year, coronary artery disease claims 223,000 lives and hip fractures claim 65,000 lives annually.45
In a model to assess the impact of HRT on life expectancy based on the risks of coronary artery disease, hip fracture and breast cancer, the benefit of HRT outweighed the risk of breast cancer in nearly all women. However, long-term HRT was not recommended for women at low risk for coronary artery disease or at high risk for breast cancer.45 Despite the HERS results showing no benefit from HRT in secondary prevention of cardiovascular disease, the recommendation of HRT for primary prevention of coronary artery disease is probably still prudent.46
For women interested in taking herbal remedies for the management of menopausal symptoms, it is important to provide basic medicinal information about these agents. Much of the data are published in German and gathered from studies performed in the 1960s. Patients should become familiar with each herb chosen, including its actions and side effects. Some herbs can cause harmful reactions such as severe diarrhea, allergic reactions, hallucinations and liver toxicity.
Many options are available for managing the symptoms and long-term risks associated with menopause. Ultimately, the available treatment choices may allow individualization of a therapeutic plan to manage menopause.