The Menopausal Patient and Hormone Replacement Therapy

Objectives

  1. Discuss the use of hormone replacement therapy for hot flashes and osteoporosis.
  2. Be familiar with new data on the effects of HRT on heart disease.
  3. Have increased knowledge about the risks of hormone replacement therapy.
  4. Be familiar with currently available hormone replacement therapy regimens.
Introduction

We live in a society that is slowly getting older. Two hundred years ago, 30% of women lived long enough to reach menopause, whereas 90% of today's women will experience the climacteric.1 Although menopause is not a disease, it is a relatively estrogen-deficient state. There are many consequences of a relative lack of estrogen that may affect health. Estrogen replacement therapy (ERT) and combination estrogen and progesterone therapy, also known as hormone replacement therapy (HRT), may ameliorate some adverse effects, but may in turn increase other risks.

Menopause is diagnosed by the findings of at least 6 months of amenorrhea in a woman over age 40 or amenorrhea combined with a FSH level above 40 pg/ml. Normal women experience ovarian failure at a mean age of 51 years, with 95% becoming menopausal between the ages of 45 to 55 years.2 Estrogen is the most effective treatment available for relief of the menopausal symptoms that many women experience.2

For the past three decades, long-term (>5 years) estrogen and combined estrogen-progestin therapy (HRT) have been routinely prescribed for prevention of coronary heart disease (CHD) and osteoporosis, based upon extensive observational data demonstrating a striking protective effect of estrogen on the heart and bone. However, data from the Women's Health Initiative (WHI) trials showed no cardiovascular benefit and some increase in risk. When considering whether or not to utilize HRT, it is important to weigh how a woman's quality of life may be improved and what risks are increased for her in particular in light of our best current data. Since this is a rapidly evolving field, regular review of the literature is necessary to keep abreast of new knowledge.
 
 

Risks and Benefits

Hot Flashes

Hot flashes occur in about 75% of menopausal women. Along with emotional lability, hot flashes are one of the main perimenopausal symptoms that lead women to seek HRT. Hot flashes typically begin as a sudden sensation of heat centered on the face and upper chest that rapidly becomes generalized. It lasts between two and four minutes, is often associated with profuse perspiration and occasionally palpitations, and is often followed by chills and shivering. Physiologic studies have determined that hot flashes represent thermoregulatory dysfunction; there is inappropriate peripheral vasodilatation with increased digital and cutaneous blood flow and perspiration, resulting in rapid heat loss and a decrease in core body temperature below normal. Hot flashes usually occur several times per day. Many women have profuse perspiration, which can be embarrassing in social situations. Untreated hot flashes usually stop spontaneously in five to six years, but some women continue to have them for many years. The best way to prevent or treat them in women with estrogen deficiency is to administer continuously dosed estrogen. Insomnia is twice as common a complaint in women who have hot flashes, and this problem is also ameliorated with HRT.3

Cardiovascular Disease

The Women's Health Initiative (WHI) is a set of clinical primary prevention trials, including two estrogen-progestin trials, in healthy postmenopausal women ages 50 to 79, which was scheduled to be completed in 2005. 4 However, the continuous conjugated estrogen 0.625 mg and medroxyprogesterone acetate (MPA) 2.5 mg per day versus placebo trial (n=16,000 women) was discontinued early because of an increased risk of breast cancer, CHD, stroke, and venous thromboembolism over an average follow-up of 5.2 years. Although significant benefits in the reduction in risk of fractures and colon cancer also were seen, there was concern that the risks of combined estrogen-progestin outweighed the benefits for many women. (The WHI ERT versus placebo trial in women who had undergone hysterectomy has not been discontinued, since neither an unfavorable nor favorable risk-benefit profile has been observed).4

The rate of coronary events increased with combined estrogen-progestin therapy (39 versus 33 per 10,000 person years, hazard ratio 1.24, nominal 95 percent CI 1.00 to 1.54). 5 Most of the excess was in nonfatal MI, with no differences seen in revascularization procedures, angina, or congestive heart failure. The difference in coronary events developed soon after randomization, with a trend toward a decline in excess risk in years two through five. There were no other predictors of risk, with the possible exception of women with high LDL. Although the combined HRT arm was discontinued early, the authors calculated that it was unlikely that a beneficial effect of HRT on CHD would have been seen in subsequent years.

Concern has been raised by the Heart and Estrogen/Progestin Replacement Study (HERS) secondary prevention trial, a randomized, double-blinded, placebo-controlled trial involving 2763 post-menopausal women with heart disease. 6 At 6.8 years, continuous estrogen-progestin therapy did not reduce the risk of CHD events in women with established CHD (HR 0.99, 95% CI 0.84 to 1.14). It showed that in the first year of ERT, there is an increased risk of thromboembolic events, but after several years of therapy, a favorable pattern of CHD events developed. Similar data was obtained on reanalysis of Coronary Drug Project. 7 This data is tempered by the findings of Grodstein et al (Nurses Health Study), who found that women who had cardiovascular disease risk factors (but not acute events) had a 49% decrease in deaths from all causes with the use of HRT. 8 Also, in a long-term continuation of the Nurses Health Study, Grodstein et al found that the rate of second events was lower in current users (relative risk, 0.38). 9

Psaty et al attempted to assess whether prothrombotic mutations modify the association between HRT use and incidence of first myocardial infarction. In their population-based, case-control study, they found that hypertensive women with the prothrombin 20210 G-->A variant had an increased risk for MI (OR = 4.32), and there was also a significant interaction between use of HRT and presence of the prothrombin variant on risk of MI (OR = 10.9). No interaction was found for the factor V Leiden mutation. 7

Stroke

In the WHI, a 31% increase in stroke risk was seen with combined estrogen-progestin use compared with placebo (intention-to-treat HR 1.31, 95% CI 1.02 to 1.68). The hazard ratios for ischemic and hemorrhagic stroke were 1.44 (95% CI 1.09 to 1.90), and 0.82 (95% CI 0.43 to 1.56), respectively. 10 Excess risk was seen in all age groups, and was independent of other known risk factors for stroke. Two large longitudinal cohort studies examined mortality resulting from stroke and found reductions of 47% and 63% in ERT/HRT users compared to never-users. 11, 12 Two studies that assessed stroke incidence showed reductions of 30% or more in ever-users compared to nonusers and never-users. 12, 13 No protection against stroke was found in current ERT/HRT users compared to never-users in the Nurses' Health Study, whose population differed from those of the other cohort studies in that it included a large number of younger women. 14

Venous Thromboembolism

There is clear evidence that venous thromboembolic events are more frequent among HRT users than nonusers. Several studies conducted during the 1990s, in addition to the HERS trial, demonstrate that the risk of venous thromboembolism is increased approximately 3- to 4-fold among current users of ERT/HRT. The increase in risk is greatest during the first year of ERT/HRT use and decreases with longer use. However, the attributable risk is low - about one additional case of venous thromboembolism in 5000 users per year. 15 In the HERS trials, the rate of venous thromboembolism increased with HRT (34 versus 16 per 10,000 person-years, HR 2.11, unadjusted 95% CI 1.58 to 2.82). 10 The increase in risk was similar for both deep vein thrombosis and pulmonary embolism.

Pulmonary embolism is a more serious event that can occur after venous thrombosis. A 1976 prospective study assessed the risk of pulmonary embolism in a cohort of 112,593 women aged 30 to 55 years, who were sent health questionnaires every 2 years until 1992. 16 Compared to never-users, it was found that current ERT/HRT users had an increased adjusted relative risk of primary pulmonary embolism of 2.1 (95% CI, 1.2-3.8). However, there was no increased risk associated with past use. The implications of a twofold increase in risk of pulmonary embolism for current ERT/HRT users aged 50 to 59 years is only about 5 additional cases per 100,000 person-years. A Cochrane Database evidence-based review found that current use of oral estrogen as HRT is associated with a 2- to 3-fold increased risk of venous thromboembolism. However, the attributable risk remains low, and this harmful effect must be weighed against the potential benefits of treatment. 17

Breast Cancer

An increase in the incidence of breast cancer has long been a concern with HRT. In the past, there have been conflicting results from many of the studies on HRT and breast cancer, and studies have shown both an increased and a decreased risk of cancer. One well-controlled, large meta-analysis found that patients who used HRT at least 5 years had a relative risk of 1.35 (or 12 extra cases of breast cancer with 20 years use per 1000 women). This effect disappeared after 5 years of non-use. 18 Another large cohort study found a breast cancer relative risk of 1.2 for estrogen use and a 1.4 relative risk with estrogen and progestin use. They also found the relative risk increased 0.01 per year for estrogen use and 0.08 per year of estrogen and progestin use. 19 This data was confirmed by the Nurses' Health Study. 14 The risk of invasive breast cancer in the WHI was significantly increased with combined hormone replacement at an average follow-up of 5.6 years (HR 1.24, unadjusted 95% CI 1.01 to 1.54). 20 The evidence is strong enough to state that a small but real increase in the incidence of breast cancer occurs with the use of ERT and HRT.

Osteoporosis

The strongest evidence of long-term physical benefits of HRT lies in its prevention of osteoporosis. Estrogen status has been shown to be more related to osteoporosis than most commonly measured lifestyle factors. 21 HRT stops the excessive loss of bone matrix that occurs in low estrogen states and may actually reverse bone loss. 22 Continued bone loss and risk of vertebral and hip fractures are significantly reduced with HRT, and bone loss resumes upon discontinuation of therapy. 23 It is believed to act mainly by inhibition of osteoclastic activity, but also may down-regulate proteins necessary for osteoclastic formation. 24 The greatest benefit is obtained in the first 5 to 7 years postmenopause. 25 However, ERT begun after age 60 and continued offers significant bone-conserving benefit. 26 HRT appears to provide bone-saving similar to ERT. 27 Estrogen also seems to decrease the bone loss associated with thyroid hormone replacement therapy. 28 Low-dose HRT (0.3 mg/d CEE and 2.5 mg/d MPA) may be as beneficial as higher doses. 29 In the WHI trial, the risk of osteoporotic fracture was reduced at the hip (HR 0.67, unadjusted 95% CI 0.47 to 0.96) and at the vertebrae and wrist (HR 0.65, unadjusted 95% CI 0.46 to 0.92; and HR 0.71, 95% CI 0.59 to 0.85, respectively). 30

Colorectal Cancer

The WHI 4 and a large meta-analysis 31 showed a significant reduction in colorectal cancer (6 fewer colorectal cancers per 10,000 person-years). Data from the Nurses' Health Study showed that women who received estrogen had a relative risk of 0.65 for the development of colorectal cancer. 32 This protective effect remained even after women who reported having screening sigmoidoscopy were excluded. One possible explanation for the protective role of estrogen is suggested by the finding of increased microsatellite instability in the colon tumors of women who had no history of hormone use near the time of their diagnosis. 33 In comparison, estrogen may not prevent recurrent polyp formation. This was suggested in a subset analysis from the National Polyp Prevention Trial, a randomized dietary intervention study of individuals with colorectal adenomas; there was no overall reduction in adenoma recurrence in patients taking HRT. 34

Ovarian Cancers

A nonsignificant increase in the risk of ovarian cancer was observed in the WHI with combined estrogen-progestin therapy (HR 1.6, 95% CI 0.8 to 3.2; 42 versus 27 cases per 100,000 person-years in the hormone and placebo groups, respectively). 35 There were no differences in the distributions of tumor grade, stage, or histology. Because of the small number of ovarian cancer cases and the limited precision in estimating effects in the trial, the authors concluded that these results should not affect a woman's decision to take HRT for symptomatic relief. A meta-analysis of studies (mostly case-control studies) found a small but significant increase in the relative risk of ovarian cancer (relative risk 1.27) in postmenopausal women who had taken estrogen for more than 10 years. 36 A prospective cohort study of over 200,000 women found an increase risk in ovarian cancer mortality with ten or more years of unopposed estrogen therapy. 37 In a second cohort study of over 44,000 women, unopposed estrogen for more than 10 years was associated with an increased risk of ovarian cancer (RR for 10 to 19 years of use 1.8; 95% CI 1.1 to 3.0). Combined estrogen-progestin therapy was not associated with any increase in risk, although the analysis was limited by the small number of ovarian cancer cases in the treated women. 38 The absolute risk of ovarian cancer with estrogen therapy is small.

Systemic Lupus Erythematosus

Estrogen appears to increase the risk of developing systemic lupus erythematosus. 39 A report from the Nurses' Health Study found a relative risk of 2.5 for current estrogen therapy and a nonsignificant risk of 1.8 for past estrogen therapy, compared with women who had never received estrogen. 40 The risk was related to the duration of estrogen therapy. On the other hand, a small controlled study of 16 postmenopausal women with systemic lupus erythematosus who were treated with estrogen found that flares of the disease were no more frequent than in women not taking estrogen. 41

Uterine Leiomyoma

Use of hormone replacement therapy in the postreproductive years may cause some women with leiomyomas to continue to have symptoms after menopause. The risk of symptoms may depend, in part, on the location of the fibroid and type of estrogen preparation. A systematic review including five randomized controlled trials 42 and subsequent prospective study 43 found that hormone replacement therapy caused myoma growth, but this typically occurred without clinical symptoms. The presence of leiomyomas is not a contraindication to hormone replacement therapy nor associated with new symptomatic fibroids in most women.

Endometrial Cancers

Treatment of postmenopausal women with estrogen alone increases the risk of endometrial hyperplasia and carcinoma. Within one year, endometrial hyperplasia can be demonstrated in 20% to 50% of women receiving unopposed estrogen. 44, 45 Furthermore, multiple case-control and prospective studies have shown an increased incidence of endometrial carcinoma with long-term unopposed estrogen, with the relative risk ranging from 3.1 to 15. 46 - 48 The risk of endometrial hyperplasia is not reduced by cyclic estrogen administration. 45 While the risk of both localized and widespread endometrial cancer is increased with long-term unopposed estrogen, the tumors that develop may be less aggressive, as survival is better in women with cancers associated with estrogen therapy. 49 In a dose-response study, lower doses of estrogen (esterified estrogens 0.3 mg daily) for two years did not increase the incidence of endometrial hyperplasia compared with no estrogen (1.7% in both groups), while doses of 0.625 and 1.25 mg were associated with higher rates of disease, 28 and 53%, respectively. 49 However, when a low-dose (0.3 mg per day of conjugated equine estrogens) was given for longer than eight years, there was a nine-fold increased risk of endometrial cancer. 50

Adding 10 to 14 days of a cyclic or continuous progestin to estrogen actually lowers the risk of endometrial hyperplasia and carcinoma below that of non-estrogen users. 35, 44, 51, 52 In the WHI, more women in the HRT group required endometrial biopsies to assess vaginal bleeding (33% versus 6% for placebo), but there was no significant difference in endometrial cancer risk between the two groups (HR 0.81, 95% CI 0.48 to 1.36). 35 In the PEPI trial, combined estrogen-progestin therapy led to marked reductions in the incidence of simple (0.8% versus 27.7%), complex (0.8% versus 23.7%), and atypical hyperplastic (0 versus 11.8%) endometrial lesions. 52 In the PEPI trial, cyclic progestin (when given at least 12 days per month) was as effective as continuous low-dose progestin. 52, 53 Shorter duration progestin therapy (<10 to 12 days) may be less protective. 48, 53 Studies show no increase of recurrences of endometrial cancer (in remission) with estrogen therapy. 17

Cognitive Function and Dementia

Although some epidemiologic studies suggested that estrogen may preserve cognitive function and prevent dementia, data from the WHI do not support these observations. The WHI Memory Study (WHIMS), an ancillary study of the WHI, assessed annual MMSE scores in 4532 postmenopausal women who were over age 65 and free of probable dementia at baseline. After a mean follow-up of approximately four years, no significant improvement in global cognitive function was seen with combined estrogen-progestin therapy compared with placebo. 54 However, more women in the HRT group had substantial and clinically important declines in MMSE total scores compared with placebo (6.7% versus 4.8%, respectively). Although these data rule out any global cognitive benefits of HRT in older, non-demented, postmenopausal women, the possibility of domain-specific cognitive benefits with HRT has not been ruled out. Combined estrogen-progestin therapy also did not prevent all-cause dementia. 55 Current short-term (up to one year) clinical trials of oral estrogen indicate that hormone replacement therapy is not an effective treatment for Alzheimer's disease.

Type 2 Diabetes Mellitus

In a post hoc analysis from the HERS trial, a secondary prevention of CHD study, 734 of 2783 women were diabetic at baseline; the remaining 2029 women (who were normoglycemic or had impaired glucose tolerance) were followed for the development of type 2 diabetes for an average of four years. 56 The cumulative incidence of type 2 diabetes was 6.2% in the HRT group compared with 9.5% in the placebo group (RH 0.65; 95% CI 0.48 to 0.89). Results were still significant after adjustment for variables such as body mass index, weight change, and waist circumference. The number needed to treat to prevent one case of diabetes was 30 (CI 18 to 103). Although combined HRT appeared to reduce the risk of type 2 diabetes mellitus, this effect is insufficient to recommend HRT as a diabetes prevention strategy in women with CHD. However, in a prospective observational study of 19,898 nurses aged 45 and over completing a questionnaire on lifestyle and use of hormone replacement therapy in 1993, Løkkegaard et al, found that current HRT users with diabetes had an increased risk of death (3.2, 1.4 to 7.5), ischaemic heart disease (4.2, 1.4 to 12.5), and myocardial infarction (9.2, 2.0 to 41.4) compared with never-users with diabetes. 57

Urinary Tract Infections

A randomized, controlled trial found that intravaginal estrogen decreased the risk of recurrence in patients with frequent urinary tract infections. This benefit may be due to normalization of the vaginal flora. 58 However, in the Heart and Estrogen/Progestin Replacement Study (HERS), a four-year study of 2763 postmenopausal women, the frequency of urinary tract infections was not decreased in those receiving estrogen compared with placebo. 59 Thus, while estrogen does not appear to reduce the frequency of urinary tract infections, it might reduce the risk of recurrence in those with frequent infections.

Urinary Incontinence

Unopposed estrogen may improve sphincter tone and bladder control in women with stress urinary incontinence, 60, 61 although some studies have failed to demonstrate this benefit. 62, 63 In the HERS trial, daily oral estrogen plus progestin increased the number of incontinent episodes when compared with placebo. 64 This issue was best addressed in a Cochrane review meta-analysis, which found estrogen therapy was an effective treatment for urinary incontinence. Approximately 50% of women treated with estrogen were cured or improved versus 25% of those taking placebo. 65 The benefit was slightly greater in women with urge rather than stress incontinence. However, combined therapy with estrogen and progestin did not improve incontinence and sometimes worsened symptoms. The effects of estrogen type, dose, or route of administration could not be addressed due to limited data. Because of the risks of prolonged administration of unopposed estrogens to women with an intact uterus, oral estrogen is not a practical long-term approach to treatment. However, vaginal estrogen is reasonable.

Urogenital Atrophy

Another common postmenopausal problem is urogenital atrophy. Sexual activity may continue late into life, and changes due to relative estrogen deficiency can impede sexual functioning. The vaginal epithelium is thicker, is more elastic, has greater lubricating ability, and has more glycogen stores under the influence of estrogen. 66 Atrophic vaginal or cervical epithelium may also cause abnormal Papanicolaou smears. Colposcopists will often prescribe estrogen for 2 to 4 weeks before a colposcopy in order to "normalize" the epithelium prior to the examination. This is generally felt to be safe, even if dysplasia or cancer is present, because the duration of therapy is short and these lesions do not express any more estrogen receptors than a normal cervix. 67

Depression

Emotional lability, depression, and loss of a sense of well-being are common during the perimenopausal period. A randomized, controlled trial in asymptomatic postmenopausal women found that estrogen therapy may improve mood and decrease mean depression scores, even in women with no menopausal symptoms. 68 In a study of 50 perimenopausal women with major depression, dysthymia, or minor depressive disorders, transdermal estradiol (0.1 mg for 12 weeks) resulted in a remission of depression in 68% of patients compared with only 20% receiving placebo (p = 0.001). 69

Gallbladder Disease

Estrogen therapy may be associated with an increased risk of gallbladder disease. In the Nurses' Health Study of almost 55,000 postmenopausal women, those currently taking estrogen were at an increased risk of cholecystectomy (relative risk 2.1) compared with never-users. 70 The risk of cholecystectomy increased with increasing duration of hormone use and higher doses of estrogen. The risk decreased substantially in women who had discontinued estrogen within the preceding one to three years (relative risk 1.6); a small but significant risk persisted for women who had stopped taking estrogen five or more years previously (relative risk 1.3). These observations are supported by the HERS trial. 71 After an average follow-up of four years, there was a marginally significant increase in biliary tract surgery in the treatment group (38%; p = 0.05). The authors calculated that for every 185 women receiving HRT, one additional woman had biliary tract surgery per year.

Bronchospasm

Estrogen therapy may be associated with the onset of asthma. In the Nurses' Health Study, for example, the relative risk of new-onset asthma in 36,094 postmenopausal women followed for ten years was significantly greater in women taking estrogen as compared with those who were not (relative risk 1.5). 72 This increased risk was dose-related; it was statistically significant only at a dose greater than 0.625 mg/day of conjugated estrogens, probably because of the small numbers of women studied. Data are conflicting on whether estrogen therapy in postmenopausal asthmatic women causes a worsening of airway function.

Other

Estrogen may reduce the risk of osteoarthritis. In a cross-sectional study of over 4,000 women, those receiving long-term estrogen therapy (>=10 years) had a 40% lower risk of hip osteoarthritis than those who had not received estrogen. 73 Similar results were found in a prospective analysis of the Framingham cohort. 74

With billions of dollars spent each year on antiaging products, it is important to note any drug effect that improves skin thickness. Estrogen preserves the thickness and the collagen content of skin in postmenopausal women 75, 76 and, via the release of transforming growth factor-beta, accelerates wound healing. 77 In addition, estrogen preserves teeth. 78, 79 The relative risk for edentia was only 0.6 in postmenopausal women taking estrogen as compared with those who did not, perhaps related to less osteoporosis of the jaw. 78

The risk of cataract formation appears to be decreased by long-term estrogen therapy. In the Framingham Heart Study, postmenopausal women who had taken estrogen for 10 years or longer had a 60% reduction in risk of nuclear lens opacities compared with control women. 80 In a second study, subcapsular as well as nuclear opacities were decreased by 70% and 80%, respectively, in women taking estrogen. 81 ERT may be associated with dry eye syndrome. 82 Analysis of the Framingham studies found a reduction in the risk of lens opacities with postmenopausal estrogen use. 83

Risks and Benefits Summary

It should be emphasized that the absolute risk of an adverse event (breast cancer or cardiovascular complication) occurring in an individual on the estrogen-progestin regimen in the WHI was extremely low (19 additional events per year per 10,000 women with HRT compared to placebo). A meta-analysis of the risks and benefits of HRT (done since the release of the WHI data) supports the WHI findings. 84

Patient Selection

For perimenopausal women with symptoms, estrogen is usually given short-term (six months to four or five years), with the goal of eventually tapering and discontinuing the estrogen. Common possible side effects include withdrawal bleeding with cyclic dosing, spotting during the first 3 to 6 months with combined continuous therapy, mastalgia, edema, and abdominal bloating.

Contraindications to HRT include pregnancy, undiagnosed abnormal genital bleeding, impaired liver function, acute thromboembolic disease, history of thromboembolic disease with hormone use, and a history of breast or endometrial carcinoma. Estrogen is contraindicated in women with a history of endometriosis, because of possible reactivation of the disease. It is also not recommended in women with active gallbladder disease and should be used with caution in patients with uterine leiomyomata or a history of menstrual migraines. Caution should also be exercised in patients with chronic liver disease, severe hypertriglyceridemia, and previous thromboembolic disease.  
 

Dosage and Administration

Until recently, the most commonly used combined continuous estrogen-progestin regimen in the United States was low-dose medroxyprogesterone (MPA) (2.5 or 5 mg daily), given each day with estrogen (conjugated estrogens 0.625 mg or its equivalent). This regimen is associated with a low risk of endometrial hyperplasia, 44, 85 prevents osteoporosis, and has the added advantage of inducing amenorrhea in 60% to 75% of women after more than six months of treatment. 86 Now, many providers are pushing the dose as low as possible to minimize risks associated with therapy. Table 1 gives forms commonly available in the United States.

Estrogens from animal sources have been widely available in oral form for many years. Now oral forms derived from plant sources and synthesized denovo also are available. Typical dosages are shown in Table 1. Oral estrogens were first derived from pregnant mares' urine, which continues to be a major source. Some animal rights groups object to conjugated equine estrogens on the grounds that collection of the mares' urine is cruel to the animals. However, most of their objections are based on old case reports and emotional arguments. Canadian animal welfare groups and veterinary groups dispute the position of PETA and its allies. 87

Estrogen - If a women has a uterus, unopposed estrogens are associated with endometrial hyperplasia and carcinoma, and so should be given with a progestin. In women who have had a hysterectomy, progestins need not be added and unopposed estrogens are most commonly used. In the past, estrogens were given for 25 days each month, with a 5-day drug-free period to simulate a "normal cycle." However, the amount of estradiol in the blood from HRT is usually below the amount present during menses in a premenopausal woman. Today, many authors advocate the use of continuous estrogen therapy because the there are no proven benefits to the drug-free intervals, the regimen becomes more complex and harder to comply with, and symptoms may recur during this period. 88

Intravaginal estrogens are effective in relieving local symptoms of estrogen deficiency, but do not have a major effect on other parameters. Short-term application of intravaginal estrogens after an abnormal Pap smear is often used to "normalize" the cervical epithelium. A novel approach is the use of an estradiol vaginal ring (Estring), which is placed high in the vagina and changed every 90 days. Studies indicate that enough estrogen is absorbed through the vagina to reduce vasomotor symptoms and improve vaginal conditions. 89

 
Table 1. Menopausal Replacement Therapy Commonly Available in the United States.
Name Estrogen Progestin/Androgen

Doses

Alora Patches estradiol none 0.05mg, 0.075mg, 0.1mg/24hr
Cenestin Tabs conjugated estrogens none 0.3mg, 0.625mg, 0.9mg, 1.25mg
Climara, Esclim patch* estradiol none 0.025mg, 0.05mg, 0.075mg, 0.1mg, 0.0375mg/24hr
Climara PRO patch estradiol levonorgestrel 0.045mg + 0.015mg/day
CombiPatch patches estradiol norethindrone acetate 0.05-0.14mg/day, 0.05-0.25mg/day
Estrace tabs* Estradiol micronized none 0.5mg, 1mg, 2mg
Estrace vaginal cream estradiol none 0.1mg/gm
Estraderm patch* estradiol none 8 0.05mg, 0.1mg/24hr
Estratest tabs esterified estrogens methyltesterone 1.25-2.5mg, 0.625-1.25mg
Estring vaginal ring estradiol none 2mg
estropipate tabs estropipate none 0.75mg, 1.5mg, 2.5mg
Femhrt 1/5, Activella tabs estradiol norethindrone 1-5 mg-mcg
Femring vaginal ring estradiol none 0.05mg, 0.1mg/day
Menest esterified estrogens none 0.3mg, 0.625mg, 1.25mg, 2.5mg
Ogen* estropipate none 0.625mg, 1.25mg, 2.5mg
Prefest estradiol norgestimate 1mg, then 1mg+0.09mg
Premarin cream conjugated estrogens none 0.625mg/gm
Premarin tabs conjugated estrogens none 0.3mg, 0.45mg, 0.625mg, 0.9mg, 1.25mg
Premphase 28 tabs conjugated estrogens medroxyprogesterone 0.625-5mg
Prempro 28 tabs conjugated estrogens medroxyprogesterone 0.3-1.5mg, 0.45-1.5mg, 28 0.625-5mg, 28 0.625-2.5mg
Vagifem vaginal tab estradiol none 0.025mg
Vivelle, Vivelle-dot patches estradiol none 0.025mg, 0.0375mg, 0.05mg, 0.075mg, 0.1mg/24hr
Aygestin tabs none norethindrone 5mg
Prometrium tabs none micronized progesterone 100mg, 200mg
Provera tabs none medroxyprogesterone 2.5mg, 5mg, 10mg
*Generic available

Progesterone - Regardless of the regimen, the lowest dose of progestin possible that still affords protection against endometrial hyperplasia should be used to minimize the adverse cardiovascular effects. In the perimenopausal period (2 years before and after menses cessation), cyclic progestins given for 10 to 14 days each cycle are the preferred method of therapy in practice. Beyond the perimenopausal period, when endogenous estrogen production has reached baseline, progestins can be given cyclically or continuously every day. Although spotting is common during the first six months of combined continuous HRT, 95% of users will experience amenorrhea in 1 year. 90 If a woman on a continuous combined therapy experiences uterine bleeding after cessation of menses, an endometrial biopsy is mandatory. 88 Progesterone synthesized from yams, which is identical to endogenous human progesterone, is now available in a micronized capsule. Norethendrone acetate and norgestimate are also available in combined regimens. Common HRT regimens are shown in Figure 1.

 

The FDA approved a pulsed-progestin HRT regimen that consists of Estradiol 1 mg for 3 days, followed by Estradiol 1 mg plus 0.09 mg norgestimate for 3 days, and continuously repeated (Ortho-Prefest). This regimen provides excellent endometrial protection and vasomotor relief, with cessation of bleeding rates comparable to other HRT regimens at lower overall doses of hormones. 91, 92 A new transvaginal, "natural," polycarbophil-based, progesterone gel (Crinone 8%) is being studied for hormone replacement therapy. It was found to be an effective and well-tolerated option for hormone replacement therapy in women with secondary amenorrhea. 93

Androgens Interest is growing in the role of androgen replacement for postmenopausal patients. Androgenic hormones are produced in the premenopausal ovaries and the adrenal glands. Androgens increase libido and protect bone mass, but also decrease HDL cholesterol. 94, 95 Estrogen-androgen combinations provide relief of somatic symptoms at a lower dose of estrogen. 96 Adverse effects such as virilization are few and can be minimized with reduction of the dosage. Watts found that combination estrogen-androgen therapy prevents postmenopausal symptoms, increases bone density, does not affect LDL or blood pressure, and decreases HDL. There were no adverse effects or liver problems in 66 patients. 95 The combination also significantly improved sexual sensation and desire in 20 women in a blinded crossover trial, 97 and the levels of sexual arousal and intercourse were significantly higher in women receiving the combination. Sexual desire, satisfaction, and frequency in postmenopausal women taking hormonal therapy were improved significantly by combined estrogen-androgen therapy. 97 In a double-blind randomized trial involving 4 months of treatment with 0.625 mg of esterified estrogens (n = 111) or the combination of 0.625 mg of esterified estrogens and 1.25 mg of methyltestosterone (n = 107), Lobos et al. found significantly improved sexual functioning in women receiving the combination of esterified estrogen and methyltestosterone. 98 A literature review by Gelfand et al found that most of the concerns about androgen therapy did not apply to the lower doses used in women. 99 It is probably prudent to avoid androgen therapy in women with low HDL cholesterol levels or cardiovascular disease. Definitive prospective data on the risks and benefits of this therapy are lacking.

 

Dosing for Androgens

Combination products (Estratest or Estratest hs)

Methyltestosterone (Android), 1.25 to 2.5 mg Qd

Micronized oral testosterone, 5 mg Bid

Testosterone proprionate 2% in petroleum applied daily to every other day

 

Androgens alone may be used to treat vasomotor symptoms. The combination of estrogen and testosterone is more commonly given (Table 1). DHEA has not been found to improve libido or increase the overall sense of well-being, and the available preparations are non-standardized. 100, 101 In women who have undergone oophorectomy and hysterectomy, transdermal testosterone (150 mcg to 300 mcg of testosterone per day) improves sexual function and psychological well-being. 102

Alternative Therapies

Progestin therapy also is effective for hot flashes. MPA 20 mg daily, Depot MPA 150 mg IM every 3 months, norethindrone acetate 10 mg daily, and megestrol acetate 20 mg twice a day have been studied. 103 Oral Prometrium also is used on the theory that the "natural" micronized progesterone has no adverse side-effects. Transdermal progesterone cream may help with hot flashes but is not effective for osteoporosis. 104 Oral progesterones may be effective for osteoporosis. Megestrol acetate (at a dose of 20 to 80 mg/day) decreased the frequency of hot flashes by 85% (versus 21% with placebo). 103 There may, however, be a transient increase in hot flashes for one to two weeks after the initiation of therapy. Weight gain is the major side effect of prolonged therapy. One potential concern is that megestrol acetate has glucocorticoid-like activity, so that adrenal insufficiency can occur after it is discontinued. 103

Biphosphonates such as alendronate (Fosamax) and risedronate (Actonel) are dosed at 35 mg once per week for prevention (osteopenia) and 70 mg once per week for treatment of osteoporosis. These drugs must be taken on an empty stomach. Recent meta-analysis shows treatment with alendronate reduces the risk of nonvertrebral fractures in menopausal women. 106, 107 It is believed to work by binding to bone resorption sites and inhibiting osteoclastic activity. There is evidence that alendronate and HRT may have synergistic effects. 108 Etidronate (Didronel) is another biphosphonate that is FDA-approved for Paget's disease but is sometimes used off-label for osteoporosis.

Raloxifene (Evista) is a selective estrogen-receptor modulator that is now available for prevention and treatment of osteoporosis. At a dose of 60 mg/day, bone density increases by 2.4% in the lumbar spine and hip over a two year period. 109 This effect is slightly less than with estrogen. The MORE (Multiple Outcomes of Raloxifene) trial found a 38% reduction in vertebral fractures in women with prevalent fractures who took raloxifene compared with placebo, and a 52% reduction in those without prior fractures. 110 It decreases LDL and does not affect breast tissue, endometrium, or HDL. It may cause hot flashes and increase the risk of clotting problems. The MORE study found that it reduced the risk of vertebral and nonvertebral fractures and increased bone mineral density compared to placebo. It also significantly reduced the risk of breast cancer (RR=0.3) and DVTs (RR=3.1). 111 It has also been found to decrease the size of uterine leiomyomas. 112 One study found that Raloxifene therapy for 4 years did not significantly affect the risk of cardiovascular events in the overall cohort, but did significantly reduce the risk of cardiovascular events in the subset of women with increased cardiovascular risk. There was no evidence that raloxifene caused an early increase in risk of cardiovascular events. 113 Raloxifene 60 mg/day for up to 30 months is not associated with vaginal bleeding or increased endometrial thickness in postmenopausal women. 114 Raloxifene treatment for three years does not affect overall cognitive scores in postmenopausal women with osteoporosis. 115 Bisphosphonates are favored as first-line therapy for established osteoporosis because they increase bone mineral density more than raloxifene, and some studies suggest that the greater the effect on bone mineral density, the greater the antifracture efficacy.

Calcitonin (Calcimar) 100 units IM or SC daily and (Miacalcin) 200 units IM, SC, or intranasally daily is effective therapy for osteoporosis and particularly for bone pain associated with fractures. It works by inhibiting osteoclastic activity. Nasal calcitonin, for example, increases bone density by 2.5% over a three-year period, 116 and reduces fracture rates (by 48 to 77%). 117, 118 Side effects are related to local nasal irritation and occasional systemic effects such as flushing or nausea. Calcitonin is typically not recommended as first-line therapy for osteoporosis because of its expense, the relative inconvenience of nasal or parenteral administration, frequent side effects, and the possible development of resistance.

Teriparatide (Forteo - recombinant human parathyroid hormone) has been approved for the treatment of osteoporosis in men and post-menopausal women who are at high risk for a fracture. It stimulates new bone formation in patients with osteoporosis by activating osteoblasts. Forteo is supplied in a disposable pen device that can be used for up to 28 days to give once-daily self-administered injections. Forteo is available in a 20 mcg dose and should be taken for a period of up to 24 months. In animal studies, there was an increase in the number of rats developing osteosarcoma. In human studies, no osteosarcomas were reported, but the possibility that humans may face an increased risk of developing this cancer cannot be ruled out. Neer et al, randomly assigned 1637 postmenopausal women with prior vertebral fractures to receive 20 or 40 mcg of parathyroid hormone or placebo, administered subcutaneously by the women daily. New vertebral fractures occurred in 14% of the women in the placebo group and in 5% and 4%, of the women in the 20-microg and 40-microg parathyroid hormone groups. As compared with placebo, the parathyroid hormone increased bone mineral density by 9% to 13% more in the lumbar spine and by 3% to 6% more in the femoral neck. Parathyroid hormone had only minor side effects (occasional nausea and headache). 119

Selective Serotonin Reuptake Inhibitors (SSRIs) relieve the symptoms of vasomotor instability and are considered a first choice by many in women who are not taking estrogen. In one trial, 221 women with a history of breast cancer and vasomotor symptoms were randomly assigned to placebo or venlafaxine (Effexor), at doses of 37.5 mg daily, 75 mg daily, or 150 mg daily. 120 After four weeks of treatment, median hot flash scores were reduced from baseline by 27%, 37%, 61%, and 61% in the four groups, respectively. Mouth dryness, anorexia, nausea, and constipation were significantly more common in the high-dose venlafaxine groups than in the placebo group. In a second trial of 165 postmenopausal patients (only 7.3% with a history of breast cancer) who were randomly assigned to paroxetine controlled release (Paxil CR) (12.5 or 25 mg/day) or placebo, median reductions in hot flash scores were 62.2% and 64.6% in the 12.5 mg and 25 mg paroxetine CR groups versus 37.8% in the placebo group. 121 The beneficial effects were of a lesser magnitude in a study of fluoxetine (Prozac) versus placebo. In a randomized crossover trial, 81 women were assigned to 20 mg/day fluoxetine or placebo for two 4-week periods. Hot flash score decreased by 50% among the women receiving fluoxetine and by 36% in the placebo group. Further improvement in hot flash scores in the fluoxetine group compared with placebo was seen in the second treatment period (p = 0.055). 122

Clonidine might be considered as initial therapy in women with hypertension. It may be given transdermally, starting with a 0.1 mg per day patch, which is left in place for one week. Clonidine may also be given orally in doses of 0.1 to 0.4 mg daily. 123 Combinations of oral clonidine (0.1 to 0.2 mg at night) and the patch are sometimes used to further reduce hot flashes that awaken women from sleep. In one placebo-controlled study, the frequency of hot flashes decreased in 80% of women treated with clonidine versus 36% with placebo. 124 In other studies the drug was less effective. 123 Its side effects, which are dry mouth, dizziness, constipation, and sedation, limit its value. Methhyldopa 500 to 1,000 mg/d also may be used and is twice as effective as placebo in relieving symptoms. Oral clonidine 0.1 mg/day is effective against tamoxifen-induced hot flashes in postmenopausal women with breast cancer. 125

Sildenafil (Viagra). A placebo-controlled study of 51 women by Caruso et al. suggests that sildenafil 25 mg may improve sexual performance of women affected by sexual difficulties. They found improvement in arousal, orgasm, frequency of sexual fantasies, frequency of sexual intercourse, and enjoyment of intercourse improved in the women treated with sildenafil. 126

Gabapentin is FDA-approved for the management of seizure disorders, but has been used off-label for other indications, such as neuropathic pain. It appears to be effective in reducing hot flush frequency. In a randomized, placebo-controlled trial in 59 symptomatic postmenopausal women, gabapentin (900 mg/day for 12 weeks) was more effective than placebo for reducing hot flush frequency (45% versus 29% for gabapentin and placebo, respectively). 127 Results were similar in a pilot study (no placebo arm) of gabapentin (doses increasing from 300 to 900 mg over three weeks) in 20 postmenopausal women. 128

Veralipride is a dopamine antagonist available only in Europe. It was highly effective in a placebo-controlled trial. 129 Total cessation of hot flashes occurred in 63 to 80% of women versus 30% in the placebo group. It has mastodynia and galactorrhea as side effects.

Phytoestrogens from soy compounds and products have been promoted as nonpharmacologic agents to treat vasomotor symptoms; however, results from clinical trials are conflicting. 130 - 134 In a review of 11 randomized clinical trials of soy or isoflavone supplementation, only three of eight trials with at least six weeks of follow-up demonstrated a beneficial effect. 133 However, six weeks is probably not long enough to reliably assess the effect of an intervention on vasomotor symptoms. The one longer-term study (six months) reported no benefit of isoflavone supplements. 134 Soy phytoestrogens may stimulate breast cancer growth, and antagonize the antitumor effect of tamoxifen. 135 Red clover is another source of isoflavones. In a trial of 252 postmenopausal women randomly assigned to receive dietary supplements derived from red clover (which contains some isoflavones not found in soy-derived products, but lacks others that are found in soy products) or placebo for 12 weeks, red clover supplements had no clinically important effect on hot flushes or other menopausal symptoms. 136 The synthetic isoflavone ipriflavone has been shown to prevent bone loss in postmenopausal women. 100 Isoflavone compounds have been shown to increase systemic arterial compliance without having any effect on lipids. 100 However, a well-done study demonstrated that ipriflavone (an isoflavone) does not prevent bone loss or affect biochemical markers of bone metabolism, and it induces lymphocytopenia in a significant number of women. 137

Black cohosh is a widely-used alternative to ERT/HRT to treat menopausal symptoms. Possible side effects include nausea, vomiting, dizziness, visual disturbances, slow heartbeat, and excessive sweating. A meta-analysis in the Annals of Internal Medicine showed that black cohosh may be effective for menopausal symptoms, especially hot flashes, but the lack of adequate long-term safety data (mainly on estrogenic stimulation of the breast or endometrium) precludes recommending long-term use. 133 Black cohosh use has been associated with acute hepatitis. 138

Herbal and Other Therapies. In a recent review in the Annals of Internal Medicine, 10 clinical trials of herbs were identified. There was a suggestion of a modest reduction in frequency of hot flushes with black cohosh, but not with ginseng, dong quai, or evening primrose oil. 133 Vitamin E, acupuncture, wild yam, and progesterone creams also were ineffective. 135 Results from the HOPE trial that prospectively followed 9541 women randomized to placebo or 400iu of Vitamin E for 5 years found no difference between treatment groups in these high-risk women. 139 See: http://dietary-supplements.info.nih.gov/ for additional herb trial information.

Urogenital atrophy may be treated with Replens (water, glycerin, mineral oil, palm oils) or other moisturizers to provide symptomatic relief. Water soluble lubricants such as Astroglide are more effective than lubricants that become more viscous after application, such as K-Y jelly. Kegel exercises, pharmacologic treatments, and pessaries may help with urinary incontinence.

Osteoporosis can be prevented with regular exercise, good diet, avoiding ETOH excess, and not smoking. Calcium - 1000 to1500 mg with 400 to 800 IU of vitamin D daily should be added to most regimens. Much interest has been generated by studies of Parathyroid hormone. Neer et al found that once-daily injections of parathyroid hormone or its amino-terminal fragments increase bone formation and bone mass, and decrease the risk of vertebral and nonvertebral fractures. 140

Regular exercise, good diet, cholesterol control, and non-smoking are always recommended for cardiovascular disease prevention. Regular exercise such as walking has been shown to reduce the risk of stroke in women in a dose-dependent manner. 115 Aspirin every day probably lowers mortality in menopausal women. Oat bran has been shown to lower LDL cholesterol (at a dose of one large bowl a day), but primary outcome studies are lacking. 116 Omega-3 fatty acids, in the form of cold-water fish or supplements of 200 mg/day, may lead to regression of CAD. 117

Conclusion

HRT can offer many benefits to postmenopausal women. A careful discussion of the risks and benefits of HRT is necessary so each patient can weigh the facts for herself. By considering personal disease-risk factors and potential life saving and quality of life benefits, each patient can then make an informed choice.

 

References

1. Marchant DJ. Supplemental estrogen replacement. Cancer 1994; 74:512-7.
2. Belchetz PE. Hormonal treatment of postmenopausal women. N Engl J Med 1994; 330:1062.
3. McKinlay SM, Brambilla DJ, Posner JG. The normal menopause transition. Maturitas 1992; 14:103-15.
4. Risks and benefits of estrogen and progestin in healthy postmenopausal women: Principal results from the Women's Health Initiative randomized controlled trial. JAMA 2002; 288:321.
5. Manson JE, Hsia J, Johnson KC, et al. N Engl J Med 2003; 349:523.
6. Grady D, Herrington D, Bittner V, et al. Cardiovascular disease outcomes during 6.8 years of hormone therapy: Heart and Estrogen/progestin Replacement Study follow-up (HERS II). JAMA 2002; 288:49.5.
7. Psaty BM, Smith NL, Lemaitre RN, Vos HL, Heckbert SR, LaCroix AZ, Rosendaal FR. Hormone replacement therapy, prothrombotic mutations, and the risk of incident nonfatal myocardial infarction in postmenopausal women. JAMA 2001; 285(7):906-13.
8. Grodstein F, Stampfer MJ, Colditz GA, Willett WC, Manson JE, Joffe M, Rosner B, Fuchs C, Hankinson SE, Hunter DJ, Hennekens CH, Speizer FE. Postmenopausal hormone therapy and mortality. N Engl J Med 1997; 336(25):1769-75.
9. Grodstein F, Manson JE, Stampfer MJ. Postmenopausal hormone use and secondary prevention of coronary events in the Nurses' Health Study. A prospective, observational study. Ann Intern Med 2001; 135(1):1-8.
10. Wassertheil-Smoller S, Hendrix SL, Limacher M, et al. Effect of estrogen plus progestin on stroke in postmenopausal women: the Women's Health Initiative: A randomized trial. JAMA 2003; 289:2673.
11. Paganini-Hill A, Ross RK, Henderson BE. Postmenopausal oestrogen treatment and stroke: A prospective study. BMJ 1988;297:519-22.
12. Finucane FF, Madans JH, Bush TL, Wolf PH, Kleinman JC. Decreased risk of stroke among postmenopausal hormone users: Results from a national cohort. Arch Intern Med 1993;153:73-9.
13. Falkeborn M, Persson I, Terént A, Adami H-O, Lithell H, Bergström R. Hormone replacement therapy and the risk of stroke: Follow-up of a population-based cohort in Sweden. Arch Intern Med 1993;153:1201-9.
14. Stampfer MJ, Colditz GA, Willett WC, Manson JE, Rosner B, Speizer FE, et al. Postmenopausal estrogen therapy and cardiovascular disease: Ten-year follow-up from the Nurses' Health Study. N Engl J Med 1991;325:756-62.
15. Daly E, Vessey MP, Hawkins MM, Carson JL, Gough P, Marsh S. Risk of venous thromboembolism in users of hormone replacement therapy. Lancet 1996;348:977-80.
16. Grodstein F, Stampfer MJ, Goldhaber SZ, Manson JE, Colditz GA, Speizer FE, et al. Prospective study of exogenous hormones and risk of pulmonary embolism in women. Lancet 1996;348:983-7.
17. Oger E, Scarabin PY. Assessment of the risk for venous thromboembolism among users of hormone replacement therapy. Drugs and Aging 1999; 14(1):55-61.
18. 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; 350:1047-59.
19. Schairer C, Lubin J, Troisi R, Sturgeon S, Brinton L, Hoover R. Menopausal estrogen and estrogen-progestin replacement therapy and breast cancer risk. JAMA 2000; 283:485-91.
20. Chlebowski, RT, Hendrix, SL, Langer, RD, et al. Influence of estrogen plus progestin on breast cancer and mammography in healthy postmenopausal women: The Women's Health Initiative Randomized Trial. JAMA 2003; 289:3243.
21. Landin-Wilhelmsen K, Wilhelmsen L, Bengtsson B. Postmenopausal osteoporosis is more related to hormone aberrations than to lifestyle factors. Clin Endocrinol 1999; 51:387-94.
22. Effects of hormone therapy on bone mineral density. Results from the postmenopausal estrogen/progestin interventions (PEPI) trial. JAMA 1996; 276:1389-96.
23. Lafferty FW, Fiske ME. Postmenopausal estrogen replacement: A long-term cohort study. Am J Med 1994; 97:66-77.
24. Hofbauer LC, Khosla S, Dunstan CR, Lacey DL, Spelsberg TC, Riggs BL. Estrogen stimulates gene expression and protein production of osteoprotererin in human osteoblastic cells. Endocrinology 1999; 140:4367-70.
25. Felson DT, Zhang Y, Hannan MT, Kiel DP, Wilson PW, Anderson JJ. The effect of postmenopausal estrogen therapy on bone density of elderly women. N Engl J Med 1993; 329:1141-6.
26. Schneider DL, Barrett-Conor EL, Morton DJ. Timing of postmenopausal estrogen for optimal bone mineral density: The Ranchero Bernado study. JAMA 1997; 277:543-7.
27. Speroff L, Rowan J, Symons J, Genant H, Wilborn W. The comparative effect on bone density, endometrium, and lipids of continuous hormones as replacement therapy (CHART study): A randomized controlled trial. JAMA 1996; 276:1397-403.
28. Schneider DL, Barrett-Conor EL, Morton DJ. Thyroid hormone use and bone mineral density in elderly women. JAMA 1994; 271:1245-9.
29. van Staa TP, Wegman S, de Vries F, Leufkens B, Cooper C. Use of statins and risk of fractures. JAMA 2001; 285(14):1850-5.
30. Cauley JA, Robbins J, Chen Z, Cummings SR. Effects of estrogen plus progestin on risk of fracture and bone mineral density: the Women's Health Initiative randomized trial. JAMA 2003; 290:1729.
31. 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.
32. Grodstein F, Martinez ME Platz EA, et al. Postmenopausal hormone use and risk for colorectal cancer and adenoma. Ann Intern Med 1998; 128:705.
33. Slattery ML, Potter JD, Curtin K, et al. Estrogens reduce and withdrawal of estrogens increase risk of microsatellite instability-positive colon cancer. Cancer Res 2001; 61:126.
34. Woodson K, Lanza E, Tangrea JA, et al. Hormone replacement therapy and colorectal adenoma recurrence among women in the Polyp Prevention Trial. J Natl Cancer Inst 2001; 93:1799.
35. Anderson GL, Judd HL, Kaunitz AM, Barad DH. Effects of estrogen plus progestin on gynecologic cancers and associated diagnostic procedures: the Women's Health Initiative randomized trial. JAMA 2003; 290:1739.
36. Garg PP, Kerlikowske K, Subak L, Grady D. Hormone replacement therapy and the risk of epithelial ovarian carcinoma. A meta-analysis. Obstet Gynecol 1998; 92:472.
37. Rodriguez C, Patel AV, Calle EE, et al. Estrogen Replacement Therapy and Ovarian Cancer Mortality in a Large Prospective Study of US Women. JAMA 2001; 285:1460.
38. Lacey JV Jr, Mink PJ, Lubin JH, et al. Menopausal hormone replacement therapy and risk of ovarian cancer. JAMA 2002; 288:334.
39. Meier CR, Sturkenboom MC, Cohen AS, Jick H. Postmenopausal estrogen replacement therapy and the risk of developing systemic lupus erythematosus or discoid lupus. J Rheumatol 1998; 25:1515.
40. Sanchez-Guerrero J, Liang M, Karlson E, et al. Postmenopausal estrogen therapy and the risk for developing SLE. Ann Intern Med 1995; 122:430.
41. Kreidstein S, Urowitz MB, Gladman DD, et al. Hormone replacement therapy in systemic lupus erythematosus. J Rheumatol 1997; 24:2149.
42. Ang WC, Farrell E, Vollenhoven B. Effect of hormone replacement therapies and selective estrogen receptor modulators in postmenopausal women with uterine leiomyomas: A literature review. Climacteric 2001; 4:284.
43. Yang C, Lee J, Hsu S, et al. Effect of hormone replacement therapy on uterine fibroids in postmenopausal women: A 3-year study. Maturitas 2002; 43:35.
44. Woodruff JD, Pickar JH. Incidence of endometrial hyperplasia in postmenopausal women taking conjugated estrogens (Premarin) with medroxyprogesterone acetate or conjugated estrogens alone. Am J Obstet Gynecol 1994; 170:1213.
45. Schiff I, Sela HK, Cramer D, et al. Endometrial hyperplasia in women on cyclic or continuous estrogen regimens. Fertil Steril 1982; 37:79.
46. Henderson, BE. The cancer question: An overview of recent epidemiologic and retrospective data. Am J Obstet Gynecol 1989; 161:1859.
47. Persson I, Adami H-O, Bergkvist L, et al. Risk of endometrial cancer after treatment with estrogens alone or in conjunction with progestogens: Results of a prospective study. BMJ 1989; 298:147.
48. Weiderpass E, Adami HO, Baron JA, et al. Risk of endometrial cancer following estrogen replacement with and without progestins. J Natl Cancer Inst 1999; 91:1131.
49. Chu J, Schweid AI, Weiss NS. Survival among women with endometrial cancer: A comparison of estrogen users and nonusers. Am J Obstet Gynecol 1982; 143:569.
50. Genant HK, Lucas J, Weiss S, et al. Low-dose esterified estrogen therapy: Effects on bone, plasma estradiol concentrations, endometrium, and lipid levels. Arch Intern Med 1997; 157:2609.
51. Beresford SA, Weiss NS, Voigt LF, McKnight B. Risk of endometrial cancer in relation to use of oestrogen combined with cyclic progestagen therapy in postmenopausal women. Lancet 1997; 349:458.
52. Effects of hormone replacement therapy on endometrial histology in postmenopausal women. The Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial. The Writing Group for the PEPI Trial. JAMA 1996; 275:370.
53. Lethaby A, Farquhar C, Sarkis A, et al. Hormone replacement therapy in postmenopausal women: Endometrial hyperplasia and irregular bleeding. Cochrane Database Syst Rev 2000; :CD000402.
54. Rapp, SR, Espeland, MA, Shumaker, SA, Henderson, VW. Effect of estrogen plus progestin on global cognitive function in postmenopausal women: The Women's Health Initiative Memory Study: A randomized controlled trial. JAMA 2003; 289:2663.
55. Shumaker SA, Legault C, Rapp SR, et al. Estrogen plus progestin and the incidence of dementia and mild cognitive impairment in postmenopausal women: the Women's Health Initiative Memory Study: A randomized controlled trial. JAMA 2003; 289:2651.
56. Kanaya AM, Herrington D, Vittinghoff E, et al. Glycemic Effects of Postmenopausal Hormone Therapy: The Heart and Estrogen/progestin Replacement Study. A Randomized, Double-Blind, Placebo-Controlled Trial. Ann Intern Med 2003; 138:1.
57. Løkkegaard E, Pedersen AT, Heitmann BL, Jovanovic Z, Keiding N, Hundrup YA, Obel EB, Ottesen B. Relation between hormone replacement therapy and ischaemic heart disease in women: Prospective observational study. BMJ 2003;326:426.
58. Raz R, Stamm WE. A controlled trial of intravaginal estriol in postmenopausal women with recurrent urinary tract infections. N Engl J Med 1993; 329:753.
59. Brown JS, Vittinghoff E, Kanaya AM, et al. Urinary tract infections in postmenopausal women: Effect of hormone therapy and risk factors. Obstet Gynecol 2001; 98:1045.
60. Bhatia NN, Bergman A, Karram MM. Effects of estrogen on urethral function in women with urinary incontinence. Am J Obstet Gynecol 1989; 160:176.
61. Makinen JI, Pitkanen YA, Salmi TA, et al. Transdermal estrogen for female stress urinary incontinence in postmenopause. Maturitas 1995; 22:233.
62. Fantl JA, Bump RC, Robinson D, et al. Efficacy of estrogen supplementation in the treatment of urinary incontinence. Obstet Gynecol 1996; 88:745.
63. Jackson S, Shepherd A, Brookes S, Abrams P. The effect of oestrogen supplementation on post-menopausal urinary stress incontinence: A double-blind placebo-controlled trial. Br J Obstet Gynaecol 1999; 106:711.
64. Grady D, Brown JS, Vittinghoff E, et al. Postmenopausal hormones and incontinence: the Heart and Estrogen/Progestin Replacement Study. Obstet Gynecol 2001; 97:116.
65. Moehrer B, Hextall A, Jackson S. Oestrogens for urinary incontinence in women. Cochrane Database Syst Rev 2003; :CD001405.10. Lafferty FW, Fiske ME. Postmenopausal estrogen replacement: A long-term cohort study. Am J Med 1994; 97:66-77.
66. Fantl JA, Cardozo L, McClish DK, et al. Estrogen therapy in the management of urinary incontinence in postmenopausal women: First report of the hormones and urogenital therapy committee. Obstet Gynecol 1994; 83:12-8.
67. Sadan O, Frohlich RP, Driscoll JA, Apostoleris A, Savage N, Zakust H. Is it safe to prescribe hormonal contraception and replacement therapy to patients with premalignant and malignant uterine cervices? Gynec Oncol 1986; 34:159-63.
68. Ditkoff EC, Crary WG, Cristo M, Lobo RA. Estrogen improves psychological function in asymptomatic postmenopausal women. Obstet Gynecol 1991; 78:991.
69. Soares CN, Almeida OP, Joffe H, Cohen LS. Efficacy of estradiol for the treatment of depressive disorders in perimenopausal women: A double-blind, randomized, placebo-controlled trial. Arch Gen Psychiatry 2001; 58:529.
70. Grodstein F, Colditz GA, Stampfer MJ. Postmenopausal hormone use and cholecystectomy in a large prospective study. Obstet Gynecol 1994; 83:5.
71. Simon JA, Hunninghake DB, Agarwal SK, et al. Effect of estrogen plus progestin on risk for biliary tract surgery in postmenopausal women with coronary artery disease. The Heart and Estrogen/progestin Replacement Study. Ann Intern Med 2001; 135:493.
72. Troisi RJ, Speizer FE, Willett WC, et al. Menopause, postmenopausal estrogen preparations, and the risk of adult-onset asthma. Am J Respir Crit Care Med 1995; 152:1183.
73. Nevitt MC, Cummings SR, Lane NE, et al. Association of estrogen replacement therapy with the risk of osteoarthritis of the hip in elderly white women. Arch Intern Med 1996; 156:2073.
74. Zhang Y, McAlindon TE, Hannan MT, et al. Estrogen replacemet therapy and worsening of radiographic knee osteoarthritis. Arthritis Rheum 1998; 41:1867.
75. Brincat M, Versi E, Moniz CF, et al. Skin collagen changes in postmenopausal women receiving different regimens of estrogen therapy. Obstet Gynecol 1987; 70:123.
76. Holland EF, Studd JW, Mansell JP, et al. Changes in collagen composition and cross-links in bone and skin of osteoporotic postmenopausal women treated with percutaneous estradiol implants. Obstet Gynecol 1994; 83:180.
77. Ashcroft GS, Dodsworth J, van Boxtel E, et al. Estrogen accelerates cutaneous wound healing associated with an increase in TGF-ß1. Nat Med 1997; 3:1209.
78. Paganini-Hill A. The benefits of estrogen replacement on oral health. The Leisure World cohort. Arch Intern Med 1995; 155:2325.
79. Krall EA, Dawson-Hughes B, Hannan MT, et al. Postmenopausal estrogen replacement and tooth retention. Am J Med 1997; 102:536.
80. Worzala K, Hiller R, Sperduto RD, et al. Postmenopausal estrogen use, type of menopause, and lens opacities: the Framingham Studies. Arch Intern Med 2001; 161:1448.
81. Freeman EE, Munoz B, Schein OD, West SK. Hormone replacement therapy and lens opacities: the Salisbury Eye Evaluation Project. Arch Ophthalmol 2001; 119:1687.
82. Schaumberg DA, Buring JE, Sullivan DA, Dana MR. Hormone replacement therapy and dry eye syndrome. JAMA 2001; 286:2114-9.
83. Worzala K, Hiller R, Sperduto RD, Mutalik K, Murabito JM, Moskowitz M, D'Agostino RB, Wilson PW. Postmenopausal estrogen use, type of menopause, and lens opacities: The Framingham studies. Arch Intern Med 2001; 161(11):1448-54.
84. Nelson HD, Humphrey LL, Nygren P, et al. Postmenopausal hormone replacement therapy: Scientific review. JAMA 2002; 288:872.
85. Weinstein L, Bewtra C, Gallagher JC. Evaluation of a continuous combined low-dose regimen of estrogen-progestin for treatment of the menopausal patient. Am J Obstet Gynecol 1990; 162:1534.
86. Archer DF, Pickar JH, Bottiglioni F. Bleeding patterns in postmenopausal women taking continuous combined or sequential regimens of conjugated estrogens with medroxyprogesterone acetate. Obstet Gynecol 1994; 83:686.
87. Jones S. The Premarin debate. Equus 1994; 202:73-7.
88. Greendale GA, Judd HL. The menopause: Health implications and clinical management. J Am Geriatr Soc 1993; 41:426-36.
89. Nash HA, Alvarez-Sanchez F, Mishell DR Jr, Fraser IS, Maruo T, Harmon TM. Estradiol-delivering vaginal rings for hormone replacement therapy. Am J Obstet Gynecol 1999; 181(6):1400-6.
90. Archer DF, Pickar JH, Bottiglioni F. Bleeding patterns in postmenopausal women taking continuous combined or sequential regimens of conjugated estrogens with medroxyprogesterone acetate. Obstet Gynecol 1994; 83:686-92.
91. Sulak PJ, Caubel P, Lane R. Efficacy and safety of a constant estrogen, pulsed-progestin regimen in hormone replacement therapy. Int J Fertil 1999; 44:286-96.
92. Casper R, Chapdeline A. Estrogen and interrupted progestin: A new concept for menopausal hormone replacement therapy. Am J Obstet Gynecol 1993; 168:1188-96.
93. Warren MP, Biller BM, Shangold MM. A new clinical option for hormone replacement therapy in women with secondary amenorrhea: Effects of cyclic administration of progesterone from the sustained-release vaginal gel Crinone (4% and 8%) on endometrial morphologic features and withdrawal bleeding. Am J Obstet Gynecol 1999; 180(1 Pt 1):42-8.
94. Raisz LG, Wiita B, Artis A, Bowen A, Schwartz S, Trahiotis M, Shoukri K, Smith J. Comparison of the effects of estrogen alone and estrogen plus androgen on biochemical markers of bone formation and resorption in postmenopausal women. J Clin Endocrinol Metab 1996; 81(1):37-43.
95. Watts NB, Notelovitz M, Timmons MC, Addison WA, Wiita B, Downey LJ. Comparison of oral estrogens and estrogens plus androgen on bone mineral density, menopausal symptoms, and lipid-lipoprotein profiles in surgical menopause. Obstet Gynecol 1995; 85(4):529-37.
96. Simon J, Klaiber E, Wiita B, Bowen A, Yang HM. Differential effects of estrogen-androgen and estrogen-only therapy on vasomotor symptoms, gonadotropin secretion, and endogenous androgen bioavailability in postmenopausal women. Menopause 1999; 6(2):138-46.
97. Sarrel P, Dobay B, Wiita, B. Estrogen and estrogen-androgen replacement in postmenopausal women dissatisfied with estrogen-only therapy. J Reprod Med 1998; 43: 847-55.
98. Lobo RA, Rosen RC, Yang HM, Block B, Van Der Hoop RG. Comparative effects of oral esterified estrogens with and without methyltestosterone on endocrine profiles and dimensions of sexual function in postmenopausal women with hypoactive sexual desire. Fertil Steril 2003;79:1341-52.
99. Gelfand MM, Wiita B. Androgen and estrogen-androgen hormone replacement therapy: A review of the safety literature, 1941 to 1996. Clin Ther 1997; 19:383-404.
100. Nachtigall LB, Nachtigall MJ, Nachtigall LE. Nonprescription alternatives to hormone replacement therapy. The Female Patient 1999; 24:59.
101. Flynn MA, Weaver-Osterholtz D, Sharpe-Timms KL, Allen S, Krause G. Dehydroepiandrosterone replacement in aging humans. J Clin Endocrinol Metab 1999; 84:1527-33.
102. Shifren JL, Braunstein GD, Simon JA, Casson PR, Buster JE, Redmond GP, Burki RE, et al. Transdermal testosterone treatment in women with impaired sexual function after oophorectomy. New Engl J Med 2000; 343(10):682-8.
103. Loprinzi CL, Michalak JC, Quella SK, O'Fallon JR, Hatfield AK, Nelimark RA, et al. Megestrol acetate for the prevention of hot flashes. N Engl J Med 1994; 331:347-52.
104. Leonetti HB, Longo S, Anasti JN. Transdermal progesterone cream for vasomotor symptoms and postmenopausal bone loss. Obstet Gynecol 1999; 94:225-8.
105. Loprinzi CL, Michalak JC, Quella SK, et al. Megestrol acetate for the prevention of hot flashes. N Engl J Med 1994; 331:347.
106. Wimalawansa SJ. A four-year randomized trial of hormone replacement and biphosphonate, alone or in combination, in women with postmenopausal osteoporosis. Am J Med 1998; 104:219-26.
107. Karpf DB, Shapiro DR, Seeman E, Ensrud KE, Johnston CC, Adami S, et al. Prevention of nonvertebral fractures by alendronate. JAMA 1997; 277:1159-64.
108. Bone HG, Greenspan SL, McKeever C, Bell N, Davidson M, Downs RW, et al. Alendronate and estrogen effects in postmenopausal women with low bone mineral density. Alendronate/Estrogen Study Group. J Clin Endocrinol Metab 2000; 85(2):720-6.
109. Delmas PD, Bjarnason NH, Mitlak BH, et al. Effects of raloxifene on bone mineral density, serum cholesterol concentrations, and uterine endometrium in postmenopausal women. N Engl J Med 1997; 337:1641.
110. Ettinger B, Black DM, Mitlak BH, et al. Reduction of vertebral fracture risk in postmenopausal women with osteoporosis treated with raloxifene. JAMA 1999; 282:637.
111. Meier CR, Schlienger R, Kraenzlin ME, Schlegel, Jick H. HMG-CoA reductase inhibitors and the risk of fractures. JAMA 2000; 283; 3205-10.
112. Palomba S, Sammartino A, Di Carlo C, Affinito P, Zullo F, Nappi C. Effects of raloxifene treatment on uterine leiomyomas in postmenopausal women. Fertil Steril 2001; 76(1):38-43.
113. Barrett-Connor E, Grady D, Sashegyi A, Anderson PW, Cox DA, Hoszowski K, et al. Raloxifene and cardiovascular events in osteoporotic postmenopausal women. JAMA. 2002;287:847-57.
114. Davies GC, Huster WJ, Shen W, Mitlak B, Plouffe L Jr, Shah A, Cohen FJ. Endometrial response to raloxifene compared with placebo, cyclical hormone replacement therapy, and unopposed estrogen in postmenopausal women. Menopause 1999; 6(3):188-95
115. Yaffe K, Krueger K, Sarkar S, Grady D, Barrett-Connor E, Cox DA, Nickelsen T. Multiple outcomes of raloxifene evaluation investigators. Cognitive function in postmenopausal women treated with raloxifene. N Engl J Med 2001; 344(16):1207-13.
116. Reginster JY, Meurmans L, Deroisy R, et al. A 5-year controlled randomized study of prevention of postmenopausal trabecular bone loss with nasal salmon calcitonin and calcium. Eur J Clin Invest 1994; 24:565.
117. Overgaard K, Hansen MA, Jensen SB, Christiansen C. Effect of salcatonin given intranasally on bone mass and fracture rates in established osteoporosis: A dose-response study. BMJ 1992; 305:556.
118. Chesnut CH, Silverman S, Andriano K, et al. A randomized trial of nasal spray salmon calcitonin in postmenopausal women with established osteoporosis: the Prevent Recurrence of Osteoporotic Fractures Study. Am J Med 2000; 109:267.
119. Neer RM, Arnaud CD, Zanchetta JR, Prince R, Gaich GA, Reginster JY, Hodsman AB, Eriksen EF, Ish-Shalom S, Genant HK, Wang O, Mitlak BH. Effect of parathyroid hormone (1-34) on fractures and bone mineral density in postmenopausal women with osteoporosis. New Engl J Med 2001; 344(19):1434-41.
120. 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.
121. Stearns V, Beebe KL, Iyengar M, Dube E. Paroxetine controlled release in the treatment of menopausal hot flashes: A randomized controlled trial. JAMA 2003; 289:2827.
122. Loprinzi CL, Sloan JA, Perez EA, et al. Phase 54 evaluation of fluoxetine for treatment of hot flashes. J Clin Oncol 2002; 20:1578.
123. Laufer LR, Erlik Y, Meldrum DR, Judd HL. Effect of clonidine on hot flashes in postmenopausal women. Obstet Gynecol 1982; 60:583.
124. Nagamani M, Kelver ME, Smith ER. Treatment of menopausal hot flashes with transdermal administration of clonidine. Am J Obstet Gynecol 1987; 156:561.
125. Pandya KJ, Raubertas RF, Flynn PJ, Hynes HE, Rosenbluth RJ, Kirshner JJ, 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(10):788-93.
126. Caruso S, Intelisano G, Lupo L, Agnello C. Premenopausal women affected by sexual arousal disorder treated with sildenafil: A double-blind, cross-over, placebo-controlled study. Br J Obstet Gynecol 2001; 108(6):623-8

127.

Guttuso T, Kurlan R, McDermott MP, Kieburtz K. Gabapentin's effects on hot flashes in postmenopausal women: A randomized controlled trial. Obstet Gynecol 2003; 101:337.
128. Loprinzi L, Barton DL, Sloan JA, et al. Pilot evaluation of gabapentin for treating hot flashes. Mayo Clin Proc 2002; 77:1159.
129. David A, Don R, Tajchner G, Weissglas L. Veralipride: Alternative antidopaminergic treatment for menopausal symptoms. Am J Obstet Gynecol 1988; 158:1107.
130. Van Patten CL, Olivotto IA, Chambers GK, et al. Effect of soy phytoestrogens on hot flashes in postmenopausal women with breast cancer: A randomized, controlled clinical trial. J Clin Oncol 2002; 20:1449.
131. Upmalis DH, Lobo R, Bradley L, et al. Vasomotor symptom relief by soy isoflavone extract tablets in postmenopausal women: A multicenter, double-blind, randomized, placebo-controlled study. Menopause 2000; 7:236.
132. Quella SK, Loprinzi CL, Barton DL, et al. Evaluation of soy phytoestrogens for the treatment of hot flashes in breast cancer survivors: A North Central Cancer Treatment Group Trial. J Clin Oncol 2000; 18:1068.
133. Kronenberg F, Fugh-Berman A. Complementary and alternative medicine for menopausal symptoms: A review of randomized, controlled trials. Ann Intern Med 2002; 137:805.
134. Nikander E, Kilkkinen A, Metsä-Heikkilä M, et al. A randomized placebo-controlled crossover trial with phytoestrogens in treatment of menopause in breast cancer patients. Obstet Gynecol 2003; 101:1213.
135. Messina MJ, Loprinzi CL. Soy for breast cancer survivors: A critical review of the literature. J Nutr 2001; 131:3095S.
136. Tice JA, Ettinger B, Ensrud K, et al. Phytoestrogen supplements for the treatment of hot flashes: The Isoflavone Clover Extract (ICE) Study: A Randomized Controlled Trial. JAMA 2003; 290:207.
137. Alexandersen P, Toussaint A, Christiansen C, Devogelaer JP, Roux C, Fechtenbaum J, et al. Ipriflavone Multicenter European Fracture Study. Ipriflavone in the treatment of postmenopausal osteoporosis: A randomized controlled trial. JAMA 2001; 285(11):1482-8.
138. Whiting PW, Clouston A, Kerlin P. Black cohosh and other herbal remedies associated with acute hepatitis. Med J Australia 2002 177 (8): 440-3.
139. The heart outcome prevention evaluation study investigators. Vitamin E supplementation and cardiovascular events in high-risk patients. N Engl J Med 2000; 342:154-60.
140. Neer RM, Arnaud CD, Zanchetta JR, Prince R, Gaich GA, Reginster JY, Hodsman AB, Eriksen EF, Ish-Shalom S, Genant HK, Wang O. Mitlak BH. Effect of parathyroid hormone (1-34) on fractures and bone mineral density in postmenopausal women with osteoporosis. N Engl J Med 2001; 344(19):1434-41.


E.J. Mayeaux, MD
updated 8/30/05


Home Index Contact CCC