For the distaff side: Hormone replacement therapy

By Sara Noble, Pharm.D., clinical associate professor, Family Medicine, University of Mississippi Medical Center; Linh ter Riet, Pharm.D., BCPS; Richard Ogletree, Pharm.D., clinical assistant professor, University of Mississippi School of Pharmacy; Deborah King, Pharm.D., assistant professor of pharmacy practice, University of Mississippi School of Pharmacy

Menopausal physiology/symptoms

Menopause, the permanent cessation of menstruation resulting from the loss of ovarian follicular activity, is defined as the "final menstrual cycle in a woman's life." The broader term, climacteric, signifies the transition from the reproductive to nonreproductive time of life for a woman. The physiologic, endocrinologic, and emotional changes that occur with this transition may span months to years. This time preceding menopause is referred to as the perimenopausal period. Natural menopause occurs between the ages of 40 and 58. The age has not changed over the past few centuries.

Two to eight years before menopause, most women experience major menstrual cycle changes. Anovulation becomes more prevalent, and generally the menstrual cycle length increases. Irregular and unpredictable cycles also occur in many women, and vaginal bleeding can last for a shorter or longer interval. Patterns of the menstrual flow can also change, with either light spotting or heavy bleeding.

Menopause can occur naturally or can be induced through surgical removal of the ovaries. Hormone replacement therapy (HRT) use following menopause refers to estrogen replacement plus progestin for women who have an intact uterus, while estrogen replacement therapy, sometimes called "unopposed" ERT, refers to the use of estrogen alone for women who do not have a uterus. Throughout this article, HRT and ERT may be used interchangeably.

Total estrogen production will decline by 70% to 80%, with the ovaries producing practically no estrogen at menopause. The most potent naturally occurring estrogens that women produce are 17-B estradiol, estrone, and estriol. The primary hormone secreted by the ovaries of premenopausal women is 17-B estradiol. Additionally, the ovaries synthesize estrone from precursors made in the adrenal gland. Estrone is also produced by adipose tissue and is the primary estrogen after the ovaries cease functioning. In the liver, both estradiol and estrone can be converted to estriol, the weakest estrogen. Estradiol may also be converted to estrone and estrone into estradiol. Table 1 lists estrogen and progestin equivalents.

Table 1
Estrogen and progestin equivalents

Dose (mg)
0.625
12.00
0.10
0.25
1.00
1.25
0.75
0.015
0.02
1.00
0.00014

Dose (mg)
10.00 mg
5.00 mg
0.15 mg
5.00 mg

During perimenopause, the ovarian follicles undergo an accelerated rate of loss until eventually the supply is depleted. From the initial supply of one to two million follicles at birth, only a few thousand follicles remain at age 40. This change is marked by elevated follicle-stimulating hormone (FSH) levels, decreased levels of inhibin, normal levels of leuteinizing hormone (LH), and slightly elevated levels of estradiol. Estradiol levels do not wane in the years before menopause but remain in the normal to slightly elevated range for six months to one year before follicular growth and development cease.

Measuring the FSH level can monitor natural menopause; however, because of the variability in FSH levels, this method is not always accurate. Therefore, natural menopause is often diagnosed retrospectively and is recognized to have occurred after 12 consecutive months of amenorrhea, for which there is no other obvious cause. Postmenopause is the time beginning just after the last menstrual period. Because of the difficulty in determining which menstrual period is the last, the postmenopausal stage is considered to begin 12 months after the last spontaneous menstrual period.

Benefits of HRT use

HRT in perimenopausal and menopausal women is used to reverse the impact of lowered estrogen levels and its related symptoms. Early, intermediate, and long-term consequences of estrogen loss are described in Table 2. There are well-documented benefits as well as risks with use of HRT.

Table 2
Effects of estrogen loss

Symptoms (early occurrence)
Hot flashes
Insomnia
Irritability
Mood disturbances

Physical changes (intermediate occurrence)
Vaginal atrophy
Urinary incontinence (overactive bladder)
Skin atrophy

Diseases (late occurrence)
Osteoporosis
Cardiovascular disease
Dementia of the Alzheimer's type
Cancers

Vasomotor symptoms. During the perimenopausal period, 10% to 25% of women experience vasomotor symptoms of hot flashes and night sweats. Hot flash refers to the sensation that the women feel, while the term hot flush is the actual physiologic condition. Hot flushes result from a disruption of the thermoregulatory center within the hypothalamus and are believed to be attributable to estrogen depletion and lack of hormonal feedback from the ovaries.

Up to 75% of all women experience some vasomotor symptoms, with 15% to 20% of women experiencing daily symptoms. With an average duration of one to two years, vasomotor symptoms can persist beyond five years in 25% of women. In women who undergo bilateral oophorectomy prior to menopause, vasomotor symptoms are often more severe, perhaps because of the sudden drop in estrogen.

Estrogen is highly effective in alleviating hot flushes and night sweats. More than 40 randomized, controlled trials (RCTs) have found that estrogen, given by oral and transdermal routes, improves vasomotor symptoms. In clinical trials, estrogen reduces the frequency of hot flashes by approximately 77% relative to placebo, as well as reducing their severity. Vasomotor symptoms are usually relieved during the first cycle of treatment and may even be relieved within days of starting HRT. Progestin therapy is also associated with reductions in vasomotor symptoms and may be used as an alternative for women with estrogen therapy contraindications.

Many women respond to a lower dose of estrogen such as 0.025 mg/day of transdermal estradiol or 0.3-0.4 mg/day versus 0.625 mg or higher of oral conjugated equine estrogens (CEE). Some women, especially younger women who have undergone oophorectomy, may require a higher than average dose of estrogen to suppress vasomotor symptoms.

RCTs have found significant improvements in quality of life and well-being in women treated with estrogen compared with those treated with placebo. This finding was recently substantiated by the Heart and Estrogen/Progestin Replacement Study (HERS), in which older menopausal women with flushing had improved mental health and fewer depressive symptoms as a result of HRT treatment.

HRT is recommended for treatment of vasomotor symptoms when benefits outweigh risks. For women who need only relief of vasomotor symptoms, continued therapy should be evaluated annually and discontinued when appropriate. Gradual tapering of the dose may minimize the recurrence of vasomotor symptoms.

Urogenital symptoms. Although vasomotor symptoms decline over time for most women, urogenital symptoms often persist or worsen. The vagina and urethra share a common embryologic origin, and estrogen deficiency causes atrophy of both. The vaginal wall becomes thin, and the vaginal glands atrophy. Vaginal and urogenital symptoms associated with menopause and aging include vaginal dryness, pain with intercourse or dyspareunia, urinary urgency and frequency, dysuria, and recurrent urinary tract infections. Estrogen therapy has been shown to relieve symptoms related to vaginal atrophy and painful intercourse. The effects of estrogen on urge or stress incontinence and dysuria are mixed. Estrogen has been reported to be beneficial and may protect against recurrent lower urinary tract infections. However, its use does not improve urinary incontinence or reduce the number of incontinence episodes.

The vaginal mucosa has a high density of estrogen receptors and responds to local application of estrogen. For a local response, topical vaginal estrogen preparations in the form of a cream or ring are as effective as systemic estrogen therapy and can be an alternative.

Osteoporosis. Osteoporosis is a skeletal disorder characterized by compromised bone strength predisposing to increased fracture risk. Bone densitometry (BMD) testing is used to diagnose osteoporosis and to determine low bone mass.

While osteoporosis is primarily a result of bone loss, it may occur in an individual who does not reach peak or optimal bone mass during childhood and adolescence. Peak bone mass is normally achieved by age 30 to 35 and is dependent on genetics, diet, and exercise. Throughout life, an adequate calcium and vitamin D intake for women is essential to achieve peak bone mass and prevent bone loss. As bone mass decreases, susceptibility to fracture increases. One out of every two women in the United States over age 50 will experience an osteoporosis-related fracture during her life. With recent advances in the understanding of its causes, diagnosis, and treatment, osteoporosis can be prevented and treated.

ERT is first-line therapy for the prevention of osteoporosis. Although lack of fracture efficacy data caused the Food & Drug Administration to remove the treatment indication for ERT in osteoporosis, the prevention claim was retained because of estrogen's consistency in increasing spine and hip BMD scores.

Since most of the trials concerning fracture reduction were observational studies, larger RCTs need to be conducted. Studies exist that evaluate HRT and its effect on BMD scores. The 36-month Postmenopausal Estrogen/Progestin Intervention Trial (PEPI) found decreases in BMD scores with increased spinal bone density by approximately 5.1% among adherent women. BMD loss in women on placebo was approximately 2.8%. Treatment regimens consisted of CEE 0.625 mg/day alone or with continuous doses of medroxyprogesterone acetate (MPA) 2.5 mg/day, cyclic MPA at 10 mg for 12 days each month, or micronized progesterone at 20 mg/day for 12 days each month.

A recently published safety follow-up analysis of the PEPI trial was conducted to determine whether women lose BMD after stopping HRT. Women who discontinued HRT after three years of therapy during the PEPI trial had annual changes of —1.01% (hip) and —1.04% (spine). The study also assessed the rate of bone loss in women with HRT cessation compared with women with no prior HRT use. No statistical difference in bone loss rate between the two groups was found. The last objective was to determine the association of long-term HRT use with continued gains in BMD. The use of HRT did not yield additional BMD gains in women who continued HRT after the PEPI trial.

In osteoporosis, a concern is when to initiate and how long HRT should be continued. Initiation has routinely been recommended as soon as possible after menopause. Accelerated bone loss may actually begin prior to the onset of amenorrhea and increases significantly after menopause. ERT is most effective when the level of bone loss is high. Bone loss is estimated at an approximate 2% annual loss for the first five years, decreasing thereafter to an approximate 1% annual loss. The effect of ERT is thought to continue as long as the duration of therapy persists. The FDA-approved dose of CEE for the prevention of osteoporosis is 0.625 mg/day. For protection against bone loss, the use of a dose lower than the commonly prescribed 0.625 mg/day of CEE plus MPA has been investigated. Conducted in women 40 to 65 years of age within four years of their last menstrual period, therapy appears to offer promise in effectively increasing BMD in early postmenopausal women.

Colorectal cancer. After lung and breast cancer, colorectal cancer ranks as the third-leading cause of cancer and death in women. Incidence begins to increase during the mid-40s and continues to rise with age. The use of postmenopausal HRT has been associated with a 20% reduction in the risk of colon cancer and a 19% reduction in the risk of colorectal cancer. In a recent meta-analysis, current users of HRT were shown to receive the greatest benefit, with a 34% risk reduction in colorectal cancer. Women should be advised of these potential benefits when considering HRT.

Cardiovascular benefits. Despite significant medical progress, CVD is still the leading cause of death in the United States, accounting for 512,904 deaths (42.5%) in women during 1999. Unfortunately the rate of CVD mortality for women continues to increase. The prevalence of CVD increases with age, from a rate of 4.6% in females ages 20 to 24, up to a rate of 79% in females over the age of 75. During the postmenopausal period, CVD prevalence in women is equivalent to the prevalence in men (48.1% versus 51%, respectively).

There are many rational reasons to believe that estrogen is cardioprotective in women. These include the higher CVD rates in men compared with premenopausal women, the increased risk of CVD increases in postmenopausal women, and the many beneficial effects of estrogen on known CVD risk factors. Postmenopausal ERT/HRT would be predicted to offer cardioprotection via several potential mechanisms.

In a meta-analysis of more than 30 observational studies, a 56% reduction in risk of a major coronary event or fatal CVD in healthy current estrogen users was seen, compared with women who have never used ERT. These data were further substantiated by the Nurses Health Study, which showed a significant decrease in the risk of major coronary heart disease among women who took HRT or ERT as compared with women who did not use hormones. Additionally, current hormone users had a lower risk of death, with the largest reduction in mortality seen in women with coronary risk factors. The Nurses Health Study, however, showed no significant association between stroke and HRT/ERT.

The PEPI trial, which used cardiovascular risk factors (high-density lipoprotein, or HDL, cholesterol; systolic blood pressure; serum insulin; and fibrinogen) rather than clinical events as measures of outcome, showed positive effects from therapy with estrogen. Women between the ages of 45 and 64 years were randomized to placebo, CEE, CEE and MPA sequentially, or CEE and MPA consecutively. All of the regimens increased HDL; however, the greatest increases were seen with CEE/MPA (4.1 mg/dl) and CEE alone (5.6 mg/dl). ERT/HRT therapy decreased mean low-density lipoprotein (LDL) cholesterol 14.5 to 17.7 mg/dl and increased mean triglycerides 11.4 to 13.7 mg/dl, compared with placebo. There were no differences among active treatments in fibrinogen, systolic blood pressure, or insulin levels.

Despite the beneficial effects of HRT seen in population studies and the documented protective effects of estrogen on cardiac risk factors, several recent cardiovascular trials have shown disappointing results in the secondary prevention of cardiovascular endpoints.

HERS evaluated the impact of HRT on cardiovascular events and death rates in women 44-79 years of age with known coronary heart disease (secondary prevention). Women were randomized to CEE 0.625/MPA 2.5 mg daily or placebo. There were no significant differences in nonfatal myocardial infarction (MI) or death between the two groups, despite an overall effect of 11% lowering of LDL cholesterol, and 10% higher HDL cholesterol in the HRT group as compared with the placebo group. Despite these benefits, the risks in this population of nonfatal MI and death in the hormone group compared with the placebo group was greater in the first years. Results of this trial have been questioned because of the drug regimen used, the older age of the participants, the length of time since menopause, the lower rate of medication compliance, the high baseline use of statins, and higher treatment rate with statins in the placebo group.

Despite many questions regarding trial results, the use of HRT for secondary prevention of cardiovascular disease is not supported. The question of benefit in primary prevention is still unanswered and probably will not be known until publication of the Women's Health Initiative (WHI), an ongoing RCT with more than 27,000 participants. Initiated in 1992, its expected completion date is 2007.

Likewise, disappointing results were also seen with a trial measuring angiographic end point data. The Estrogen Replacement and Atherosclerosis (ERA) Trial was the first randomized angiographic end point trial to test the effect of ERT and HRT on the progression of atherosclerosis. The trial, conducted in postmenopausal women with documented coronary stenosis, showed no benefit of CEE alone or in combination with MPA on angiographic progression of disease over a three-year period, despite reductions in LDL cholesterol and increases in HDL cholesterol. Because the ERA trial also included an estrogen-only arm that showed no benefit over placebo, the questions regarding cardioprotective effects due to the use of MPA were nullified. The rates of clinical cardiovascular events were also similar among the treatment groups. However, like the HERS trial, the results of this trial have also been questioned due to the drug regimen, the older age of the participants (average age of 65.8 years), and the length of time since menopause before ERT/HRT was instituted.

Another secondary prevention study published evaluated the effect of estrogen on stroke prevention. The Women's Estrogen for Stroke Trial (WEST) showed no protective benefit of estrogen on secondary prevention of recurrent strokes in postmenopausal women with cerebrovascular disease.

Based on the available data, the American Heart Association (AHA) published recommendations concerning HRT and CVD in July 2001. AHA recommends that HRT not be initiated for the secondary prevention of CVD. The decision to continue or stop HRT in women with CVD who have been undergoing long-term HRT should be based on noncoronary benefits and risks and patient preference. For primary prevention, AHA recommends that initiation and continuation of HRT be based on established noncoronary benefits and risks, possible coronary benefits and risks, and patient preference.

Cognition. Women are two to three times more likely to develop Alzheimer's disease than are men. The effects of HRT on cognitive decline or dementia risk in healthy postmenopausal women are being examined. Postulated mechanisms are that HRT might enable the breakdown of beta-amyloid precursors and thus prevent development of neurofibrillary tangles. HRT use might also enhance dendritic spine density, thus promoting neuronal circuitry. A meta-analysis that examined the effects of HRT on cognitive decline or dementia risks in healthy postmenopausal women found a reduced risk of dementia in HRT users. Other studies, but not all, have suggested that estrogen use may decrease the chance of developing Alzheimer's disease. Larger RCTs are needed to establish HRT's role in delaying or preventing Alzheimer's and to further define the optimal dose, formulation and, duration of use.

Risks of HRT use

Endometrial cancer. Worldwide, the age-standardized incidence rate of endometrial cancer is 6.4 per 100,000 women. The risk of death from endometrial cancer appears to be increased with estrogen use. Conjugated estrogens are associated with significantly higher endometrial cancer risk than synthetic ones. The risk of endometrial cancer diminishes with time since last use but still persists even five years after discontinuation of unopposed estrogen.

Irregular bleeding is more likely under a continuous rather than a sequential estrogen-progestogen regimen, but at longer duration of treatment, continuous therapy is more protective than sequential therapy in preventing endometrial hyperplasia. There is strong, consistent evidence that unopposed ERT is associated with increased rates of endometrial hyperplasia/cancer and irregular bleeding, and the risk is proportional to the duration of therapy and the dose. The addition of progestogens, either in continuous combined or sequential regimens, helped to prevent the development of endometrial hyperplasia.

Women with an intact uterus should receive progesterone along with estrogen to lower their risk of developing endometrial hyperplasia/cancer. From the recent meta-analyses, regimens with the lowest risk appear to be continuous regimens with a synthetic estrogen.

Venous thromboembolism (VTE). Based on the available evidence, current use of HRT therapy increases a woman's risk of developing VTE approximately two- to threefold. Therefore, HRT therapy should be avoided in women with a previous history of documented idiopathic or recurrent VTE. Additionally, AHA guidelines recommend that if a woman on HRT develops an acute CVD event or is immobilized, discontinuation of HRT or VTE prophylaxis during hospitalization should be considered.

Breast cancer. Breast cancer is the most common neoplastic disease in women, although lung cancer is the leading cause of death. The incidence of breast cancer increases with age. It is estimated that one in 24 women aged 40 to 59 will develop invasive breast cancer, and this incidence increases to one in 14 women aged 60 to 79. The estimated lifetime breast cancer risk for women is one in eight.

In addition to age, breast cancer is thought to be related to estrogen exposure. Menarche before age 12, menopause after age 55, and nulliparity all contribute to longer exposure. A family history is recognized as a positive risk factor. The inherited susceptibility genes, BRCA1 and BRCA2, predispose individuals to breast cancer. Studies have also shown a link between breast cancer and smoking, heavy alcohol consumption, obesity after menopause, and a high-fat diet.

It is currently unknown whether increased breast density due to HRT carries the same risk for breast cancer as having naturally dense breasts. Data from the PEPI trial indicated that approximately 25% of women who used HRT had an increase in breast density on their mammograms. This is a concern because other studies have shown that women whose mammograms show at least 75% dense tissue are at increased risk for breast cancer.

Although postmenopausal women can suffer the complications of CVD and osteoporosis-related fractures, fear concerning breast cancer occurrence due to HRT use predominates. Breast cancer fear is a determinant in whether women will initiate and continue HRT. Women should be advised of the current evidence and helped to understand that breast cancer risks cited in most studies are relative risks. Relative risks (RR) compare risks among groups. For example, if the risk of a woman aged 50 developing breast cancer over a period of 20 years is six per 100 women, then a 50% increase means that the number of women will increase to nine per 100 women.

Numerous clinical questions regarding breast cancer risks should be addressed. Recent studies, primarily observational, give some guidance. A reanalysis of data on 52,705 women with breast cancer and 108,411 women without breast cancer examined the relationship between HRT and breast cancer risk. Addressing the question of whether there is an increase in breast cancer incidence in women on HRT, study investigators reported that breast cancer risk did not increase with duration of HRT of four years or less. A statistically significant increase in RR to 1.35 was found in women with duration of HRT use of five years or longer. This increased risk of breast cancer largely disappeared after discontinuation of HRT use. It was also determined from this study and others that the per annum increase in breast cancer ranges from 1.7% with ERT to 5.4% with HRT. Cyclic progestin use had a higher associated risk (7.6%) versus the use of continuous progestin (1.8%). Other recent studies have also identified an increased risk of developing breast cancer with an increased duration of HRT.

Earlier, primarily observational studies showed inconsistent results. The Collaborative Group and Iowa Women's Health Study data show that HRT use in women with positive family histories was not associated with a statistically significant higher rate of breast cancer than in nonusers, 61 versus 46 cases per 10,000 person-years, respectively.

In breast cancer survivors, pregnancy with its high estrogen levels has not affected recurrence. Also, breast cancer that does develop in women taking HRT has a more favorable profile. It is usually the localized, lobular histologic type versus the more invasive breast cancer that can spread regionally or to distant sites. Clinical studies evaluating estrogen and breast cancer mortality show a significant decrease in death rates from breast cancer in estrogen users. Estrogen use in estrogen receptor negative breast cancer survivors after primary treatment of the cancer is currently under investigation. The WHI study will provide some definitive answers to the questions of breast cancer risks associated with HRT.

Ovarian cancer. Ovarian cancer is the fifth most commonly diagnosed cancer among U.S. women. The incidence of ovarian cancer worldwide is 6.5 per 100,000 females. The lifetime risk of ovarian cancer is low, and any increase in risks must be evaluated in context to the overall potential risks and benefits of HRT to a particular patient. Established risk factors include older age, family history of ovarian cancer, BRCA1 and BRCA2 gene mutations, and possibly infertility. Oral contraceptive use and a history of full-term pregnancy are protective. The association of HRT and ovarian cancer is less clear, with two recent meta-analyses showing conflicting results. One meta-analysis showed an increased risk of developing invasive epithelial ovarian cancer in women who used HRT. However, the second meta-analysis showed no increased risk in women using HRT, even though several studies were included in both analyses.

In 2001, a prospective U.S. cohort study also showed an association between HRT use and ovarian cancer. Women enrolled in the Cancer Prevention Study II, with no baseline history of cancer, hysterectomy, or ovarian surgery, were monitored for development of ovarian cancer. Baseline users, former users, and nonusers of HRT were followed to determine the mortality risk from ovarian cancer. A total of 944 ovarian cancer deaths were recorded during the 14 years of follow-up. Women who were baseline users of HRT had higher death rates from ovarian cancer than did women who never used HRT, and the risk was slightly, but not significantly, increased among former ERT users. The duration of HRT use was associated with increased risk in both users and former users. Baseline users with 10 or more years of use had double the risk, while former users with 10 or more years of use had 59% increased risk. The risk was slightly, but not significantly, increased among baseline and former users with fewer than 10 years of HRT.

Gallbladder disease. A review of published studies reported that ERT increases the chance of gallstone formation. With a history of gallbladder disease, HRT should be used cautiously if these women have not had a cholecystectomy.

Adherence issues

Several studies evaluating initiation and persistence with HRT have shown poor results. Some 20% to 30% of women never fill their first prescription. Previous use of oral contraceptives also significantly influenced likelihood of continuing HRT. An analysis of adherence rates with HRT shows that only 75% of patients renewed their first dispensed prescription, and 43% continued their treatment beyond one year. Only 20% of women continued to receive their HRT after four years. Better compliance rates were associated with less than 60 years of age, lower estrogen dosage of less than 0.9 mg/day, and a gynecologist as the initial prescribing physician. Combination of progestins with estrogen was not associated significantly with better rates than estrogen alone. However, continuous versus sequential HRT therapy, rather than ERT, has been associated with improved persistence. Women separated from their partners and women with a higher body mass index were more likely to discontinue therapy.

Data from a recent survey provide some insight to nonadherence factors, with weight gain (67%), breast tenderness (51%), edema (41%), and return of monthly bleeding (36%) being most frequently cited as adverse effects. Women identified weight gain, loss of sexual desire, and irregular bleeding as the most bothersome. However, women who experienced irregular bleeding, edema/abdominal camps, and pelvic pain were more likely to discontinue treatment. In women older than age 65, breast swelling/tenderness (59%) and bloating (18%) were the most frequently cited primary reasons for discontinuance rather than bleeding (9%)/spotting (13%).

Despite the benefits of long-term HRT on preserving bone mass, the majority of women tend to utilize short-term treatment. The cyclical bleedings induced by sequential progestin administration are often unacceptable to women. Lower HRT dosage regimens may relieve menopausal symptoms while avoiding hormone-related side effects leading to discontinuation. Continuous progestin administration provides endometrial protection and is associated with higher persistence rates.

Counseling regarding potential benefits, side effects, and risks associated with HRT could have significant impact on long-term adherence rates. Providing insight and involving women in decisions regarding HRT will also assist in the decision on whether or not to utilize HRT.

Herbal therapies

Many women seek the use of products they consider to be "natural" and "safe" for treatment of menopausal symptoms. Regardless of why women use herbal therapies, pharmacists need to be informed about their use. Phytoestrogens–plant chemicals classified as isoflavones, coumestans and lignans–are similar in structure to human estrogens. Displaying high-affinity binding for the estrogen receptor B, phytoestrogens are thought to have both weak estrogenic and anti-estrogenic activity. Isoflavone phytoestrogens are found in foods such as soy products, whole grain cereals, seeds, and certain fruits and vegetables. Red clover, chickpeas, and other legumes are also isoflavone sources.

Soy (Glycine max) foods and supplements, popular as natural HRT alternatives, are commonly used as fiber, mineral, and protein sources. As a legume, soy has been used in Asian populations for centuries. High soy intake has been associated with a decrease in menopausal symptoms and osteoporosis, as well as a lower incidence of heart disease and several types of cancer.

Epidemiological studies demonstrating the value of soy for menopausal symptoms have involved societies with a high intake of dietary soy. In follow-up, clinical studies evaluating the effects of soy isoflavones on the vasomotor symptoms of menopause have yielded mixed results. While most of the trials showed a decrease in vasomotor symptoms with use of soy supplements, similar benefits were observed with the use of a placebo. Three recent reports, however, have shown benefits for soy isoflavones. In addition to reductions in hot flashes ranging from 76% to 81%, statistically significant improvements were seen in 12 of the 15 parameters studied. These included palpitations (77% versus 17% with placebo), sleep disturbances (69% versus 16%), and nervousness (56% versus 14%).

Soy shows the most promise in the area of cardiovascular health. Diets rich in soy have shown beneficial effects in lowering cholesterol. The use of isolated soy protein appears beneficial as well. The FDA has allowed soy protein to be promoted as a dietary approach to reduce cardiovascular risk. Because of inconclusive data at this point, soy isoflavones should not be taken as treatment for osteoporosis and osteoporotic fractures.

There has been great interest in the use of soy supplements for control of menopausal symptoms in breast cancer patients. Human studies in this area have been somewhat disappointing. The picture becomes even more confusing with animal data showing that genistein, the major isoflavone present in soy, can decrease the effectiveness of tamoxifen. Use of soy isoflavones in breast cancer survivors, especially with concomitant tamoxifen use, should be discouraged until more data emerge.

Since soy isoflavones bind to estrogen receptors, other potential drug interactions include oral contraceptives, ERT, and tamoxifen. Soy protein may also decrease the absorption of thyroid hormones, and patients using thyroid supplements should separate doses by at least two hours.

Red clover (Trifolium pratense), another isoflavone phytoestrogen used for menopausal symptoms, has not been validated in clinical trials. As with trials of soy supplements, a beneficial response was seen to red clover; however, it was not different from that seen with placebo. Limited published clinical data exist evaluating the effect of red clover on bone and cholesterol. As with soy, the theoretical possibility exists for estrogen-related drug interactions.

Black cohosh (Cimicifuga racemosa) has been used in Europe for many years for relief of menopausal hot flushes. Several clinical trials have demonstrated the benefits of black cohosh in decreasing these vasomotor symptoms. Black cohosh was initially thought to have estrogenic properties. Animal studies and in vitro studies have indicated the possibility of estrogenic activity, though these findings have been contradicted by the results of other studies. In clinical trials where vaginal cytology and hormonal profiles were assessed in menopausal women, estrogenic activity has not been observed.

Because of the apparent lack of estrogenic effects, black cohosh supplements are often recommended for patients with a history of breast cancer. However, the most recent study of black cohosh in this patient population failed to demonstrate an advantage over placebo.

Wild yam (Dioscorea villosa) products are widely promoted as natural alternatives to progestin therapy. Wild yam is sometimes used orally but usually applied topically. For menopausal symptoms, use is based on the theory that the diosgenin, the major plant component, will be converted within the body to steroid hormones, especially progesterone, via the intermediate metabolite, dehydroepiandrosterone (DHEA). While diosgenin is used to synthesize steroidal drugs used in HRT, oral contraceptive products, and also DHEA, this conversion has not been shown in humans.

In some animal models, diosgenin has shown some activities often thought to be estrogen mediated, including stimulation of mammary gland growth and osteoporosis protection. Although wild yam has some components that may bind to progesterone receptors, progestogenic bioactivity has not been demonstrated. Ingestion of diosgenin has not been shown to cause an increase in progesterone and, in one study, was even associated with a mild suppression. A recent study compared the effects of a topical wild yam extract cream with a placebo cream in menopausal women. Some symptoms decreased with the investigational cream, but there was no difference between the active and placebo groups. After three months of treatment, no changes were seen in weight, blood pressure, lipid, or glucose levels. There were also no changes in FSH, estradiol, or serum or salivary progesterone. The authors concluded that although the cream seemed safe, there was little effect on menopausal symptoms.

Conclusion

In recent years, the roles of ERT and HRT have become even more confusing for both patients and healthcare providers. As one of the most frequently sought providers of information, pharmacists must understand the complex issues regarding the risks and benefits of ERT and HRT. Though our understanding of these issues continues to evolve, clearly decisions on appropriate therapy must be individualized and rely on women's personal goals and desired benefits. Pharmacists can be instrumental in assisting women to make well-informed decisions on the use of ERT and HRT by providing information, giving support, encouraging adherence, and explaining the currently understood risks and benefits of therapy.

For the distaff side: Hormone replacement therapy.

Drug Topics

2002;21.