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Selective Estrogen Receptor Modulators and Phytoestrogens: New Therapies for the Postmenopausal Woman

  • Lorraine A. Fitzpatrick
    Correspondence
    Address reprint requests and correspondence to Lorraine A. Fitzpatrick, MD, Endocrine Research Unit, Mayo Clinic Rochester, 200 First St SW, Rochester, MN 55905
    Affiliations
    Division of Endocrinology, Metabolism, Nutrition, and Internal Medicine, Mayo Clinic Rochester, Rochester, Minn
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      Estrogen deficiency in the postmenopausal woman results in numerous symptomatic and asymptomatic manifestations, including vasomotor symptoms, osteoporosis, heart disease, bladder and vaginal symptoms, and cardiovascular disease. Estrogen replacement therapy is associated with amelioration of these problems but has attendant risks. A newer class of drugs, the selective estrogen receptor modulators, provides both estrogen agonist and antagonist properties, depending on the target tissue. This article discusses the mechanism by which selective estrogen receptor modulators may vary in their end-organ effects and reviews the clinical studies associated with these compounds. Phytoestrogens are widely used in the United States, but little information is available regarding their potential long-term effects.
      ERT (estrogen replacement therapy), FDA (Food and Drug Administration), HDL (high-density lipoprotein), HRT (hormone replacement therapy), LDL (low-density lipoprotein), SERMs (selective estrogen receptor modulators)
      Although estrogen replacement therapy (ERT) remains the mainstay of treatment of postmenopausal symptoms and prevention of subsequent health issues related to menopause, not all women can tolerate some forms. of estrogen. The advent of pharmaceutical agents with mixed estrogen agonist and antagonist properties has allowed a subset of women to enjoy benefits from selective actions of estrogenlike compounds.
      Estrogen deficiency in the postmenopausal woman usually first manifests as vasomotor symptoms. The hot flushes can be disruptive and disturb sleep patterns, outcomes resulting in fatigue, depression, insomnia, and irritability. Absence of estrogen action occurs at other target sites such as bone, heart, and brain, although clinical manifestations may not become apparent until years later. The effect of estrogen on the preservation of bone is well documented, and bone loss begins with a decrease in estrogen levels during the perimenopausal period.
      • Lindsay R
      • Cosman F
      Skeletal effects of estrogen analogs.
      The possible resultant fractures can lead to severe disability with pulmonary, gastrointestinal, or bladder symptoms and loss of independence due to compression fractures of the spine and hip fractures. Observational studies have indicated an increased risk of cardiovascular disease in estrogen-deficient women. In Western society, cardiovascular disease is the most common cause of death in women older than 50 years. Studies of cognition have also implicated a positive influence of estrogen.
      Because life expectancy is age 80 years for women in Western countries and the average age of menopause is close to age 50 years, approximately 30 years can be associated with an “estrogen-deficiency” state. Use of estrogen in the postmenopausal woman clearly has health benefits but, as with many pharmacological interventions, also has attendant risks. Unopposed estrogen therapy in standard doses is associated with an increased risk of endometrial hyperplasia and cancer, which can be attenuated by concurrent administration of a progestin. The risk of breast cancer in women taking estrogen remains controversial, and many studies indicate no increased risk with ERT.
      • Marsden J
      • Baum M
      • Sacks NPM
      Hormone replacement therapy in women with previous breast cancer.
      Other studies suggest an effect associated with dose or duration of use (or both).
      • Colditz GA
      Relationship between estrogen levels, use of hormone replacement therapy, and breast cancer.
      The risk of thromboembolic events is slightly increased in estrogen users.
      Because of these and other adverse effects and liabilities, long-term compliance for hormone replacement therapy (HRT) is poor. Estimates are that only 20% of eligible women in the United States are prescribed some form of HRT and that 50% discontinue treatment within the first year. Agents with better risk-to-benefit profiles may greatly enhance long-term compliance.

      New Insights Into Estrogen Action: Estrogen Receptors

      New pharmaceutical agents called selective estrogen receptor modulators (SERMs) are being used clinically and in trials for the treatment of symptoms associated with estrogen deficiency. To understand how an agent can have mixed agonist and antagonist effects on a particular target tissue, a review of the manner in which the estrogen receptor binds to its ligand is helpful. The ligand in this case, estradiol, binds to and activates a receptor. The receptor binds to tissue-specific hormone-regulating elements and activates transcription within the cell nucleus. Activation of transcription results in gene activation. With this traditional model, understanding how the SERM compounds can have distinct actions in specific tissues has been difficult.
      The estrogen receptor, like other steroid receptors, binds auxiliary proteins that enhance or inhibit its activity (Figure 1). Thus, when a SERM binds to the estrogen receptor, these “coactivators” may vary and alter the final action of the SERM. In addition to this change in SERM-receptor interactions, SERMs can bind to specific (and different) DNA sequences in the cell with differing intensity of action or gene activation. When this degree of complexity is combined with the recent identification of more than 1 estrogen receptor, termed estrogen receptor α and estrogen receptor β, the possible combinations of receptor activation and subsequent gene activation multiply rapidly.
      Figure thumbnail gr1
      Figure 1An estrogen agonist or antagonist crosses the cell membrane and binds to its receptor. Estrogen receptors then dimerize, at which time they can undergo conformational changes. This dimerization may be with an identical receptor or with a different type of estrogen receptor. The dimeric receptor-ligand complex then binds to adapter proteins, which can inhibit or enhance the action of the receptor-ligand complex. This results in gene activation. Thus, there are several steps along the way in which tissue-specific effects can occur. Dimerization may occur with different types of estrogen receptors within a certain tissue. Specific tissues may contain different enhancers or inhibitors as accessory proteins and thus alter the final estrogen action. Finally, different genes may be “turned on” in specific tissues, an outcome resulting in different end points from estrogen action.
      In summary, these are multiple steps in the cell pathway where a ligand such as estradiol or 1 of the SERMs can exert specific tissue effects: binding to 1 of 2 estrogen receptors (α vs β), altered affinity of binding to activation of a repressor or activating protein in the target tissue, and activation of diverse and specific gene sequences (Figure 1).

      First-Generation Serms: Tamoxifen

      As early as the 1940s, triphenylethylene compounds were evaluated for their effects on target tissues. These early compounds had little effect as antitumor agents, and tamoxifen, a compound with a greatly improved toxicity profile, was not introduced until 1969.
      Tamoxifen is an example of a partial estrogen agonist, a term often used to describe antiestrogen.
      • Smith LL
      Antiestrogen therapy: uncertainties and risk assessment.
      Tamoxifen was approved by the Food and Drug Administration (FDA) in 1969 to antagonize the growth of estrogen-dependent breast tumor cells and is used as adjuvant therapy for surgical mastectomy in breast cancer patients. Tamoxifen binds to estrogen receptors and blocks the effect of endogenous estrogens in some tissues. Most studies with tamoxifen suggest that it has a partial protective effect on the human skeleton. Tamoxifen has been shown to prevent skeletal changes in ovariectomized rats, an action confirming this estrogenlike effect on bone. The effects of tamoxifen on bone and mineral metabolism in premenopausal women remain unknown, although tamoxifen was recently shown to reduce the risk of breast cancer in younger women. The National Cancer Institute/National Surgical Adjuvant Breast and Bowel Project's Breast Cancer Prevention Trial released data for premenopausal women in April 1998. In a 5-year study of 13,388 high-risk women, tamoxifen reduced the risk of breast cancer by 45%. The FDA has approved tamoxifen for the prevention of breast cancer in high-risk women. However, an interim analysis of a smaller, less powerful European-based trial of tamoxifen for the prevention of breast cancer, published in July 1998, indicated no protective effect of the drug.
      Tamoxifen has estrogenlike effects on the cardiovascular system. Tamoxifen increases high-density lipoprotein (HDL) cholesterol and decreases low-density lipoprotein (LDL) cholesterol (Table 1) in breast cancer patients. Venous thrombosis is an adverse effect of tamoxifen, with an incidence similar to that with estrogen. The effect of tamoxifen on the uterus has only recently been appreciated; with long-term use, endometrial hyperplasia with subsequent risk of endometrial cancer has been described. The most common adverse reactions include hot flushes, vaginal discharge, and irregular menses. Currently, tamoxifen is used as adjuvant therapy for prevention of breast cancer recurrence. The usual dose is 10 mg twice a day for up to 5 years. In a patient with an intact uterus, monitoring with yearly vaginal ultrasonography or endometrial biopsy is necessary to prevent endometrial hyperplasia. Alternatively, some clinicians use a progesterone to antagonize the endometrium in a manner similar to that with traditional HRT.
      Table 1Estrogen Agonist/Antagonist Actions on Various Factors
      HDL = high-density lipoprotein; LDL = low-density lipoprotein.
      + = positive effect; - = no effect; ++ = strongly positive effect; ↑ = increased; ↓ = decreased; ? = unknown.
      Factor17P-Estradiol (oral)
      Note that other preparations of β-estradiol may vary in actions depending on the route of administration. Additionally, other oral estrogens used for hormone replacement therapy may have varying effects on target tissues.
      RaloxifeneTamoxifen
      Bone++++
      HDL cholesterolNo effect
      LDL cholesterol
      Total cholesterol
      Stimulation of endometrium++
      Cognition+??
      Thrombosis+++
      * HDL = high-density lipoprotein; LDL = low-density lipoprotein.
      + = positive effect; - = no effect; ++ = strongly positive effect; ↑ = increased; ↓ = decreased; ? = unknown.
      Note that other preparations of β-estradiol may vary in actions depending on the route of administration. Additionally, other oral estrogens used for hormone replacement therapy may have varying effects on target tissues.

      Other Serms In Development

      Droloxifene (3-hydroxytamoxifen) was developed in Germany in the late 1970s. The drug has been tested for the treatment of metastatic breast cancer and osteoporosis in postmenopausal women.
      Droloxifene has a 10-fold higher binding affinity for estrogen receptor-positive breast cancer cells than does tamoxifen. In animal studies, droloxifene has antiestrogenic activity in the immature rat uterine weight test but also causes a partial increase in uterine weight when administered alone. Numerous clinical trials have evaluated droloxifene in patients with metastatic breast cancer who previously received chemotherapy or hormone therapy (or both).
      • Haarstad H
      • Lonning PE
      • Gundersen S
      • Wist E
      • Raabe N
      • Kvinnsland S
      Influence of droloxifene on metastatic breast cancer as first-line endocrine treatment.
      Response rates ranged from 0% to 70%, with most responses occurring in perimenopausal or postmenopausal patients. Unfortunately, uterotropic effects limit its usefulness in the patient who has not had a hysterectomy.
      • Gradishar WJ
      • Jordan VC
      Clinical poiential of new antiestrogens.
      Toremifene is a triphenylethylene that, like tamoxifen, has been approved by the FDA for use in the treatment of breast cancer. Patient tolerability and efficacy against metastatic breast cancer are comparable between tamoxifen and toremifene.
      • Gershanovich M
      • Garin A
      • Ballina D
      • Kurvet A
      • Kangas L
      • Ellmen J
      • Eastern European Study Group
      A phase III comparison of two toremifene doses to tamoxifen in postmenopausal women with advanced breast cancer.
      The side-effect profile of toremifene is similar, in some respects, to that of tamoxifen: an increase in hot flushes and in thromboembolic events. Endometrial hyperplasia can also be an undesirable end point. In 1 clinical study that compared toremifene (40 mg/d) and tamoxifen (20 mg/d) in postmenopausal women with breast cancer, bone mineral density was increased at the Ward triangle by 5% and in the spine by 2% in those treated with tamoxifen. In contrast, women taking toremifene experienced a slight decrease in bone mineral density (0.3%-0.9%).
      • Marliunen MB
      • Hietanen P
      • Tiitinen A
      • Ylikorkala O
      Comparison of effects of tamoxifen and toremifene on bone biochemistry and bone mineral density in postmenopausal breast cancer patients.
      • Saarto T
      • Blomqvist C
      • Ehnholm C
      • Taskinen MR
      • Elomaa I
      Antiatherogenic effects of adjuvant antiestrogens: a randomized trial comparing the effects of tamoxifen and toremifene on plasma lipid levels in postmenopausal women with node-positive breast cancer.
      Toremifene significantly decreased total cholesterol and LDL cholesterollevels in a randomized trial of postmenopausal women with node-positive breast cancer. In contrast with tamoxifen, which decreased HDL cholesterol levels by 5%, toremifene increased HDL cholesterol levels by 14%.9
      Other SERMs are also under evaluation for efficacy and safety.

      Raloxifene: Fda-Approved For Treatment Of Postmenopausal Osteoporosis

      Raloxifene has a binding affinity for the estrogen receptor equivalent to that of estradiol. This compound is a potent inhibitor of the growth of breast cancer cells in culture. Raloxifene is an antiestrogen that has little agonist action on the uterus when administered alone. In the 1980s, phase 1 studies of raloxifene were conducted in healthy male subjects. No clinically adverse events were noted. A phase 2 trial of raloxifene in women with metastatic breast cancer refractory to tamoxifen therapy was completed. Fourteen patients received raloxifene daily for up to 8 months. The drug was well tolerated, but no objective responses were observed.
      • Balfour JA
      • Goa KL
      Raloxifene.
      An international clinical trial
      • Cummings SR
      • Norton L
      • Eckert S
      • MORE Investigators
      • et al.
      Raloxifene reduces the risk of breast cancer and may decrease the risk of endometrial cancer in postmenopausal women: two-year findings from the Multiple Outcomes of Raloxifene Evaluation (MORE) Trial [abstract].
      • Conrad EA
      Postmenopausal breast cancer risk reduced by raloxifene (RAL). Conrad Notes [serial online]. June 1998; doc. 6.
      evaluated the activity of raloxifene in hormone receptor–positive postmenopausal patients with metastatic breast cancer who had not previously received hormonal therapy or chemotherapy for metastatic disease. In that breast cancer surveillance study, a 72% decrease in new breast cancers was noted at 24 months after treatment with raloxifene
      The ability of raloxifene to maintain bone density in rat studies led to the clinical testing of raloxifene as a treatment of osteoporosis. Raloxifene significantly decreased markers of bone resorption in postmenopausal women but was less effective than conjugated estrogens (0.625 mg/d). Raloxifene in 3 doses or placebo was administered to 601 postmenopausal women. Women receiving raloxifene had significant increases from baseline in bone mineral density of the lumbar spine, hip, and total body. Women receiving placebo had a decrease in bone mineral density. At the end of 2 years, women receiving raloxifene, 60 mg/d, had a 2.4% increase in the lumbar spine compared with those receiving placebo and a 2.4% increase for the total hip (Figure 2). A direct comparison of the effect of raloxifene and estrogen has not been published. However, the absolute levels of bone mineral density gained with raloxifene seem to be less than the gains realized by treatment with estrogen or alendronate.
      Figure thumbnail gr2
      Figure 2Effect of raloxifene on bone mineral density at the lumbar spine, total hip, femoral neck, and total body.
      (From Delmas and associates.
      • Delmas PD
      • Bjamason NH
      • Mitlak BH
      • et al.
      Effects of raloxifene on bone mineral density, serum cholesterol concentrations, and uterine endometrium in postmenopausal women.
      Copyright © 1997 Massachusetts Medical Society. All rights reserved.)
      In an unpublished clinical trial regarding the use of raloxifene to prevent bone loss in postmenopausal osteoporosis, at 24 months, the reduction in the frequency of new vertebral fractures was 50%. This result is independent of baseline fractures, age, prior use of HRT, or hysterectomy. The study was not designed to show efficacy on fracture rates at the hip or other sites.
      One of the major problems with ERT is stimulation of uterine tissue. Endometrial thickness was similar in the raloxifene- and placebo-treated postmenopausal women at all times during 1 study.
      • Delmas PD
      • Bjamason NH
      • Mitlak BH
      • et al.
      Effects of raloxifene on bone mineral density, serum cholesterol concentrations, and uterine endometrium in postmenopausal women.
      • Khovidhunkit W
      • Shoback DM
      Clinical effects of raloxifene hy-drochloride in women.
      Endometrial biopsy specimens showed no evidence of endometrial proliferation after 8 weeks of treatment with raloxifene After 1 year of treatment with raloxifene, another group of postmenopausal women had no change in uterine volume or endometrial thickness. In premenopausal women, administration of raloxifene did not alter the menstrual cycle or inhibit ovulation. In the presence of high circulating levels of estrogen (premenopausal women), the effect of raloxifene on the uterus is blunted. Major adverse effects in this trial included a slightly higher incidence of leg cramps (5.9% vs 1.9%) and hot flushes (24.6% vs 18.3%) in the treatment group than in the placebo group. The incidence of breast tenderness and vaginal bleeding was similar to the placebo group and significantly less than the estrogen-treated group. The risk of venous thromboembolism was similar to the risk with ERT. This 3-fold increase in risk is comparable to 2 to 3 cases per 10,000 women per year.
      Raloxifene has been approved for the prevention and treatment of osteoporosis at a dose of 60 mg/d. Adverse effects are few and include an increased risk of thromboembolic phenomena (similar to the incidence with oral estrogens), hot flushes, and leg cramps.
      • Balfour JA
      • Goa KL
      Raloxifene.

      Serms: What About Other Target Tissues?

      Few studies have addressed the effects of the SERMs on other tissues that respond to estrogen. The role of estrogen in the prevention of heart disease, the preservation of cognition' and even the prevention of colon cancer has been the subject of several studies of varying power.
      Several studies have indicated that estrogen has a positive effect on memory and cognition. In epidemiological studies, estrogen delayed the onset of Alzheimer disease, and in small clinical trials, women with Alzheimer disease who are treated with estrogen show improvement in cognitive functioning. The role of the SERMs in cognition remains speculative. One study evaluated the effects of cognition and mood in raloxifene-treated postmenopausal women. No difference was found in cognition or mood in treated patients vs placebo recipients, but the measures of depression and cognition were not validated for estrogen; thus, interpretation of the results is difficult. Further longterm studies with estrogen and the SERMs may provide additional evidence for the enhancement of cognition and more understanding of the mechanism of dementia.
      The effect of raloxifene on cardiovascular risk factors has been partially evaluated. Favorable effects on serum lipid levels have been noted in postmenopausal women treated with raloxifene In 1 study of postmenopausal women, serum concentrations of total cholesterol (−6.4%) and LDL cholesterol (−10.1%) decreased in all raloxifenetreated groups, but concentrations of HDL cholesterol and triglycerides did not change. In a second study of 390 postmenopausal women, HDL2 cholesterol was increased in the raloxifene-treated group compared with the placebo group. In animal models, different results reflect the differences in species, dose, duration and end points. In a rabbit model, raloxifene inhibited cholesterol accumulation in the aorta. In a primate model, raloxifene did not protect against accumulation of plaque compared with estrogen therapy.
      • Clarkson TB
      • Anthony MS
      • Jerome CP
      Lack of effect of raloxifene on coronary artery atherosclerosis of postmenopausal monkeys.
      The cardioprotective effect of estrogen is due to numerous additional properties such as regulation of vasoconstriction, improvements in hepatic cholesterol metabolism, and production of nitrous oxide. Many of these properties have not yet been fully evaluated in women taking raloxifene. Therefore, assessing the overall long-term effect of raloxifene on the cardiovascular system is difficult. The effects on lipid levels vary among the SERMs. Whether this translates to substantial differences in the development of atherosclerosis remains to be proved.

      Phytoestrogen: The Natural Estrogen?

      Phytoestrogens have long had a role in the treatment of various disorders.
      • Tham DM
      • Gardner CD
      • Haskell WL
      Clinical review 97: potential health benefits of dietary phytoestrogens; a review of the clinical, epidemiologiesl, and mechanistic evidence.
      • Murkies AL
      • Wilcox G
      • Davis SR
      Clinical review 92: phytoestrogens.
      Hippocrates used Queen Anne's lace, a plant phytoestrogen, to enhance contraception. The estrogenic effect of phytoestrogens was first recognized as a reproductive disorder in sheep after the sheep ingested a specific type of clover. Many phytoestrogens with mixed estrogen agonist and antagonist properties have been identified. In general, phytoestrogens are more soluble than estrogens but also are capable of exerting systemic effects. A wide variety of commonly consumed foods contain appreciable amounts of different phytoestrogens. Phytoestrogens consist of at least 20 compounds from 300 plants and are found in such common foods as parsley, garlic, soybeans, wheat, rice, dates, pomegranates, cherries, and coffee. In general, they are weaker than natural estrogens, easily broken down, and not stored in tissue. Accumulating evidence from molecular and cellular experiments and animal studies may confirm health benefits of phytoestrogens in relation to cardiovascular diseases, cancer, osteoporosis, and menopausal symptoms.
      Herbs have traditionally been used for treating various health problems, and many herbs contain estrogen receptor-binding properties; the most common are soy, licorice, red clover, thyme, turmeric, hops, and verbena. Other herbs that may contain progesterone-binding properties include oregano, verbena, turmeric, thyme, red clover, and damiana. Estrogen receptor-binding herbal extracts tend to behave as estrogen agonists, similar to estradiol, whereas progesterone-binding extracts could be neutral or act as estrogen antagonists.
      Studies have suggested a protective role for phytoestrogens against several types of cancer, including breast, uterine, and prostate. However, the epidemiological studies cited are often fraught with genetic bias; thus, interpretation of data is difficult. Results from animal studies are also difficult to interpret: in a study of dietary lignin, an insoluble fiber component of cabbage, serum estradiol levels did not change, but the development of uterine cancer was enhanced in these animals.
      Isoflavonoids are a class of flavonoids derived from soybean-based foods. Two dietary isoflavonoids, genistein and daidzein, have estrogenlike activity. In 1 recently published study,
      • Hodgson JM
      • Puddey IB
      • Beilin LJ
      • Mori TA
      • Croft KD
      Supplementation with isoflavonoid phytoestrogens does not alter scrum lipid concentrations: a randomized controlled trial in humans.
      46 men and 13 postmenopausal women who were not receiving HRT participated in a randomized, double-blind, placebo-controlled trial of a 2-way parallel design of 8 weeks' duration. Subjects received 1 tablet containing 55 mg of isoflavonoids, predominantly in the form of genistein, or 1 placebo tablet taken with the evening meal. Subjects continued with their usual diet and physical activity. Assessment of compliance was determined by measurement of isoflavonoids and metabolites in urine samples. No significant differences occurred in serum total, LDL, and HDL cholesterol levels; triglyceride levels; or lipoprotein(a) levels from baseline for those patients treated after 8 weeks of intervention. Excretion of urinary isoflavonoids did not correlate with changes in serum lipid and lipoprotein(a) levels.
      • Hodgson JM
      • Puddey IB
      • Beilin LJ
      • Mori TA
      • Croft KD
      Supplementation with isoflavonoid phytoestrogens does not alter scrum lipid concentrations: a randomized controlled trial in humans.
      In another study,
      • Maskarinec G
      • Singh S
      • Meng L
      • Franke AA
      Dietary sov intake and urinary isoflavone excretion among women from a multiethnic population.
      102 women were monitored to determine the association between urinary isoflavone excretion and self-reported soy intake. Overnight samples were analyzed for phytoestrogens and were compared with dietary self-report in patients of Caucasian, native Hawaiian, Chinese, Japanese, and Filipino ancestry. Japanese women excreted more daidzein, genistein, and glycitein than did Caucasian women. Caucasian women excreted slightly more coumestrol. Soy intake differed significantly among ethnic groups, and a strong correlation was noted between urinary isoflavone excretion and self-reported soy intake.
      • Maskarinec G
      • Singh S
      • Meng L
      • Franke AA
      Dietary sov intake and urinary isoflavone excretion among women from a multiethnic population.
      In a study of women in Wisconsin,
      • Shoff SM
      • Newcomb PA
      • Mares-Perlman JA
      • et al.
      Usual consumption of plant foods containing phytoestrogens and sex hormone levels in postmenopausal women in Wisconsin.
      the number of standard servings per week of whole grain products from dark breads correlated with total testosterone levels. These data were consistent with the possibility that consumption of some phytoestrogen-containing foods may affect levels of testosterone in postmenopausal women.
      • Shoff SM
      • Newcomb PA
      • Mares-Perlman JA
      • et al.
      Usual consumption of plant foods containing phytoestrogens and sex hormone levels in postmenopausal women in Wisconsin.
      In an animal study designed to evaluate cortical bone turnover,
      • Lees CJ
      • Ginn TA
      Soy protein isolate diet does not prevent increased conical bone turnover in ovariectomized macaques.
      41 ovariectomized cynomolgus monkeys were divided into 4 groups and fed a casein and lacto-albuminbased diet with or without 17β-estradiol or a soy proteinbased diet with or without β-estradiol for 7 months. 17β-Estradiol suppressed ovariectomy-induced increases in bone formation rates, regardless of dietary protein source. Soy protein alone did not prevent increased bone turnover and actually increased bone turnover compared with the casein and lacto-albumin–based diet. In humans,
      • Gennari C
      • Agnusdei D
      • Crepaldi G
      • et al.
      Effect of ipriflavone-a synthetic derivative of natural isoflavones-on bone mass loss in the early years after menopause.
      56 women with low vertebral bone density who were less than 5 years postmenopausal were randomly allocated to receive a synthetic derivative of a natural isoflavone, ipriflavone, or placebo. Bone mineral density declined after 2 years in women taking only calcium but did not change in those receiving ipriflavone. A significant difference between treatments was evident at years 1 and 2 (−4.9% change in bone mineral density in the placebo-treated group compared with 0.4% in the ipriflavone-treated subjects). The incidence of gastrointestinal discomfort or adverse reactions was similar in the placebo and treatment groups. The investigators concluded that administration of ipriflavone is associated with a reduction in bone turnover rate.
      The possibility that phytoestrogens may relieve hot flushes associated with menopause has resulted in a proliferation of soy-based products available for consumption. Japanese women are reported to have a low frequency of hot flushes, but the validity of this being due to ingestion of phytoestrogens has been challenged. Several human studies have indicated a decrease in hot flushes in postmenopausal women in response to soy proteins, linseed, soy flour, or a combination of these. However, many of these studies revealed no correlation between hot flushes and vaginal cytology, suggesting that some of the positive results may be due to the natural decrease in hot flushes over time. Overall, assessing an appropriate formulation and dosage of phytoestrogens is difficult, and long-term effects on other target tissues (uterus, heart, brain) remain unknown.
      Little is known about the actions of phytoestrogens on the uterus, heart, brain, and bone. Although these compounds have recently gained widespread use, optimal dose and potential adverse effects remain unknown. Definitive long-term studies in a controlled clinical setting are necessary to assess efficacy vs risk for the phytoestrogens.

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