Phytoestrogens: a potential role in hormone replacement therapy

Phytoestrogens are plant substances that are recognized to have varying degrees of estrogenic activity. As the demographics of our society move toward an aging population, obstetrician/gynecologists should be prepared to care for the growing numbers of perimenopausal and menopausal women. While hormone replacement therapy (HRT) has been shown to have many benefits, its use is still somewhat controversial. Studies show that only 10% of women eligible for HRT actually use it, reflecting the controversy as well as the lack of education of both providers and patients. Given the imperfections of traditional HRT, other options are being explored. These include the development of new “designer estrogens,” as well as alternative therapies. Unfortunately, because a clinician’s training is in traditional medicine, patients frequently learn more about these alternatives from the lay press than from their physicians. Therefore it is our responsibility to educate ourselves with scientific data about these therapies, the better to inform and guide our patients. With this goal in mind, this article reviews the current literature on phytoestrogens, which may provide an alternative to standard HRT.     

Patient communication in hormone therapy

Common regimens of HRT therapy are reviewed, including common routes of hormone administration. Inconsistent patterns of HRT use are discussed, including the reasons women most often give for discontinuing hormone therapies. Specific issues related to misperceptions and fears regarding HRT are clarified, and specific, focused patient education formats are discussed to address women's common concerns about HRT. Obstacles to HRT use are elucidated, with suggestions for clinicians about how to communicate more effectively with women: clinicians must focus on emotional and physical aspects of HRT choices and tailor therapies to the individual patient. Discussing frankly the very serious concerns of women regarding the association between lobular breast cancer and endometrial cancer is important; discussing and preparing women for possible side effects helps patients cope better if and when side effects occur. Finally, offering a wide variety of HRT therapies provides women with a broader choice if an initial regimen is unsuccessful.     

Cost-effectiveness of raloxifene and hormone replacement therapy in postmenopausal women: impact of breast cancer risk.

OBJECTIVE: To examine the life expectancy and cost-effectiveness of hormone replacement therapy (HRT) and raloxifene therapy in healthy 50-year-old postmenopausal women. METHODS: We performed a cost-effectiveness analysis using a Markov model, discounting the value of future costs and benefits to account for their time of occurrence. RESULTS: Both HRT and raloxifene therapy increase life expectancy and are cost-effective relative to no therapy for 50-year-old postmenopausal women. For women at average breast cancer and coronary heart disease risk, lifetime HRT increases quality-adjusted life expectancy more (1.75 versus 1.32 quality-adjusted life years) and costs less ($3802 versus $12,968) than lifetime raloxifene therapy. However, raloxifene is more cost-effective than HRT for women at average coronary risk who have a lifetime breast cancer risk of 15% or higher or who receive 10 years or less of postmenopausal therapy. Raloxifene is also the more cost-effective alternative if HRT reduces coronary heart disease risk by less than 20%. CONCLUSIONS: Assuming the benefit of HRT in coronary heart disease prevention from observational studies, long-term HRT is the most cost-effective alternative for women at average breast cancer and coronary heart disease risk seeking to extend their quality-adjusted life expectancy after menopause. However, raloxifene is the more cost-effective alternative for women at average coronary risk with one or more major breast cancer risk factors (first-degree relative, prior breast biopsy, atypical hyperplasia or BRCA1/2 mutation). These results can help inform decisions about postmenopausal therapy until the results of large scale randomized trials of these therapies become available.     

Personal use of HRT by postmenopausal women doctors and doctors' wives in the north of Italy.

This study aimed to describe the prevalence of hormone replacement therapy (HRT) use by women doctors and doctors' wives in northern Italy, to explore the relationship between their personal characteristics and HRT use, and to gather information about the use of alternative remedies. A questionnaire was mailed to all physicians born between 1935 and 1955 included in the database of the Medical Register of Turin County (Northern Italy). The questions were meant to explore medical, behavioral, and professional characteristics; personal use of HRT; reasons for and against HRT use; side effects and use of other therapies. 56.5% of postmenopausal women who completed the questionnaire had used HRTand 68.3% of them were current users. The median duration of HRT use was 3.7 years. Only 18.5% of the women had used HRT for 5 years or more; in this case, HRT was started significantly earlier than in the other groups. More than 50% had taken oral HRT, while 39% had used patches; estrogens only had been taken by 21.9%. HRT users had a significantly lower basal body mass index and more vasomotor and dystrophic symptoms at menopause onset compared with non-HRT users. More women on HRT were in good physical health and had an active sex life. Previous breast cancer and family history of cardiovascular diseases were inversely associated with HRT use. The main reason for not taking HRT or stopping it was fear of breast cancer (43.7% and 34.8%, respectively); irregular bleeding and weight gain were also frequently reported as a reason for HRT (30% and 22%). Overall, 22% of women had used alternative drugs to alleviate menopausal symptoms or prevent menopause-related diseases, mainly tibolone (21% among never HRT users and 2% among HRT users; p = 0.015) and phytoestrogens. The prevalence and duration of use of HRT by Italian physicians is consistent with the available data from other Western countries, and is much higher than in the general population. This is in contrast with the very low prevalence of use in the general population and may lead, in the near future, to a larger use of HRT in Italy.     

Hormone replacement therapy in women with a history of breast cancer.

Health care professionals in modern Western societies will meet an increasing number of women surviving breast cancer. How the menopause of these women should be treated is still an open question. Use of hormone replacement therapy (HRT) may, at least in theory, increase the risk for recurrence of cancer, but its categoric refusal is a double-edged sword because it also denies these women all the undisputable health benefits HRT provides. This refusal is not, however, supported by the observational data available so far on this question, because HRT has not increased the risk for breast cancer recurrence. In fact, it is well established that HRT abolishes hot flushes and improves significantly these patients' quality of life. At present, we have no effective nonhormonal alternatives for the control of vasomotor symptoms, and the efficacy of phytoestrogens in the treatment of menopausal symptoms is unproven. Selective estrogen receptor modulators (SERMs) which protect against osteoporosis and perhaps also against breast cancer, and which may have beneficial effects on the cardiovascular system, aggravate hot flushes and are therefore not useful, at least in the first postmenopausal years. In some countries, progestins are often prescribed for the control of such patients' vasomotor symptoms, but their safety has never been assessed in clinical trials, and in theory they can be harmful. Randomized clinical trials (RCT) on the use of HRT in breast cancer survivors are underway, but their completion will take years, and even these may be open to criticism. Tibolone may appear to be an appealing alternative for HRT, but it should also be studied with RCTs in this indication. At present, a patient with a history of breast cancer must be given balanced information as to the possible benefits and risks of HRT, and she herself must make the decision whether or not to start HRT.     

Hormone replacement therapy: curse or blessing?

There is a controversial discussion on the risks and benefits of hormonal replacement therapy (HRT), and many women and doctors have revised their opinions of HRT over the last few years. Complementary and alternative therapies can be considered an option to treat menopausal symptoms. The following issue summarizes the actual knowledge of treatment options of menopausal symptoms.     

Long-term effects of two different continuous combined regimens of hormone replacement therapy on well-being.

Our aim was to compare the effect on well-being of two different continuous combined hormone replacement therapies (HRT) in women starting treatment ('starters') and women switching from mainly sequential HRT ('switchers'). The design was a randomized, double-blind, 1-year, prospective study, including 249 postmenopausal women treated with 0.625 mg conjugated estrogen (CE)/5 mg medroxyprogesterone acetate (MPA) or 2 mg estradiol/1 mg norethisterone acetate (NETA) continuously. The main outcome measure was well-being, reported daily on a validated symptom scale during treatment cycles 1, 2, 6 and 13. Both treatment groups, starters and switchers, improved significantly in episodes of sweating during the first 6 months (p < 0.05). Women treated with estradiol/NETA experienced more breast tenderness compared to women using CE/MPA during the whole study period (p < 0.001), whereas there were no differences in negative mood symptoms between treatment groups. Starters experienced improved well-being during the whole study, whereas switchers experienced a transient improvement during the first 2 months. Overall, negative mood symptoms were more frequently reported by women with a history of premenstrual syndrome (PMS) (p < 0.05). Progestogen side-effects were more pronounced with estradiol/NETA than with CE/MPA combinations. Individual factors, such as previous PMS and previous HRT use, should be taken into consideration when prescribing HRT.     

A comprehensive approach to the menopause: so far, one size should fit all

Although extensive studies have indicated that the benefits of hormone replacement therapy outweigh the risks, many women and health care providers have concerns about safety and side effects. Many alternative therapies are popular with patients, and menopausal women in the United States spent more than $600 million in 1999 alone purchasing these therapies. Several of the more commonly used alternative therapies for the menopause are critically appraised in this article. For women who choose not to take estrogen, and for those who do, the additional benefits of calcium, vitamin D, exercise, stress reduction, and different dietary and lifestyle adaptations may enhance the quality of life as they age. Although they have the potential for being effective and safe options, there has been limited clinical research for the other alternative therapies. Gynecologists and other health care providers should be aware of the lack of evidence for the effectiveness of most of these therapies when they address patient's questions and concerns. Our information about alternative therapies will increase in the coming years. Ultimately, the growing number of available treatment choices will allow individualization of the treatment. Nevertheless, until prospective studies with prolonged follow-up are conducted to evaluate the risks and benefits of different alternative therapies, hormone replacement therapy, which is better studied, will remain the treatment of first choice, and "one size fits all" will continue to describe the management plan for most peri- and postmenopausal women at least in the near future. LEARNING OBJECTIVES: After completion of this article, the reader will be able to summarize the various alternatives to hormonal therapy for menopausal symptoms, describe the effects of phytoestrogens in the management of menopausal symptoms, and explain the origin and clinical use of the more common herbal therapies.     

Premature ovarian failure.

Premature ovarian failure (POF) is gonadal failure before the age of 40 years. Several rare causes have been discovered yet we still fail to identify the cause in many cases. Although it was once thought to be a permanent condition, a substantial number of patients experience spontaneous remissions and even pregnancy. HRT remains the cornerstone of treatment and the only proven method of achieving pregnancy in these patients is by ovum donation. New alternatives to HRT and fertility preservation are under development. Basic understanding of ovarian physiology and pathogenesis of POF is necessary for the development of newer therapies.     

Determinants of hormonal replacement therapy in recently postmenopausal women.

Although the efficacy of hormonal replacement therapy (HRT) on the consequences of the menopause is not questioned, it appears that in Europe and in the USA only a small proportion of women are users of HRT. In this study, we examined the prevalence and the determinants of HRT among 1986 French menopausal women, aged 45 to 55 years, presenting to a preventive medicine centre. Overall, 8.1% of women reported current use of HRT. The estrogen preparation most commonly reported was transcutaneous 17 beta-oestradiol. The first determinant of current HRT was birth-place. Women born in France were nearly four times more likely to be on treatment than foreign-born women. A surgical menopause multiplied the probability of current HRT by 2, as did a high level of education. An age at first pregnancy of more than 20 and less than 4 children were also positively linked with HRT use. Even in this population of recently menopausal women, volunteering to undergo health evaluation, the prevalence of HRT was low. The reservations towards HRT may be partly due to the women themselves, and partly due to the physicians. It seems very important to inform the medical profession about the risks and benefits of HRT, and to understand more precisely the reasons why so few women use HRT.     

PRIMARY AND SECONDARY PREVENTION STRATEGIES AMONG OLDER POSTMENOPAUSAL WOMEN

Women may choose to initiate, reinitiate, or discontinue hormone replacement therapy (HRT) at any time beyond the perimenopausal period. HRT, exercise, and nutrition are reviewed in terms of their potential benefits as primary and secondary preventive therapies against coronary heart disease, osteoporosis, breast and genital cancers, and the maintenance of cognitive function among older postmenopausal women. Lifestyle alternatives involving nutrition and exercise that offer many of the same benefits as HRT are discussed. Since both pharmacologic and lifestyle interventions offer significant benefit for primary and secondary prevention of disease and disability, each should be offered to women for consideration as they enter the perimenopausal period. Additionally, each can be recommended for initiation even at much older ages and subsequent to adverse health occurrences, such as the experience of breast or genital cancer or a cardiac event. Each should be sustained over the long term. The decision whether to discontinue these interventions among the most elderly will be influenced by other quality of life considerations. © 1998 by the American College of Nurse-Midwives.     

Effect of estrogens on skin aging and the potential role of selective estrogen receptor modulators.

Estrogens have a profound influence on skin. The relative hypoestrogenism that accompanies menopause exacerbates the deleterious effects of both intrinsic and environmental aging. Estrogens prevent skin aging. They increase skin thickness and improve skin moisture. Beneficial effects of hormone replacement therapy (HRT) on skin aging have been well documented, but HRT cannot obviously be recommended solely to treat skin aging in menopausal women. Topical estrogen application is highly effective and safe if used by a dermatologist with expertise in endocrinology. The question of whether estrogen alternatives such as phytoestrogens and selective estrogen receptor modulators are effective estrogens for the prevention of skin aging in postmenopausal women remains unanswered. However, preliminary data indicate that such treatment may be of benefit for skin aging treatment.     

Menopausal symptoms and alternative medicine

With the large number of women entering the perimenopausal and menopausal age range in the next decade, use of alternatives to standard hormone replacement therapy will increase. Women’s views of conventional hormone replacement and trends toward “complementary and alternative medicines” have contributed to an increased use of alternative treatments for menopausal symptoms. Growing media coverage and lay literature available on “natural” therapies for the climacteric are making it virtually impossible for practitioners to remain unfamiliar with the various regimens. Information on phytoestrogens, natural progesterones, mineral and vitamin supplements, herbal treatments, exercise, relaxation, acupuncture and homeopathy is flooding the market. Although alternatives to conventional hormone therapy are becoming mainstream, scientific evidence on the safety and efficacy of “natural” therapies is limited. Lack of standardization of alternative supplements and lack of regulation also make it difficult for both consumers and practitioners to evaluate these therapies. Well-designed, controlled studies are needed to obtain further information about these regimens. This, however, is no excuse for practitioners to be unaware of what products are available and their possible benefits and adverse effects. The evidence for various alternative therapies for menopausal symptoms is reviewed in both the lay and medical literature.     

Hormone replacement therapy in women with a history of breast cancer

Health care professionals in modern Western societies will meet an increasing number of women surviving breast cancer. How the menopause of these women should be treated is still an open question. Use of hormone replacement therapy (HRT) may, at least in theory, increase the risk for recurrence of cancer, but its categoric refusal is a double-edged sword because it also denies these women all the undisputable health benefits HRT provides. This refusal is not, however, supported by the observational data available so far on this question, because HRT has not increased the risk for breast cancer recurrence. In fact, it is well established that HRT abolishes hot flushes and improves significantly these patients' quality of life. At present, we have no effective nonhormonal alternatives for the control of vasomotor symptoms, and the efficacy of phytoestrogens in the treatment of menopausal symptoms is unproven. Selective estrogen receptor modulators (SERMs) which protect against osteoporosis and perhaps also against breast cancer, and which may have beneficial effects on the cardiovascular system, aggravate hot flushes and are therefore not useful, at least in the first postmenopausal years. In some countries, progestins are often prescribed for the control of such patients' vasomotor symptoms, but their safety has never been assessed in clinical trials, and in theory they can be harmful. Randomized clinical trials (RCT) on the use of HRT in breast cancer survivors are underway, but their completion will take years, and even these may be open to criticism. Tibolone may appear to be an appealing alternative for HRT, but it should also be studied with RCTs in this indication. At present, a patient with a history of breast cancer must be given balanced information as to the possible benefits and risks of HRT, and she herself must make the decision whether or not to start HRT.     

Taking an integrated approach: managing women with phytoestrogens

An integrated approach can be employed when counselling women about menopausal management options, where lifestyle, complementary therapies and hormone replacement therapy (HRT) are discussed. Women might opt to use an alternative approach to HRT for a variety of reasons, e.g. fear of side-effects and risks or contraindications to HRT. There are many choices of dietary and herbal approaches for menopausal symptoms, which essentially divide into food supplements and herbal medicines. The choice can often be overwhelming and confusing for the woman. Of concern, the evidence for efficacy and safety of some of these complementary therapies can be extremely limited or non-existent. In order to enable women to make a fully informed choice, it is important that, when a recommendation is made regarding a specific complementary therapy, it should focus on preparations for which a significant dataset exists for efficacy and safety and in which there is ongoing research and development. One of the most extensively studied food supplements has been the phytoestrogenic preparation containing red clover isoflavones. There have been six randomized trials thus far studying the impact on vasomotor symptoms, three of which have shown a significant benefit compared to placebo. There are also data from small randomized and observational trials showing positive outcomes for surrogate markers of osteoporosis and cardiovascular disease. A recent study using validated depression scales has shown that women using red clover isoflavones may also derive psychological benefits. Safety data are reassuring for the endometrium and breast, although further studies would be welcome, particularly in women with significant medical risks.     

Factors associated with climacteric symptoms and the use of hormone replacement therapy

BACKGROUND: To investigate factors associated with climacteric symptoms and the use of hormone replacement therapy (HRT). METHODS: A random sample of women aged 46, 50, 54, 58 and 62 years resident in Goteborg, Sweden (n=5,990) were invited by letter to complete a postal questionnaire concerning the menopause and HRT use. RESULTS: The response rate was 76% (n=4,504). Women with a higher education, who exercised regularly and who had regular spare-time activities felt better and had fewer climacteric complaints (p<0.001) compared to lower educated women, women who exercised infrequently and women who had no spare-time activities. Climacteric symptoms were associated with dryness symptoms (dry eyes, skin, hair and mouth), bilateral salpingo-oophorectomy (SOE), use of psychotropical drugs and use of alternative remedies, previous hysterectomy and full-time occupation. Stepwise multiple regression analysis showed significant correlations between vasomotor symptoms and various dryness symptoms, no menstrual periods and use of alternative remedies. Current HRT-users (13%) had used estrogens for 4.0 years and past users (14%) for 4.3 years. A correlation (p<0.005) was found between HRT use and previous use of contraceptive pills, use of alternative remedies and hysterectomy. Education, occupation and the frequency of exercise did not influence the prevalence of HRT use. CONCLUSIONS: This study has shown that the experience of climacteric symptoms and well-being is associated with many different factors. Women with a higher education and those who exercised regularly were more often symptom-free. HRT use was associated with previous use of contraceptive pills, use of alternative remedies and hysterectomy.     

Continuous, combined hormone replacement: randomized comparison of transdermal and oral preparations.

OBJECTIVE: To compare two new transdermal, continuous, combined formulations and an oral regimen of hormone replacement therapy (HRT) with respect to endometrial hyperplasia, bleeding patterns, and climacteric symptoms in postmenopausal women. METHODS: This was a randomized, open, parallel-group trial during 1 year in 441 postmenopausal women who received either a 10-cm2 patch of 0.025 mg estradiol (E2) and 0.125 mg norethisterone acetate, a 20-cm2 patch of 0.05 mg E2 and 0.25 mg norethisterone acetate twice weekly, or tablets of 2 mg E2 and 1 mg norethisterone acetate once daily. The efficacy variables were frequency of endometrial hyperplasia after 1 year of treatment, number of bleeding and spotting days from the fourth to sixth treatment months, relief of climacteric symptoms, and tolerability. RESULTS: The frequency of endometrial hyperplasia was no more than 2% after 1 year of treatment in all groups. One case of simple hyperplasia was detected among the women treated with 10-cm2 patches and two among those treated with oral HRT. From the fourth to sixth treatment months, amenorrhea occurred in 73%, 47%, and 66% of the women in the 10-cm2, 20-cm2, and oral HRT groups, respectively. The 10-cm2 patches and oral treatment were associated with fewer bleeding days than were the 20-cm2 patches (P<.001). During the last 3 months of the treatment year, amenorrhea was found in 100 subjects (86%) for 10-cm2 patches, 61 (65%) for 20-cm2 patches, and in 85 (79%) for oral HRT. All treatments alleviated the climacteric symptoms to a comparable extent. CONCLUSION: In postmenopausal women, 10-cm2 patches relieved climacteric symptoms and prevented endometrial hyperplasia at least as effectively as oral HRT. Amenorrhea was induced early in a high percentage of women using 10-cm2 patches and oral HRT, and these therapies seemed to be convenient, effective, and safe for estrogen deficiency symptoms in postmenopausal women.