Alternative Treatment for Menopause
Table Of Contents
Maida Taylor, MD, MPH
THE “CRISIS” OF CONFIDENCE IN SEX HORMONES|
|THE “CRISIS” OF CONFIDENCE IN SEX HORMONES|
Hormone replacement therapy (HRT) came into widespread use between 1941 and 1942 with the approval first of diethylstilbestrol and then conjugated equine estrogens for human use. Before that time, extracts from animal sources and synthetic steroids were available in extremely small quantities at very high prices. The 1950s and 1960s witnessed an extraordinary proliferation and distribution of sex steroids, not only for HRT but for contraception as well. Such a boom was bound to harbinger a bust as is true in the life cycle of innovations, and in 1968 a series of medical publications cited an increased risk of “vascular” disease in women using oral contraceptives.1,2 These vascular episodes included rare arterial events and numerous venous events, and we now know that most morbidity and mortality were confined to oral contraceptive users who smoked.3–5 Adverse publicity about oral contraceptives continued to mount and included a small but highly curable number cases of endometrial cancer in women using sequential birth control pills, pills with relatively high doses of estrogen and progestin given for only a short part of the cycle. The adversities overshadowed the positive impact of oral contraceptives on women's lives. Barbara Seaman published The Doctors' Case Against the Pill in 1968 and helped to fuel a wave of doubt and doom that still washes over us even in the new millennium. Hearings were convened in the US Senate, giving further vent and adding to the imbroglio. By 1977, the US Food and Drug Administration (FDA) in response to pressure from consumer and feminist groups, especially the National Women's Health Network and Consumers Union, mandated the distribution of the package insert with all hormonal preparations, with specific warnings on the risk of cancer and other complications and side effects. The bad taste of these events still lingers. The staff and students at a prestigious Ivy League university were surveyed in 1993; over 35% indicated that they thought the pill caused cancer, and 10% indicated that the pill caused myocardial infarction.6
The conflagration continued, when in 1975, several papers were published documenting an increased rate of endometrial cancer due to the effect of unopposed estrogen used for hormone replacement. Also, in 1989, Bergkvist raised the first warning about possible increased rates of breast cancer with the use of postmenopausal hormone replacement.7 Hormones were demonized, characterized as an expensive, exploitative marketing gimmick that very well might be injurious to women's health.
Providers of conventional gynecologic care, like Sisyphus, repeatedly keep trying to push HRT into a acceptable position, only to have negative publicity send the load crashing back down the hillside. Research confirming the hazards of HRT are more likely to get in scientific journals and then are more likely to be picked up for the front page of the morning newspaper. Good news does not sell, thus bad news hits us day after day. Several recent studies have cast an ever-darkening shadow of doubt about the reputed benefits of HRT. The Heart and Estrogen/Progestin Replacement Study (HERS) trial dashed hopes that estrogen would improve the health outcomes in women with preexisting heart disease.8 The Women's Health Initiative issued an advisory in 2000 about an increase in “vascular” events in HRT users in that ongoing long-term trial. Two journal articles recently reported that HRT failed to slow the progression of active Alzheimer's disease.9,10 The FDA withdrew the osteoporosis treatment indication for estrogen because treatment studies using estrogen in women with antecedent fractures had not been done.
Couple these jabs and punches with the perception that estrogen causes breast cancer, blood clots, and weight gain, and women and physicians have been increasingly uncertain about the utility of HRT. Moreover, with bisphosphonate-selective estrogen receptor modulators for osteoporosis, and with selective serotonin reuptake inhibitors for vasomotor symptoms, why would any woman assume the risk of breast cancer and deep vein thrombosis associated with HRT, even if those risks are small and are associated with minimal increases in mortality? Although primary care providers meter their words and talk about balancing risk and benefits, women are seeking help from venues that they believe, rightly or wrongly, offer a higher degree of safety and trust.
Alternative medicine has been defined as “medical interventions that are neither taught widely in US medical schools nor generally available in US hospitals.” In a 1991 survey, 60 million Americans used alternative medical therapies in 1990 at a cost totaling $13.7 billion.11 The survey was repeated in 1997, and the use of at least 1 of the 16 alternative therapies increased from 33.8% to 42.1%.12 Alternative medicine visits exceeded visits to primary care providers, and 70% of such encounters were never discussed with the patient's regular personal physician.
Astin13 surveyed more than 1000 individuals as to why they used alternative medicine. The highest rates of use were seen in the persons aged 35 to 49 years and 50 to 64 years, with usage totaling 42% and 44%, respectively. Three theories were proposed as tentative predictors of use of alternatives therapies: (1) dissatisfaction with conventional medicine as ineffective, impersonal, overly technological or costly, or yielding adverse outcomes; (2) need for personal control, viewing alternatives as less authoritarian, more empowering, and offering more personal autonomy; and (3) philosophical congruence, that is, the perception that alternatives are more compatible with personal values or ethical/religious belief systems. Predictors of alternative care use included higher educational level, poorer health status, holistic orientation to health, a transformational experience changing one's worldview, and several chronic health conditions such as anxiety, back problems, chronic pain, and urinary tract problems. Cultural factors predicting higher rates of alternative medicine use included environmentalism, feminism, spirituality, and personal growth psychology. Dissatisfaction with conventional medicine was not a significant predictor of use of alternative medicine. Only 4.4% of respondents said that they relied primarily on alternative therapies.
Eisenberg14 characterized the alternative medicine community as an “invisible mainstream,” invisible not to the health consumer, but obviously out of sight and mind of the conventional medical community, at least until very recently. Out-of-pocket expenditures for alternative therapies were estimated at $27 billion in 1997, more than the outof-pocket expenditures for all physician services in that same year. Recently, third-party carriers have started providing coverage for alternative therapies, sometimes assessing an extra premium for such “expanded benefits.” This form of coverage has come in response to patient demand. This sends a challenge to physicians: how to advise patients about alternative medicine and how to determine which therapies are safe and effective. Eisenberg states wisely that “As more patients use over-the-counter herbs, botanicals, and supplements, physicians should discuss such practices with their patients, if only to safeguard their health.” Proper counseling about alternative therapies requires knowledge and time. The use of alternative therapies is now so widely pervasive that inquiry about such practices must be part of all health encounters.
Current estimates are that only 10% to 25% of eligible menopausal women take conventional HRT. Of those given prescriptions for HRT, only 50% have them filled. After 1 year, only 40% to 60% of women who started HRT will continue use.15,16 Low rates of use are due to a number of factors.
Fear of breast cancer is the main reason women refuse to start hormone therapy. In many layperson's vocabulary, the word “hormone” connotes “cancer causer.” When discussing HRT with patients, physicians can assure them that even if HRT increases the incidence of breast cancer, there is every reason to believe that the death rates are decreased, due in part to earlier detection, more limited disease, and more favorable cell type in hormone users. However, women are not solely concerned about dying, but rather are fearful of the debilitation and disfigurement associated with treatment of breast cancer. Breast cancer is seen as a slow, lingering death, full of pain and suffering, suffering that is increased and prolonged by conventional medical offerings such as surgery, radiation, chemotherapy, and other “horrors” yet to be invented by the medical/industrial cancer establishment. Almost all women have friends and relatives with breast cancer, an immediate reality that cannot be calmed with cold statistics from studies and trials.
Mastodynia occurs in 10% to 40% of women receiving HRT.17 Although breast pain, with or without attendant breast swelling, is not a harbinger or risk for breast cancer, pain can frighten women and often prompts them to stop HRT.
Discontent with HRT is further promoted by that fact that hormone use leads to uterine bleeding. As physicians, we can aggravate and inflame patient anxiety with the following paradox. We tell women that postmenopausal bleeding may be a sign of endometrial cancer. We then place women on hormones that they “know” cause cancer. Then when they have bleeding, paradoxically, we tell them it is “normal” and to ignore it. These seemingly contradictory messages undermine confidence in conventional medicine and its practitioners. Physicians have been led to believe, based on outcomes of clinical trials, that unscheduled bleeding will resolve on continuous combined regimens within 6 months of starting HRT. A recent study by Ettinger18 found that 20% of women receiving continuous combined therapy continue to have breakthrough bleeding into the second year of treatment, and that 30% to 40% of women receiving sequential therapy experience abnormal or off-cycle bleeding as well. In addition, women do not want to continue to have menstrual-like flow for the rest of their adult lives.
Women are convinced that hormones, not life style, lead to midlife obesity. The Rancho Bernardo study19 found that estrogen users weigh less at the outset but are equal in weight to nonusers at the end of the study period. This suggests that the users have gained more to “catch up” to the heavier nonusers. Estrogen does decrease metabolic rate and lowers fat utilization,20 and progestins can have anabolic effects and may stimulate appetite for some. Conversely, Haarbo21 reported that abdominal fat deposition was significantly lower in HRT users than in nonusers. Although all women in this Finnish study gained weight, HRT users gained less overall weight and fat than nonusers. Nonetheless, women are convinced that hormones contribute to middle-aged spread.
Clinical impression and experience suggest that approximately 10% of women experience some degree of mood disturbance associated with the progestational arm of HRT. Menopause per se does not increase the incidence of psychiatric disorders, suicides, or hospitalization. Moreover, progestins have not been documented to cause mood disorders de novo. The progestin in HRT may, by downregulating estrogen receptors, worsen mood in susceptible women. The indictment of medroxyprogesterone acetate as a cause of depression and agitation is so widespread that women have come to expect HRT, in general, to lead to dysphoria. Women with and without their doctors knowledge, let alone permission, often discontinue the use of progestins or modify the dose of progestin, in many cases taking amounts below the levels needed for endometrial protection. No data exist on the incidence of dysphoric reactions with progestins other than medroxyprogesterone acetate, but clinical experience suggests that micronized progesterone, norgestrel and norethindrone can cause mood impairment in rates and intensity similar to medroxyprogesterone acetate. The only comparative data come from the Postmenopausal Estrogen/Progestin Interventions (PEPI) trial, where the incidence of anxiety and cognitive complaints, assessed by self-administered questionnaire at years 1 and 3 of the trial, were equal in the placebo, estrogen, estrogen plus medroxyprogesterone acetate, and estrogen plus micronized progesterone groups.22
The use of HRT promotes the concept of menopause as a deficiency disease, requiring medical management. The medicalization of menopause requires a high degree of dependency on the medical establishment—insurance, physicians, and pharmacies—and so greatly lessens the real and perceived autonomy of the patient. Laywomen take great umbrage with the classification of menopause as a deficiency disease. Menopause, when viewed sociologically, has been classed as a passage and transition in life, status, and role, not as a disease. Although they are fearful of long-term disability in the far-off future, women are also fearful of dependency now. Women worry about becoming “hooked” on estrogen, and about becoming overly dependent on doctors. The growth of alternative therapies for menopause has burgeoned because women want to retain some control in the face of the inevitabilities of aging.
Although alternative care may not offer medical advances or advantages that can be proven by statistical objectification, they offer subjective superiority that patients find exceedingly appealing. Visits to alternative “healers” are unhurried. The settings are comfortable. Therapies are proffered with universal guarantees of success, coupled with overwhelming optimism. There is an emphasis on individualization, even when it is not needed for therapeutic success. Medical practice, in contrast, requires us to provide informed consent and disclosure of a well-balanced slate of benefits and risks. Alternative and complementary practitioners appear to have a vast tableau of choices: nutrition, herbs, teas, foods, minerals, body therapy, meditations, and more. Physicians seem to have only one limited offering—hormones. The world of complementary medicine has seemingly co-opted preventive care as well, often acting as though alternative practitioners were the first on the planet to discover the benefits of a healthy diet and regular exercise. Complementary and alternative medicine (CAM) covers an expansive array of offerings, as represented in part by listings found in MEDLINE (Table 1).
In the past, only a small segment of the research done on alternative medicine has been accessible through conventional medical information sources. MEDLINE has added the following listing of headings relevant to CAM and has expanded its database to include more diverse publications. Still, much of the information is not readily available other than in abstract form, and abstracts frequently tell only part of the story; thus, the quality of the publications cannot be assessed. Studies tend to be small and often are not blinded or randomized. Criteria like those used in developing a “best” evidence protocol are difficult, if not impossible to apply under these circumstance. The following opinions are based on the best evidence to date, and major changes occur almost daily in this field as new reports and papers come to press.
The North American Menopause Society reported in 1997 that more than 50% of menopausal women surveyed reported trying to maintain a healthy weight, eat a balanced diet, take vitamins and calcium supplements, and engage in regular exercise as menopausal wellness interventions. Six percent reported using acupuncture, and 30% reported using either plant estrogens, natural hormones, or herbal therapies. It is a small stepwise progression from taking calcium to taking a bone “supplement” with boron and magnesium added, to taking megavitamins and using herbals and botanicals. Clearly, the use of plant-derived substances as substitutes for hormones is the most common CAM practice used in the treatment of menopause-related conditions.
The term herbal refers to only the herbaceous parts of plants, the leaves and stems, not the seeds, flowers, fruits, and roots; the term botanical includes foods and supplements derived from any plant part.
Almost every society has some sort of herbal or botanical tradition of healing, and at least 30% of modern medicines are refinements of plant-based products. Before the use of hormone isolates and synthetic hormones, a wide array of nonsteroidal and botanical medicines were used for menopausal management. The 1899 Merck Manual listed an amusing array of “drugs” for the climacteric including sedatives, narcotics, vasodilators, purgatives, homeopathic medicines, and ovarian extracts. The botanicals offered include belladonna, black cohosh, marijuana, and opium (Table 2).
In botanical medicine, different plants and even different parts of the same plant are said to have different therapeutic actions. Different varieties are said to have different activity; for example the distinctions drawn about the effects of Asian versus American versus Siberian ginseng. Different botanicals are recommended for different symptoms of menopause, and no one substance is cited as a panacea (except for estrogen) for all ailments. Thus, menopausal botanical remedies often are made from a combination of plants to address a wide array of symptoms. Within traditional Chinese herbal medicine, the substances compounded together are often said to work in concert and to act synergistically, thereby producing an effect that cannot be achieved when trying to use isolates or single botanical agents. Thus, we have herbals recommended either alone or in combination for management of one or more conditions, including vasomotor symptoms, sleep disorders, flagging libido, urogenital atrophy, mood disorders, fatigue, and memory impairment. Table 3 lists botanicals commonly recommended for symptom management.
ANGELICA ( ANGELICA ARCHANGELICA L, ANGELICA ATROPURPUREA L ).
Angelica, which is used to flavor Benedictine and Chartreuse, offers no proof for any of its therapeutic claims and uses. Cases of toxicity have been reported when large amounts have been taken to try to induce abortion. Toxicity and mutagenicity are concerns. Patients should be told not to use angelica because it holds potential for photosensitization and cancer induction.
BLACK COHOSH ( CIMICIFUGA RACEMOSA L NUTT, FAMILY RANUNCULACEAE ).
Black cohosh has a variety of folk names, including black snakeroot and bugbane. Black cohosh was the main ingredient in Lydia Pinkham's Vegetable Compound, and an ethanol extract is sold over the counter as Remifemin in the United States and Europe. The company that manufacturers Remifemin publishes a monograph containing a series of clinical trials. A cursory glance at these studies gives one the impression that black cohosh offers profound palliation for “neurovegetative” menopausal symptoms such as anxiety, depression, and other mood disturbances, and significant reductions in the Kupperman's Menopausal Index. Closer scrutiny reveals that some studies are of very short duration and some are done in women with one or both ovaries in situ, and that in some, the women treated with estrogen have little or no improvement in symptoms. Black cohosh, as well as a number of other plants, are reputed to have estrogenic activity, and therefore are listed in herbal text books as contraindications for women with estrogen-sensitive disease processes. Table 4 lists botanicals claiming to have estrogenic effects in humans or animals. Reassuringly, these studies show no estrogen-like effects on target tissues traditionally used as in vivo measures of estrogen effect. Black cohosh shows not effect on endometrial thickness and vaginal maturation index, and no change in serum luteinizing hormone (LH), follicle-stimulating hormone (FSH), estradiol, and prolactin.23 Clinical studies recommend 20 mg of extract twice daily, occasionally 40 mg twice daily. The literature recommends use for no more than 6 months. There is no reason cited for this proscription, except for a lack of long-term studies.
*Clinical trials data available.
· Research does not support claims of estrogenic effects measured in vivo and in vitro assessments.
Black cohosh should not be confused with blue cohosh, Caulophyllum thalictroides, which has weak nicotine activity and is thought to have toxic potential. Obstetricians should be alerted to the fact that both black and blue cohosh are “prescribed” during the late third trimester of pregnancy and are also given in enemas to stimulate contractions in desultory labor, an herbal practice that appears to be completely unsubstantiated.
CHASTEBERRY OR VITEX ( AGNUS CASTUS L VERBENACEAE)
is also known as Chaste tree, Monk's pepper, agnus castus, Indian spice, sage tree hemp, and tree wild pepper. Studies have shown that vitex contains hormone-like substances that bind competitively to sex hormone receptors, producing antiandrogenic effects, hence its use as an anaphrodisiac said to reduce libido in males. Antithetically, vitex is recommended to boost libido in postmenopausal women. Studies suggest that vitex can be used to treat the inadequate luteal phase, and that it restore LH-releasing activity. It is also recommended for vaginal dryness and depression at menopause. Vitex's purported antihormonal activity explains its proposed role in treating mastalgia. In a double-blind randomized trial using vitex versus pyridoxine, Wuttke and colleagues24 demonstrated no difference in self-assessed scoring in women with premenstrual tension syndrome. Very little quality evidence exists to support the claims about vitex.
DONG QUAI, DANG GUI, TANG KUEI ( ANGELICA POLYMORPHA MAXIM, VAR SINESIS OLIV, AKA A. SINENSIS [OLIV] DIELS).
Dong quai is a type of angelica. The root stock is advised for virtually every gynecologic ailment. Again, no substantiation exists for the claims made about dong quai, other than “the Chinese have used it for centuries.” A recent study in San Francisco found that dong quai was no better than placebo in alleviating menopausal symptoms and demonstrated no detectable changes in endogenous steroid levels, nor did it appear to affect vaginal maturation or endometrial thickness.25 The study has been criticized for using 4.5 mg because a traditional herbal practitioner may use 10 or even 12 g/day. Moreover, critics state that dong quai is never used alone, but always in combination with other herbs to produce the synergy needed for clinical efficacy. We await studies of such a product. Products are sold and “experts” do, however, frequently recommend dong quai as a single herbal. More importantly, dong quai contains numerous coumarin-like substances, acts as an anticoagulant, and is photosensitizing. Given the lack of data supporting efficacy, and anticoagulant and other potential side effects, dong quai should not be used for menopausal management.
EVENING PRIMROSE (EVENING PRIMROSE, EVENING STAR, OENOTHERA BIENNIS L, FAMILY ONAGRACEAE ).
Evening primrose produces seeds rich in oils containinggamolenic acid. Because the whole plant is edible and often is used in pickles, soups, and sautés, the seeds are pressed to extract the oils. Available commercial preparations contain both the gamma and cis forms of linolenic acid, typically 45 mg gamolenic acid plus 365 mg cis-linolenic acid. Patients are told to use 1 to 12 capsules a day at a cost of 25- per capsule. Consequently, primrose oil is expensive. Well-controlled clinical trials show that evening primrose oil is ineffective in treating premenstrual syndrome and vasomotor symptoms during menopause.26,27
GINSENG ( PANAX GINSENG).
Ginseng is reputed to be an adaptogen, helping people deal with internal and environmental stressors. It is supposedly estrogenic, easing menopausal symptoms. Ginseng is promoted to boost athletic performance and stamina. The great hook, as it is for many herbal products, is the promise of weight loss without dieting or exercise. The side effects reported with ginseng have not been well studied. They are said to include irritability, tachycardia, insomnia, and restlessness. Because many ginseng products are highly adulterated, often with large quantities of caffeine, the side effect profile might be the result of the additives. The same is applied to a wide array of botanicals (Table 5) and although most of the research in the field has been done on American and Korean varieties of Panax, some “experts” say that Eleuthera is more effective but less often studied. Most claims reside with research done in rats; a very limited body of information is available from clinical trials.
Lindgren and associates28,29 presented two abstracts on the effects of ginseng on quality of life in postmenopausal women at the North American Menopause Society meeting in Toronto in 1998. The first study included 178 women undergoing active treatment and 176 placebo cases studied for using measures of estrogenicity, including vaginal maturation index, FSH, and estradiol. No differences were seen in controls versus estrogen users. A separate study of 191 women undergoing active treatment and 191 placebo controls demonstrated no improvement in vasomotor symptoms. The improvements were seen in scales measuring depression, general health, and well-being.
There is no evidence that ginseng improves athletic performance, despite claims made in radio and television ads. A physiology study found no difference in oxygen consumption, exercise time, workload, plasma lactate, and hematocrit at peak levels, or for heart rate and rate of perceived exertion at 150 watts, 200 watts, and peak in 20 male and 8 female college students after a 3-week supplementation period of 200 mg of 7% Panax ginseng.30
More importantly, the American Botanical Council tested 54 ginseng products. They found minimal amounts of ginseng in 60%, no ginseng in 25%, and a high degree of adulteration with caffeine. As a specific remedy for menopausal complaints, ginseng has scant documentation of efficacy. Patients in the United States are being cheated more often than not when purchasing ginseng preparations. If this fact were known, it might cause consumers to be more cautious about their expenditures for ginseng products.
LICORICE ( GLYCYRRHIZA GLABRA L LEGUMINOSAE ROOT).
Licorice is one of a number of botanicals, including ginseng, fenugreek, sarsaparilla, gotu kola, dong quai, and wild yam, claiming estrogen-like activity. Commercial uses include as a sweetening agent, happily in beers and unhappily in cigarettes. Licorice candies sold in the United States generally are flavored with anise oil. Before the synthesis of mineralocorticoids, licorice was used to treat Addison's disease. The glycyrrhizin in licorice root blocks 11-β-hydroxysteroid dehydrogenase, which converts cortisol to cortisone, thus increasing renal cortisol levels, in turn lowering levels of rennin and aldosterone. The resultant hypertension often persists for months after consumption ceases. As little as 0.5 to 1.5 g of licorice taken daily for little as 1 week may produce signs of pseudoaldosteronism: fatigue, hypertension, sodium retention, potassium wasting, and congestive heart failure.31,32 Evidence of its steroidal effects include decrease in serum testosterone in males.33 Deglycyrrhizinated (DGL) licorice extract loses its clinical efficacy. But even DGL licorice contains 3% glycyrrhizin and holds some potential for harm. Its use in menopause relies on folk wisdom and laboratory evidence that one component of licorice, glycesterone, displays weak estrogenic activity equal to approximately 1/533 of estradiol in laboratory tests. Many multiple botanicals for menopause list licorice on their boxes, although the amounts are usually small. However, this is undocumented by any regulatory process. Physicians should ask all patients with unexplained hypertension about herbal use, particularly herbs supposedly containing licorice. Its use for menopause cannot be confirmed. Recent reports state that licorice ingestion can lower testosterone in men.33
Phytoestrogens are naturally occurring plant sterols capable of exerting effects similar to estrogen. Phytoestrogens are broken into three groups:
Studies of populations in which large amounts of soy-based phytoestrogens are consumed report lower rates of a wide variety of cancers, including breast, endometrium, prostate, intestine, and pancreas. In countries such as China and Japan, where the local diet is high in soy foods, women appear to have few menopausal ailments, and, coincidentally, the incidence of breast, endometrial, and prostate cancers are also markedly reduced when compared with Westernized countries.
Asian diets typically contain 40 to 80 mg/day isoflavones, whereas American diets average less than 3 mg/day. Although American and European diets tend to elevate plasma levels of sex hormones and decrease sex hormone-binding globulin concentrations, thus increasing the exposure of peripheral tissues to the effects of circulating estrogens,34 high soy diets act through several mechanisms to lower effective circulating and tissue levels of steroids. High isoflavone intake decreases LH levels and secondarily decreases estrogen production. Bean products are rich sources of diphenols, which are thought to lower cancer risk by modifying hormone metabolism and production and limiting cancer cell growth. Bean foods also provide large amounts of fiber, and fiber modifies the level of sex hormones by increasing gastrointestinal motility. Fiber alters bile acid metabolism and partially interrupts the enterohepatic circulation,35 causing increased estrogen excretion by decreasing the rate of estrogen reuptake in the enterohepatic system.
A recently published study by Lu36 helps to elucidate the magnitude of altered steroid metabolism induced by high isoflavone intake. Women were fed 36 oz of soy milk a day for one menstrual cycle. The calculated intake of isoflavone in this amount of soy milk is approximately 100 mg of daidzein (mostly as daidzin) and 100 mg of genistein (mostly as genistin). Serum 17 beta-estradiol levels dropped by 31% to 81% at various times in the menstrual cycle during the feeding cycle. Luteal phase progesterone levels fell by 35% and dehydroepiandrosterone sulfate levels by 14% to 30%. Steroid levels remained lower for an additional two or three menstrual cycles. Menstrual cycle length increased from 28.3 to 31.8 ± 5.1 days during the month of soy milk and did not return to prestudy length until five to six cycles later.
This study offers two profound pieces of information. First, when isoflavone intake is increased, endogenous endocrine function modifies very rapidly thereafter. Second, the effects of such dietary modification are long lived, disappearing slowly over time. These findings suggest that although a lifetime of exposure to isoflavones clearly modifies risks, initiation of dietary changes later in life might substantially modify risk in a very short interval thereafter. Like quitting smoking or starting exercise, it may never be too late to start enjoying the benefits of soy-based foods. Interventional trials examining the effects of soy-based foods and isoflavone supplements are presently underway. The FDA dubbed soy a “heart healthy” food in 1999, and soy product manufacturers put this claim on their labels if the foodstuff contains at least 6.25 g of soy per serving.
Very few interventional trials have been done assessing the impact of isoflavones on menopausal symptoms such as hot flashes, dyspareunia, and vaginal dryness. Several trials are currently in progress,37 and oral abstracts were reported in 1996 at the Second International Symposium on the Role of Soy in Preventing and Treating Chronic Disease. In abstracts, a nutritional bar containing 40 mg of isoflavones did not ameliorate hot flashes, although a supplement containing isoflavone 160 mg/day produced a 50% reduction in the frequency and intensity of mild to moderate vasomotor symptoms.
Albertazzi and colleagues38 recently published a double-blind, parallel, randomized placebo-controlled trial in 104 women. Using an isolated soy protein supplement in powder form and a casein placebo, the control group experienced a 30% reduction in hot flashes, whereas soy users experienced a 45% reduction. The 30% decline in symptoms in the placebo group cautions us, once again, about being overly enthusiastic about anecdotal information about alternatives. Although soy offered a moderate benefit, estrogen replacement mitigates hot flashes by 90%. For women with severe and frequent hot flashes, soy may not offer effective symptom relief. There are no studies on the concomitant use of soy and estrogen for symptom control. Table 6 lists prepared soy foods that are becoming increasingly available. Most foods contain 1.2 to 1.5 mg of isoflavone per gram of soy, although some sources have higher concentrations, such as tempeh. To get 80 to 160 mg from typical dietary sources is difficult and entails eating about 20% to 25% of daily caloric intake as soy. Relying on one food source for such a large portion of calories will lead to nutritional deficits. The easy solution to getting lots of isoflavones is to use isoflavone-rich foods such as tempeh, or isoflavone-rich supplements such as soy shake mixes and soy bars.
Soy products are excellent sources of plant proteins, and using them as a substitute for animal protein holds the promise of lowered rates of malignancy and vascular disease. Studies are underway to assess whether supplementation with isoflavones can lower that rates of primary breast cancer or alter the rates of recurrent in women with antecedent breast cancer. It remains to be seen whether whole soy-based foods, soy isolates, or isoflavones are effective in modifying patterns of disease. Presently, we can estimate that between 40 to 160 mg/day of isoflavones may be highly beneficial.
No interventional trials have been done assessing the impact of additional dietary soy or isolated isoflavone supplements on bone mass losses. A genistein-derived synthetic isoflavone, ipriflavone, slows bone reabsorption and stimulates bone collagen synthesis. Ipriflavone 600 mg/day is approved in Europe and Japan for treatment of osteoporosis and has been found to slow or reverse bone loss in natural menopause,39 in rapid phase bone loss immediately after surgical menopause,40 and in women with gonadotropin agonist-induced bone loss.41
Several commercial isoflavone preparations are currently being promoted in the United States. Promensil is produced from red clover. According to the technical information provided by the manufacturer, each 500-mg tablet contains approximately 200 to 230 mg of dried aqueous alcoholic extracted Trifolium pratense (red clover), and contains four isoflavones: biochanin A, formononetin, daidzein, and genistein in the ratios 20:12:1:1. Most of the biochanin and formononetin are rapidly demethylated after absorption to genistein and daidzein, respectively. Conversion is incomplete, so that some residual detectable amounts of these two isoflavones remain in the circulation and exert some biological activity. Promotional literature from the manufacturer cites general studies on isoflavones and cancer. A recent single-arm study of this product in 16 women showed a 40% to 60% decrease in the number of flashes, number of night-time flashes, and the severity of vasomotor symptoms.42 The study had no placebo controls, and because virtually all trials of estrogen for vasomotor symptoms find a 40% placebo response, this trial should be regarded with general skepticism.
Estroven is a supplement derived from soybean and pureria root, containing 50 mg isoflavones with black cohosh, kava kava, calcium, boron, vitamin E, B12, folic acid, thiamine (B1), riboflavin (B2), niacin (B3), and selenium. Advertising material from the manufacturer vaguely states that in consumer trials, 70% of women felt that Estroven met or exceeded their expectations after 14 days of use. This type of study has little scientific validity.
RED CLOVER ( TRIFOLIUM PRATENSE L FABACEAE)
is a forage plant containing phenols and tannins. In Australia, sheep grazed on large amounts of subterranean red clover were rendered sterile because of disruption of estrus cycles. No studies in humans can be found about extracts or concentrates of red clover affecting female endocrine functions. As noted previously in the section on phytoestrogens, Promensil, a red clover derivative, exerts its effects through concentrated levels of isoflavones synthesized from the plant, not from coumestans.
SAW PALMETTO ( SERENOA REPENS [BATR], S. SERRULATA [MICHX] NICHOLS ).
In Europe, a fat-solubilized form of saw palmetto is used to treat benign prostatic hypertrophy. The plant extract has minor estrogen-like activity, estimated to be <fra1/10>, that of estradiol, whereas purified beta sitosterol derived from the plant has estrogenicity equal to one tenth the activity of estradiol. Saw palmetto is also touted to have antiandrogenic activity, but the mechanism is unknown. Its use in menopause to stimulate flagging libido seems inconsistent with other claims made and is not supported by any source material.
ST. JOHN'S WORT ( HYPERICUM PERFORATUM ).
Extracts of this flower have been used for centuries to treat mild to moderate depression. The constituents include hypericin, pseudohypericin, hyperforin, and flavonoids. Several mechanisms of action for the psychotropic effects of St. John's Wort (SJW) have been proposed but not confirmed, including (1) inhibiting monoamine oxidase (MAO) and catechol methyl-transferase (COMT); (2) decreasing corticotropin-releasing hormone and then decreasing levels of cortisol or affecting GABA receptors in the brain; and (3) blocking serotonin receptors. Hypericin does not appear to be an MAO inhibitor and is no longer thought to be the substance responsible for the effects of SJW. Preparations previously standardized to the hypericin content now are being prepared to a standardized level of hyperforin, usually 0.5%.
Hypericum perforatum is sold in Germany as an antidepressant, perhaps even more commonly prescribed than traditional antidepressants, and estimates of use in the United States top $45 million dollars in sales. Although products sold in Germany are manufactured to strict guidelines, regulation and standardization are virtually nonexistent in the United States, and patients are not necessarily getting what they pay for. The Los Angeles Times had the potency of 10 SJW products tested and found that 3 contained less than half the amount on the label. Only three had the doses listed. Reports that Hypericum perforatum compares favorably to antidepressant drugs like amitriptyline, imipramine, and, more recently, fluoxetine, are exaggerated. The doses of antidepressant used in most studies were marginal and subtherapeutic, whereas the amounts of SJW are generally high.43
Side effect profiles in studies seem to document that SJW is safer and better tolerated. Most studies have looked at mild to moderate depression, seasonal affective disorder, and depression in the elderly. Studies in severe depression are lacking. Fifteen controlled trials have been reported and assessed by meta-analysis by Linde and colleagues.44 Combined analysis of 1757 subjects found that hypericin <1.2 mg/day provides a 61% improvement in mild to moderate depression, whereas higher doses up to 2.7 mg/day produce a 75% rate of improvement. In July 1999, the National institutes of Mental Health began a 3-year study testing SJW against a selective serotonin reuptake inhibitor (SSRI) and placebo.
An emerging body of literature documents profound drug-herb interactions with SJW. In particular, SJW decreases serum concentrations of cyclosporine, decreases international normalized ratio (INR) resulting from use of warfarin, and lowers serum levels of the protease inhibitor indinivar. SJW has also been found to lower levels of theophylline, amitriptyline, and the steroids in oral contraceptives. Therefore, patients who are using or who have recently discontinued the use of MAO inhibitors or SSRIs are cautioned not to use SJW for several weeks, if not months, after stopping these drugs, and visa versa. Fugh-Berman45 summarized drug-herb interactions in a recent article and cited evidence of drug-herb interactions attributable to SJW, including mild serotonin syndrome in patients who mix SJW (Hypericum perforatum) with SSRI and decreased bioavailability of digoxin, theophylline, cyclosporine, and phenprocoumon when these drugs are combined with SJW. The effects appear to be due to potent stimulation of metabolism in the cytochrome P450 system by SJW.
A 30-day supply of SJW costs around $15, considerably less than the retail price of the pharmaceutical SSRIs, which typically cost about $55 per month. Sporadic reports of interaction with analgesics such as meperidine and tramadol, anesthetics, sedatives, sex steroids, lithium, reserpine, and even dextromethorphan-containing cough medicines should cause unease. Moreover, given these problems and the anticoagulant activity of many herbals, anesthesiologists are asking for a 2- to 3-week washout of all botanicals before elective surgeries. Because emergency surgeries and traumas cannot be anticipated, it would be prudent for practitioners to advise against the use of SJW in general.
UVA URSI ( ARCTOSTAPHYLOS UVA URSI L ).
Uva ursi, also commonly known as bearberry and mountain box, is widely recommended as a urinary aseptic and bladder sedative. It contains the phenolic glycoside arbutin, which produces hydroquinone, a mild urinary septic, but this conversion only takes place when urine is alkalinized.
Uva ursi should not be regarded as a substitute for antibiotics in active urinary infection. Hydroquinone, the active ingredient, is potentially toxic. One gram (equal to 6 to 20 g of plant material) may induce tinnitus, nausea, vomiting, shortness of breath, seizures, and loss of consciousness, and 5 g is clearly lethal.
VALERIAN ROOT ( VALERIANA OFFICINALIS L VALERIANACEAE ).
Valerian root, the common valerian or garden heliotrope, has been used for ages as a tranquilizer and soporific. The effective constituent has never been identified but is thought to be a γ-aminobutyric acid (GABA) derivative. Note that a similar GABA-like compound has been found in chamomile, which also is proffered as a herbal sleep aid. Little is known about its actions, effects or potential drug-drug interactions. Before the common use of benzodiazepines and barbiturates, many psychiatric disorders were treated with valerian. There are few reports of valerian toxicity, but dystonic reactions and visual disturbances have been mentioned in the literature, perhaps because of other drugs used concomitantly or contamination or adulteration. Recently, a case of seizures was reported when a man taking high doses of valerian abruptly stopped taking it. 45a When taken as an extract, tea, or alcohol tincture, it seems to provide some mild, limited sedating and calming effects without the lingering metabolites that continue to circulate after taking diazepam. When L-tryptophan was taken off the market, valerian enjoyed a mild upswing in popularity. Despite its lack of toxicity, many botanical practitioners recommend against its use during pregnancy and lactation.
In 1998, the US Pharmacopoeia began publishing a series of updated monographs on botanical medicines and has stated that data on the use of valerian are not good enough to prove that it is effective. Therefore, USP advisory panels “do not support its use.”46
WILD YAM CREAM.
Yam creams containing extract from Diascorea villosa, the Mexican yam, claim to provide effects similar to natural progesterone. Purportedly, the plant sterol diosgenin is converted into progesterone in the body and alleviates “estrogen dominance.” There is no pathway for conversion of diosgenin to progesterone in vivo. This process can only be done in the laboratory. Even in natural medicine quarters, the cognizanti have come to realize that a “wild yam scam” has been perpetrated.47 Wild yam cream is ineffective and expensive. A 1-month supply costs more than $25, whereas a month of Premarin or Estrace cream costs less than $20. Practitioners should be aware, however, that yam creams are often adulterated with progesterone; progesterone creams adulterated with estrogens, and pharmaceutical grade estrogen creams are also being sold in health food stores. Any uterine bleeding in a woman using these creams or gels deserves thorough evaluation, including appropriate studies to rule out endometrial hyperplasia or neoplasia.
Patients have come to believe that sincere and empathic treatment of menopause resides in the world of alternative medical practices. Women are suspicious and critical of what they see as profiteering and commercialism in mainstream medicine, a system seemingly dominated by managed-care corporations, insurance companies, and pharmaceutical giants. Given the recent outpouring of negative reports contradicting the presumed benefits of conventional hormone therapies, women and even some researchers in the field say believe that there are simply not enough data about hormones. Many providers and patients are then seduced by the words botanical, herbal, and natural, suspending all disbelief, and are using these products with unquestioning abandon. The term natural has lost all semblance of meaning and integrity. It has become an amorphous catch-all suggesting purity, simplicity, and reliability, when it actually may suggest that a product is untested, unregulated, and unstudied.
By being well versed and well acquainted in alternative therapies, allopathic physicians may be able to maintain open lines of communications with women reluctant to use conventional hormone therapy. When scientific studies support the claims made for complementary care, practitioners may seek to incorporate such practices in the treatment of symptoms unresponsive to or poorly controlled by conventional medical interventions—for example, using acupuncture for chronic pain syndromes. By having ready and reliable information on CAM, we can assist women in making intelligent choices. We also can greatly improve our ability to create treatment plans that harmonize with the physical, emotional, and philosophical aspects of women's lives, thereby providing more supportive care. Excellent information is available from several sources listed in the Suggested Readings and Resources.
4. Ramcharan S, Pellegrin FA, Ray RM, Hsu JP: The Walnut Creek Contraceptive Drug Study: A Prospective Study of the Side Effects of Oral Contraceptives, Volume III, an Interim Report: A Comparison of Disease Occurrence Leading to Hospitalization or Death in Users and Nonusers of Oral Contraceptives. Bethesda: National Institutes of Health; 1981. Center for Population Research Monographs, NIH publication no. 81–564
8. Hulley S, Grady D, Bush T et al: Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. Heart and Estrogen/Progestin Replacement Study (HERS) Research Group. JAMA 280: 605, 1998
9. Mulnard RA, Cotman CW, Kawas C et al: Estrogen replacement therapy for treatment of mild to moderate Alzheimer disease: A randomized controlled trial. Alzheimer's Disease Cooperative Study. JAMA 283: 1007, 2000
18. Ettinger B, Li DK, Klein R: Unexpected vaginal bleeding and associated gynecologic care in postmenopausal women using hormone replacement therapy: Comparison of cyclic versus continuous combined schedules Fertil Steril 69: 865, 1998
19. Reubinoff BE, Wurtman J, Rojansky N et al: Effects of hormone replacement therapy on weight, body composition, fat distribution, and food intake in early postmenopausal women: A prospective study. Fertil Steril 64: 963, 1995
22. Greendale GA, Reboussin BA, Hogan P et al: Symptom relief and side effects of postmenopausal hormones: Results from the Postmenopausal Estrogen/Progestin Interventions trial. Obstet Gynecol 92: 982, 1998
24. Wuttke W, Grokow CH, Jarry J: Dopaminergic compounds in Vitex agnus castus. In Loew D, Rietbrock N (eds): Phytopharmaka in Forschung und klinischer Answendung, pp 81–91. Darmstardt, Steinkopff Verlag, 1995
28. Lindgren R, Matteson LA, Meier W, Wiklund I: Effects of ginseng on quality of life in postmenopausal women. Presented at the North American Menopause Society 8th Annual Meeting, Toronto, Sept 4-6, 1998, Abstract S1
29. Lindgren R, Mattson L-A, Meler W et al: Has Ginsana G 115 estrogenic effects when measured by maturity index, plasma FSH and estradiol? Presented at the North American Menopause Society 8th Annual Meeting, Toronto, Sept 4-6, 1998, Abstract S7
33. Armanini D, Bonanni G, Palermo M: Reduction of serum testosterone in men by licorice (letter). N Engl J Med 341: 1158, 1999
36. Lu LJ, Anderson KE, Grady JJ et al: Effects of soya consumption for one month on steroid hormones in premenopausal women: Implications for breast cancer risk reduction. Cancer Epidemiol Biomarkers Prev 5: 63, 1996
41. Gambacciani M, Spinetti A, Piaggesi L et al: Ipriflavone prevents the bone mass reduction in premenopausal women treated with gonadotropin hormone-releasing hormone agonists. Bone Miner 26: 19, 1994
43. Vorbach EU, Arnoldt KH, Hubner WD: Efficacy and tolerability of St. John's wort extract LI 160 versus imipramine in patients with severe depressive episodes according to ICD-10. Pharmacopsychiatry Suppl 2: 81, 1997