Alternatives to Conventional Hormone Replacement Therapy

MAIDA TAYLOR, MD, MPH, FACOG Assistant Clinical Professor University of California San Francisco Department of Reproductive Sciences, Obstetrics and Gynecology San Francisco, California

COMPLIMENTARY THERAPIES 1997, 23(8):514-532

Alternative medicines have become "mainstream" in their popularity and economic size. The most highly promoted and popular types of alternative medicines used for menopause are discussed, including mineral and vitamin supplements, phytoestrogens, natural hormones, and botanical/plant medicines.

More than 8 million women in the United States will turn 50 this year. As cohorts who were born between 1947 and 1957 turn age 50 in the next decade, the medical world will encounter the largest number of menopausal women ever.

The treatment of the perimenopausal transition, menopausal symptoms and complications of estrogen deficiency has begun an inexorable and dramatic ascent. Although health professionals strongly advocate the use of estrogen replacement, fewer than one in four candidates actually take postmenopausal estrogens.

The print media, radio, television, bookstores, health food stores, and the Internet are replete with ads and promotions for alternatives to hormones, and women are buying these alternatives, as are Americans in general.

Physicians, nurses, and other practitioners must understand the forces that drive patients away from the conventional path and onto the roads less traveled. In fact, alternative medicine is no longer a poor relation of conventional medicine. Alternatives have become mainstream in their popularity and economic size.

Before assessing whether alternative therapies offer significant benefits and whether they can, substitute for current therapies, conventional hormone therapy must be subjected to some degree of scrutiny. If alternatives and complementary therapies are to be held to a high standard of epidemiologic proof and evidenced-based medicine, the same standards must be applied to conventional drug therapies. Moreover, a critical review of conventional hormone replacement therapy (HRT) may help explain, why women seem so reluctant to take hormones, despite the apparently overwhelmingly positive impact they have on osteoporotic and cardiovascular risk.

After weighing the evidence about HRT, this article looks at the most highly promoted and, popular types of alternative medicines used for menopause, including mineral and vitamin supplements, phytoestrogens, natural hormones, and botanical/plant medicines. It is not practical to cover all the alternative health systems and practices used during menopause, since such practices vary from region to region, depending on the local religions, cultural, and immigrant populations.

THE ALTERNATIVE HEALTH INDUSTRY

One American in three uses complementary therapies at some time. Two recent articles outlined the scope of the new-age medical world.1,2 Sales of herbals, botanicals, and other nutritional additives, many of which are in fact "crude drugs," amounted to $ 1.5 billion, with herbs and herbal tea sales alone totaling $467 million in sales.

The true magnitude of the alternative health market is hard to estimate, but it presently is thought to be around $6 to $8 billion a year. Americans spend $94 million on books on herbs and related topics. Sales in the more than 8,000 natural and health food stores in the United States have increased 15% annually in recent years. The use of folk medicines and healers appears in virtually all cultures in all countries.

The European market for botanicals is three times larger than that in the United States, with European pharmaceutical houses such as Boehringer, Boots, and Ciba-Geigy, marketing botanical products along separate but parallel tracks alongside their conventional pharmaceutical lines. In Germany alone, over-the-counter botanical sales have reached $7 billion. Physicians routinely prescribe botanicals along with conventional pharmaceuticals for many illnesses. Many of agents were found in the United States Pharmacopeia (USP) until FDA review failed to find evidence of efficacy.

Supporters of plant medicines assert that with the cost of bringing a new drug to market being more than $231 million manufacturers have little interest in old plant drugs that cannot be patented.3 Proponents of plant medicines argue that safe and effective treatments are being ignored and that the public being pushed by physicians into using more toxic, potent "synthetic" drugs.Research exists documenting the efficacy of botanical medicines, but much of that literature is not available in English. The German government reviews research on botanicals, publishes 410 monographs on plant medicines, and distributes patient information pamphlets on botanicals in pharmacies. The English version will be published in September 1997. Health food and supplement shops exist in almost mall in the United States, in even remote communities. Practitioners in every community will encounter traditional Chinese medicine, stress reduction, chiropractic manipulation, homeopathy, and plant medicine practice. Complications and poisoning from improper use of alternatives are not confined to large urban centers on the East and West Coast.

Much of alternative care operates outside the mazelike, set of obstacles created by third-party health payers; alternative care may actually be more easily accessible to American health consumers. The lay public often does not know what distinguishes clinically trained and licensed health professionals from alternative practitioners, some of whom have impressive credentials, but many of whom have no formal training or licensing. For example, health consumers might be hard-pressed to distinguish a massage therapist from a physical therapist or a homeopath from an osteopath.

Often, consumers seem not to care about training and credentialing. A large segment of the lay community has come to believe that alternative providers are more sincere and honest than medical personnel and that natural remedies hold fewer risks. Patients believe that the commercial forces driving medical practices in the United States are subverting quality and compassion.

One only has to listen to talk radio or attend a cancer support group to hear rhetoric damning and demeaning the mainstream. At the least, doctors are viewed as ignorant of simple things that induce wellness, such as diet, supplements, and plant medicines. In the extreme, adherents of alternatives rant about medical oncologists who do not want to find a cheap and simple cure for cancer, because they make vast amounts of money by poisoning cancer victims with outrageously expensive, toxic products proffered by greedy pharmaceutical companies. When the gap is this wide, it is difficult if not impossible to cross over. While a small number of consumers completely eschew mainstream medicine, most users of alternatives take a pluralistic tack and combine the use of conventional medicines with that of botanicals and other alternatives.

CONVENTIONAL HORMONAL REPLACEMENT THERAPY

The health benefits offered by estrogen hormone replacement therapy seem irrefutable. Publications in the medical literature repeatedly enumerate reductions in risk of coronary vascular disease by at least 50%,5 and in osteoporotic fracture by as much as 80%. Not only does estrogen therapy hold an important place in coronary disease prevention, but evidence now suggests that HRT has a place in secondary heart disease treatment by lessening mortality in those with angiographic evidence of coronary disease,6 and helping to maintain the patency of bypass grafts7 and angioplasties.8,9 HRT ameliorates the overt symptoms of estrogen deficit, including hot flashes, insomnia, night sweats, vaginal dryness, and sexual dysfunction, which are not life-threatening but do impinge on the quality of life far more than the early progress of vascular disease and bone loss, both of which are silent and insidious.

Although other interventions, including vitamins, clonidine, antidepressants, and other nonhormonal measures have been used to mitigate symptoms and have success rates between 30% to 60%, hormone replacement lessens symptoms by an unchallenged 80% to 90% . Estrogens currently available in the United States include oral preparations and transdermal patches and an intravaginal ring. The low-dose ring, is indicated only for amelioration of urogenital atrophy and does not have documented systemic or preventive effects; the dose is so low that it does not require progestational opposition to protect the endometrium (Table 1).

LIMITATIONS OF CURRENT RESEARCH ON HRT

Until recently, most studies of estrogen replacement have been observational not experimental and have centered on white middle class populations. The dosage, regimen, and duration of hormone use have varied greatly. To some measure the positive impact of HRT has been the result of selection of what epidemiologists term "walking well" biases.10 Starting in 1969, after the Nelson Hearings convened in Congress to investigate vascular disease in oral contraceptive users, estrogens were deemed dangerous for high-risk women. Gynecologic textbooks and the Physicians Desk Reference listed myocardial infarction, stroke, migraine, diabetes, obesity, and other risks for heart disease and a family history of those conditions as contraindications to the use of estrogen.11 Selectively, for a decade and more, the only women using estrogen tended to be those who were by genetic endowment and health performance, the healthiest, while the sickly women were taken off of estrogen; such at risk women often were not even allowed to start taking estrogens. HRT users have been found to be better educated, have better lipid profiles, exercise more, and have lower blood pressure than nonusers at the start of a prospective study of the effects of HRT.12 A meta-analysis by Grady and colleagues suggests that the only groups for whom estrogen replacement therapy (ERT)

Table 1

Currently Available Estrogens

1. Synthetic

Diethylstilbestrol (DES) 0. 1,0.25,0.5,1,5 ma

Ethinyl estradiol (Estinyl) 0.02,0.05,0.5 rng

2. Natural

Conjugated estrogens (Premarin) 0.3,0.625,0.9,1.25,2.5 mg

Piperazine estrone sulfate (Ogen, Orthoest 0.3,0.625,1.25,2.5, 5 mg

o Esterified estrone (Estratab) 0.3,0.624,1.25,2.5 mg

Micronized estradiol (Estrace) 0.5, 1, 2 mg

Estradiol transdermal patch (alora)(Climara) (Estraderm) (Fempatch) (Vivelle) 0.025, 0.0375, 0.05, 0.1 mg (not all brands able in all dosages)

Vaginal ring (E String)

Source: Physicians¹ Desk Reference'. Montvale, NJ: Medical Economics Company, Inc; 1997.

offers unequivocal benefits are women who are very high risk of cardiovascular disease (CVD) or those status post hysterectomy.13 A more recent analysis of the impact of hormone replacement on life expectancy by Col and associates advises that while benefits exist for all women, except those with two first-degree relatives with breast cancer low-risk women, those with no risk factors for CVD or osteoporosis who also have two first-degree relatives with breast cancer, "... should not receive hormone therapy."14

There is no current consensus on the optimal duration of hormone replacement use. The recommendation that estrogen should be taken lifelong seems unsubstantiated. Experts in the field, extrapolating from the fact that bone and cardiovascular protection seem to lapse after 10 years, coyly suggest, that use of HRT should continue until 10 years before a woman dies. Data published in 1995 showed that if HRT was used for less than 9 years bone mass by age 80 was only 3% higher in the HRT user group than in nonusers,15 suggesting that unless estrogen is used for the very long term, the benefits are nil. On the other hand, recent data from the Rancho Bernardo Study16 shows that estrogen use by women for 9 years, starting after age 60 years, resulted in almost equal bone conservation compared with estrogen use from the outset of menopause.

It may be that estrogen is best for symptoms women aged 50 to 60 years, best for bone in women aged 60 to 70 years, and best for heart disease secondary treatment and prevention in those aged 70 to 80 years (Table 2).

Unanswered questions about optimal dose and duration of HRT demand rigorous and highly refined epidemiologic data. The answers will not be available for the generation of women who enter menopause in the near future. The massive controversy about estrogens and breast cancer is an even more challenging Gordian knot for biostatisticians, epidemiologists, and clinicians. The variables in the equations are so numerous that teasing out significant threads may be all but impossible (Table 3). Current opinion is that if ERT does increase the risk of breast cancer, the increase is small, with a relative risk between 1.25 and 1.40. From a patient's perspective, however, exogenous estrogens are an entirely avoidable risk, and even a small increase in risk for a disease of high prevalence creates a huge increase in incidence.

For women who are at high risk of vascular disease, particularly those with male relatives who died before the age of 50 years or female relatives who died before age 60, and for those with a family history of osteoporosis, estrogen is a safe, inexpensive, highly effective means of disease prevention. For those at moderate risk, the benefits continue to accrue. However, in low-risk women, because of the possibility of an increase in breast cancer and the inconvenience of side effects such as breakthrough bleeding, estrogen replacement may not be warranted. Women with inherited vigor and longevity do not derive the same absolute reductions in disease that are evident in those with poor genetic endowments and high-risk health behaviors.

WHY WOMEN REJECT HORMONE REPLACEMENT THERAPY

Given a lack of consensus among health professionals, coupled with a constant counterculture attack on conventional HRT, it is no wonder that only 10% to 25% of menopausal women take HRT. Of prescriptions written for HRT, only 50% are filled, and after 1 year, less than 40% of women who started HRT continue. Twenty percent of women experience few symptoms and are at low risk of CVD or osteoporosis and may not need HRT, yet fewer than one in four of the remaining 80% ever uses HRT. The leading reasons women refuse or discontinue HRT are: (1) Fear of malignancy: The most significant obstacle limiting the acceptance of HRT is the almost universal belief that hormones cause cancer. In the lexicon of many lay persons, the word "hormone" connotes "cancer causation." Starting with

Table 2

Currently Approved Regimens for Osteoporosis Treatment and Prevention

Estrace 0.5 mg/day

Estraderm 0.05 mg twice weekly

Estratab Application pending

Estratest Application pending

Premarin 0.625 mg/day

Prempro 0.625/2.5 mg/day

Premphase 0.625/5 mg/day x 14 days, 0.625 mg/day x 14 days

Ogen 0.625 mg/day

Source: Physicians¹ Desk Reference'. Montvale, NJ: Medical Economics Company, Inc; 1997.

Table 3

Variables Relevant to Breast Cancer Risk and Hormone Replacement Therapy

Duration of use

Recency of use

Latency of use

Estrogen type

Estrogen dosage

Estrogen route: oral, transdermal, transvaginal

Regimen: continuous, intermittent

Estrogen with or without progestin

Progestin type

Progestin dosage

Family history breast cancer: pre- or post- menopausal

Benign breast disease with or without atypia

Obesity: childhood, teen, adult, menopause

Ovarian status

Age of menopause

Barbara Seaman's two books, The Doctors' Case Against the Pill 17 and The Controversy in Women's Hormones, 18 and persisting now with the publication of Dr. Susan Love's Hormone Book,19 women have been told that estrogen is the major reason for the increased incidence and prevalence of breast cancer in the past 25 years.

Women ages 40 to 60 years are far more fearful of disfigurement and disability than death, and breast cancer, the leading cause of cancer deaths in this age group, provokes images of a long, lingering death, full of pain and suffering increased and prolonged by surgery, radiation, chemotherapy, and other horrors yet to be invented. While breast cancer is viewed with fear, heart disease is viewed as a relatively good kind of death: sudden, acute, and swift. Breast cancer pervades newly menopausal women's consciousness, since almost all women this age have had friends and relatives with breast cancer, an emotional reality that cannot be erased with studies, trials, and publications.

While medical experts debate the role estrogens play in breast cancer causation, we do know that estrogen, in the absence of progestation opposition, increases the incidence of endometrial cancer. Though they may also offer some other therapeutic benefits, the principal reason progestins are included in HRT regimens is to protect against endometrial proliferation. In 1995,20 the PEPI group reported that medroxyprogesterone acetate countered some of the estrogen induced improvements in lipid profile. Concerns were raised that the positive impact of estrogen would be lessened by progestins, and shortly thereafter, some members of internal medicine and primary care community began advocating for the use of unopposed estrogen to avoid any mitigation of cardio-protection by the progestin. They reasoned that the endometrial malignancies that might result would be justifiable in view of reduction in cardiovascular disease. The rationalization for this rather extreme view was that the endometrial malignancies induced by estrogen therapy were "good cancers" diagnosed at early stage, evidencing slow growth, and culminating in high cure rates. Gynecologists, and women, tended not to be so cavalier about endometrial cancer and subsequent hysterectomy. Significant morbidity and mortality result from hysterectomy even for Stage I/Grade 1 endometrial cancer. With members of the medical community appearing to advocate for the use of a cancer-inducing drug, women viewed estrogen and the doctors promoting it with even greater suspicion. The most recent publication of the PEPI group has found that estrogen and combined estrogen/progestin regimens yielded similar reductions in the end point of interest­cardiovascular death rates.21 (2) Other Side Effects: The medical literature assures practitioners that women using continuous HRT, usually conjugated estrogen 0.625 mg plus medroxyprogesterone acetate (MPA) 2.5 mg daily, will have some minor breakthrough bleeding in the first 3 months of use. In an informal survey of nurses and primary care providers, many report seeing rates of more than 60%, especially when continuous HRT is used in the younger or newly menopausal woman, who still may have abundant endometrium. The discordance between what women are told to expect by providers about breakthrough bleeding and what they actually experience again undermines their confidence in conventional medical therapy.

Although gynecology texts claim that hormone replacement therapy does not cause weight gain, women are convinced that hormones, not lifestyle promote mid-life obesity. The Rancho Bernardo study 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 with the heavier, nonusers. Estrogen does decrease metabolic rate and, lowers fat utilization23 whereas progestins can have, anabolic effects and may stimulate appetite in some. Haarbo and associates reported that abdominal fat deposition is significantly lower in hormone, replacement therapy users.24 Although all women in this Finnish study gained weight, the hormone replacement therapy users gained less overall weight and fat than nonusers. Nonetheless, whether weight gain with hormone replacement therapy is perceived, real, or coincidental, women are convinced that HRT makes them fat. In a society that is obsessed with appearance and weight this perception undermines the acceptability of exogenous hormones. Mastadynia occurs in many women who are on hormone replacement therapy. Although breast pain, with or without attendant breast swelling is not a harbinger or risk for breast cancer, mastalgia frightens women and often leads them to stop taking hormones.

Although clinical impressions and experiences suggest that approximately 10% of women experience some degree of mood dysphoria when taking progestins, objective assessments have found no increase in mood disturbance from MPA.25 Whereas the incidence of pre-existent mood disorders may be equal in users and nonusers, women with underlying mood problems appear to suffer exacerbation when MPA is added, while symptoms remain at bay during the estrogen-only phase of the cycle. Indictment of MPA as a cause of depression and agitation is so widespread that women have come to expect hormone replacement therapy in general to cause dysphoria. If affective changes occur hormone replacement therapy, women may stop taking hormones entirely, cut their progestin dose without informing their health provider, or discontinue using the progestin while continuing with all unopposed ERT regimen, again without telling their provider. No data exists on the incidence of dysphoric reactions with progestins other than medroxrone acetate, but clinical experience that micronized progesterone, norgestrel and porethinedrone can cause mood impairment in rates that are similar to MPA. (3) Social Issues: By starting HRT, a woman commits to the medical management of menopause. Laywomen take great umbrage at the classification of menopause as a deficiency disease. Menopause, when viewed sociologically, is seen 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 aging, which is not controllable. When women begin using nonmedical alternatives, they perceive they are doing something of which their physicians do not approve. Moreover, high-risk women may be distracted and diverted from therapies with documented benefits.

Whereas alternative care may not offer medical advances or advantages that can be proven by statistical objectification, it offers subjective superiority that patients find exceedingly appealing, such as unhurried visits, comfortable settings, guarantees of success, overwhelming optimism, and individualization, even when it is not needed for therapeutic success. While medical therapies must provide full informed consent and disclosure, alternative therapies can make sweeping global claims to a wide array of unconfirmed benefits, while alleging to have no serious side effects or risks (Table 4). Furthermore, alternative and complementary practitioners appear to have a vast tableau of choices: nutrition, herbs, teas, foods, minerals, body therapy, meditations, and more, whereas physicians seem to have only one limited offering - hormones.

MINERAL & VITAMIN SUPPLEMENTS

Calcium. The current RDA for calcium has been recently revised upward to more adequately compensate or current dietary customs and needs (Table 5). Adequate calcium intake clearly slows bone mass loss after menopause, but it cannot arrest losses.26 Improved calcium intake enhances the positive effects of exercise27 and estrogen on bone mass.28 The greatest enhancement in bone mass accretion results from prepubertal calcium supplementation.29 Calcium supplementation after menopause may be too little too late, because 90%

Table 4

Patient Perceptions Regarding Alternative and Conventional Medicine

Source: Modified from Buckman R, Sabbagh K. Magic or Medicine: An Investigation of Healing and Healers. Toronto, Ont: Key Porter Books, 1993.

of bone mass accumulates by age 25. Dietary calcium intake after menopause is low, and most older women should be taking supplements. When recommending a calcium supplement, select one requiring fewer tablets and having a higher dose of elemental calcium per tablet per cost. Tablets that rapidly disintegrate or that can be chewed provide increased surface area for absorption. Absorption is greatest when gastric pH is low and taking supplements with meals helps absorption. Absorption also increases at night, and an optimal approach to supplementation is taking 500 mg at bed time. If more than 500 mg a day is indicated, the dose can be divided. Children absorb 75% of calcium load, but adults only absorb 30% to 50% of a calcium load. After age 70 even less is absorbed, because gastrointestinal acidity decreases with age. Using the citrated form of calcium salt reportedly improves absorption, especially in those with reduced acidity, although recent studies dispute these claims.30 Estrogen also improves gastrointestinal absorption. Occasional cessation of calcium supplements helps to

Table 5

Recommended Daily Allowance for Calcium

Source:National Institutes of Health. Gopher://gopher.nih.gov/00/clin/cdcs/individual/ 97.calcm.

down-regulate receptors and keep absorption high. Patients can be reassured that missing a few doses of calcium is actually beneficial. An excellent guide to selecting calcium supplements appeared in the Tufts University Health and Nutrition Letter."

Patients should be warned about the high levels of lead and other heavy metals that are found in oyster shell-derived calcium. In 1997, the FDA reported that some brands of calcium contained much higher amounts of lead than others, but all the brands tested were within the acceptable limits set by the agency.

Magnesium & Boron. Other supplements that are promoted as adjuvants for maintaining bone mass integrity include magnesium and boron. Magnesium acts by aiding and improving gastrointestinal calcium absorption. Some practitioners insist that to optimize calcium absorption, calcium and magnesium must be taken together in a ratio of 2: 1. Magnesium has a number of health benefits, including improved calcium absorption, increased gastrointestinal motility, stool softening, and others.

Magnesium deficiency is rare, however, and in the face of adequate calcium intake, supplementation with magnesium is not necessary.32 Similarly, boron acts as a cofactor in magnesium metabolism.33 Boron deficiency will exacerbate magnesium deficiency, but boron deficiency is even rarer t magnesium deficit, except in premature infants and alcoholics. Supplements of these minerals offer no benefits for those with normal nutrition. For those with poor diets or nutritional restrictions, the amount of magnesium and boron in a good general mineral pill is sufficient.

Chromium. Diet and weight loss products almost all contain chromium picolinate, using 200 mg per dose, and commonly 800 to 1,000 mg/day, Chromium is supposed to increase metabolic rate, increase fat burning, and improve glucose utilization, the usual things sedentary overweight people want to hear. Animal studies on chromium and its ligands have found increased lean body mass, decreased fat mass, decreased growth of tumors, improved insulin activity, and increased life span in rats fed high doses. The same effects can be induced in animals by placing them on moderate calorie restriction. In humans, chromium picolinate and other salts have phenformin-like activity,34 but only in those with insulin resistance; no improvement is seen in glucose uptake in normal persons. The role of chromium supplements in individuals with deficiency or glucose intolerance remains to be defined. High-output endurance athletes may need. supplemental chromium, but the amounts found in standard over-the-counter multivitamin and mineral supplements are probably sufficient. Brewer's yeast is an excellent natural dietary source of chromium but it causes abundant and foul flatulence. In a well-controlled, randomized trial in collegiate weightlifters, supplemental and placebo groups engaged in an intensive program of weight training, The two groups had no evidence of differences in body composition after the training period.35

The presumed safety of chromium picolinate and picolinic acid has been questioned in a recent paper, Chromosomal damage was induced both by the chromium picolinate salt and the ligand in hamster ovary egg germ cells, raising the possibility of mutagenesis and carcinogenesis. The effects were seen with concentrations that were achievable in the serum of humans who take the current recommended doses; they were not seen with chromium nicotinate. Patients should be informed of this report. At this time, chromium supplements appear to have no, documented clinical utility in normal adults.

Vitamin D. Most adults who drink milk receive sufficient amounts of vitamin D. Only those persons with specific vitamin deficiency syndromes, those living in extreme northern latitudes, and house bound elderly need routine supplements.37 Because of seasonal declines in sunlight, people living in the northern regions of the United States need supplements in the winter months. (Fig. 1) Current recommendations range from 400 to 1,000 IU/day.

Portland Boise Minneapolis Chicago Boston

Figure 1.­Geography of Vitamin D Supplementation (Source: Tufts Diet and Nutrition Newsletter. 1996;Oct:3 [P.O. Box 57857, Boulder, CO 80322-7857])

PHYTOESTROGENS

Plants and botanicals that are reputed to have estrogenic activity include ginseng, fenugreek, licorice, sarsaparilla, gotu kola, wild Mexican yam, and dong quai. Phytoestrogens are defined as naturally occurring plant sterols that may exert effects similar to estrogen. They fall into the following three groups.

Isoflavones, particularly, genistein and daidzein, are plant sterol molecules found in soy and garbanzo beans, and in other legumes. They are most often consumed in products like tempeh, soy, miso and tofu

Lignans are a constituent of the cell wall of plants, and they are bioavailable through the activity of intestinal bacterial on grains. The highest amounts are found in seed oils, especially flaxseed

Cournestans have steroidlike activity, but they are not very important as a source of phytoestrogens for humans. High concentrations found in red clover, sunflower seeds, and bean sprouts are known to have estrogenic effects when they are ingested by animals, the most well-known example being subterranean clover that causes sterility in Australian sheep.

Soy-derived phytoestrogens are abundant in traditional Asian diets (Table 6). In population-based studies, research shows that in countries like China and Japan, where the local diet is high in soy based foods, women express few menopausal complaints and coincidentally have a low incidence of breast cancer. A similar trend is seen for prostate cancer and soy intake in Asian males.

Asian women typically ingest 40 to 80 mg of isoflavones per day, whereas Americans average less than 3 mg/day. In clinical trials, a high intake of isoflavones depresses LH levels, thereby exerting some antiestrogenic effect.

Ipriflavone, another isoflavone, slows bone reabsorption and stimulates collagen synthesis in bone. Pharmaceutical-quality ipriflavone has been approved in Europe and Japan for the treatment of osteoporosis, and a pharmaceutical supplement with 600 mg/day increases bone mass in postmenopausal women.38 Work in Finland has found a significant inverse relationship between isoflavone intake and coronary heart disease in both women and men.39 A similar study in male health professionals ill the United States40 has not demonstrated any statistically significant

Foodstuff	Serving Size	Isoflavones
Tofu, tempeh	100 g	62-112 mg
Miso	120 g	40 mg
Soy milk	250 g	40 mg
Texturized soy protein	100 g	138 mg
Soy beans roasted	100 g	162 mg
Green soy	100 g	135 mg

Source: Knight DC, Eden JA. A review of the clinical effects of phytoestrogens. Obstet Gynecolo. 1996;87:897- 904.

correlation between coronary diseases rates and isoflavone intake. However, a recent meta- analysis found that high soy intake correlates well with an improved lipid profile in the United States population.41 Persky and others agree that there is sufficient "... epidemiologic evidence support[ing] the hypothesis that phytoestrogens inhibit cancer formation and growth in humans."42

As yet there have been no interventional studies published on the impact of isoflavones on menopausal symptoms such as hot flashes, dyspareunia, and vaginal dryness. Several trials are currently in progress.43

Foods rich in phytoestrogens have benefits that range far beyond the treatment of menopausal symptoms. Soy products are an excellent source of plant proteins, and their use as a substitute for red meat in the diet may provide considerable improvement in lipid profile and cardiac risk. If they prove to ameliorate menopausal symptoms and mitigate cardiac and cancer risks, health professionals should actively advocate their increased consumption. Mexican yams, the source of dioscorea used for steroid production in the past, have been advocated as a food source of estrogen and/or progesterone. Yams, to have a significant biologic effect, need to be eaten raw and in huge quantities, and are not a viable source of hormonal supplementation.

Natural Progesterone & Estrogens. In reading and reviewing materials about natural hormones, secondary sources often cite primary sources selectively or inaccurately. Promoters of natural hormones supply patients and professionals with extensive bibliographic materials, but after close scrutiny and careful review, many of the references cited in support of natural hormones often do not even mention natural hormones. Papers that make claims about progesterone frequently refer to studies that have used MPA as the progestin.

Much of the promotional literature on comparative estrogenology misquotes or misrepresents the primary sources. Animal data are extrapolated directly to human applications, although there may be vastly different physiologic responses to dietary and pharmacoloaic therapies. While maintaining a healthy degree of skepticism about the claims made for natural hormones, it must be acknowledged that the abuses and misuses of data are not confined to the alternative medical community; poor science permeates the conventional medical literature as well.

Topical Progesterone. A major segment of providers and consumers involved in menopause management have come to believe that there is a substantive difference between naturally occurring and synthetic progestins (Table 7). Synthetic progestins have been indicted as the cause of mood changes and dysphoria during HRT use, and that medroxyprogesterone acetate detracts from the estrogen-induced improvements in lipid profiles, as discussed earlier. In an effort to find substitutes for MPA, a number of natural progesterone products are being promoted. Alternative pharmacies are compounding creams for topical administration containing extracts of wild yam or natural progesterone. Wild yam creams provide no active hormones. Plants do produce sterols, called saponins, with structures similar to progesterone. Saponins first are hydrolyzed to sapogenins; the two principles being sarsasapogenin and diosgenin. These sterols can be used as precursors for the progesterone steroid skeleton, which in turn, can be used as the precursor for adrenal steroid synthesis. The sterols in wild yams cannot be converted in vivo to active compounds, and the amounts in yam creams are negligible. Commercially prepared topical progesterone creams are usually USP progesterone, most of which is manufactured by Pharmacia

Types of Progestational Agents

1. Natural

• Progesterone

• Suppositories

• Micronized powder

• Progestasert IUD

II. Synthetic

• 17-hydroxyprogesterones (17 acetoxy- progestins and C-21 compounds)

• Medroxyprogesterone acetate (MPA)

• Megestrol acetate

• Cyproterone acetate

• Dydrogesterone

• Medrogestone

-19-nortestosterones (C-19 compounds)

• Norethindrone acetate

• Norethindrone

• Ethynodiol diacetate

• Lynestrenol

- 18 ethyl group

• Norgestrel, levo norgestrel

• Desogestrel

• Norgestimate

• Gestodene

Upjohn and then sold in bulk to compounding pharmacies making capsules, oils, tabs, gels, etc. Over the counter progesterone creams that are being promoted as substitutes for hormone replacement therapy often claim to have estrogenic, progestation and androgenic actions. Some alternative practitioners even tell patients that they use these creams as substitutes for oral progestins HRT regimens. No data exist documenting that over the counter topical progesterone can prevent endometrial proliferative changes induced by oral or transdermal estrogen. The most commonly cited reference for the claims made about natural progesterone is a volume written by Dr. John R. Lee, Natural Progesterone: The Multiple Roles of a Remarkable Hormone.46 While claiming that natural progesterone is the optimal steroid hormone replacement, the bibliography of the book actually includes few studies using natural progesterone. The vast majority of the references mentioned are studies using medroxyprogesterone acetate or C-19 nor testosterone derivatives, the progestins found in oral contraceptives.

Dr. Lee has published the results of studies of a series of 100 patients who used progesterone cream a treatment for osteoporosis.46 During the 3-year study period, he cites an average increase in bone mineral density in the lumbar spine of 14% in 63 women who were studied serially, with the greatest improvements seen in those with the worst bone density at the outset. No controls were included, and in his concluding remarks, Dr. Lee says: "It does not require [a] double-blind, placebo-controlled experiment to conclude that progesterone, used in this fashion, is of great benefit in treating (and preventing) osteoporosis."

No other published reports on the use of topical micronized progesterone have been found in the medical literature that is accessible by on-line search, and no reports exist on the use of oral micronized progesterone alone for bone preservation or accretion. One study that used oral norethindrone alone does document increases in bone mass in postmenopausal women47 another finds that oral MPA slows the rate of bone loss in the spine but not in other sites.48 Transdermal progesterone gels are available in other countries. Research is also under way on transdermal delivery of estrogen and progesterone in a combination patch. Ross reported that transdermal estradiol in a combination patch with norethisterone (norethindrone) resulted in similar bleeding patterns compared with transdermal estradiol plus oral MPA.49

Though transdermal progesterone is well absorbed, many of the topical creams do not contain sufficient amounts of progesterone to achieve effective serum levels. Topical progesterone products have been tested to determine how much steroid is actually present and the amounts vary from undetectable to more than 500 mg per ml. Though not reported in print as yet, a verbal communication recently indicated that many "natural progesterone" creams contain medroxyprogesterone acetate as well.

Many women report relief from perimenopausal and menopausal symptoms when using topical creams. -Absorption of topical progesterone may be sufficient to alter the levels of other steroids, or the binding of other hormones. Without controlled trials claims about the therapeutic effects of topical progesterone cannot be supported since in the natural course of menopause, symptoms wax and wane.

No biopsy-confirmed studies exist documenting that the topical progesterone in cosmetic creams exerts sufficient activity to counteract the endometrial proliferation induced during administration of exogenous estrogen. Therefore, women using who use progesterone creams as a form of progestational opposition while taking estrogens should be treated as if they are taking unopposed estrogen. Annual endometrial biopsies, as advised by the ACOG Technical Bulletin50 are the current standard of practice for patients using unopposed HRT.

Outlandish claims have been made for natural progesterone (Table 8). A medication that claims to improve the temperament of children whose mother used it during pregnancy should be regarded with general skepticism.

• Prevents breast and endometrial cancer
• Produces especially well adjusted children when taken during pregnancy
• Aids in milk production during nursing
• Treats endometriosis
• Lessens dysmenorrhea
• Helps thyroid hormone action
• Restores proper cell oxygen
• Normalizes blood clotting
• Normalizes blood sugar
• Diuretic
• Stimulates osteoplasts
• Protects against fibrocystic disease
• Prevents and shrinks myomata
• Natural antidepressant
• Prevents the androgenic dominance of androstenedione as a cause of increased body hair postmenopausal and of male pattern balding
• Restores libido

Source: Lee JR. Natural Progesterone: The Multiple Roles of a Remarkable Hormone. Sebastopol, CA: BLL Publishing; 1993.

Oral Micronized Progesterone. Oral micronized progesterone is used more commonly used in Europe than in the United States for progestational opposition in HRT regimens and is represented in one of the arms of the on- going PEPI trials. The dose for adequate endometrial opposition is 300 mg/day,51 in divided doses (100 mg in morning and 200 mg at night), because of its short half-life. Research reports from Europe suggest that lesser amounts may be adequate.52 Micronized progesterone (MP) is touted as "producing excellent blood levels without the unwanted effects (such as fluid retention, breast tenderness, weight gain, and depression) of the synthetics"53 and is promoted as an alternative for women experiencing problems with MPA. These claims are not substantiated, but they have become menopausal lore.

Note that the C-19 nortestosterones-norethindrone and norgestrel-can be used in appropriate doses for progestational opposition.

A new hormone replacement therapy combination pill that contains ethinyl estradiol and norethindrone acetate is currently in clinical trials.54 Holistic and naturopathic practitioners consider androgen-derived C-19 nortestosterone progestins to be even less "user friendly" than medroxyprogesterone acetate. In reality, micronized progesterone, MPA, and other synthetic progestins are all capable of producing similar effects and may be poorly tolerated by a number of women.

Natural Estrogens. Only two synthetic estrogens have been extensively used: ethinyl estradiol, the estrogen used in all oral contraceptive formulations in current use, and diethylstilbestrol, which is no longer used in humans. The remaining estrogens in clinical use are combinations of or single estrogens, all of which occur naturally in humans or animals. Alternative practitioners strongly criticize the use of conjugated equine estrogens, because they do not naturally occur in humans. Emotional ethical arguments are also advanced about the treatment of the horses in the production of the pregnant mare's urine, the source of conjugated equine estrogens (Table 9).

Table 9

Comparison of Conjugate Equine Estrogens, and Esterified Estrogens

Source: Ansbacher R. Estrogens: conjugated and esterified therapeutic substitution. Female Pat. 1994; 19:14-20.

Not all estrogens are equal. Estrogens vary in their dose equivalency and have differential metabolic effects on different tissues or end organs. For example, micronized estradiol 1 mg is equivalent to conjugated estrogens 0.625 mg when measuring effects on liver function, but micronized estradiol 0.5 mg is adequate to produce changes in bone density seen with conjugated estrogen 0.625 mg.9

For purposes of postmenopausal replacement, the doses equal to 0.625 mg of conjugated estrogens are:

The alternative community has come to embrace estriol as the estrogen choice. Estriol is the predominant estrogen produced by the placenta, and it has been theorized that high levels of estriol during gestation protect estrogen-sensitive tissues from the neoplastic-inducing effects of the other estrogen estradiol and estrone.

An old, modest body of literature exists which states that estriol protects against breast and endometrial cancers. Research by Lemon found that estriol limits the growth of breast cancer in Sprague-Dawley female rats that were fed carcinogenic substances.55 Estriol also has been found to induce regression and remission of breast cancer in rats and humans.56

Epidemiologic data show that women who had an early first age of pregnancy excrete more estriol than nulliparous women. Asian women excrete more estriol than American women, those who move to the United States suffer increased rates of breast cancer, while evidencing declining urinary estriol.57

In 1978, Follinstad published a commentary in JAMA titled "Estriol, the Forgotten Estrogen?"58 In it he implies that levels of estriol after menopause somehow foment the villany¹ of estrone and estradiol, thereby inducing high rates of breast cancer in postmenopausal women. Citing published and unpublished data from Lemon and others, Follinstad reported a 37% induction of remission or arrest of growth of metastatic lesions in women with advanced breast cancer. Note that there is an even larger body of literature accrued in the 1970s on the use of DES as an anti breast cancer treatment, often used in conjunction with chemotherapy.59 In high doses, DES induced regression in 20% of cases of breast cancer. Later studies failed to confirm these findings.60 After DES was implicated in the causation of clear-cell carcinoma of the vagina and cervix in the daughters women who took the hormone during pregnancy, essentially banned for human use.

Estriol failed to live up to its promise as a cancer treatment, but it did not suffer the ignominity heaped on DES. Estriol is used in Europe orally, topically, and in vaginal gels, usually in combination with other estrogens. Alternative pharmacies in the United States are compounding ERT pills, gels, and capsules that contain 10% estradiol, 10% estrone, and 80% estriol.

More recent literature reports that when estriol is given in doses equivalent to estradiol, and administered more frequently to compensate for its rapid excretion estriol induces endometrial hyperplasia.51 The impressions that estriol exerted a protective effect was due to the fact that it has a very low biologic activity. It is rapidly cleared and binds to estrogen receptors with 1/3 to 1/2 of the affinity of estradiol. It does not appear to competitively interfere with estradiol binding, nor does it limit the histologic changes induced by estradiol. Biopsies of the endometrium in women who were treated with estradiol only, and the two in combination showed similar histologic changes.62 Although breast cancer rates in premenopausal women correlate inversely with estriol excretion, in posttmenopausal women high levels of estriol excretion, which correlate with serum levels, are associated with higher rates of breast cancer. No data indicate that exogenous supplementation with estriol lowers the incidence of postmenopausal breast cancer.

"Triest" estrogen preparations do' mitigate symptoms. Anecdotally, a patient taking a "triest" pill was tested, her estrone and estradiol were well within the therapeutic range. Through bioconversion, all exogenous postmenopausal preparations that are available in the United States achieve remarkably similar though not identical serum levels of estrone and estradiol.63 As a result, it is not at all surprising that a "triest" preparation achieves appropriate therapeutic levels of estradiol and estrone.

Although topical gels and creams are not popular in the United States as drug delivery systems, they are used extensively in Europe. Estrogens in gel form are so well absorbed that serum levels over 200 pg/ml can easily occur. The instructions for use of gels in Europe strongly suggest that serum levels be measured to assure that patients are in a safe therapeutic range.

If patients elect to use gels and compounded oral designer estrogens from alternative pharmacies, serum estradiol and estrone should be measured. Doses should be adjusted if not in therapeutic range; an acceptable level for estradiol is 60-100 pg/ml. Levels over 150 pg/ml are considered excessive. It is doubtful that designer estrogens are worth the extra effort and cost they impose. These estrogens are however an option for women who have had problems with other formulations.

Dehydroepiandrosterone (DHEA). Although it is not strictly a menopausal treatment, DHEA is presently being promoted as an anti-aging miracle drug and many women are using it for menopause-related complaints. Available as a supplement in drug, grocery and discount outlet stores, DHEA sits beside the wide array of vitamins, botanicals, and body-building formulas. The claims made for DHEA include improved immunity, slowed aging, increased energy, improved lipids, and heightened mood and libido. The current fad feeds off of miscues and inaccuracies about the significance of endogenous levels of DHEA and its sulfated prohormone, DHEAS.

DHEA and DHEAS are easily converted to other more potent androgens, including testosterone,androstenedione, and dihydrotestosterone. As might be expected, DHEAS, like other androgens, is rela-tively low until just before to the onset of prepuber-tal development, and its rise may well be one of the hormonal triggers of puberty. DHEA then peaks at age 25, with levels declining steadily after age 30. DHEA becomes almost undetectable by age 70. DHEA improves lean body mass64 glucose toler-ance,65 and the immune response in mice.66 Its mode of action is not well defined, perhaps acting as a weak antiglucocorticoid, androgen, estrogen, or all of these.

Observational studies of DHEA levels in cardiovascular disease in humans are inconsistent. Khaw67 found that high endogenous measurements of DHEA were associated with lower cardiac mortality in men, but did not correlate with non fatal myocardial infarction rates. No correlation between DHEAS levels and cardiovascular mortality in women has been seen. Casson and Buster68 recently summarized their experience with DHEA, particularly in menopausal women. They treated women with 50 mg/day, and found numerous changes in laboratory indicators, including "enhanced natural killer (NK) cell number and cytotoxicity ... increased stimulated lymphocyte interleukin-6...increased insulin binding and degradation." Clinically, they mention reports of improved well-being, increased REM sleep, greater immune response to vaccination in the elderly, and other short-term effects. A study is under way at Stanford University using DHEA, 200 mg/day in systemic lupus erythematosis patients in an attempt to decrease long-term dependence on prednisone.69

Adverse events after taking DHEA include jaundice, elevated liver functions, virilization, adverse effect on lipids in high doses, and possibly hepatocarcinogenicity. Casson and Buster assert that "... at present, long-term efficacy and safety data do not exist" regarding DHEA supplements. They advise keeping doses for women under 50 mg/day, and tell physicians to check liver functions, lipids, and serum testosterone on a regular basis.

Women of reproductive age should not take DHEA, especially if they are at any risk of pregnancy, because of possible masculinization of a female fetus. The National Institute on Aging, a division of the National Institutes of Health, in April 1997 posted a advisory saying that "... scientists are concerned about the dangerous side effects associated with some of the supplements and about the possibility of undiscovered health risks."70 Over-the-counter DHEA sales were actually banned by the FDA in 1985. The products currently marketed are synthesized by conversion of dioscorea from wild yam to produce the androgenic steroid, thereby maintaining its classification as a food supplement. Health food stores also sell dioscorea, a precursor of DHEA production, but bioconversion does not take place in vivo in humans. Until further work proves its benefits and determines its safety, people should not take DHEA. Any adverse events that are attributable to DHEA should be reported to the FDA MEDWATCH.

Botanicals Used in Menopause. Whereas the term "herbal" refers to only the leaves and stems, not the seeds, flowers, fruits, and roots; the term "botanical" includes foods and supplements derived from any plant part. The therapeutic value of plant medicines, even an accepted formulation like digitalis, continues to be a area of controversy and challenge.

In the US, patients take bits and parts from different herbal and botanical practices, including European, colonial American, Asian and Latin American and concoct mixes that may have interactions and toxicities that cannot be anticipated. Fortunately the botanicals used to treat menopause, rnenstrual disorders and aging are relatively safe and benign.

Table 10 lists botanicals commonly, use in menopause. For more detailed information and reference material about these botanicals see "he Honest Herbal by Varro Tyler.71

Dandelion and raspberry, which are often cited in herbal texts for treating female menstrual reproductive problems, have no therapeutic value they are simply foods, and offer little medicinal value aside from providing pleasant, noncaffeinated drinks when brewed as teas.

Scientific literature or documentation could not be found about vitex or motherwort, and no further comments can be made about their purported uses, benefits, or dangers.

Angelica (angelica archangelica L., angelica atropurpurea72 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 advised not to angelica because the potential for photosensitization and cancer induction.

Black Cohosh (cimicifuga racemosa L. Nutt, family, Ranunculaceae) goes by many names including black snakeroot and bugbane. Not all plants called snakeroot in folk medicine are synonymous with black cohosh. Medicinal uses include menstrual regulation. It was one of the main constituents in Lydia Pinkham's Vegetable Compound and is used in an over-the-counter German menopausal preparation called "Remifemin." It binds to estrogen receptors and reduces luteinizing hormone levels in ovariectomized rats. These findings have been interpreted to mean that black cohosh has estrogenic activity. Clinical trials are underway using a combination of herbals, including black cohosh for alleviation of menopause symptoms. Black cohosh is not related to blue cohosh. Blue cohosh, Caulophyllum thalictroides, has very weak nicotine like activity offering the potential for toxicity. It is considered dangerous.

Damiana (Turnera diffusa Willd. Var. aphrodisiaca [L.F. Ward]) has been used in patent medicines the past 100 years and has long enjoyed great popularity because of its supposed aphrodisiac effects. No documentation exists for its claims, save hearsay.

Dong Quai, dang gui, Tang Kuei (Angelica polymorpha Maxim. var Sinesis Oliv, aka A. sinensiu (Oliv) Diels) is also a type of angelica. The root stock is advised for virtually every gynecologic ailment. The root stock is advised for virtually every gynecologic ailment. Again, no substantiation exists for the claims about dong quai, other than "th