ALT MED FOR MENOPAUSE

When your menopausal patient chooses alternative therapy

By Judi L. Chervenak, MD

A critical look at black cohosh, soy, chasteberry, and related supplements finds some evidence to support their use, but randomized large-scale clinical trials to definitively prove their worth are sorely needed.

Our patients spend billions of dollars a year on over-the-counter products. After the WHI findings were released, many women became fearful about using hormone replacement therapy or abruptly stopped using it. As you no doubt know, that often translated into recurring hot flashes, which in turn prompted many to turn to "natural" alternative remedies. While these therapies may help to ameliorate some women's symptoms, their mechanisms of action, safety, and possible drug interactions have not yet been clearly established.

Many menopausal symptoms affect quality of life. Hot flashes can be disturbing not only during the day but also when patients try to get to sleep. The resulting poor sleep patterns not only lead to fatigue, but irritability, and changes in mood, socialization, and interpersonal relationships. Of course, not all fatigue is caused by hormonally induced night sweats. Systemic diseases can also have their onset during the climacteric. The accompanying changes in mood, sleep, and fatigue may confound the diagnosis of other conditions like hypothyroidism, diabetes, sleep apnea, chronic fatigue syndrome, primary adrenal failure, depression, and Cushing's disease. If a woman self medicates without being evaluated thoroughly by her health-care provider, these conditions might be missed.

What's causing the hot flashes?

While hot flashes are reported all over the world, there are differences in their prevalence from country to country. The prevalence of reported hot flashes associated with spontaneous menopause range from 60% in one Swedish study to 82% in an American population.^1,2 Women in developing countries report fewer symptoms than in industrialized countries.³ It appears that in addition to hormonal changes, sociocultural factors play a role in menopausal symptoms.

Hot flashes occur as estrogen levels decline, and are often precipitated by the "roller coaster" estrogen levels that accompany the perimenopause. However, clinicians need to be aware that other as yet undiscovered factors may contribute to hot flashes; hormonal levels may not play an exclusive role. That conclusion is based in part on studies that have looked at plasma urinary and vaginal hormone levels, which are similar in postmenopausal women with and without hot flashes.^4,5

Evaluating alternative therapies

Alternative medicine has been defined as "...medical interventions that are neither widely taught in US medical schools nor generally available in US hospitals."⁶ About 42% of women between 35 and 49 and 44% of those between the ages of 50 and 64 use these remedies during the perimenopausal and early postmenopausal years.⁷ Common therapies include black cohosh, dong quai, vitamin E, soy, chasteberry, St. John's wort, red clover, and wild yam cream.

Women often turn to these therapies because they think that they are a safe way to ameliorate symptoms and because HRT has been implicated as a possible cause of breast cancer. Keep in mind, however, that if these alternative remedies are effective in relieving symptoms, it may be because they themselves have hormonal activity. And that in itself calls into question their safety.

In 1994, when the Dietary Supplement Health and Education Act became law, manufacturers were held responsible for the safety of such supplements. But since these products are defined as neither food nor drug, they do not need FDA approval and remain under minimal federal regulation; their supposed safety was assumed but not proven.

A closer look at individual remedies

Here are some of the most widely used herbal and nutritional therapies for vasomotor and other climacteric symptoms, along with the clinical research supporting or questioning their worth.

Black cohosh. Also known as Cimicifuga racemosa, this herb is available under several brand names, one of the most well-known being Remifemin. It's derived from the root of a plant used by native North American Indians and has been used for centuries to treat women's reproductive disorders; it's among the most widely used alternative therapies for vasomotor symptoms.⁸ In Germany, where the herb is government regulated and widely prescribed, it is used to treat depression, sleep disturbances, and hot flashes.

Some placebo-controlled trials have shown that black cohosh and soy may ameliorate symptoms in some women. In most patients, however, they do not appear to be as effective as HRT. Similarly, black cohosh does not appear to affect bone. Randomized, placebo-controlled studies regarding long-term efficacy, safety, and side effects have not yet been published.⁹ And the mechanism of action for the purported relief of vasomotor symptoms has yet to be elucidated.

Many nonplacebo-controlled studies done outside of the US, which have been noted in the German Commission E Monographs, suggest that black cohosh is effective against hot flashes. However, a placebo-controlled, randomized US trial of breast cancer patients (n=85) using tamoxifen found that the herb was no more effective than placebo in reducing hot flashes, although it did reduce sweating.¹⁰

Dong quai. In one randomized clinical trial, dong quai was no more helpful than placebo in relieving menopausal symptoms.¹¹ Since it is a common ingredient often used in combination with other therapies, be sure to warn patients that it may have coumarin-like activity and can therefore interfere with anticoagulant therapy.

In studies involving the human breast cancer cell line MCF-7, and in oophorectomized mice, dong quai and ginseng have been shown to induce the growth of MCF-7 cells by 16- and 27-fold, respectively, over that of untreated control cells. These same herbs did not activate human estrogen receptor alpha, or human estrogen receptor beta, however, nor did they affect in vivo mouse uterine weight after 4 days. This suggests that dong quai and ginseng may stimulate growth of the human breast cancer cells, independent of estrogenic activity. Therefore, women should be cautious about using these therapies in or to prevent breast cancer until further research is done.¹²

Chasteberry. The German Commission E Monographs state that this herb may bind to androgen receptors, thus creating an antiandrogenic environment. It also inhibits prolactin and prevents progesterone insufficiency. While the decrease in prolactin has the potential to relieve breast tenderness, the mechanism by which chasteberry relieves other perimenopausal symptoms is unclear.

St. John's wort. St. John's Wort is commonly used for mild-to-moderate depression, anxiety, seasonal affective disorders, and sleep disorders. In Germany, it is prescribed 20 times more often than fluoxetine. A double-blind, randomized, placebo-controlled multicenter trial failed to prove it was more effective than placebo for the treatment of major depression, however.¹³

While it is standardized to its hypericin component, its mechanism of action remains unclear. It is postulated to have an MAO-like effect and/or interact with serotonin.

In March of 2000, the British Health Ministry issued a warning that stated "The Medicines which may be affected by St. John's wort include some medications for the treatment of HIV (AZT)...heart conditions (digitalis and digoxin)...asthma (theophylline) and the oral contraceptive pill."

Vitamin E. Observational studies suggest that this nutrient may help prevent heart disease and cancer. It is essentially safe, unless excessive quantities are consumed, and relatively inexpensive. However, at least one randomized clinical trial has shown that the vitamin does not relieve vasomotor symptoms.¹⁴

Red clover. Extracts of red clover (Trifolium pratense) are commonly used to relieve vasomotor symptoms because they are a source of phytoestrogens and therefore perceived as a natural form of HRT. In a binding assay for progesterone and estradiol, it ranked in the top 5% of 150 tested herbs.¹⁵ In animal studies, red clover has estrogenic effects, including enlargement of the vulva, uterus, udder, and teats.¹⁶ In Australia in the 1940s, an epidemic of "clover disease" occurred when grazing sheep consumed Trifolium subterraneum and experienced infertility and abnormal lactation. Like red clover, subterranean clover contains large amounts of phytoestrogens.¹⁷

Two double-blind, placebo-controlled studies were designed to evaluate whether or not the herb relieved menopausal symptoms. Neither found any benefit.^18,19 Three trials showed no significant increase in endometrial thickness after 6 months or less of exposure to red clover.^18,20-21 It has been suggested that the isoflavones in red clover have an antiproliferative effect on the endometrium compared to estrogen. However, a randomized, placebo-controlled clinical study of red clover using immunohistochemical proliferation markers did not demonstrate an antiproliferative effect on the endometrium.²² Therefore, the question regarding long-term safety of red clover persists. Longer study periods are necessary to determine its effects on endometrial stimulation.²³

Another potential concern is that some clover species have coumarins and that micro-organisms can act on the clover to produce dicoumarol, an anticoagulant from which warfarin anticoagulants are derived.^23,24 No published studies to date have investigated the potential role of coumarins on tests of blood clotting and coagulation.

Soy. Observational studies suggest that soy-based diets can improve serum lipoproteins—when compared to an animal protein diet—reduce the risk of fractures, and relieve menopausal symptoms.^25-27

While epidemiologic studies have found that Japanese women living in Japan have fewer reproductive cancers, this benefit is diminished when they migrate to Hawaii and is further lost when they migrate to the mainland US. A causative factor may be the type of soy used in Japan, when compared to the soy used in mainland US. In Japan, women tend to eat more fermented soy products in a lower-fat, lower-calorie diet rich in omega-3 fatty acids. They also consume significantly more daily isoflavones than are consumed in the US. However, soy contains more than just isoflavones; it also has coumestans and lignans. Alcohol processing of soy's isoflavones removes biologically active forms. The soy milk, tofu products, and homogenized isoflavone tablets commonly purchased in US supermarkets and health food stores may not necessarily have the same actions as those consumed by Japanese women living in Japan.

While some studies suggest soy may relieve hot flashes, others do not. A placebo-controlled randomized, double-blind study (n=80) of women (average age 49) showed that 4 months of divided-dose therapy of 100 mg/day of isoflavones was associated with significant improvements in perimenopausal symptoms such as hot flashes, weakness, insomnia, and headache.²⁸ But in a randomized, placebo-controlled study (n=155) using a dose equivalent to 150 mg of soy isoflavones, once a day for 4 weeks, no differences were observed.²⁹ Yet another randomized, placebo-controlled study (n=177) using a dose equivalent to 150 mg of soy isoflavones for 12 weeks found that while the frequency of hot flashes was decreased from placebo at 6 weeks, there was no difference at 12 weeks.³⁰ The current consensus of the North American Menopause Society is that data on soy and hot flashes are inconclusive.³¹

Wild yam cream. Proponents of wild yam cream claim it is a "natural source of DHEA and progesterone." These topical creams are commonly sold in health food stores and over the Internet as an alternative to progesterone. Proponents also assert that the creams increase libido, improve bone density, prevent breast and endometrial cancer, and can substitute for prescribed hormonal therapy.

Unfortunately, the human body is not biochemically capable of converting the diosgenin in wild yam to a biologically active form of progesterone. Similarly no prospective, randomized, double-blind studies exist to date, and no appropriate clinical trials have been performed to determine whether the over-the-counter progesterone creams even contain enough progestin to alter hormone blood levels or estrogen over-stimulation of the uterus. No valid claims can be made as yet regarding reduction in rates of endometrial or breast cancer.

Other nonhormonal approaches to hot flashes

For women who cannot or will not use hormonal therapy, other options include behavioral modification, antidepressants, and clonidine.

Behavioral modification includes keeping a symptom diary to better understand what triggers and relieves hot flashes; layering clothing; keeping cool; and avoiding spicy food, alcohol, and caffeine. Stress management, paced respirations, and relaxation techniques may also be useful, especially when a woman senses an impending hot flash. Relaxation and deep abdominal breathing (6–8 breaths per minute) have been shown to decrease hot flashes by about 40%.^32,33

Patients often want a pill that will act as a panacea for all their problems, including decreased libido. The media has given a lot of attention to the benefits of androgens, and yet hormones may not be responsible for changes in libido in all patients. For some, night sweats and disturbed sleep may affect a woman's sense of well-being and that in turn may reduce her sexual drive. Be sure to evaluate these factors before offering prescription or nonprescription therapy.

A symptom diary may help pinpoint causes of decreased libido in some patients. For example, one patient presented requesting medication for her decreased libido. When we took an initial history, she vehemently denied that her decreased libido had anything to do with her spousal relationship. After keeping her diary, however, she found a link between diminished libido and arguments regarding television and the in-laws. After adjusting her behavior, her libido improved without any type of medication.

When evaluating any study regarding relief of hot flashes, it's important to recognize that placebo alone is associated with approximately a 20% to 30% decrease in hot flashes.³⁴

Antidepressants can also relieve vasomotor symptoms.Venlafaxine is a combined serotonin and norepinephrine reuptake inhibitor found to decrease the frequency and severity of hot flashes in a 2-week placebo-controlled randomized trial. In doses of 75 mg/day, it decreased hot flashes by an average of 60%.³⁵ A longer term, 8-week follow-up study using open-label venlafaxine (75 mg/day) supported these findings. The 60% decrease in hot flashes persisted throughout the longer study period, without an increase in toxicity.³⁶ Side effects included dry mouth, loss of appetite, and nausea, which improved with time.

In patients with moderate-to-severe hot flashes that affect daily living and for whom hormonal therapy is not an option, a trial of venlafaxine may be warranted. For these patients, 37.5 mg is recommended for the first week (with food). Hot flashes should improve by the second week of therapy. If vasomotor symptoms persist, increase the dose up to 75 mg, depending on response.

Fluoxetine, a selective serotonin-reuptake inhibitor, has been shown to decrease hot flashes by 50% in a 4-week placebo-controlled trial of 81 women with a history of, or who are at risk for breast cancer; patients on placebo saw a 36% improvement.³⁷

Other drugs. Clonidine can reduce hot flashes by 45%, compared to 25% in placebo, but it can have intolerable side effects including hypotension, fatigue, constipation, drowsiness, insomnia, and dry mouth.^34,38

Bellergal, a combination of phenobarbital and belladonna alkaloids, has potential intolerance problems, including nausea. Today's newer nonhormonal agents relieve symptoms better and are safer.

Conclusion

Vasomotor symptoms persist as a real quality-of-life issue for many women, which is why it's important to encourage women to discuss their signs, symptoms, and medications (prescription and nonprescription). While "natural" therapies may ameliorate symptoms in some patients, the mechanisms of action, safety, and possible drug interactions have yet to be definitively established for many of these agents.

Well-designed, prospective studies, with sufficient power to overcome study confounders, are forthcoming for some of these products, so in the future, we can better customize patient care. As with any prescribed drug therapy, not knowing the potential risks of alternative and complementary therapies doesn't eliminate these risks. If a patient is using over-the-counter products and doing well, then it may not be necessary to tell her to stop. However, should she present with irregular bleeding, or unusual or new onset of complaints that coincide with the use of the "natural" therapy, then it may be prudent to consider whether or not they may play a role in the onset of symptoms.

Dr. Chervenak is on the advisory board and speakers' program for Berlex and Pfizer.

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21. Baber RJ, Clifton Bligh P, Fulcher G, et al. The effect of an isoflavone dietary supplement (P-081) on serum lipids, forearm bone density and endometrial thickness in postmenopausal women (abstract). In: Proceedings of the North American Menopause Society, 10th Annual Conference, 1999.

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36. Barton D, La VB, Loprinzi C, et al. Venlafaxine for the control of hot flashes: results of a longitudinal continuation study. Oncol Nurs Forum. 2002;29:33-40.

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38. Pandya KJ, Raubertas RF, Flynn PJ, et al. Oral clonidine in postmenopausal patients with breast cancer experiencing tamoxifen induced hot flashes: a University of Rochester Cancer Center Community Clinical Oncology Program study. Ann Intern Med. 2000;132:788-793.

Dr. Chervenak is Assistant Professor of Ob/Gyn, and Reproductive Endocrinology and Infertility, Albert Einstein College of Medicine, Bronx, N.Y.

 

Judi Chervenek. When your menopausal patient chooses alternative therapy. Contemporary Ob/Gyn May 1, 2003;48:110-121.