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Treating hot flushes without hormone replacement therapy
- Ask your patients about complementary and alternative therapies; 21% of women say they use complementary or alternative therapies only, and another 25% say they use both conventional and alternative methods.
- Women who take 50 mg of soy isoflavones daily report a 10% to 20% absolute risk reduction (number needed to treat, 5–10) in the frequency of hot flashes. The duration of this effect is unknown.
- Black cohosh yields up to an 80% improvement in hot flashes.
- Patients should use an alternative therapy for at least 1 month and keep a symptom diary to adequately assess its effect.
Physicians may recommend alternative treatments for hot flashes with the same confidence they have in prescription drugs if they understand the expected results, risks and benefits, and interactions with other medications.
For treatment of hot flashes, an increasing number of menopausal women are choosing plantbased alternatives to hormone replacement therapy (HRT). Despite HRT’s proven efficacy in treating this plaguing symptom, many patients are fearful that HRT might lead to an increased risk of breast or uterine cancer, increase the risk of vascular disease including heart attack, or cause unpleasant side effects such as mood swings, depression, or continued menstrual periods.1
Dr. Seibel, an expert in non-hormone replacement therapy and a proponent of soy, provides his view of options in this important area. He argues that treatment with the more promising soy and black cohosh preparations is worth considering as part of a careful “N of 1” trial. Read this issue’s Clinical Inquiry, “What nonhormonal therapies are effective for postmenopausal vasomotor symptoms?” (pages 324–329), and you be the judge. —Jeffrey L. Susman, MD
One study of 2500 postmenopausal women found that 20% to 30% never fill their initial HRT prescriptions, 10% of those who use estrogen do so only intermittently, an additional 20% discontinue their therapy within 8 months, and only 15% to 20% of women will take HRT for more than a year.2
HRT is contraindicated in about 10% of postmenopausal women3 ; the Womens’ Health Initiative4 and the Heart and Estrogen/progestin Replacement Study5 (HERS) trials have suggested caution in using HRT even for those without contraindications.
With such an enormous number of women either unwilling or unable to take HRT, it is important to consider the alternatives you can offer.6,7 (See “How pervasive are alternative therapies?”) Whichever alternative treatment you and a patient select, give it at least 1 month (and preferably 3 months) to assess its effectiveness. Keeping a symptom diary will allow patients to objectively track their progress.
So-called alternative approaches to menopause are used so widely it might be more accurate to consider hormone replacement therapy as the true alternative medicine. Statistics presented at the National Institutes of Health on October 27, 2000, indicate that nearly half of all menopausal women are using complementary therapies—including vitamins, herbs, and soy products—to help treat their symptoms. Twenty-one percent of the women surveyed used complementary or alternative therapies alone, and 25% said they used both conventional and alternative methods.
Taken together, that is more than twice the 19% who said they used conventional hormone replacement therapy only. Given this enormous usage, it should come as no surprise that, in 2001, the dietary supplement industry likely exceeded $12 billion in sales in the United States alone.4 For many women, the decision to use an alternative is not so much dissatisfaction with conventional treatment, but that they regard the complementary agents as more congruent with their own values, beliefs, and philosophical orientations toward health and life.5
Soy
Much of the excitement about the health benefits of soy—a staple of the Asian diet for 5000 years—stems from epidemiological studies. The Asian diet, which is rich in isoflavones, is associated with a reduced risk of breast cancer, heart disease, and osteoporosis. Asian women also report fewer hot flashes than do their Western counterparts.8 One study showed that women in Western countries have an 80% incidence of hot flashes, while Asian women living in China have an incidence of only 20%.9
Clearly, factors other than soy also must be considered before we can make a direct cause-and-effect correlation. To that end, many studies have been conducted on the health benefits of soybeans, a rich source of the isoflavones genistein and daidzein.
Physiologic activity
Isoflavones are phytoestrogens with a hetero-cyclic phenol structure that is similar to estrogen. Their potency is between 1 x 104 and 1 x 103 the activity of 17Β-estradiol.10 Although their potency is low, their serum concentrations can reach levels several orders of magnitude higher than those of physiologic estrogens. It is generally believed that isoflavones act as a selective estrogen receptor modulator, exerting antiestrogenic effects in the high-estrogen environment of premenopause and estrogenic effects in the low-estrogen environment of post-menopause.
Clinical efficacy
Hot flushes. An increasing number of studies suggest that soy and soy isoflavones—in the form of soy flour, soy protein, and dietary supplements—may play an important role in the treatment of hot flushes. In general, the average amount of isoflavones consumed in a typical Asian diet is approximately 50 mg/day. (One gram of soy protein contains approximately 1 mg of isoflavones.)
Unfortunately, clinical trial data are confounded by varying preparations of soy, length of therapy, outcomes measured, and small sample sizes. The absolute risk reduction of soy preparations versus placebo or comparators in positive trials ranges from 10% to 20% (number needed to treat [NNT]=6–10) when frequency of hot flushes is the outcome measured (Table 1).11-15
Placebo effect. All soy studies also confirm the existence of a placebo effect on the treatment of hot flushes. The large placebo effect and varied efficacy has left many skeptics questioning the clinical efficacy of soy products.16
I believe that thinking is wrong. Women who have hot flushes tend to have lower sleep efficiencies and longer REM latencies than women who do not experience this vasomotor symptom.17 By lowering the frequency of hot flushes, soy may produce greater sleep efficiencies and improve quality of life.
TABLE 1
Positive trials* of soy in the treatment of hot flushes
| Absolute risk reduction of hot flushes (%) | ||||||
|---|---|---|---|---|---|---|
| Study | N | Design | Soy | Control | NNT | LOE† |
| Murkies 199511 | 58 | 45 g soy flour | 42 | 25 | 6 | 1b |
| Brzezinski 199712 | 73/72 | Mostly soy, 1/4 diet, some flaxseed | 54 | 35 | ||
| Albertazzi 199813 | 51/53 | 60 g soy protein | 43.6 | 31.3 | 8.1 | 2b |
| Scambia 200014 | 39 | 50 mg/d isoflavones | 45 | 25 | 1b | |
| Upmalis 200015 | 177 | 50 mg/d isoflavones | 30 | 20 | 1b | |
| From Seibel MM, The soy solution for menopause: an alternative to estrogen. New York, NY: Fireside Press, 2003. | ||||||
| *None of the above trials were of high quality—all either had a large number of dropouts, substantial divergence of outcomes, a small “n” (number of subjects) or other substantive methodological concerns. | ||||||
| NNT, number needed to treat; LOE, level of evidence | ||||||
| †See page 290 for a description of strength of recommendation. | ||||||
Safety
Soy has been safely consumed by hundreds of millions of people without complications, with t he possible exception of soy allergies (Table 2). The literature suggests it is safe and effective in dosages of either 40 g of soy protein or 50 mg of soy isoflavones per day. Soy does not stimulate the uterine lining and may be protective of the endometrium if taken with estrogen.
The incidence of breast cancer is one fourth as high in Asia as in the US; many studies have shown soy to be protective of breast tissue. However, soy may stimulate breast tissue in women with a history of breast cancer. The evidence in these areas is conflicting and controversial.
In contrast to herbal alternatives to HRT, soy has been thought to lower cholesterol, make blood vessels more elastic (increase vascular elasticity), and slow osteoclast activity in bones. It is also an excellent source of protein, and is lactose- and cholesterol-free.18
TABLE 2
Remedies for hot flushes and their adverse effects, interactions, and contraindications
| Adverse effects | Important drug interactions | Contraindications | |
|---|---|---|---|
| Soy | Bloating, flatulence | Thyroid hormone, if taken simultaneously | Use with caution in patients being treated for hypothyroidism (soy may bind thyroid medication, thus lowering absorption; patients on thyroid hormone should use soy only in supplement form or take at a time distant from thyroid medication) |
| Black cohosh | Abdominal pain, nausea, headaches, dizziness, trembling limbs | Iron therapy medications | Patients with iron deficiencies; use cautiously in patients with breast cancer or high risk of breast cancer |
| Dong quai | Photodermatitis, rash | Warfarin (effects potentiated) | Patients with coagulopathies or very heavy menstruation and acute viral infections such as colds or influenza; pregnancy |
| Evening primrose oil | Nausea, softening of stools, headaches, seizures | Anticonvulsant and tricyclic antidepressants | Patients taking anticonvulsants and tricyclic antidepressants (lowers efficacy) |
| Red clover | Blood thinning | Anticoagulants such as coumadin, heparin, clopidrogel, pentoxifylline, or aspirin | Patients with coagulopathies |
Black cohosh
A member of the buttercup family, black cohosh (Actaea [formerly Cimicifuga] racemosa) has a long history in folk medicine, especially among Native Americans, who boiled the root in water and drank the resulting beverage to treat dysmenorrhea, labor pain, upset stomach, and arthritis. In Germany, extracts of black cohosh have been used since the 1940s.
Many substances have been identified in the rhizome, but it is uncertain what the majority of them do or, in fact, which are active ingredients.19 The effectiveness of black cohosh is based on the total amount of triterpenoid glycosides, typically standardized to 2.5%.20
Several studies, most of them in the German literature, have shown that black cohosh yields a significant improvement in hot flushes, with reductions of up to 80% reported (level of evidence [LOE]: 2b).21-23 The usual dosage is 40 drops of the extract twice daily for 6 to 8 weeks, or one to two 20-mg tablets twice daily with liquid (not to be chewed or sucked).
Side effects are uncommon, but occasional stomach pains and intestinal discomfort, dizziness, nausea, severe headaches, stiffness, and trembling limbs have been noted. Germany’s Commission E, which is similar to the US Food and Drug Administration, recommends that black cohosh not be used for more than 6 months, since no studies have been conducted for longer periods.
Black cohosh has weak estrogenic effect on the breast and should be used cautiously in patients with breast cancer or a high risk of breast cancer. A 2-month double-blind, randomized controlled trial of black cohosh in breast cancer survivors demonstrated no short-term side effects; however, therapy was only significantly beneficial in relieving sweating and ineffective in reducing flushes.24 The long-term effects are unknown. A recent systematic review suggests that the side effects of black cohosh are transient, and severe adverse event reports are unproven (Table 2).24
Dong quai
Dong quai, a common Chinese herb extracted from the Angelica sinensis root, has become popular in the US. In contrast to China, where it is sold as part of a mixture that includes several other herbs, dong quai typically is sold in the US as a single herb.
Although some women report improvements in their vasomotor symptoms, there have been very few studies on the effects of dong quai on menopause. In one 24-week study of 71 postmenopausal women, researchers could not demonstrate a significant difference between dong quai and placebo in alleviating vasomotor symptoms (LOE: 2b).25 The investigators suggested that studying the effects of dong quai alone, rather than in combination with other herbs, may have been a factor in their findings.
Two caveats: Dong quai increases photosensitivity, so women taking the herb should be cautioned that too much exposure to sunlight may result in a rash. Also it has been reported to potentiate the effects of warfarin (Table 2). It should not be used during pregnancy.26
Evening primrose
Native Americans consumed the leaves, roots, and seedpods of evening primrose (Oenothera biennis) for food, and made extracts from it to treat a variety of conditions. Today, the flowers and seeds are pressed to make oil that is high in the omega-6 fatty acid gamma-linolenic acid (known as GLA) and essential polyunsaturated fatty acids, which convert into prostaglandins. Evening primrose oil also is a good source of linoleic acid.
Although there are a number of good studies in which evening primrose oil has been used to successfully treat eczema and several other conditions with few side effects, it appears to have no benefit over placebo for hot flushes (LOE: 2b).27
Patients should be warned that mild upset stomach, indigestion, nausea, softening of stools, and mild headaches may occasionally occur. Also, evening primrose is contraindicated in women taking seizure medications or antipsychotics because it lowers the seizure threshold in patients on phenothiazines (Table 2).
Red clover
Red clover (Trifolium pratense) is a plant that contains the phytoestrogens formononetin, biochanin A, daidzein, and genistein. It was originally used by Native Americans to treat whooping cough, gout, and cancer.
Two clinical trials conducted in Australia failed to demonstrate that red clover extract was more effective than placebo in reducing vasomotor symptoms (LOE: 2b).28,29 However, one recent presentation found that women who took 40 mg of red clover per day—the recommended dosage—experienced a significant reduction in hot flushes.30
There is still little information on whether red clover will have any effect on the uterine lining or breast tissue. Because red clover contains coumarin-like substances, high dosages may cause the blood to thin (Table 2).31
1. Salamone LM, Pressman AR, Seeley DG, Cauley JA. Estrogen replacement therapy. A survey of older women’s attitudes. Arch Int Med 1996;156:1293-1297.
2. Ravnikar VA. Compliance with hormone therapy. Am J Obstet Gynecol 1987;156:1332-1334.
3. Kessel B. Alternatives to estrogen for menopausal women. Proc Soc Esp Biol Med 1998;217:38-44.
4. Roussouw JE, Anderson GL, Prentice RL, et al. Risks and benefits of estrogen plus progestin in healthy post-menopausal women: principal results from the Women’s Health Initiative randomized controlled trial. JAMA 2002;288:321-333.
5. Grady D, Herrington D, Bittner V, et al. Cardiovascular disease outcomes during 6.8 years of hormone replacement therapy: Heart and Estrogen/progestin Replacement Study follow-up (HERS II). JAMA 2002;288:49-57.
6. Seibel MM. The role of nutrition and nutritional supplements in women’s health. Fertil Steril 1999;72:579-591.
7. Astin JA. Why patients use alternative medicine: results of a national study. JAMA 1998;279:1548-1553.
8. Haines CJ, Chung TKH, Leung DHY. A prospective study of the frequency of acute menopausal symptoms in Hog Dong Chinese women. Maturitas 1994;18:175-181.
9. Tang GWK. The climacteric of Chinese factory workers. Maturitas 1994;19:177-182.
10. Markiewicz L, Garey J, Adlercreutz H, Gurpide E. In vitro bioassays of non-steroidal phytoestrogens. J Steroid Biochem Mol Biol 1993;45:399-405.
11. Murkies AL, Lombard C, Strauss BJD, Wilcox G, Burger HG, Morton MS. Dietary flour supplementation decreases postmenopausal hot flushes: effect of soy and wheat. Maturitas 1995;21:189-195.
12. Brzezinski A, Adlercreutz H, Shaoul R, Rosler A, Shmueli A, Tanos V, Schenker JG. Short-term effects of phytoestrogen-rich diet on postmenopausal women. Menopause 1997;4:89-94.
13. Albertazzi P, Pansini F, Bonaccorsi G, Zanotti L, Forini E, De Aloysio D. The effect of dietary soy supplementation on hot flushes. Obstet Gynecol 1998;91:6-11.
14. Scambia G, Mango D, Signorile PG, et al. Clinical effects of a standardized soy extract in postmenopausal women: a pilot study. Menopause 2000;7:105-111.
15. Upmalis DH, Lobo R, Bradley L, Warren M, Cone FL, Lamia CA. Vasomotor symptom relief by soy isoflavone extract tablets in postmenopausal women: a multicenter, double-blind, randomized, placebo-controlled study. Menopause 2000;7:236-242.
16. Kronenberg F, Fugh-Berman A. Complementary and alternative medicine for menopausal symptoms: a review of randomized, controlled trials. Ann Intern Med 2002;137:805-811.
17. Shaver JLF, Giblin E, Paulsen V. Sleep quality subtypes in midlife women. Sleep 1991;14:18-23.
18. From Seibel MM. The soy solution for menopause: an alternative to estrogen. New York, NY: Fireside Press, 2003.
19. Struck D, Tegtmeier M, Harnishfeger G. Flavones in extracts of Cimicifuga racemosa. Planta Med 1997;63:289-290.
20. Beuscher N. Cimicifuga racemosa L.Black Cohosh. HerbalGram 1996;19-27.
21. Vorberg G. Therapy of climacteric complaints. Zeitschrift fur Allgemeinmedizin 1984;60:626-629.
22. Warnecke G. Influence of a phytopharmaceutical on climacteric complaints. Die Meizinische Welt 1985;36:871-874.
23. Stoll W. Phytopharmacon influences atrophic vaginal epithelium: double-blind study—Cimicifuga vs. estrogenic substances. Therapeuticum 1987;1:23-31.
24. Jacobson JS, Troxel AB, Evans J, et al. Randomized trial of black cohosh for the treatment of hot flashes among women with a history of breast cancer. J Clin Oncol 2001;19:2739-2745.
25. Huntley A, Ernst E. A systematic review of the safety of black cohosh. Menopause 2003;10:58-64.
26. Hirata JD, Swiers LM, Zell B, Small R, Ettinger B. Does dong quai have estrogenic effects in postmenopausal women? A double-blind placebo-controlled trial. Fertil Steril 1997;68:981-986.
27. Page RL 2nd, Lawrence JD. Potentiation of warfarin by dong quai. Pharmacotherapy 1999;19:870-876.
28. Chenoy R, Hussain S, Tayob Y, O’Brien PMS, Moss MY, Morse PF. Effect of oral gamalenic acid from evening primrose oil on menopausal flushing. BMJ 1994;308:501-503.
29. Barber RJ, Templeman C, Morton T, Delley GE, Weat L. Randomized placebo-controlled trial of an isoflavone supplement and menopausal symptoms in women. Climacteric 1999;2:85-92.
30. Knight DC, Howes JB, Eden JA. The effect of Promensil an isoflavone extract, on menopausal symptoms. Climacteric 1999;2:79-84.
31. Nachtigall LB, LaGrega L, Lee WW, et al. The effects of isoflavones derived from red clover on vasomotor symptoms and endometrial thickness. 9th International Menopause Society World Congress on Menopause, October 17-21, 1999.
32. Fugh-Berman A, Kronenberg F. Red clover (Trifolium pratense) for menopausal women: current state of knowledge. Menopause 2001;8:333-337.
- Ask your patients about complementary and alternative therapies; 21% of women say they use complementary or alternative therapies only, and another 25% say they use both conventional and alternative methods.
- Women who take 50 mg of soy isoflavones daily report a 10% to 20% absolute risk reduction (number needed to treat, 5–10) in the frequency of hot flashes. The duration of this effect is unknown.
- Black cohosh yields up to an 80% improvement in hot flashes.
- Patients should use an alternative therapy for at least 1 month and keep a symptom diary to adequately assess its effect.
Physicians may recommend alternative treatments for hot flashes with the same confidence they have in prescription drugs if they understand the expected results, risks and benefits, and interactions with other medications.
For treatment of hot flashes, an increasing number of menopausal women are choosing plantbased alternatives to hormone replacement therapy (HRT). Despite HRT’s proven efficacy in treating this plaguing symptom, many patients are fearful that HRT might lead to an increased risk of breast or uterine cancer, increase the risk of vascular disease including heart attack, or cause unpleasant side effects such as mood swings, depression, or continued menstrual periods.1
Dr. Seibel, an expert in non-hormone replacement therapy and a proponent of soy, provides his view of options in this important area. He argues that treatment with the more promising soy and black cohosh preparations is worth considering as part of a careful “N of 1” trial. Read this issue’s Clinical Inquiry, “What nonhormonal therapies are effective for postmenopausal vasomotor symptoms?” (pages 324–329), and you be the judge. —Jeffrey L. Susman, MD
One study of 2500 postmenopausal women found that 20% to 30% never fill their initial HRT prescriptions, 10% of those who use estrogen do so only intermittently, an additional 20% discontinue their therapy within 8 months, and only 15% to 20% of women will take HRT for more than a year.2
HRT is contraindicated in about 10% of postmenopausal women3 ; the Womens’ Health Initiative4 and the Heart and Estrogen/progestin Replacement Study5 (HERS) trials have suggested caution in using HRT even for those without contraindications.
With such an enormous number of women either unwilling or unable to take HRT, it is important to consider the alternatives you can offer.6,7 (See “How pervasive are alternative therapies?”) Whichever alternative treatment you and a patient select, give it at least 1 month (and preferably 3 months) to assess its effectiveness. Keeping a symptom diary will allow patients to objectively track their progress.
So-called alternative approaches to menopause are used so widely it might be more accurate to consider hormone replacement therapy as the true alternative medicine. Statistics presented at the National Institutes of Health on October 27, 2000, indicate that nearly half of all menopausal women are using complementary therapies—including vitamins, herbs, and soy products—to help treat their symptoms. Twenty-one percent of the women surveyed used complementary or alternative therapies alone, and 25% said they used both conventional and alternative methods.
Taken together, that is more than twice the 19% who said they used conventional hormone replacement therapy only. Given this enormous usage, it should come as no surprise that, in 2001, the dietary supplement industry likely exceeded $12 billion in sales in the United States alone.4 For many women, the decision to use an alternative is not so much dissatisfaction with conventional treatment, but that they regard the complementary agents as more congruent with their own values, beliefs, and philosophical orientations toward health and life.5
Soy
Much of the excitement about the health benefits of soy—a staple of the Asian diet for 5000 years—stems from epidemiological studies. The Asian diet, which is rich in isoflavones, is associated with a reduced risk of breast cancer, heart disease, and osteoporosis. Asian women also report fewer hot flashes than do their Western counterparts.8 One study showed that women in Western countries have an 80% incidence of hot flashes, while Asian women living in China have an incidence of only 20%.9
Clearly, factors other than soy also must be considered before we can make a direct cause-and-effect correlation. To that end, many studies have been conducted on the health benefits of soybeans, a rich source of the isoflavones genistein and daidzein.
Physiologic activity
Isoflavones are phytoestrogens with a hetero-cyclic phenol structure that is similar to estrogen. Their potency is between 1 x 104 and 1 x 103 the activity of 17Β-estradiol.10 Although their potency is low, their serum concentrations can reach levels several orders of magnitude higher than those of physiologic estrogens. It is generally believed that isoflavones act as a selective estrogen receptor modulator, exerting antiestrogenic effects in the high-estrogen environment of premenopause and estrogenic effects in the low-estrogen environment of post-menopause.
Clinical efficacy
Hot flushes. An increasing number of studies suggest that soy and soy isoflavones—in the form of soy flour, soy protein, and dietary supplements—may play an important role in the treatment of hot flushes. In general, the average amount of isoflavones consumed in a typical Asian diet is approximately 50 mg/day. (One gram of soy protein contains approximately 1 mg of isoflavones.)
Unfortunately, clinical trial data are confounded by varying preparations of soy, length of therapy, outcomes measured, and small sample sizes. The absolute risk reduction of soy preparations versus placebo or comparators in positive trials ranges from 10% to 20% (number needed to treat [NNT]=6–10) when frequency of hot flushes is the outcome measured (Table 1).11-15
Placebo effect. All soy studies also confirm the existence of a placebo effect on the treatment of hot flushes. The large placebo effect and varied efficacy has left many skeptics questioning the clinical efficacy of soy products.16
I believe that thinking is wrong. Women who have hot flushes tend to have lower sleep efficiencies and longer REM latencies than women who do not experience this vasomotor symptom.17 By lowering the frequency of hot flushes, soy may produce greater sleep efficiencies and improve quality of life.
TABLE 1
Positive trials* of soy in the treatment of hot flushes
| Absolute risk reduction of hot flushes (%) | ||||||
|---|---|---|---|---|---|---|
| Study | N | Design | Soy | Control | NNT | LOE† |
| Murkies 199511 | 58 | 45 g soy flour | 42 | 25 | 6 | 1b |
| Brzezinski 199712 | 73/72 | Mostly soy, 1/4 diet, some flaxseed | 54 | 35 | ||
| Albertazzi 199813 | 51/53 | 60 g soy protein | 43.6 | 31.3 | 8.1 | 2b |
| Scambia 200014 | 39 | 50 mg/d isoflavones | 45 | 25 | 1b | |
| Upmalis 200015 | 177 | 50 mg/d isoflavones | 30 | 20 | 1b | |
| From Seibel MM, The soy solution for menopause: an alternative to estrogen. New York, NY: Fireside Press, 2003. | ||||||
| *None of the above trials were of high quality—all either had a large number of dropouts, substantial divergence of outcomes, a small “n” (number of subjects) or other substantive methodological concerns. | ||||||
| NNT, number needed to treat; LOE, level of evidence | ||||||
| †See page 290 for a description of strength of recommendation. | ||||||
Safety
Soy has been safely consumed by hundreds of millions of people without complications, with t he possible exception of soy allergies (Table 2). The literature suggests it is safe and effective in dosages of either 40 g of soy protein or 50 mg of soy isoflavones per day. Soy does not stimulate the uterine lining and may be protective of the endometrium if taken with estrogen.
The incidence of breast cancer is one fourth as high in Asia as in the US; many studies have shown soy to be protective of breast tissue. However, soy may stimulate breast tissue in women with a history of breast cancer. The evidence in these areas is conflicting and controversial.
In contrast to herbal alternatives to HRT, soy has been thought to lower cholesterol, make blood vessels more elastic (increase vascular elasticity), and slow osteoclast activity in bones. It is also an excellent source of protein, and is lactose- and cholesterol-free.18
TABLE 2
Remedies for hot flushes and their adverse effects, interactions, and contraindications
| Adverse effects | Important drug interactions | Contraindications | |
|---|---|---|---|
| Soy | Bloating, flatulence | Thyroid hormone, if taken simultaneously | Use with caution in patients being treated for hypothyroidism (soy may bind thyroid medication, thus lowering absorption; patients on thyroid hormone should use soy only in supplement form or take at a time distant from thyroid medication) |
| Black cohosh | Abdominal pain, nausea, headaches, dizziness, trembling limbs | Iron therapy medications | Patients with iron deficiencies; use cautiously in patients with breast cancer or high risk of breast cancer |
| Dong quai | Photodermatitis, rash | Warfarin (effects potentiated) | Patients with coagulopathies or very heavy menstruation and acute viral infections such as colds or influenza; pregnancy |
| Evening primrose oil | Nausea, softening of stools, headaches, seizures | Anticonvulsant and tricyclic antidepressants | Patients taking anticonvulsants and tricyclic antidepressants (lowers efficacy) |
| Red clover | Blood thinning | Anticoagulants such as coumadin, heparin, clopidrogel, pentoxifylline, or aspirin | Patients with coagulopathies |
Black cohosh
A member of the buttercup family, black cohosh (Actaea [formerly Cimicifuga] racemosa) has a long history in folk medicine, especially among Native Americans, who boiled the root in water and drank the resulting beverage to treat dysmenorrhea, labor pain, upset stomach, and arthritis. In Germany, extracts of black cohosh have been used since the 1940s.
Many substances have been identified in the rhizome, but it is uncertain what the majority of them do or, in fact, which are active ingredients.19 The effectiveness of black cohosh is based on the total amount of triterpenoid glycosides, typically standardized to 2.5%.20
Several studies, most of them in the German literature, have shown that black cohosh yields a significant improvement in hot flushes, with reductions of up to 80% reported (level of evidence [LOE]: 2b).21-23 The usual dosage is 40 drops of the extract twice daily for 6 to 8 weeks, or one to two 20-mg tablets twice daily with liquid (not to be chewed or sucked).
Side effects are uncommon, but occasional stomach pains and intestinal discomfort, dizziness, nausea, severe headaches, stiffness, and trembling limbs have been noted. Germany’s Commission E, which is similar to the US Food and Drug Administration, recommends that black cohosh not be used for more than 6 months, since no studies have been conducted for longer periods.
Black cohosh has weak estrogenic effect on the breast and should be used cautiously in patients with breast cancer or a high risk of breast cancer. A 2-month double-blind, randomized controlled trial of black cohosh in breast cancer survivors demonstrated no short-term side effects; however, therapy was only significantly beneficial in relieving sweating and ineffective in reducing flushes.24 The long-term effects are unknown. A recent systematic review suggests that the side effects of black cohosh are transient, and severe adverse event reports are unproven (Table 2).24
Dong quai
Dong quai, a common Chinese herb extracted from the Angelica sinensis root, has become popular in the US. In contrast to China, where it is sold as part of a mixture that includes several other herbs, dong quai typically is sold in the US as a single herb.
Although some women report improvements in their vasomotor symptoms, there have been very few studies on the effects of dong quai on menopause. In one 24-week study of 71 postmenopausal women, researchers could not demonstrate a significant difference between dong quai and placebo in alleviating vasomotor symptoms (LOE: 2b).25 The investigators suggested that studying the effects of dong quai alone, rather than in combination with other herbs, may have been a factor in their findings.
Two caveats: Dong quai increases photosensitivity, so women taking the herb should be cautioned that too much exposure to sunlight may result in a rash. Also it has been reported to potentiate the effects of warfarin (Table 2). It should not be used during pregnancy.26
Evening primrose
Native Americans consumed the leaves, roots, and seedpods of evening primrose (Oenothera biennis) for food, and made extracts from it to treat a variety of conditions. Today, the flowers and seeds are pressed to make oil that is high in the omega-6 fatty acid gamma-linolenic acid (known as GLA) and essential polyunsaturated fatty acids, which convert into prostaglandins. Evening primrose oil also is a good source of linoleic acid.
Although there are a number of good studies in which evening primrose oil has been used to successfully treat eczema and several other conditions with few side effects, it appears to have no benefit over placebo for hot flushes (LOE: 2b).27
Patients should be warned that mild upset stomach, indigestion, nausea, softening of stools, and mild headaches may occasionally occur. Also, evening primrose is contraindicated in women taking seizure medications or antipsychotics because it lowers the seizure threshold in patients on phenothiazines (Table 2).
Red clover
Red clover (Trifolium pratense) is a plant that contains the phytoestrogens formononetin, biochanin A, daidzein, and genistein. It was originally used by Native Americans to treat whooping cough, gout, and cancer.
Two clinical trials conducted in Australia failed to demonstrate that red clover extract was more effective than placebo in reducing vasomotor symptoms (LOE: 2b).28,29 However, one recent presentation found that women who took 40 mg of red clover per day—the recommended dosage—experienced a significant reduction in hot flushes.30
There is still little information on whether red clover will have any effect on the uterine lining or breast tissue. Because red clover contains coumarin-like substances, high dosages may cause the blood to thin (Table 2).31
- Ask your patients about complementary and alternative therapies; 21% of women say they use complementary or alternative therapies only, and another 25% say they use both conventional and alternative methods.
- Women who take 50 mg of soy isoflavones daily report a 10% to 20% absolute risk reduction (number needed to treat, 5–10) in the frequency of hot flashes. The duration of this effect is unknown.
- Black cohosh yields up to an 80% improvement in hot flashes.
- Patients should use an alternative therapy for at least 1 month and keep a symptom diary to adequately assess its effect.
Physicians may recommend alternative treatments for hot flashes with the same confidence they have in prescription drugs if they understand the expected results, risks and benefits, and interactions with other medications.
For treatment of hot flashes, an increasing number of menopausal women are choosing plantbased alternatives to hormone replacement therapy (HRT). Despite HRT’s proven efficacy in treating this plaguing symptom, many patients are fearful that HRT might lead to an increased risk of breast or uterine cancer, increase the risk of vascular disease including heart attack, or cause unpleasant side effects such as mood swings, depression, or continued menstrual periods.1
Dr. Seibel, an expert in non-hormone replacement therapy and a proponent of soy, provides his view of options in this important area. He argues that treatment with the more promising soy and black cohosh preparations is worth considering as part of a careful “N of 1” trial. Read this issue’s Clinical Inquiry, “What nonhormonal therapies are effective for postmenopausal vasomotor symptoms?” (pages 324–329), and you be the judge. —Jeffrey L. Susman, MD
One study of 2500 postmenopausal women found that 20% to 30% never fill their initial HRT prescriptions, 10% of those who use estrogen do so only intermittently, an additional 20% discontinue their therapy within 8 months, and only 15% to 20% of women will take HRT for more than a year.2
HRT is contraindicated in about 10% of postmenopausal women3 ; the Womens’ Health Initiative4 and the Heart and Estrogen/progestin Replacement Study5 (HERS) trials have suggested caution in using HRT even for those without contraindications.
With such an enormous number of women either unwilling or unable to take HRT, it is important to consider the alternatives you can offer.6,7 (See “How pervasive are alternative therapies?”) Whichever alternative treatment you and a patient select, give it at least 1 month (and preferably 3 months) to assess its effectiveness. Keeping a symptom diary will allow patients to objectively track their progress.
So-called alternative approaches to menopause are used so widely it might be more accurate to consider hormone replacement therapy as the true alternative medicine. Statistics presented at the National Institutes of Health on October 27, 2000, indicate that nearly half of all menopausal women are using complementary therapies—including vitamins, herbs, and soy products—to help treat their symptoms. Twenty-one percent of the women surveyed used complementary or alternative therapies alone, and 25% said they used both conventional and alternative methods.
Taken together, that is more than twice the 19% who said they used conventional hormone replacement therapy only. Given this enormous usage, it should come as no surprise that, in 2001, the dietary supplement industry likely exceeded $12 billion in sales in the United States alone.4 For many women, the decision to use an alternative is not so much dissatisfaction with conventional treatment, but that they regard the complementary agents as more congruent with their own values, beliefs, and philosophical orientations toward health and life.5
Soy
Much of the excitement about the health benefits of soy—a staple of the Asian diet for 5000 years—stems from epidemiological studies. The Asian diet, which is rich in isoflavones, is associated with a reduced risk of breast cancer, heart disease, and osteoporosis. Asian women also report fewer hot flashes than do their Western counterparts.8 One study showed that women in Western countries have an 80% incidence of hot flashes, while Asian women living in China have an incidence of only 20%.9
Clearly, factors other than soy also must be considered before we can make a direct cause-and-effect correlation. To that end, many studies have been conducted on the health benefits of soybeans, a rich source of the isoflavones genistein and daidzein.
Physiologic activity
Isoflavones are phytoestrogens with a hetero-cyclic phenol structure that is similar to estrogen. Their potency is between 1 x 104 and 1 x 103 the activity of 17Β-estradiol.10 Although their potency is low, their serum concentrations can reach levels several orders of magnitude higher than those of physiologic estrogens. It is generally believed that isoflavones act as a selective estrogen receptor modulator, exerting antiestrogenic effects in the high-estrogen environment of premenopause and estrogenic effects in the low-estrogen environment of post-menopause.
Clinical efficacy
Hot flushes. An increasing number of studies suggest that soy and soy isoflavones—in the form of soy flour, soy protein, and dietary supplements—may play an important role in the treatment of hot flushes. In general, the average amount of isoflavones consumed in a typical Asian diet is approximately 50 mg/day. (One gram of soy protein contains approximately 1 mg of isoflavones.)
Unfortunately, clinical trial data are confounded by varying preparations of soy, length of therapy, outcomes measured, and small sample sizes. The absolute risk reduction of soy preparations versus placebo or comparators in positive trials ranges from 10% to 20% (number needed to treat [NNT]=6–10) when frequency of hot flushes is the outcome measured (Table 1).11-15
Placebo effect. All soy studies also confirm the existence of a placebo effect on the treatment of hot flushes. The large placebo effect and varied efficacy has left many skeptics questioning the clinical efficacy of soy products.16
I believe that thinking is wrong. Women who have hot flushes tend to have lower sleep efficiencies and longer REM latencies than women who do not experience this vasomotor symptom.17 By lowering the frequency of hot flushes, soy may produce greater sleep efficiencies and improve quality of life.
TABLE 1
Positive trials* of soy in the treatment of hot flushes
| Absolute risk reduction of hot flushes (%) | ||||||
|---|---|---|---|---|---|---|
| Study | N | Design | Soy | Control | NNT | LOE† |
| Murkies 199511 | 58 | 45 g soy flour | 42 | 25 | 6 | 1b |
| Brzezinski 199712 | 73/72 | Mostly soy, 1/4 diet, some flaxseed | 54 | 35 | ||
| Albertazzi 199813 | 51/53 | 60 g soy protein | 43.6 | 31.3 | 8.1 | 2b |
| Scambia 200014 | 39 | 50 mg/d isoflavones | 45 | 25 | 1b | |
| Upmalis 200015 | 177 | 50 mg/d isoflavones | 30 | 20 | 1b | |
| From Seibel MM, The soy solution for menopause: an alternative to estrogen. New York, NY: Fireside Press, 2003. | ||||||
| *None of the above trials were of high quality—all either had a large number of dropouts, substantial divergence of outcomes, a small “n” (number of subjects) or other substantive methodological concerns. | ||||||
| NNT, number needed to treat; LOE, level of evidence | ||||||
| †See page 290 for a description of strength of recommendation. | ||||||
Safety
Soy has been safely consumed by hundreds of millions of people without complications, with t he possible exception of soy allergies (Table 2). The literature suggests it is safe and effective in dosages of either 40 g of soy protein or 50 mg of soy isoflavones per day. Soy does not stimulate the uterine lining and may be protective of the endometrium if taken with estrogen.
The incidence of breast cancer is one fourth as high in Asia as in the US; many studies have shown soy to be protective of breast tissue. However, soy may stimulate breast tissue in women with a history of breast cancer. The evidence in these areas is conflicting and controversial.
In contrast to herbal alternatives to HRT, soy has been thought to lower cholesterol, make blood vessels more elastic (increase vascular elasticity), and slow osteoclast activity in bones. It is also an excellent source of protein, and is lactose- and cholesterol-free.18
TABLE 2
Remedies for hot flushes and their adverse effects, interactions, and contraindications
| Adverse effects | Important drug interactions | Contraindications | |
|---|---|---|---|
| Soy | Bloating, flatulence | Thyroid hormone, if taken simultaneously | Use with caution in patients being treated for hypothyroidism (soy may bind thyroid medication, thus lowering absorption; patients on thyroid hormone should use soy only in supplement form or take at a time distant from thyroid medication) |
| Black cohosh | Abdominal pain, nausea, headaches, dizziness, trembling limbs | Iron therapy medications | Patients with iron deficiencies; use cautiously in patients with breast cancer or high risk of breast cancer |
| Dong quai | Photodermatitis, rash | Warfarin (effects potentiated) | Patients with coagulopathies or very heavy menstruation and acute viral infections such as colds or influenza; pregnancy |
| Evening primrose oil | Nausea, softening of stools, headaches, seizures | Anticonvulsant and tricyclic antidepressants | Patients taking anticonvulsants and tricyclic antidepressants (lowers efficacy) |
| Red clover | Blood thinning | Anticoagulants such as coumadin, heparin, clopidrogel, pentoxifylline, or aspirin | Patients with coagulopathies |
Black cohosh
A member of the buttercup family, black cohosh (Actaea [formerly Cimicifuga] racemosa) has a long history in folk medicine, especially among Native Americans, who boiled the root in water and drank the resulting beverage to treat dysmenorrhea, labor pain, upset stomach, and arthritis. In Germany, extracts of black cohosh have been used since the 1940s.
Many substances have been identified in the rhizome, but it is uncertain what the majority of them do or, in fact, which are active ingredients.19 The effectiveness of black cohosh is based on the total amount of triterpenoid glycosides, typically standardized to 2.5%.20
Several studies, most of them in the German literature, have shown that black cohosh yields a significant improvement in hot flushes, with reductions of up to 80% reported (level of evidence [LOE]: 2b).21-23 The usual dosage is 40 drops of the extract twice daily for 6 to 8 weeks, or one to two 20-mg tablets twice daily with liquid (not to be chewed or sucked).
Side effects are uncommon, but occasional stomach pains and intestinal discomfort, dizziness, nausea, severe headaches, stiffness, and trembling limbs have been noted. Germany’s Commission E, which is similar to the US Food and Drug Administration, recommends that black cohosh not be used for more than 6 months, since no studies have been conducted for longer periods.
Black cohosh has weak estrogenic effect on the breast and should be used cautiously in patients with breast cancer or a high risk of breast cancer. A 2-month double-blind, randomized controlled trial of black cohosh in breast cancer survivors demonstrated no short-term side effects; however, therapy was only significantly beneficial in relieving sweating and ineffective in reducing flushes.24 The long-term effects are unknown. A recent systematic review suggests that the side effects of black cohosh are transient, and severe adverse event reports are unproven (Table 2).24
Dong quai
Dong quai, a common Chinese herb extracted from the Angelica sinensis root, has become popular in the US. In contrast to China, where it is sold as part of a mixture that includes several other herbs, dong quai typically is sold in the US as a single herb.
Although some women report improvements in their vasomotor symptoms, there have been very few studies on the effects of dong quai on menopause. In one 24-week study of 71 postmenopausal women, researchers could not demonstrate a significant difference between dong quai and placebo in alleviating vasomotor symptoms (LOE: 2b).25 The investigators suggested that studying the effects of dong quai alone, rather than in combination with other herbs, may have been a factor in their findings.
Two caveats: Dong quai increases photosensitivity, so women taking the herb should be cautioned that too much exposure to sunlight may result in a rash. Also it has been reported to potentiate the effects of warfarin (Table 2). It should not be used during pregnancy.26
Evening primrose
Native Americans consumed the leaves, roots, and seedpods of evening primrose (Oenothera biennis) for food, and made extracts from it to treat a variety of conditions. Today, the flowers and seeds are pressed to make oil that is high in the omega-6 fatty acid gamma-linolenic acid (known as GLA) and essential polyunsaturated fatty acids, which convert into prostaglandins. Evening primrose oil also is a good source of linoleic acid.
Although there are a number of good studies in which evening primrose oil has been used to successfully treat eczema and several other conditions with few side effects, it appears to have no benefit over placebo for hot flushes (LOE: 2b).27
Patients should be warned that mild upset stomach, indigestion, nausea, softening of stools, and mild headaches may occasionally occur. Also, evening primrose is contraindicated in women taking seizure medications or antipsychotics because it lowers the seizure threshold in patients on phenothiazines (Table 2).
Red clover
Red clover (Trifolium pratense) is a plant that contains the phytoestrogens formononetin, biochanin A, daidzein, and genistein. It was originally used by Native Americans to treat whooping cough, gout, and cancer.
Two clinical trials conducted in Australia failed to demonstrate that red clover extract was more effective than placebo in reducing vasomotor symptoms (LOE: 2b).28,29 However, one recent presentation found that women who took 40 mg of red clover per day—the recommended dosage—experienced a significant reduction in hot flushes.30
There is still little information on whether red clover will have any effect on the uterine lining or breast tissue. Because red clover contains coumarin-like substances, high dosages may cause the blood to thin (Table 2).31
1. Salamone LM, Pressman AR, Seeley DG, Cauley JA. Estrogen replacement therapy. A survey of older women’s attitudes. Arch Int Med 1996;156:1293-1297.
2. Ravnikar VA. Compliance with hormone therapy. Am J Obstet Gynecol 1987;156:1332-1334.
3. Kessel B. Alternatives to estrogen for menopausal women. Proc Soc Esp Biol Med 1998;217:38-44.
4. Roussouw JE, Anderson GL, Prentice RL, et al. Risks and benefits of estrogen plus progestin in healthy post-menopausal women: principal results from the Women’s Health Initiative randomized controlled trial. JAMA 2002;288:321-333.
5. Grady D, Herrington D, Bittner V, et al. Cardiovascular disease outcomes during 6.8 years of hormone replacement therapy: Heart and Estrogen/progestin Replacement Study follow-up (HERS II). JAMA 2002;288:49-57.
6. Seibel MM. The role of nutrition and nutritional supplements in women’s health. Fertil Steril 1999;72:579-591.
7. Astin JA. Why patients use alternative medicine: results of a national study. JAMA 1998;279:1548-1553.
8. Haines CJ, Chung TKH, Leung DHY. A prospective study of the frequency of acute menopausal symptoms in Hog Dong Chinese women. Maturitas 1994;18:175-181.
9. Tang GWK. The climacteric of Chinese factory workers. Maturitas 1994;19:177-182.
10. Markiewicz L, Garey J, Adlercreutz H, Gurpide E. In vitro bioassays of non-steroidal phytoestrogens. J Steroid Biochem Mol Biol 1993;45:399-405.
11. Murkies AL, Lombard C, Strauss BJD, Wilcox G, Burger HG, Morton MS. Dietary flour supplementation decreases postmenopausal hot flushes: effect of soy and wheat. Maturitas 1995;21:189-195.
12. Brzezinski A, Adlercreutz H, Shaoul R, Rosler A, Shmueli A, Tanos V, Schenker JG. Short-term effects of phytoestrogen-rich diet on postmenopausal women. Menopause 1997;4:89-94.
13. Albertazzi P, Pansini F, Bonaccorsi G, Zanotti L, Forini E, De Aloysio D. The effect of dietary soy supplementation on hot flushes. Obstet Gynecol 1998;91:6-11.
14. Scambia G, Mango D, Signorile PG, et al. Clinical effects of a standardized soy extract in postmenopausal women: a pilot study. Menopause 2000;7:105-111.
15. Upmalis DH, Lobo R, Bradley L, Warren M, Cone FL, Lamia CA. Vasomotor symptom relief by soy isoflavone extract tablets in postmenopausal women: a multicenter, double-blind, randomized, placebo-controlled study. Menopause 2000;7:236-242.
16. Kronenberg F, Fugh-Berman A. Complementary and alternative medicine for menopausal symptoms: a review of randomized, controlled trials. Ann Intern Med 2002;137:805-811.
17. Shaver JLF, Giblin E, Paulsen V. Sleep quality subtypes in midlife women. Sleep 1991;14:18-23.
18. From Seibel MM. The soy solution for menopause: an alternative to estrogen. New York, NY: Fireside Press, 2003.
19. Struck D, Tegtmeier M, Harnishfeger G. Flavones in extracts of Cimicifuga racemosa. Planta Med 1997;63:289-290.
20. Beuscher N. Cimicifuga racemosa L.Black Cohosh. HerbalGram 1996;19-27.
21. Vorberg G. Therapy of climacteric complaints. Zeitschrift fur Allgemeinmedizin 1984;60:626-629.
22. Warnecke G. Influence of a phytopharmaceutical on climacteric complaints. Die Meizinische Welt 1985;36:871-874.
23. Stoll W. Phytopharmacon influences atrophic vaginal epithelium: double-blind study—Cimicifuga vs. estrogenic substances. Therapeuticum 1987;1:23-31.
24. Jacobson JS, Troxel AB, Evans J, et al. Randomized trial of black cohosh for the treatment of hot flashes among women with a history of breast cancer. J Clin Oncol 2001;19:2739-2745.
25. Huntley A, Ernst E. A systematic review of the safety of black cohosh. Menopause 2003;10:58-64.
26. Hirata JD, Swiers LM, Zell B, Small R, Ettinger B. Does dong quai have estrogenic effects in postmenopausal women? A double-blind placebo-controlled trial. Fertil Steril 1997;68:981-986.
27. Page RL 2nd, Lawrence JD. Potentiation of warfarin by dong quai. Pharmacotherapy 1999;19:870-876.
28. Chenoy R, Hussain S, Tayob Y, O’Brien PMS, Moss MY, Morse PF. Effect of oral gamalenic acid from evening primrose oil on menopausal flushing. BMJ 1994;308:501-503.
29. Barber RJ, Templeman C, Morton T, Delley GE, Weat L. Randomized placebo-controlled trial of an isoflavone supplement and menopausal symptoms in women. Climacteric 1999;2:85-92.
30. Knight DC, Howes JB, Eden JA. The effect of Promensil an isoflavone extract, on menopausal symptoms. Climacteric 1999;2:79-84.
31. Nachtigall LB, LaGrega L, Lee WW, et al. The effects of isoflavones derived from red clover on vasomotor symptoms and endometrial thickness. 9th International Menopause Society World Congress on Menopause, October 17-21, 1999.
32. Fugh-Berman A, Kronenberg F. Red clover (Trifolium pratense) for menopausal women: current state of knowledge. Menopause 2001;8:333-337.
1. Salamone LM, Pressman AR, Seeley DG, Cauley JA. Estrogen replacement therapy. A survey of older women’s attitudes. Arch Int Med 1996;156:1293-1297.
2. Ravnikar VA. Compliance with hormone therapy. Am J Obstet Gynecol 1987;156:1332-1334.
3. Kessel B. Alternatives to estrogen for menopausal women. Proc Soc Esp Biol Med 1998;217:38-44.
4. Roussouw JE, Anderson GL, Prentice RL, et al. Risks and benefits of estrogen plus progestin in healthy post-menopausal women: principal results from the Women’s Health Initiative randomized controlled trial. JAMA 2002;288:321-333.
5. Grady D, Herrington D, Bittner V, et al. Cardiovascular disease outcomes during 6.8 years of hormone replacement therapy: Heart and Estrogen/progestin Replacement Study follow-up (HERS II). JAMA 2002;288:49-57.
6. Seibel MM. The role of nutrition and nutritional supplements in women’s health. Fertil Steril 1999;72:579-591.
7. Astin JA. Why patients use alternative medicine: results of a national study. JAMA 1998;279:1548-1553.
8. Haines CJ, Chung TKH, Leung DHY. A prospective study of the frequency of acute menopausal symptoms in Hog Dong Chinese women. Maturitas 1994;18:175-181.
9. Tang GWK. The climacteric of Chinese factory workers. Maturitas 1994;19:177-182.
10. Markiewicz L, Garey J, Adlercreutz H, Gurpide E. In vitro bioassays of non-steroidal phytoestrogens. J Steroid Biochem Mol Biol 1993;45:399-405.
11. Murkies AL, Lombard C, Strauss BJD, Wilcox G, Burger HG, Morton MS. Dietary flour supplementation decreases postmenopausal hot flushes: effect of soy and wheat. Maturitas 1995;21:189-195.
12. Brzezinski A, Adlercreutz H, Shaoul R, Rosler A, Shmueli A, Tanos V, Schenker JG. Short-term effects of phytoestrogen-rich diet on postmenopausal women. Menopause 1997;4:89-94.
13. Albertazzi P, Pansini F, Bonaccorsi G, Zanotti L, Forini E, De Aloysio D. The effect of dietary soy supplementation on hot flushes. Obstet Gynecol 1998;91:6-11.
14. Scambia G, Mango D, Signorile PG, et al. Clinical effects of a standardized soy extract in postmenopausal women: a pilot study. Menopause 2000;7:105-111.
15. Upmalis DH, Lobo R, Bradley L, Warren M, Cone FL, Lamia CA. Vasomotor symptom relief by soy isoflavone extract tablets in postmenopausal women: a multicenter, double-blind, randomized, placebo-controlled study. Menopause 2000;7:236-242.
16. Kronenberg F, Fugh-Berman A. Complementary and alternative medicine for menopausal symptoms: a review of randomized, controlled trials. Ann Intern Med 2002;137:805-811.
17. Shaver JLF, Giblin E, Paulsen V. Sleep quality subtypes in midlife women. Sleep 1991;14:18-23.
18. From Seibel MM. The soy solution for menopause: an alternative to estrogen. New York, NY: Fireside Press, 2003.
19. Struck D, Tegtmeier M, Harnishfeger G. Flavones in extracts of Cimicifuga racemosa. Planta Med 1997;63:289-290.
20. Beuscher N. Cimicifuga racemosa L.Black Cohosh. HerbalGram 1996;19-27.
21. Vorberg G. Therapy of climacteric complaints. Zeitschrift fur Allgemeinmedizin 1984;60:626-629.
22. Warnecke G. Influence of a phytopharmaceutical on climacteric complaints. Die Meizinische Welt 1985;36:871-874.
23. Stoll W. Phytopharmacon influences atrophic vaginal epithelium: double-blind study—Cimicifuga vs. estrogenic substances. Therapeuticum 1987;1:23-31.
24. Jacobson JS, Troxel AB, Evans J, et al. Randomized trial of black cohosh for the treatment of hot flashes among women with a history of breast cancer. J Clin Oncol 2001;19:2739-2745.
25. Huntley A, Ernst E. A systematic review of the safety of black cohosh. Menopause 2003;10:58-64.
26. Hirata JD, Swiers LM, Zell B, Small R, Ettinger B. Does dong quai have estrogenic effects in postmenopausal women? A double-blind placebo-controlled trial. Fertil Steril 1997;68:981-986.
27. Page RL 2nd, Lawrence JD. Potentiation of warfarin by dong quai. Pharmacotherapy 1999;19:870-876.
28. Chenoy R, Hussain S, Tayob Y, O’Brien PMS, Moss MY, Morse PF. Effect of oral gamalenic acid from evening primrose oil on menopausal flushing. BMJ 1994;308:501-503.
29. Barber RJ, Templeman C, Morton T, Delley GE, Weat L. Randomized placebo-controlled trial of an isoflavone supplement and menopausal symptoms in women. Climacteric 1999;2:85-92.
30. Knight DC, Howes JB, Eden JA. The effect of Promensil an isoflavone extract, on menopausal symptoms. Climacteric 1999;2:79-84.
31. Nachtigall LB, LaGrega L, Lee WW, et al. The effects of isoflavones derived from red clover on vasomotor symptoms and endometrial thickness. 9th International Menopause Society World Congress on Menopause, October 17-21, 1999.
32. Fugh-Berman A, Kronenberg F. Red clover (Trifolium pratense) for menopausal women: current state of knowledge. Menopause 2001;8:333-337.
Treating hot flushes without hormone replacement therapy
- About 21% of women surveyed use complementary or alternative therapies alone, and 25% said they used both conventional and alternative methods.
- Women who take 50 mg of soy isoflavones daily typically report a 40% to 50% reduction in hot flushes.
- Black cohosh yields up to an 80% improvement in hot flushes.
- Doses of 40 mg of red clover per day effect a significant reduction in hot flushes.
Roughly 4,000 women in the United States turn 50 daily, joining the ranks of the 40 million American women currently menopausal. A survey published by the North American Menopause Society in 1998 found that the most common reason that women in this age group visit their physicians is to seek relief from everyday menopausal symptoms such as hot flushes. While temporary, hot flushes can last up to 2 years and are a result of changes in estrogen levels.
Women in Western countries have an 80% incidence of hot flushes.
Despite HRT’s proven efficacy in treating this plaguing symptom, many patients are fearful that HRT might lead to an increased risk of breast or uterine cancer or that it may cause unpleasant side effects such as mood swings, depression, or continued menstrual periods.1 One study of 2,500 postmenopausal women found that 20% to 30% never fill their initial HRT prescriptions, 10% of those who use estrogen do so only intermittently, and an additional 20% discontinue their therapy within 8 months.2 Furthermore, HRT is contraindicated in about 10% of postmenopausal women.3
With such an enormous number of women either unwilling or unable to take HRT, it is important to consider what alternatives an Ob/Gyn can offer for treating vasomotor symptoms. These choices certainly aren’t new. If we look back to the 1899 Merck Manual, recommendations included ammonia, camphor, Cannabis indica, opium, and suc ovarian (the “juice” from cow ovaries crushed at the slaughterhouse). While these therapeutic agents have fallen by the wayside, a number of alternative treatments for hot flushes are in use today by an increasing number of menopausal women.
How pervasive are alternative therapies?
So-called alternative approaches to menopause are used so widely that it might be more accurate to consider HRT as the true alternative medicine. Statistics presented at the National Institutes of Health on October 27, 2000, indicate that nearly half of all menopausal women are using complementary therapies, including vitamins, herbs, and soy products, to help treat their symptoms. Twenty-one percent of the women surveyed used complementary or alternative therapies alone, and 25% said they used both conventional and alternative methods. Taken together, that is more than twice the 19% who said they used conventional HRT only. Given this enormous usage, it should come as no surprise that, in 2001, the dietary supplement industry likely exceeded $12 billion in sales in the United States alone.4 For many women, the decision to use an alternative is not so much dissatisfaction with conventional treatment, but that they regard the complementary agents as more congruent with their own values, beliefs, and philosophical orientations toward health and life.5 This article will review some of the more commonly used alternatives that women use for the treatment of hot flushes. Patients should take an alternative for at least 1 month before initiating another one, to determine if it is achieving the desired effect.
Soy
Much of the excitement about the health benefits of soy, a staple of the Asian diet for 5,000 years, stems from epidemiological studies. The Asian diet, which is rich in isoflavones, is associated with a reduced risk of breast cancer, heart disease, and osteoporosis. Asian women also report fewer hot flushes than do their Western counterparts.6 One study showed that women in Western countries have an 80% incidence of hot flushes, while Asian women living in China have an incidence of only 20%.7 Clearly, factors other than soy also must be considered before we can make a direct cause-and-effect correlation. To that end, many studies have been conducted on the health benefits of soybeans, a rich source of the isoflavones genistein and daidzein.
Data suggest that soy is safe and effective in dosages of 40 g of soy protein or 50 mg of soy isoflavones per day.
Isoflavones are phytoestrogens with a heterocyclic phenol structure that is similar to estrogen. Their potency is between 1×104 and 1×103 the activity of 17β-estradiol.8 Although their potency is low, their serum concentrations can reach levels several orders of magnitude higher than those of physiologic estrogens. It is generally believed that isoflavones act as a selective estrogen receptor modulator (SERMs), exerting antiestrogenic effects in the high-estrogen environment of premenopause and estrogenic effects in the low-estrogen environment of postmenopause.
An increasing number of studies suggest that soy and soy isoflavones—in the form of soy flour, soy protein, and dietary supplements—may play an important role in the treatment of hot flushes (Table 1). In general, the average amount of isoflavones consumed in a typical Asian diet is approximately 50 mg. (One gram of soy protein contains approximately 1 mg of isoflavones.) As shown in the table below, all of the methods of taking soy decrease the number and/or severity of hot flushes.
All of the soy studies also confirm the existence of a placebo effect on the treatment of hot flushes. Even so, the soy group typically reports a 15% to 20% greater reduction in symptoms than does the placebo group. This difference between the soy and control groups has led skeptics to believe that the differences may be statistically significant but clinically insignificant. I believe that thinking is wrong. Women who have hot flushes tend to have lower sleep efficiencies and longer REM latencies than women who do not experience this vasomotor symptom.14 By lowering the frequency of hot flushes by 40% or more, patients who take soy will have 40% or more greater sleep efficiencies. That may improve their quality of life sufficiently to make HRT unnecessary.
Soy has been safely consumed by hundreds of millions of people without complications, with the possible exception of soy allergies (Table 2, 3, and 4). The literature suggests it is safe and effective in dosages of either 40 g of soy protein or 50 mg of soy isoflavones per day. Soy does not stimulate the uterine lining and may be protective of the endometrium if taken with estrogen. The incidence of breast cancer is one-fourth as high in Asia as it is in the United States; many studies have shown soy to be protective of breast tissue. However, soy may stimulate breast tissue in women with a history of breast cancer.
TABLE 1
The role of soy in the treatment of hot flushes
| STUDY | NO. PATIENTS | DESIGN | ↓FLUSHES SOY (%) | ↓FLUSHES CONTROL (%) |
|---|---|---|---|---|
| Murkies 1995 | 58 | 45 g soy flour | 40 | 25 |
| Brzezinski 1997 | 73/72 | Mostly soy 1/4 diet, some flaxseed | 54 | 35 |
| Albertazzi 1998 | 51/53 | 60 g soy protein | 45 | 30 |
| Scambia 2000 | 20/19 | 50 mg/d isoflavones | 45 | 25 |
| Upmalis 2000 | 177 | 50 mg/d isoflavones | 30 | 20 |
| SOURCE: Seibel MM. The Soy Solution for Menopause: An Alternative to Estrogen. New York, NY: Fireside Press; 2002. | ||||
TABLE 2
Adverse effects
| SOY |
|
| BLACK COHOSH |
|
| DONG QUAI |
|
| EVENING PRIMROSE OIL |
|
| RED CLOVER |
|
| HRT |
|
TABLE 3
Drug interactions
| SOY |
|
| BLACK COHOSH |
|
| DONG QUAI |
|
| EVENING PRIMROSE OIL |
|
| RED CLOVER |
|
| HRT |
|
TABLE 4
Contraindications
| SOY |
|
| BLACK COHOSH |
|
| DONG QUAI |
|
| EVENING PRIMROSE OIL |
|
| RED CLOVER |
|
| HRT |
|
Black cohosh
A member of the buttercup family, black cohosh has a long history in folk medicine, especially among Native Americans who boiled the root in water and drank the resulting beverage to treat dysmenorrhea, labor pain, upset stomach, and arthritis. In Germany, extracts of black cohosh have been used since the 1940s.
Many substances have been identified in the rhizome, but it is uncertain what the majority of them do or, in fact, which are active ingredients.15 The effectiveness of black cohosh is based on the total amount of triterpenoid glycosides, typically standardized to 2.5%.16
Several studies, most of them in the German literature, have shown that black cohosh yields a significant improvement in hot flushes, with reductions of up to 80% reported.17-19 The usual dosage is 40 drops of the extract twice daily for 6 to 8 weeks, or one to two 20-mg tablets twice daily with liquid (not to be chewed or sucked).
Side effects are uncommon, but occasional stomach pains and intestinal discomfort, dizziness, nausea, severe headaches, stiffness, and trembling limbs have been noted. Germany’s Commission E, which is similar to the U.S. Food and Drug Administration (FDA), recommends that black cohosh not be used for more than 6 months since no studies have been conducted for longer periods of time. Although most data on the safety of black cohosh with regard to breast tissue are reassuring, use caution when administering it to a patient with a history of breast cancer, as black cohosh is a weak estrogen (Table 2, 3, and 4).
Dong quai (Angelica sinensis)
Dong quai, a common Chinese herb extracted from the Angelica sinensis root, has become popular in the U.S. In contrast to China, where it is sold as part of a mixture that includes several other herbs, dong quai typically is sold in the U.S. as a single herb.
Although some women report improvements in their vasomotor symptoms, there have been very few studies on the effects of dong quai on menopause. In one study of 71 postmenopausal women over a 24-week period, researchers could not demonstrate a difference between dong quai and placebo in alleviating vasomotor symptoms.20 The investigators suggested that studying the effects of dong quai alone, rather than in combination with other herbs, may have been a factor in their findings.
Two caveats: Dong quai increases photosensitivity, so women taking the herb should be cautioned that too much exposure to sunlight may result in a rash. Also, it has been reported to potentiate the effects of warfarin (Table 2, 3, and 4). It should not be used during pregnancy.21
Evening primrose (Oenothera biennis)
Native Americans consumed the leaves, roots, and seedpods of this plant for food, and made extracts from it to treat a variety of conditions. Today, the flowers and seeds are pressed to make oil that is high in gammalinolenic acid (GLA) and essential polyunsaturated fatty acids, which convert into prostaglandins. Evening primrose oil also is a good source of linoleic acid and the omega-6 fatty acid γ-linoleic acid.
Because red clover contains warfarin, high dosages may cause the blood to thin.
Although there are a number of good studies in which evening primrose oil has been used to successfully treat eczema and several other conditions with few side effects, it appears to have no benefit over placebo for hot flushes.22
Patients should be warned that mild upset stomach, indigestion, nausea, softening of stools, and mild headaches may occasionally occur. Also, evening primrose is contraindicated in women taking conventional medication for temporal lobe epilepsy or schizophrenia, as the substance decreases the efficacy of those drugs (Table 2, 3, and 4).
Red clover (Trifolium pratense)
Red clover is a plant that contains the phytoestrogens formononetin, biochanin A, daidzein, and genistein. It was originally used by Native Americans to treat whooping cough, gout, and cancer.
Two clinical trials conducted in Australia failed to demonstrate that red clover extract was more effective than placebo in reducing vasomotor symptoms.23,24 However, one study found that women who took 40 mg of red clover per day—the recommended dosage—experienced a significant reduction in hot flushes.25
There is still little information on whether red clover will have any effect on the uterine lining or breast tissue. Because red clover contains warfarin, high dosages may cause the blood to thin (Table 2, 3, and 4).
Conclusion
Whether to take HRT is one of the major decisions women in perimenopause or early menopause have to make. The overwhelming majority will decide against it, either out of fear of potential risks or simply to avoid unpleasant side effects. In fact, several studies have shown that only 15% to 20% of women will take HRT for more than a year.2 Even women who do agree to take HRT frequently demonstrate poor compliance.
But patients who decline HRT do need—and will have—other choices to help them weather vasomotor symptoms that can greatly disrupt their lives. Many women find these plant-based alternatives an important option that allows them to control their hot flushes without taking HRT.
As clinicians start to recommend alternative supplements to their menopausal patients, they should do so with an understanding of the expected results, potential risks and benefits, and how the recommendation may interact with other medications. If these guidelines are followed, physicians may recommend alternative treatments with the same confidence they have in prescription drugs.
The author reports no financial relationship with any companies whose products are mentioned in this article.
1. Salamone LM, Pressman AR, Seeley DG, Cauley JA. Estrogen replacement therapy. A survey of older women’s attitudes. Arch Int Med. 1996;156:1293-1297.
2. Ravnikar VA. Compliance with hormone therapy. Am J Obstet Gynecol. 1987;156:1332-1334.
3. Kessel B. Alternatives to estrogen for menopausal women. Proc Soc Esp Biol Med. 1998;217(1):38-44.
4. Seibel MM. The role of nutrition and nutritional supplements in women’s health. Fertil Steril. 1999;72:579-591.
5. Astin JA. Why patients use alternative medicine: results of a national study. JAMA. 1998;279:1548-1553.
6. Haines CJ, Chung TKH, Leung DHY. A prospective study of the frequency of acute menopausal symptoms in Hog Dong Chinese women. Maturitas. 1994;18:175-181.
7. Tang GWK. The climacteric of Chinese factory workers. Maturitas. 1994;19:177-182.
8. Markiewicz L, Garey J, Adlercreutz H, Gurpide E. In vitro bioassays of non-steroidal phytoestrogens. J Steroid Biochem Mol Biol. 1993;45:399-405.
9. Murkies AL, Lombard C, Strauss BJD, Wilcox G, Burger HG, Morton MS. Dietary flour supplementation decreases postmenopausal hot flushes: effect of soy and wheat. Maturitas. 1995;21:189-195.
10. Brzezinski A, Adlercreutz H, Shaoul R, Rosler A, Shmueli A, Tanos V, Schenker JG. Short-term effects of phytoestrogen-rich diet on postmenopausal women. Menopause. 1997;4:89-94.
11. Albertazzi P, Pansini F, Bonaccorsi G, Zanotti L, Forini E, De Aloysio D. The effect of dietary soy supplementation on hot flushes. Obstet Gynecol. 1998;91:6-11.
12. Scambia G, Mango D, Signorile PG, et al. Clinical effects of a standardized soy extract in postmenopausal women: a pilot study. Menopause. 2000;7:105-111.
13. Upmalis DH, Lobo R, Bradley L, Warren M, Cone FL, Lamia CA. Vasomotor symptom relief by soy isoflavone extract tablets in postmenopausal women: a multicenter, double-blind, randomized, placebo-controlled study. Menopause. 2000;7:236-242.
14. Shaver JLF, Giblin E, Paulsen V. Sleep quality subtypes in midlife women. Sleep. 1991;14:18-23.
15. Struck D, Tegtmeier M, Harnishfeger G. Flavones in extracts of Cimicifuga racemosa. Planta Med. 1997;63:289-290.
16. Beuscher N. Cimicifuga racemosa L.—Black Cohosh. HerbalGram Spring. 1996;19-27.
17. Vorberg G. Therapy of climacteric complaints. Zeitschrift fur Allgemeinmedizin. 1984;60:626-29.
18. Warnecke G. Influence of a phytopharmaceutical on climacteric complaints. Die Meizinische Welt. 1985;36:871-874.
19. Stoll W. Phytopharmacon influences atrophic vaginal epithelium: double-blind study—Cimicifuga vs. estrogenic substances. Therapeuticum. 1987;1:23-31.
20. Hirata JD, Swiers LM, Zell B, Small R, Ettinger B. Does dong quai have estrogenic effects in postmenopausal women? A double-blind placebo-controlled trial. Fertil Steril. 1997;68:981-986.
21. Page RL, 2nd, Lawrence JD. Potentiation of warfarin by dong quai. Pharmacotherapy. 1999;19(7):870-876.
22. Chenoy R, Hussain S, Tayob Y, O’Brien PMS, Moss MY, Morse PF. Effect of oral gamalenic acid from evening primrose oil on menopausal flushing. Br Med J. 1994;308:501-503.
23. Barber RJ, Templeman C, Morton T, Delley GE, Weat L. Randomized placebo-controlled trial of an isoflavone supplement and menopausal symptoms in women. Climacteric. 1999;2:85-92.
24. Knight DC, Howes JB, Eden JA. The effect of Promensil™ an isoflavone extract on menopausal symptoms. Climacteric. 1999;2:79-84.
25. Nachtigall LB, LaGrega L, Lee WW, et al. The effects of isoflavones derived from red clover on vasomotor symptoms and endometrial thickness. 9th International Menopause Society World Congress on the Menopause, October 17-21, 1999.
MACHELLE M. SEIBEL, MD
Dr. Seibel is a reproductive endocrinologist at Caritas Norwood Hospital in Norwood, Mass; clinical professor of gynecology and obstetrics at the University of Massachusetts School of Medicine; and medical director of Inverness Medical Innovations, Inc, in Waltham, Mass.
MACHELLE M. SEIBEL, MD
Dr. Seibel is a reproductive endocrinologist at Caritas Norwood Hospital in Norwood, Mass; clinical professor of gynecology and obstetrics at the University of Massachusetts School of Medicine; and medical director of Inverness Medical Innovations, Inc, in Waltham, Mass.
MACHELLE M. SEIBEL, MD
Dr. Seibel is a reproductive endocrinologist at Caritas Norwood Hospital in Norwood, Mass; clinical professor of gynecology and obstetrics at the University of Massachusetts School of Medicine; and medical director of Inverness Medical Innovations, Inc, in Waltham, Mass.
- About 21% of women surveyed use complementary or alternative therapies alone, and 25% said they used both conventional and alternative methods.
- Women who take 50 mg of soy isoflavones daily typically report a 40% to 50% reduction in hot flushes.
- Black cohosh yields up to an 80% improvement in hot flushes.
- Doses of 40 mg of red clover per day effect a significant reduction in hot flushes.
Roughly 4,000 women in the United States turn 50 daily, joining the ranks of the 40 million American women currently menopausal. A survey published by the North American Menopause Society in 1998 found that the most common reason that women in this age group visit their physicians is to seek relief from everyday menopausal symptoms such as hot flushes. While temporary, hot flushes can last up to 2 years and are a result of changes in estrogen levels.
Women in Western countries have an 80% incidence of hot flushes.
Despite HRT’s proven efficacy in treating this plaguing symptom, many patients are fearful that HRT might lead to an increased risk of breast or uterine cancer or that it may cause unpleasant side effects such as mood swings, depression, or continued menstrual periods.1 One study of 2,500 postmenopausal women found that 20% to 30% never fill their initial HRT prescriptions, 10% of those who use estrogen do so only intermittently, and an additional 20% discontinue their therapy within 8 months.2 Furthermore, HRT is contraindicated in about 10% of postmenopausal women.3
With such an enormous number of women either unwilling or unable to take HRT, it is important to consider what alternatives an Ob/Gyn can offer for treating vasomotor symptoms. These choices certainly aren’t new. If we look back to the 1899 Merck Manual, recommendations included ammonia, camphor, Cannabis indica, opium, and suc ovarian (the “juice” from cow ovaries crushed at the slaughterhouse). While these therapeutic agents have fallen by the wayside, a number of alternative treatments for hot flushes are in use today by an increasing number of menopausal women.
How pervasive are alternative therapies?
So-called alternative approaches to menopause are used so widely that it might be more accurate to consider HRT as the true alternative medicine. Statistics presented at the National Institutes of Health on October 27, 2000, indicate that nearly half of all menopausal women are using complementary therapies, including vitamins, herbs, and soy products, to help treat their symptoms. Twenty-one percent of the women surveyed used complementary or alternative therapies alone, and 25% said they used both conventional and alternative methods. Taken together, that is more than twice the 19% who said they used conventional HRT only. Given this enormous usage, it should come as no surprise that, in 2001, the dietary supplement industry likely exceeded $12 billion in sales in the United States alone.4 For many women, the decision to use an alternative is not so much dissatisfaction with conventional treatment, but that they regard the complementary agents as more congruent with their own values, beliefs, and philosophical orientations toward health and life.5 This article will review some of the more commonly used alternatives that women use for the treatment of hot flushes. Patients should take an alternative for at least 1 month before initiating another one, to determine if it is achieving the desired effect.
Soy
Much of the excitement about the health benefits of soy, a staple of the Asian diet for 5,000 years, stems from epidemiological studies. The Asian diet, which is rich in isoflavones, is associated with a reduced risk of breast cancer, heart disease, and osteoporosis. Asian women also report fewer hot flushes than do their Western counterparts.6 One study showed that women in Western countries have an 80% incidence of hot flushes, while Asian women living in China have an incidence of only 20%.7 Clearly, factors other than soy also must be considered before we can make a direct cause-and-effect correlation. To that end, many studies have been conducted on the health benefits of soybeans, a rich source of the isoflavones genistein and daidzein.
Data suggest that soy is safe and effective in dosages of 40 g of soy protein or 50 mg of soy isoflavones per day.
Isoflavones are phytoestrogens with a heterocyclic phenol structure that is similar to estrogen. Their potency is between 1×104 and 1×103 the activity of 17β-estradiol.8 Although their potency is low, their serum concentrations can reach levels several orders of magnitude higher than those of physiologic estrogens. It is generally believed that isoflavones act as a selective estrogen receptor modulator (SERMs), exerting antiestrogenic effects in the high-estrogen environment of premenopause and estrogenic effects in the low-estrogen environment of postmenopause.
An increasing number of studies suggest that soy and soy isoflavones—in the form of soy flour, soy protein, and dietary supplements—may play an important role in the treatment of hot flushes (Table 1). In general, the average amount of isoflavones consumed in a typical Asian diet is approximately 50 mg. (One gram of soy protein contains approximately 1 mg of isoflavones.) As shown in the table below, all of the methods of taking soy decrease the number and/or severity of hot flushes.
All of the soy studies also confirm the existence of a placebo effect on the treatment of hot flushes. Even so, the soy group typically reports a 15% to 20% greater reduction in symptoms than does the placebo group. This difference between the soy and control groups has led skeptics to believe that the differences may be statistically significant but clinically insignificant. I believe that thinking is wrong. Women who have hot flushes tend to have lower sleep efficiencies and longer REM latencies than women who do not experience this vasomotor symptom.14 By lowering the frequency of hot flushes by 40% or more, patients who take soy will have 40% or more greater sleep efficiencies. That may improve their quality of life sufficiently to make HRT unnecessary.
Soy has been safely consumed by hundreds of millions of people without complications, with the possible exception of soy allergies (Table 2, 3, and 4). The literature suggests it is safe and effective in dosages of either 40 g of soy protein or 50 mg of soy isoflavones per day. Soy does not stimulate the uterine lining and may be protective of the endometrium if taken with estrogen. The incidence of breast cancer is one-fourth as high in Asia as it is in the United States; many studies have shown soy to be protective of breast tissue. However, soy may stimulate breast tissue in women with a history of breast cancer.
TABLE 1
The role of soy in the treatment of hot flushes
| STUDY | NO. PATIENTS | DESIGN | ↓FLUSHES SOY (%) | ↓FLUSHES CONTROL (%) |
|---|---|---|---|---|
| Murkies 1995 | 58 | 45 g soy flour | 40 | 25 |
| Brzezinski 1997 | 73/72 | Mostly soy 1/4 diet, some flaxseed | 54 | 35 |
| Albertazzi 1998 | 51/53 | 60 g soy protein | 45 | 30 |
| Scambia 2000 | 20/19 | 50 mg/d isoflavones | 45 | 25 |
| Upmalis 2000 | 177 | 50 mg/d isoflavones | 30 | 20 |
| SOURCE: Seibel MM. The Soy Solution for Menopause: An Alternative to Estrogen. New York, NY: Fireside Press; 2002. | ||||
TABLE 2
Adverse effects
| SOY |
|
| BLACK COHOSH |
|
| DONG QUAI |
|
| EVENING PRIMROSE OIL |
|
| RED CLOVER |
|
| HRT |
|
TABLE 3
Drug interactions
| SOY |
|
| BLACK COHOSH |
|
| DONG QUAI |
|
| EVENING PRIMROSE OIL |
|
| RED CLOVER |
|
| HRT |
|
TABLE 4
Contraindications
| SOY |
|
| BLACK COHOSH |
|
| DONG QUAI |
|
| EVENING PRIMROSE OIL |
|
| RED CLOVER |
|
| HRT |
|
Black cohosh
A member of the buttercup family, black cohosh has a long history in folk medicine, especially among Native Americans who boiled the root in water and drank the resulting beverage to treat dysmenorrhea, labor pain, upset stomach, and arthritis. In Germany, extracts of black cohosh have been used since the 1940s.
Many substances have been identified in the rhizome, but it is uncertain what the majority of them do or, in fact, which are active ingredients.15 The effectiveness of black cohosh is based on the total amount of triterpenoid glycosides, typically standardized to 2.5%.16
Several studies, most of them in the German literature, have shown that black cohosh yields a significant improvement in hot flushes, with reductions of up to 80% reported.17-19 The usual dosage is 40 drops of the extract twice daily for 6 to 8 weeks, or one to two 20-mg tablets twice daily with liquid (not to be chewed or sucked).
Side effects are uncommon, but occasional stomach pains and intestinal discomfort, dizziness, nausea, severe headaches, stiffness, and trembling limbs have been noted. Germany’s Commission E, which is similar to the U.S. Food and Drug Administration (FDA), recommends that black cohosh not be used for more than 6 months since no studies have been conducted for longer periods of time. Although most data on the safety of black cohosh with regard to breast tissue are reassuring, use caution when administering it to a patient with a history of breast cancer, as black cohosh is a weak estrogen (Table 2, 3, and 4).
Dong quai (Angelica sinensis)
Dong quai, a common Chinese herb extracted from the Angelica sinensis root, has become popular in the U.S. In contrast to China, where it is sold as part of a mixture that includes several other herbs, dong quai typically is sold in the U.S. as a single herb.
Although some women report improvements in their vasomotor symptoms, there have been very few studies on the effects of dong quai on menopause. In one study of 71 postmenopausal women over a 24-week period, researchers could not demonstrate a difference between dong quai and placebo in alleviating vasomotor symptoms.20 The investigators suggested that studying the effects of dong quai alone, rather than in combination with other herbs, may have been a factor in their findings.
Two caveats: Dong quai increases photosensitivity, so women taking the herb should be cautioned that too much exposure to sunlight may result in a rash. Also, it has been reported to potentiate the effects of warfarin (Table 2, 3, and 4). It should not be used during pregnancy.21
Evening primrose (Oenothera biennis)
Native Americans consumed the leaves, roots, and seedpods of this plant for food, and made extracts from it to treat a variety of conditions. Today, the flowers and seeds are pressed to make oil that is high in gammalinolenic acid (GLA) and essential polyunsaturated fatty acids, which convert into prostaglandins. Evening primrose oil also is a good source of linoleic acid and the omega-6 fatty acid γ-linoleic acid.
Because red clover contains warfarin, high dosages may cause the blood to thin.
Although there are a number of good studies in which evening primrose oil has been used to successfully treat eczema and several other conditions with few side effects, it appears to have no benefit over placebo for hot flushes.22
Patients should be warned that mild upset stomach, indigestion, nausea, softening of stools, and mild headaches may occasionally occur. Also, evening primrose is contraindicated in women taking conventional medication for temporal lobe epilepsy or schizophrenia, as the substance decreases the efficacy of those drugs (Table 2, 3, and 4).
Red clover (Trifolium pratense)
Red clover is a plant that contains the phytoestrogens formononetin, biochanin A, daidzein, and genistein. It was originally used by Native Americans to treat whooping cough, gout, and cancer.
Two clinical trials conducted in Australia failed to demonstrate that red clover extract was more effective than placebo in reducing vasomotor symptoms.23,24 However, one study found that women who took 40 mg of red clover per day—the recommended dosage—experienced a significant reduction in hot flushes.25
There is still little information on whether red clover will have any effect on the uterine lining or breast tissue. Because red clover contains warfarin, high dosages may cause the blood to thin (Table 2, 3, and 4).
Conclusion
Whether to take HRT is one of the major decisions women in perimenopause or early menopause have to make. The overwhelming majority will decide against it, either out of fear of potential risks or simply to avoid unpleasant side effects. In fact, several studies have shown that only 15% to 20% of women will take HRT for more than a year.2 Even women who do agree to take HRT frequently demonstrate poor compliance.
But patients who decline HRT do need—and will have—other choices to help them weather vasomotor symptoms that can greatly disrupt their lives. Many women find these plant-based alternatives an important option that allows them to control their hot flushes without taking HRT.
As clinicians start to recommend alternative supplements to their menopausal patients, they should do so with an understanding of the expected results, potential risks and benefits, and how the recommendation may interact with other medications. If these guidelines are followed, physicians may recommend alternative treatments with the same confidence they have in prescription drugs.
The author reports no financial relationship with any companies whose products are mentioned in this article.
- About 21% of women surveyed use complementary or alternative therapies alone, and 25% said they used both conventional and alternative methods.
- Women who take 50 mg of soy isoflavones daily typically report a 40% to 50% reduction in hot flushes.
- Black cohosh yields up to an 80% improvement in hot flushes.
- Doses of 40 mg of red clover per day effect a significant reduction in hot flushes.
Roughly 4,000 women in the United States turn 50 daily, joining the ranks of the 40 million American women currently menopausal. A survey published by the North American Menopause Society in 1998 found that the most common reason that women in this age group visit their physicians is to seek relief from everyday menopausal symptoms such as hot flushes. While temporary, hot flushes can last up to 2 years and are a result of changes in estrogen levels.
Women in Western countries have an 80% incidence of hot flushes.
Despite HRT’s proven efficacy in treating this plaguing symptom, many patients are fearful that HRT might lead to an increased risk of breast or uterine cancer or that it may cause unpleasant side effects such as mood swings, depression, or continued menstrual periods.1 One study of 2,500 postmenopausal women found that 20% to 30% never fill their initial HRT prescriptions, 10% of those who use estrogen do so only intermittently, and an additional 20% discontinue their therapy within 8 months.2 Furthermore, HRT is contraindicated in about 10% of postmenopausal women.3
With such an enormous number of women either unwilling or unable to take HRT, it is important to consider what alternatives an Ob/Gyn can offer for treating vasomotor symptoms. These choices certainly aren’t new. If we look back to the 1899 Merck Manual, recommendations included ammonia, camphor, Cannabis indica, opium, and suc ovarian (the “juice” from cow ovaries crushed at the slaughterhouse). While these therapeutic agents have fallen by the wayside, a number of alternative treatments for hot flushes are in use today by an increasing number of menopausal women.
How pervasive are alternative therapies?
So-called alternative approaches to menopause are used so widely that it might be more accurate to consider HRT as the true alternative medicine. Statistics presented at the National Institutes of Health on October 27, 2000, indicate that nearly half of all menopausal women are using complementary therapies, including vitamins, herbs, and soy products, to help treat their symptoms. Twenty-one percent of the women surveyed used complementary or alternative therapies alone, and 25% said they used both conventional and alternative methods. Taken together, that is more than twice the 19% who said they used conventional HRT only. Given this enormous usage, it should come as no surprise that, in 2001, the dietary supplement industry likely exceeded $12 billion in sales in the United States alone.4 For many women, the decision to use an alternative is not so much dissatisfaction with conventional treatment, but that they regard the complementary agents as more congruent with their own values, beliefs, and philosophical orientations toward health and life.5 This article will review some of the more commonly used alternatives that women use for the treatment of hot flushes. Patients should take an alternative for at least 1 month before initiating another one, to determine if it is achieving the desired effect.
Soy
Much of the excitement about the health benefits of soy, a staple of the Asian diet for 5,000 years, stems from epidemiological studies. The Asian diet, which is rich in isoflavones, is associated with a reduced risk of breast cancer, heart disease, and osteoporosis. Asian women also report fewer hot flushes than do their Western counterparts.6 One study showed that women in Western countries have an 80% incidence of hot flushes, while Asian women living in China have an incidence of only 20%.7 Clearly, factors other than soy also must be considered before we can make a direct cause-and-effect correlation. To that end, many studies have been conducted on the health benefits of soybeans, a rich source of the isoflavones genistein and daidzein.
Data suggest that soy is safe and effective in dosages of 40 g of soy protein or 50 mg of soy isoflavones per day.
Isoflavones are phytoestrogens with a heterocyclic phenol structure that is similar to estrogen. Their potency is between 1×104 and 1×103 the activity of 17β-estradiol.8 Although their potency is low, their serum concentrations can reach levels several orders of magnitude higher than those of physiologic estrogens. It is generally believed that isoflavones act as a selective estrogen receptor modulator (SERMs), exerting antiestrogenic effects in the high-estrogen environment of premenopause and estrogenic effects in the low-estrogen environment of postmenopause.
An increasing number of studies suggest that soy and soy isoflavones—in the form of soy flour, soy protein, and dietary supplements—may play an important role in the treatment of hot flushes (Table 1). In general, the average amount of isoflavones consumed in a typical Asian diet is approximately 50 mg. (One gram of soy protein contains approximately 1 mg of isoflavones.) As shown in the table below, all of the methods of taking soy decrease the number and/or severity of hot flushes.
All of the soy studies also confirm the existence of a placebo effect on the treatment of hot flushes. Even so, the soy group typically reports a 15% to 20% greater reduction in symptoms than does the placebo group. This difference between the soy and control groups has led skeptics to believe that the differences may be statistically significant but clinically insignificant. I believe that thinking is wrong. Women who have hot flushes tend to have lower sleep efficiencies and longer REM latencies than women who do not experience this vasomotor symptom.14 By lowering the frequency of hot flushes by 40% or more, patients who take soy will have 40% or more greater sleep efficiencies. That may improve their quality of life sufficiently to make HRT unnecessary.
Soy has been safely consumed by hundreds of millions of people without complications, with the possible exception of soy allergies (Table 2, 3, and 4). The literature suggests it is safe and effective in dosages of either 40 g of soy protein or 50 mg of soy isoflavones per day. Soy does not stimulate the uterine lining and may be protective of the endometrium if taken with estrogen. The incidence of breast cancer is one-fourth as high in Asia as it is in the United States; many studies have shown soy to be protective of breast tissue. However, soy may stimulate breast tissue in women with a history of breast cancer.
TABLE 1
The role of soy in the treatment of hot flushes
| STUDY | NO. PATIENTS | DESIGN | ↓FLUSHES SOY (%) | ↓FLUSHES CONTROL (%) |
|---|---|---|---|---|
| Murkies 1995 | 58 | 45 g soy flour | 40 | 25 |
| Brzezinski 1997 | 73/72 | Mostly soy 1/4 diet, some flaxseed | 54 | 35 |
| Albertazzi 1998 | 51/53 | 60 g soy protein | 45 | 30 |
| Scambia 2000 | 20/19 | 50 mg/d isoflavones | 45 | 25 |
| Upmalis 2000 | 177 | 50 mg/d isoflavones | 30 | 20 |
| SOURCE: Seibel MM. The Soy Solution for Menopause: An Alternative to Estrogen. New York, NY: Fireside Press; 2002. | ||||
TABLE 2
Adverse effects
| SOY |
|
| BLACK COHOSH |
|
| DONG QUAI |
|
| EVENING PRIMROSE OIL |
|
| RED CLOVER |
|
| HRT |
|
TABLE 3
Drug interactions
| SOY |
|
| BLACK COHOSH |
|
| DONG QUAI |
|
| EVENING PRIMROSE OIL |
|
| RED CLOVER |
|
| HRT |
|
TABLE 4
Contraindications
| SOY |
|
| BLACK COHOSH |
|
| DONG QUAI |
|
| EVENING PRIMROSE OIL |
|
| RED CLOVER |
|
| HRT |
|
Black cohosh
A member of the buttercup family, black cohosh has a long history in folk medicine, especially among Native Americans who boiled the root in water and drank the resulting beverage to treat dysmenorrhea, labor pain, upset stomach, and arthritis. In Germany, extracts of black cohosh have been used since the 1940s.
Many substances have been identified in the rhizome, but it is uncertain what the majority of them do or, in fact, which are active ingredients.15 The effectiveness of black cohosh is based on the total amount of triterpenoid glycosides, typically standardized to 2.5%.16
Several studies, most of them in the German literature, have shown that black cohosh yields a significant improvement in hot flushes, with reductions of up to 80% reported.17-19 The usual dosage is 40 drops of the extract twice daily for 6 to 8 weeks, or one to two 20-mg tablets twice daily with liquid (not to be chewed or sucked).
Side effects are uncommon, but occasional stomach pains and intestinal discomfort, dizziness, nausea, severe headaches, stiffness, and trembling limbs have been noted. Germany’s Commission E, which is similar to the U.S. Food and Drug Administration (FDA), recommends that black cohosh not be used for more than 6 months since no studies have been conducted for longer periods of time. Although most data on the safety of black cohosh with regard to breast tissue are reassuring, use caution when administering it to a patient with a history of breast cancer, as black cohosh is a weak estrogen (Table 2, 3, and 4).
Dong quai (Angelica sinensis)
Dong quai, a common Chinese herb extracted from the Angelica sinensis root, has become popular in the U.S. In contrast to China, where it is sold as part of a mixture that includes several other herbs, dong quai typically is sold in the U.S. as a single herb.
Although some women report improvements in their vasomotor symptoms, there have been very few studies on the effects of dong quai on menopause. In one study of 71 postmenopausal women over a 24-week period, researchers could not demonstrate a difference between dong quai and placebo in alleviating vasomotor symptoms.20 The investigators suggested that studying the effects of dong quai alone, rather than in combination with other herbs, may have been a factor in their findings.
Two caveats: Dong quai increases photosensitivity, so women taking the herb should be cautioned that too much exposure to sunlight may result in a rash. Also, it has been reported to potentiate the effects of warfarin (Table 2, 3, and 4). It should not be used during pregnancy.21
Evening primrose (Oenothera biennis)
Native Americans consumed the leaves, roots, and seedpods of this plant for food, and made extracts from it to treat a variety of conditions. Today, the flowers and seeds are pressed to make oil that is high in gammalinolenic acid (GLA) and essential polyunsaturated fatty acids, which convert into prostaglandins. Evening primrose oil also is a good source of linoleic acid and the omega-6 fatty acid γ-linoleic acid.
Because red clover contains warfarin, high dosages may cause the blood to thin.
Although there are a number of good studies in which evening primrose oil has been used to successfully treat eczema and several other conditions with few side effects, it appears to have no benefit over placebo for hot flushes.22
Patients should be warned that mild upset stomach, indigestion, nausea, softening of stools, and mild headaches may occasionally occur. Also, evening primrose is contraindicated in women taking conventional medication for temporal lobe epilepsy or schizophrenia, as the substance decreases the efficacy of those drugs (Table 2, 3, and 4).
Red clover (Trifolium pratense)
Red clover is a plant that contains the phytoestrogens formononetin, biochanin A, daidzein, and genistein. It was originally used by Native Americans to treat whooping cough, gout, and cancer.
Two clinical trials conducted in Australia failed to demonstrate that red clover extract was more effective than placebo in reducing vasomotor symptoms.23,24 However, one study found that women who took 40 mg of red clover per day—the recommended dosage—experienced a significant reduction in hot flushes.25
There is still little information on whether red clover will have any effect on the uterine lining or breast tissue. Because red clover contains warfarin, high dosages may cause the blood to thin (Table 2, 3, and 4).
Conclusion
Whether to take HRT is one of the major decisions women in perimenopause or early menopause have to make. The overwhelming majority will decide against it, either out of fear of potential risks or simply to avoid unpleasant side effects. In fact, several studies have shown that only 15% to 20% of women will take HRT for more than a year.2 Even women who do agree to take HRT frequently demonstrate poor compliance.
But patients who decline HRT do need—and will have—other choices to help them weather vasomotor symptoms that can greatly disrupt their lives. Many women find these plant-based alternatives an important option that allows them to control their hot flushes without taking HRT.
As clinicians start to recommend alternative supplements to their menopausal patients, they should do so with an understanding of the expected results, potential risks and benefits, and how the recommendation may interact with other medications. If these guidelines are followed, physicians may recommend alternative treatments with the same confidence they have in prescription drugs.
The author reports no financial relationship with any companies whose products are mentioned in this article.
1. Salamone LM, Pressman AR, Seeley DG, Cauley JA. Estrogen replacement therapy. A survey of older women’s attitudes. Arch Int Med. 1996;156:1293-1297.
2. Ravnikar VA. Compliance with hormone therapy. Am J Obstet Gynecol. 1987;156:1332-1334.
3. Kessel B. Alternatives to estrogen for menopausal women. Proc Soc Esp Biol Med. 1998;217(1):38-44.
4. Seibel MM. The role of nutrition and nutritional supplements in women’s health. Fertil Steril. 1999;72:579-591.
5. Astin JA. Why patients use alternative medicine: results of a national study. JAMA. 1998;279:1548-1553.
6. Haines CJ, Chung TKH, Leung DHY. A prospective study of the frequency of acute menopausal symptoms in Hog Dong Chinese women. Maturitas. 1994;18:175-181.
7. Tang GWK. The climacteric of Chinese factory workers. Maturitas. 1994;19:177-182.
8. Markiewicz L, Garey J, Adlercreutz H, Gurpide E. In vitro bioassays of non-steroidal phytoestrogens. J Steroid Biochem Mol Biol. 1993;45:399-405.
9. Murkies AL, Lombard C, Strauss BJD, Wilcox G, Burger HG, Morton MS. Dietary flour supplementation decreases postmenopausal hot flushes: effect of soy and wheat. Maturitas. 1995;21:189-195.
10. Brzezinski A, Adlercreutz H, Shaoul R, Rosler A, Shmueli A, Tanos V, Schenker JG. Short-term effects of phytoestrogen-rich diet on postmenopausal women. Menopause. 1997;4:89-94.
11. Albertazzi P, Pansini F, Bonaccorsi G, Zanotti L, Forini E, De Aloysio D. The effect of dietary soy supplementation on hot flushes. Obstet Gynecol. 1998;91:6-11.
12. Scambia G, Mango D, Signorile PG, et al. Clinical effects of a standardized soy extract in postmenopausal women: a pilot study. Menopause. 2000;7:105-111.
13. Upmalis DH, Lobo R, Bradley L, Warren M, Cone FL, Lamia CA. Vasomotor symptom relief by soy isoflavone extract tablets in postmenopausal women: a multicenter, double-blind, randomized, placebo-controlled study. Menopause. 2000;7:236-242.
14. Shaver JLF, Giblin E, Paulsen V. Sleep quality subtypes in midlife women. Sleep. 1991;14:18-23.
15. Struck D, Tegtmeier M, Harnishfeger G. Flavones in extracts of Cimicifuga racemosa. Planta Med. 1997;63:289-290.
16. Beuscher N. Cimicifuga racemosa L.—Black Cohosh. HerbalGram Spring. 1996;19-27.
17. Vorberg G. Therapy of climacteric complaints. Zeitschrift fur Allgemeinmedizin. 1984;60:626-29.
18. Warnecke G. Influence of a phytopharmaceutical on climacteric complaints. Die Meizinische Welt. 1985;36:871-874.
19. Stoll W. Phytopharmacon influences atrophic vaginal epithelium: double-blind study—Cimicifuga vs. estrogenic substances. Therapeuticum. 1987;1:23-31.
20. Hirata JD, Swiers LM, Zell B, Small R, Ettinger B. Does dong quai have estrogenic effects in postmenopausal women? A double-blind placebo-controlled trial. Fertil Steril. 1997;68:981-986.
21. Page RL, 2nd, Lawrence JD. Potentiation of warfarin by dong quai. Pharmacotherapy. 1999;19(7):870-876.
22. Chenoy R, Hussain S, Tayob Y, O’Brien PMS, Moss MY, Morse PF. Effect of oral gamalenic acid from evening primrose oil on menopausal flushing. Br Med J. 1994;308:501-503.
23. Barber RJ, Templeman C, Morton T, Delley GE, Weat L. Randomized placebo-controlled trial of an isoflavone supplement and menopausal symptoms in women. Climacteric. 1999;2:85-92.
24. Knight DC, Howes JB, Eden JA. The effect of Promensil™ an isoflavone extract on menopausal symptoms. Climacteric. 1999;2:79-84.
25. Nachtigall LB, LaGrega L, Lee WW, et al. The effects of isoflavones derived from red clover on vasomotor symptoms and endometrial thickness. 9th International Menopause Society World Congress on the Menopause, October 17-21, 1999.
1. Salamone LM, Pressman AR, Seeley DG, Cauley JA. Estrogen replacement therapy. A survey of older women’s attitudes. Arch Int Med. 1996;156:1293-1297.
2. Ravnikar VA. Compliance with hormone therapy. Am J Obstet Gynecol. 1987;156:1332-1334.
3. Kessel B. Alternatives to estrogen for menopausal women. Proc Soc Esp Biol Med. 1998;217(1):38-44.
4. Seibel MM. The role of nutrition and nutritional supplements in women’s health. Fertil Steril. 1999;72:579-591.
5. Astin JA. Why patients use alternative medicine: results of a national study. JAMA. 1998;279:1548-1553.
6. Haines CJ, Chung TKH, Leung DHY. A prospective study of the frequency of acute menopausal symptoms in Hog Dong Chinese women. Maturitas. 1994;18:175-181.
7. Tang GWK. The climacteric of Chinese factory workers. Maturitas. 1994;19:177-182.
8. Markiewicz L, Garey J, Adlercreutz H, Gurpide E. In vitro bioassays of non-steroidal phytoestrogens. J Steroid Biochem Mol Biol. 1993;45:399-405.
9. Murkies AL, Lombard C, Strauss BJD, Wilcox G, Burger HG, Morton MS. Dietary flour supplementation decreases postmenopausal hot flushes: effect of soy and wheat. Maturitas. 1995;21:189-195.
10. Brzezinski A, Adlercreutz H, Shaoul R, Rosler A, Shmueli A, Tanos V, Schenker JG. Short-term effects of phytoestrogen-rich diet on postmenopausal women. Menopause. 1997;4:89-94.
11. Albertazzi P, Pansini F, Bonaccorsi G, Zanotti L, Forini E, De Aloysio D. The effect of dietary soy supplementation on hot flushes. Obstet Gynecol. 1998;91:6-11.
12. Scambia G, Mango D, Signorile PG, et al. Clinical effects of a standardized soy extract in postmenopausal women: a pilot study. Menopause. 2000;7:105-111.
13. Upmalis DH, Lobo R, Bradley L, Warren M, Cone FL, Lamia CA. Vasomotor symptom relief by soy isoflavone extract tablets in postmenopausal women: a multicenter, double-blind, randomized, placebo-controlled study. Menopause. 2000;7:236-242.
14. Shaver JLF, Giblin E, Paulsen V. Sleep quality subtypes in midlife women. Sleep. 1991;14:18-23.
15. Struck D, Tegtmeier M, Harnishfeger G. Flavones in extracts of Cimicifuga racemosa. Planta Med. 1997;63:289-290.
16. Beuscher N. Cimicifuga racemosa L.—Black Cohosh. HerbalGram Spring. 1996;19-27.
17. Vorberg G. Therapy of climacteric complaints. Zeitschrift fur Allgemeinmedizin. 1984;60:626-29.
18. Warnecke G. Influence of a phytopharmaceutical on climacteric complaints. Die Meizinische Welt. 1985;36:871-874.
19. Stoll W. Phytopharmacon influences atrophic vaginal epithelium: double-blind study—Cimicifuga vs. estrogenic substances. Therapeuticum. 1987;1:23-31.
20. Hirata JD, Swiers LM, Zell B, Small R, Ettinger B. Does dong quai have estrogenic effects in postmenopausal women? A double-blind placebo-controlled trial. Fertil Steril. 1997;68:981-986.
21. Page RL, 2nd, Lawrence JD. Potentiation of warfarin by dong quai. Pharmacotherapy. 1999;19(7):870-876.
22. Chenoy R, Hussain S, Tayob Y, O’Brien PMS, Moss MY, Morse PF. Effect of oral gamalenic acid from evening primrose oil on menopausal flushing. Br Med J. 1994;308:501-503.
23. Barber RJ, Templeman C, Morton T, Delley GE, Weat L. Randomized placebo-controlled trial of an isoflavone supplement and menopausal symptoms in women. Climacteric. 1999;2:85-92.
24. Knight DC, Howes JB, Eden JA. The effect of Promensil™ an isoflavone extract on menopausal symptoms. Climacteric. 1999;2:79-84.
25. Nachtigall LB, LaGrega L, Lee WW, et al. The effects of isoflavones derived from red clover on vasomotor symptoms and endometrial thickness. 9th International Menopause Society World Congress on the Menopause, October 17-21, 1999.