Menopause: a review of botanical dietary supplements
2005; Elsevier BV; Volume: 118; Issue: 12 Linguagem: Inglês
10.1016/j.amjmed.2005.09.044
ISSN1555-7162
Autores Tópico(s)Estrogen and related hormone effects
ResumoSince the release of the Women's Health Initiative (WHI) findings, an increasing number of dietary supplement products specifically targeting women in menopause have appeared in the American marketplace. This growth highlights the need for a critical evaluation of the tolerability and effectiveness of these products. The purpose of this article is to assess the evidence for safety and benefit of botanical monopreparations used for relief of menopause-related symptoms. The Cochrane Library and Medline databases were searched from January 1966 to October 2004, using a detailed list of terms related to botanicals and menopausal symptoms. Studies were considered eligible (1) if they were controlled trials of a botanical monopreparation administered orally for a minimum of 6 weeks to perimenopausal or postmenopausal women with hot flashes and (2) if they included a placebo or comparative treatment arm. Topical preparations, botanical combinations, and dietary interventions, such as soy food or protein, were not included. No language restrictions were imposed on the search. A total of 19 studies met the inclusion criteria. The majority of studies indicate that extract of black cohosh (Actaea racemosa L.) improves menopause-related symptoms; however, methodologic shortcomings in the trials were identified. To date, 4 case reports of possible hepatotoxicity have been published, although previous safety reviews suggest that black cohosh is well tolerated and that adverse events are rare when it is used appropriately. The results of 6 clinical studies on soy (Glycine max L.) isoflavone extracts are mixed. Moreover, the composition and dose of soy supplements varies widely across studies, making comparisons and definitive conclusions difficult. One study challenged the long-term safety of high-dose soy isoflavone extract (150 mg/day for 5 years) on the uterine endometrium. Clinical data from 5 controlled trials assessing the efficacy of semipurified isoflavone red clover (Trifolium pratense L.) leaf extracts to reduce hot flash frequency and severity or to relieve symptoms associated with the domains of the Greene Menopausal Symptom Scale are contradictory. The largest study showed no benefit for reducing symptoms associated with menopause for 2 different red clover isoflavone products compared with placebo. No significant adverse events have been reported in the literature. Single clinical trials do not support the use of dong quai (Angelica sinensis L.), ginseng (Panax ginseng C.A. Mey), or evening primrose seed oil (Oenothera biennis L.) for improving menopausal symptoms. We conclude that black cohosh extracts appear to ease menopausal symptoms; ongoing studies funded by the National Institutes of Health (NIH) will provide more definitive safety and efficacy data. Soy isoflavone extracts appear to have minimal to no effect, although definitive conclusions are difficult given the wide variation in product composition and dose. Long-term safety of higher dosage (150 mg/day) soy isoflavone extracts is uncertain. Semipurified isoflavone red clover leaf extracts have minimal to no effect in reducing menopausal symptoms. Dong quai, ginseng extract, and evening primrose seed oil appear to be ineffective in ameliorating menopausal symptoms at the dosages and in the preparations used in these studies. Since the release of the Women's Health Initiative (WHI) findings, an increasing number of dietary supplement products specifically targeting women in menopause have appeared in the American marketplace. This growth highlights the need for a critical evaluation of the tolerability and effectiveness of these products. The purpose of this article is to assess the evidence for safety and benefit of botanical monopreparations used for relief of menopause-related symptoms. The Cochrane Library and Medline databases were searched from January 1966 to October 2004, using a detailed list of terms related to botanicals and menopausal symptoms. Studies were considered eligible (1) if they were controlled trials of a botanical monopreparation administered orally for a minimum of 6 weeks to perimenopausal or postmenopausal women with hot flashes and (2) if they included a placebo or comparative treatment arm. Topical preparations, botanical combinations, and dietary interventions, such as soy food or protein, were not included. No language restrictions were imposed on the search. A total of 19 studies met the inclusion criteria. The majority of studies indicate that extract of black cohosh (Actaea racemosa L.) improves menopause-related symptoms; however, methodologic shortcomings in the trials were identified. To date, 4 case reports of possible hepatotoxicity have been published, although previous safety reviews suggest that black cohosh is well tolerated and that adverse events are rare when it is used appropriately. The results of 6 clinical studies on soy (Glycine max L.) isoflavone extracts are mixed. Moreover, the composition and dose of soy supplements varies widely across studies, making comparisons and definitive conclusions difficult. One study challenged the long-term safety of high-dose soy isoflavone extract (150 mg/day for 5 years) on the uterine endometrium. Clinical data from 5 controlled trials assessing the efficacy of semipurified isoflavone red clover (Trifolium pratense L.) leaf extracts to reduce hot flash frequency and severity or to relieve symptoms associated with the domains of the Greene Menopausal Symptom Scale are contradictory. The largest study showed no benefit for reducing symptoms associated with menopause for 2 different red clover isoflavone products compared with placebo. No significant adverse events have been reported in the literature. Single clinical trials do not support the use of dong quai (Angelica sinensis L.), ginseng (Panax ginseng C.A. Mey), or evening primrose seed oil (Oenothera biennis L.) for improving menopausal symptoms. We conclude that black cohosh extracts appear to ease menopausal symptoms; ongoing studies funded by the National Institutes of Health (NIH) will provide more definitive safety and efficacy data. Soy isoflavone extracts appear to have minimal to no effect, although definitive conclusions are difficult given the wide variation in product composition and dose. Long-term safety of higher dosage (150 mg/day) soy isoflavone extracts is uncertain. Semipurified isoflavone red clover leaf extracts have minimal to no effect in reducing menopausal symptoms. Dong quai, ginseng extract, and evening primrose seed oil appear to be ineffective in ameliorating menopausal symptoms at the dosages and in the preparations used in these studies. When the Women's Health Initiative (WHI) was discontinued owing to unanticipated increases in risk for breast cancer, stroke, heart attack, and blood clots among women taking estrogen plus progestin, the search for alternative treatments that were perceived to offer beneficial effects with less risk intensified. Some women turned to botanical dietary supplements with the presumption that these "natural substances" are relatively safe and effective. Whether these presumptions are correct remains to be seen. Although botanical remedies have been used for centuries, many products in the American marketplace bear little resemblance to the simple preparations of the past. Potent, concentrated products extracted via a range of solvents may be consumed for prolonged periods, often in combination with over-the-counter and prescription drugs—unique circumstances when compared with use of the apothecary of yesteryear. Thus, a "long history" of use cannot be presupposed, and questions of safety and efficacy must continue to be entertained. The purpose of this article is to systematically assess the evidence for safety and benefit of single constituent botanical products (often referred to as monopreparations) for the treatment of menopause-related symptoms. This review is based on the most rigorous scientific studies published in peer-reviewed literature. The Cochrane Library and Medline databases were searched from January 1966 to October 2004, using a detailed list of terms related to botanicals and menopausal symptoms. Terms used in the search included the following: menopause, hot flashes, climacteric, herb, botanical, phyto-, phytoestrogen, isoflavone, soy, black cohosh, Cimicifuga, Actaea, red clover, Trifolium, dong quai, Angelica, licorice, wild yam, Dioscorea, ginseng, Panax, evening primrose oil, γ-linolenic acid, hops, kava, Piper methysticum, St. John's wort, Hypericum, chastetree, Vitex, valerian, and motherwort. References were then reviewed to identify additional studies. Studies were considered eligible (1) if they were controlled trials of a botanical monopreparation administered orally for a minimum of 6 weeks to perimenopausal or postmenopausal women with hot flashes and (2) if they included a placebo or comparative treatment arm. Topical preparations, botanical combinations, and dietary interventions, such as soy food or protein, were not included. No language restrictions were imposed. A total of 19 studies met the inclusion criteria. The root and rhizome of black cohosh, an indigenous North American herb, have been researched for >30 years for the relief of menopause-related symptoms. German health authorities endorse the use of black cohosh extract for premenstrual discomfort, dysmenorrhea, and menopause.1Blumenthal M. Busse W. Goldberg A. et al.The Complete German Commission E Monographs. Integrative Medicine Communications, Boston1998Google Scholar Similarly, the World Health Organization (WHO)2World Health OrganizationWHO Monographs on Selected Medicinal Plants. Vol 2. World Health Organization, Geneva2002: 55-65Google Scholar recognizes its use for "treatment of climacteric symptoms such as hot flushes, profuse sweating, sleeping disorders and nervous irritability." The North American Menopause Society3North American Menopause SocietyTreatment of menopause-associated vasomotor symptoms position statement of the North American Menopause Society.Menopause. 2004; 11: 11-33Crossref PubMed Scopus (396) Google Scholar recommends black cohosh, in conjunction with lifestyle approaches, as a treatment option for women with mild menopause-related symptoms. Of 13 published trials identified for black cohosh, 5 met criteria for inclusion in this review (Table 1).4Warnecke G. Influence of a phytopharmaceutical on climacteric complaints.Med Welt. 1985; 36: 871-874Google Scholar, 5Stoll W. Phytopharmaceutical influences of atrophic vaginal epithelium double-blind study on Cimicifuga versus an estrogen preparation.Therapeutikon. 1987; 1: 23-32Google Scholar, 6Lehmann-Willenbrock W. Riedel H.H. Clinical and endocrinologic examinations concerning therapy of climacteric symptoms following hysterectomy with remaining ovaries.Zentralbl Gynakol. 1988; 110: 611-618PubMed Google Scholar, 7Jacobson J.S. Troxel A.B. 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: 2739-2745Crossref PubMed Scopus (334) Google Scholar, 8Wuttke W. Seidlova-Wuttke D. Gorkow C. The Cimicifuga preparation BNO 1055 vs. conjugated estrogens in a double-blind placebo-controlled study effects on menopause symptoms and bone markers.Maturitas. 2003; 44: S67-S77Abstract Full Text Full Text PDF PubMed Scopus (237) Google ScholarTable 1Controlled trials of black cohoshStudyNSampleControlTreatmentPrimary Outcome MeasuresResultsWarnecke4Warnecke G. Influence of a phytopharmaceutical on climacteric complaints.Med Welt. 1985; 36: 871-874Google Scholar60Peri- and postmenopausal womenCEs (0.6 mg/day) or diazepam (2 mg/day) for 12 wk40 drops Remifemin⁎Remifemin (black cohosh; Schaper & Brummer GmbH & Co. KG, Salzgitter, Germany). Remifemin preparations are standardized to contain 1 mg triterpene glycosides (expressed as 27-deoxyactein (23-epi-26-deoxyactein) in each dose, equivalent to 20 mg root/rhizome. liquid extract bid (4 mg/day 27-deoxyactein) for 12 wkKI, HAM-A score, Global Impressions, and Self-Assessment Depression ScaleAll 3 groups showed significant decrease in neurovegetative and psychological symptoms. Black cohosh and estrogen groups experienced proliferation of vaginal epithelium. No significant adverse effects noted.Stoll5Stoll W. Phytopharmaceutical influences of atrophic vaginal epithelium double-blind study on Cimicifuga versus an estrogen preparation.Therapeutikon. 1987; 1: 23-32Google Scholar80Postmenopausal womenCEs (0.625 mg/day) or placebo for 12 wkRemifemin 4 mg (27-deoxyactein) bid for 12 wk (equivalent to 80 mg bid extract)KI, HAM-A scoreRemifemin group had most pronounced reduction in KI and HAM-A scores compared with estrogen and placebo groups (P <0.001). Remifemin group had most significant change in proliferation of vaginal epithelium (P <0.01).Lehmann-Willenbrock and Riedel6Lehmann-Willenbrock W. Riedel H.H. Clinical and endocrinologic examinations concerning therapy of climacteric symptoms following hysterectomy with remaining ovaries.Zentralbl Gynakol. 1988; 110: 611-618PubMed Google Scholar60Surgically menopausal womenEstriol (1 mg/day) or CEs (1.25 mg/day) or estrogen + progestin therapy (2 mg/day estradiol + 1 mg/day norethisterone acetate) for 6 moRemifemin 4 mg bid (27-deoxyactein) for 6 mo (equivalent to 80 mg bid extract)KIAuthors concluded that all 3 groups had decreased KI; no significant difference. Remifemin group had no change in LH or FSH level.Jacobson et al7Jacobson J.S. Troxel A.B. 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: 2739-2745Crossref PubMed Scopus (334) Google Scholar85Women with vasomotor symptoms and history of breast cancerPlacebo for 60 days20 mg bid of an unspecified black cohosh product for 60 days4-day hot flash diary; menopausal symptom questionnaireBlack cohosh was not significantly more efficacious than placebo for hot flash number or intensity; sweating was the only symptom with significantly greater improvement over placebo. No change in FSH or LH level in either group.Wuttke et al8Wuttke W. Seidlova-Wuttke D. Gorkow C. The Cimicifuga preparation BNO 1055 vs. conjugated estrogens in a double-blind placebo-controlled study effects on menopause symptoms and bone markers.Maturitas. 2003; 44: S67-S77Abstract Full Text Full Text PDF PubMed Scopus (237) Google Scholar62Postmenopausal womenCE (0.6 mg/day); or placebo for 12 wkCR BNO 1055/Menofem†Menofem (CR BNO aqueous ethanolic extract of black cohosh; Bionorica AG, Neumarket, Germany). (40 mg/day) for 12 wkMRSStatistically significant reduction in MRS score; however, reduction in hot flashes (item 1 on MRS) did not differ significantly between groups. Beneficial effect on bone metabolism and vaginal cytology reported in both CE and CR BNO groups. CR BNO had no effect on endometrial thickness, which was increased by CE.CE = conjugated estrogen; FSH = follicle-stimulating hormone; HAM-A = Hamilton Anxiety Rating Scale; KI = Kupperman Index; LH = luteinizing hormone; MRS = Menopause Rating Scale. Remifemin (black cohosh; Schaper & Brummer GmbH & Co. KG, Salzgitter, Germany). Remifemin preparations are standardized to contain 1 mg triterpene glycosides (expressed as 27-deoxyactein (23-epi-26-deoxyactein) in each dose, equivalent to 20 mg root/rhizome.† Menofem (CR BNO aqueous ethanolic extract of black cohosh; Bionorica AG, Neumarket, Germany). Open table in a new tab CE = conjugated estrogen; FSH = follicle-stimulating hormone; HAM-A = Hamilton Anxiety Rating Scale; KI = Kupperman Index; LH = luteinizing hormone; MRS = Menopause Rating Scale. Most studies indicate that black cohosh extract reduces some symptoms associated with menopause; however, methodologic shortcomings and variations in product and dosage limit definitive conclusions. The randomized, double-blind study by Stoll5Stoll W. Phytopharmaceutical influences of atrophic vaginal epithelium double-blind study on Cimicifuga versus an estrogen preparation.Therapeutikon. 1987; 1: 23-32Google Scholar reported a statistically significant (P <0.001) reduction in Kupperman Index (KI) and Hamilton Anxiety Rating Scale (HAM-A) scores among women assigned to black cohosh compared with those given conjugated estrogens or placebo. Daily hot flash incidence decreased from 4.9 to 0.7 in the black cohosh group, from 5.2 to 3.2 in the estrogen group, and from 5.1 to 3.1 in the placebo group. Attrition bias may have occurred; 12 of 30 women dropped out of the estrogen group between weeks 5 and 8 due to "perceived lack of efficacy," a finding that, in itself, raises questions about the study. Lehmann-Willenbrock and Riedel6 found black cohosh reduced KI scores as effectively as hormone therapy (HT). However, their study suffered from small sample size, lack of a placebo arm, lack of blinding, and no description of the randomization process. The trial by Warnecke4Warnecke G. Influence of a phytopharmaceutical on climacteric complaints.Med Welt. 1985; 36: 871-874Google Scholar reported "highly significant reduction" in all outcome measures, but it did not report calculations or provide analytical details. The study lacked a placebo arm and included diazepam—a drug not typically used for relief of menopausal symptoms—in 1 treatment arm. Wuttke and coworkers8Wuttke W. Seidlova-Wuttke D. Gorkow C. The Cimicifuga preparation BNO 1055 vs. conjugated estrogens in a double-blind placebo-controlled study effects on menopause symptoms and bone markers.Maturitas. 2003; 44: S67-S77Abstract Full Text Full Text PDF PubMed Scopus (237) Google Scholar found a statistically significant reduction in the Menopause Rating Scale (MRS) score among women taking black cohosh compared with those assigned to placebo; however, reduction in hot flashes (item 1 on the MRS) did not differ significantly between the black cohosh and placebo groups. Jacobson and colleagues7Jacobson J.S. Troxel A.B. 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: 2739-2745Crossref PubMed Scopus (334) Google Scholar failed to detect any reduction in hot flash frequency or severity among breast cancer survivors taking black cohosh. This study included a large number of participants (69%) taking tamoxifen, a drug known to induce hot flashes, and thus limited the generalization of the results to women going through natural menopause and not taking tamoxifen. Our understanding of the mechanism of action of black cohosh is a work in progress, but recent research suggests a nonhormonal effect.9Mahady G.B. Is black cohosh estrogenic?.Nutr Rev. 2003; 61: 183-186Crossref PubMed Scopus (41) Google Scholar An abstract reporting increased metastases from breast to lung in mice given black cohosh has raised questions concerning safety for women with breast cancer10Davis V.L. Jayo M.J. Hardy M.L. et al.Effects of black cohosh on mammary tumor development and progression in MMTV-neu transgenic mice.2003Google Scholar; however, other studies in animals have not found an effect on mammary tumors.11Freudenstein J. Dasenbrock C. Nisslein T. Lack of promotion of estrogen-dependent mammary gland tumors in vivo an isopropanolic Cimicifuga racemosa extract.Cancer Res. 2002; 62: 3448-3452PubMed Google Scholar, 12Nisslein T. Freudenstein J. Concomitant administration of an isopropanolic extract of black cohosh and tamoxifen in the in vivo tumor model of implanted RUCA-I rat endometrial adenocarcinoma cells.Toxicol Lett. 2004; 150: 271-275Crossref PubMed Scopus (27) Google Scholar Four case reports13Lontos S. Jones R.M. Angus P.W. Gow P.J. Acute liver failure associated with the use of herbal preparations containing black cohosh.Med J Aust. 2003; 179: 390-391PubMed Google Scholar, 14Whiting P.W. Clouston A. Kerlin P. Black cohosh and other herbal remedies associated with acute hepatitis.Med J Aust. 2002; 177: 440-443PubMed Google Scholar, 15Cohen S.M. O'Connor A.M. Hart J. Merel N.H. Te H.S. Autoimmune hepatitis associated with the use of black cohosh a case study.Menopause. 2004; 11: 575-577Crossref PubMed Scopus (94) Google Scholar, 16Levitsky J. Alli T.A. Wisecarver J. Sorrell M.F. Fulminant liver failure associated with the use of black cohosh.Dig Dis Sci. 2005; 50: 538-539Crossref PubMed Scopus (68) Google Scholar purportedly link black cohosh use with acute liver disease in 5 patients. Evaluation of these reports is difficult, however, because 2 of the 5 cases involved combination herbal products, 3 cases failed to analyze suspected products for purity and identification, and 1 case did not report the brand or dose of black cohosh consumed. No serious adverse events have been reported in published clinical trials, and 2 safety reviews have found black cohosh extract to be well tolerated and adverse events to be rare when it is taken for up to 6 months.17Dog T.L. Powell K.L. Weisman S.M. Critical evaluation of the safety of Cimicifuga racemosa in menopause symptom relief.Menopause. 2003; 10: 299-313Crossref PubMed Google Scholar, 18Huntley A. The safety of black cohosh (Actaea racemosa, Cimicifuga racemosa).Expert Opin Drug Saf. 2004; 3: 615-623Crossref PubMed Scopus (25) Google Scholar There is a wide variety of black cohosh products and formulations available in the American marketplace, including combination preparations. Clinical trials have been conducted on 2 proprietary preparations. The majority of studies used Remifemin (Schaper & Brummer GmbH & Co. KG, Salzgitter, Germany), although the method of extraction in this preparation has changed over time from hydroethanolic (60% ethanol by volume) to isopropyl alcohol (40% by volume) and the dosage form has changed from liquid to tablets, thus complicating any comparison of research trials. In 2 recent studies, investigators used CR BNO 1055, an aqueous ethanolic extract (58% vol/vol), sold as Klimadynon and Menofem (Bionorica AG, Neumarket, Germany). It is unclear whether pharmacologic equivalence can be assumed between products. The dose of extract used in clinical trials is 40 to 160 mg/day. Most published reviews19Fugate S.E. Church C.O. Nonestrogen treatment modalities for vasomotor symptoms associated with menopause.Ann Pharmacother. 2004; 38: 1482-1499Crossref PubMed Scopus (43) Google Scholar, 20Huntley A.L. Ernst E. A systematic review of herbal medicinal products for the treatment of menopausal symptoms.Menopause. 2003; 10: 465-476Crossref PubMed Scopus (130) Google Scholar, 21Kligler B. Black cohosh.Am Fam Physician. 2003; 68: 114-116PubMed Google Scholar, 22Taylor M. Alternatives to HRT an evidence-based review.Int J Fertil Womens Med. 2003; 48: 64-68PubMed Google Scholar, 23Kronenberg F. Fugh-Berman A. Complementary and alternative medicine for menopausal symptoms a review of randomized, controlled trials.Ann Intern Med. 2002; 137: 805-813Crossref PubMed Scopus (480) Google Scholar, 24Borrelli F. Ernst E. Cimicifuga racemosaa systematic review of its clinical efficacy.Eur J Clin Pharmacol. 2002; 58: 235-241Crossref PubMed Scopus (71) Google Scholar lend support for the contention that black cohosh extract is beneficial for the relief of menopause-related symptoms; however, clinical trials published to date suffer from methodologic shortcomings that necessarily temper endorsement of this botanical. It is hoped that ongoing National Institutes of Health (NIH)–funded clinical studies will provide more definitive information regarding safety and efficacy of black cohosh for the alleviation of menopausal symptoms.
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