Does scientific evidence support the use of non-prescription supplements for treatment of acute menopausal symptoms such as hot flushes?Abstract The objective of the present review was to critically evaluate the scientific evidence for efficacy of non-prescription supplements (NPS NPS National Park Service NPS Naval Postgraduate School NPS Net Promoter Score (customer management) NPS Non-Point Source pollution NPS Native Plant Society NPS Norfolk Public Schools (Virginia) ) available for treatment of acute menopausal symptoms; and where available, to identify constituents, specify dosage, propose mechanisms and indicate safety concerns. A Medline search identified 24 clinical trials assessing efficacy of seven NPS for treatment of hot flushes in symptomatic menopausal women; 19 were randomised Adj. 1. randomised - set up or distributed in a deliberately random way randomized irregular - contrary to rule or accepted order or general practice; "irregular hiring practices" placebo-controlled trials. Articles were located on black cohosh black cohosh see actaeaspicata. , dong quai dong quai (doong kwa) (-kwi) Angelica sinensis (Chinese angelica), or its root, a preparation of which is used for gynecologic disorders. dong quai n. , evening primrose oil evening primrose oil one of the few plant oils containing ?-linolenic acid. Obtained from seeds of Oenothera biennis, it is used for its anti-inflammatory effects in the treatment of skin diseases. , ginseng ginseng (jĭn`sĕng), common name for the Araliaceae, a family of tropical herbs, shrubs, and trees that are often prickly and sometimes grow as climbing forms. , isoflavonoid phytoestrogens Phytoestrogens Compounds found in plants that can mimic the effects of estrogen in the body. Mentioned in: Premenstrual Syndrome phytoestrogens, n.pl plant-derived estrogen analogs. (from red clover red clover of Vermont. [Flower Symbolism: Golenpaul, 644] See : Flower, State red clover symbolic of diligence. [Flower Symbolism: Jobes, 350] See : Industriousness or soy) and sage. Evidence for each NPS was tabulated according to according to prep. 1. As stated or indicated by; on the authority of: according to historians. 2. In keeping with: according to instructions. 3. study design and menopausal outcomes. Findings from 13 randomised placebo-controlled trials, using isoflavonoids from red clover or soy, demonstrated significant efficacy for six studies (46%) with reductions in moderate to severe flushes by 10-44% compared with placebo; seven studies (54%) reported no significant improvements. In vitro in vitro /in vi·tro/ (in ve´tro) [L.] within a glass; observable in a test tube; in an artificial environment. in vi·tro adj. In an artificial environment outside a living organism. studies indicate that isoflavonoids have significant oestrogenic oestrogenic (ōˈ·es·tr activity, providing a supporting mechanism. One controlled trial controlled trial Clinical research A clinical study in which one group of participants receives an experimental drug while the other receives either a placebo or an approved–'gold standard' therapy. See Blinding, Double-blinded. reported that an extract of sage and alfalfa alfalfa (ălfăl`fə) or lucern (l sûn`), perennial leguminous plant (Medicago sativa significantly reduced severe hot flushes by
60% compared with placebo. Two controlled trials reported that black
cohosh improved overall menopause symptom scores; however, no data were
available specifically on hot flushes. In conclusion, evidence from a
small number of placebo-controlled trials suggested that further
research is warranted to test efficacy of red clover, soy, sage and
black cohosh for treatment of hot flushes in menopausal women. To date,
controlled trials do not support use of dong quai, evening primrose oil
and ginseng for treatment of hot flushes.
Key words: complementary and alternative medicines The term complementary and alternative medicine (CAM) is an umbrella term for alternative medicine and complementary medicine. Alternative medicine describes practices used in place of conventional medical treatments. , hot flush, isoflavonoids, menopause, soy protein Soy protein is generally regarded as the storage protein held in discrete particles called protein bodies which are estimated to contain at least 60–70% of the total soybean protein. , women's health Women's Health Definition Women's health is the effect of gender on disease and health that encompasses a broad range of biological and psychosocial issues. (Nutr Diet 2005;62:138-151) Introduction Controversies surrounding the safety of hormone therapy Hormone therapy Treating cancers by changing the hormone balance of the body, instead of by using cell-killing drugs. Mentioned in: Breast Cancer, Thyroid Cancer hormone therapy (HT) have prompted increased interest in non-prescription supplements (NPS) available for treatment of menopausal symptoms. In contrast to HT, NPS are often perceived as natural and, therefore, may represent a safer and more appropriate alternative to HT. However, little is known about their efficacy and the scientific rationale for their use. In view of the increasing community interest and marketing of these supplements, and their traditional use in some cultures, assessment of the scientific evidence supporting NPS is warranted. In the present review, the term NPS includes all tablets, powders or tinctures purchased without a doctor's prescription that are taken to treat menopausal symptoms. Other terms frequently used include herbal remedies, HT alternatives and complementary and alternative medicines. The present review focuses on evidence supporting the use of NPS for the treatment of acute symptoms of menopause, particularly hot flushes. Although assessed in some of the trials, efficacy for other symptoms less specifically associated with menopause, such as anxiety and muscle aches, is beyond the scope of the present review. Hot flushes are one of the most common symptoms reported by women undergoing the menopausal transition. The underlying pathophysiology pathophysiology /patho·phys·i·ol·o·gy/ (-fiz?e-ol´ah-je) the physiology of disordered function. path·o·phys·i·ol·o·gy n. 1. of hot flushes is not well understood; however, a relationship with declining oestrogen oes·tro·gen n. Variant of estrogen. oestrogen see estrogen. levels is assumed; hot flushes peak in the perimenopausal perimenopausal adjective Referring to a period of a ♀'s life–age 45 to 55-ish–in which menstrual periods become irregular; perimenopause is immediately before, during and after menopause. See Menopause. period, when oestrogen levels are fluctuating, and usually subside sub·side intr.v. sub·sid·ed, sub·sid·ing, sub·sides 1. To sink to a lower or normal level. 2. To sink or settle down, as into a sofa. 3. To sink to the bottom, as a sediment. 4. with age, suggesting sensitivity to relative rather than absolute oestrogen concentration. (1) Many NPS are designed to provide an ingredient with purported oestrogenic activity. Previous published reviews have assessed the evidence supporting use of NPS for treatment of both acute symptoms associated with menopause, such as hot flushes, and chronic conditions, such as cardiovascular disease Cardiovascular disease Disease that affects the heart and blood vessels. Mentioned in: Lipoproteins Test cardiovascular disease and osteoporosis. (2-9) The present review expands upon previous work by focusing in greater depth on acute menopausal symptoms and assessing a range of NPS including black cohosh, dong quai, evening primrose oil, ginseng, sage and phytoestrogens. Investigation of alternatives to HT for treatment of symptomatic menopausal women is a rapidly evolving area. Five reviews were identified that focused on acute symptoms, of which four did not include studies published after 2002. (10-13) The most recently published study investigated phytoestrogens alone. (14) Authors concluded that there was insufficient evidence insufficient evidence n. a finding (decision) by a trial judge or an appeals court that the prosecution in a criminal case or a plaintiff in a lawsuit has not proved the case because the attorney did not present enough convincing evidence. to support the use of phytoestrogens for treatment of hot flushes and other menopausal symptoms; however, one limitation was that conclusions were drawn from studies that included phytoestrogen-rich diets, for which it is not possible to blind subjects to placebo or intervention status. The aim of the present review is to provide health professionals with a critical evaluation of the scientific evidence for efficacy of the NPS available for treatment of acute symptoms of menopause, particularly hot flushes; and where available, to identify constituents, specify dosage, propose mechanisms and indicate safety concerns. Methods Search strategy for identification of studies The search strategy identified relevant studies published from 1940 up to March 2004. The following databases were searched: MEDLINE (ScienceDirect), PUBMED, PROQUEST and the Cochrane Controlled Trials Register. Keywords used were: black cohosh, dong quai, evening primrose oil, ginseng, liquorice, red clover, sage, soy, kudzu kudzu (k d`z ), plant of the family Leguminosae (pulse family), native to Japan. , hormone
replacement therapy Hormone Replacement Therapy DefinitionHormone replacement therapy (HRT) is the use of synthetic or natural female hormones to make up for the decline or lack of natural hormones produced in a woman's body. and alternatives, phytoestrogens, isoflavonoids, menopause, hot flush, menopause supplement and non-prescription supplement. The literature review identified intervention studies intervention studies, n.pl the epidemiologic investigations designed to test a hypothesized cause and effect relation by modifying the supposed causal factor(s) in the study population. on the efficacy of seven types of NPS for treatment of acute symptoms of menopause: black cohosh, dong quai, evening primrose oil, ginseng, red clover and soy isoflavonoids, and sage. Criteria for selection of studies Selection criteria for types of studies were non-restrictive because of the small number of randomised placebo-controlled trials for all supplements, apart from isoflavonoids. Consequently, non-randomised and uncontrolled intervention trials were included. Studies were included if subjects were otherwise-healthy women with menopausal symptoms; women with hormone-sensitive conditions such as breast cancer were not included. In total, 19 randomised controlled trials were identified. Interventions to test the efficacy of NPS for menopause have measured a range of outcomes such as indices of general or psychological health and markers of hormonal status. However, the present review focused only on outcomes specifically associated with menopause, including frequency and severity of hot flushes or night sweats, and scales designed to measure overall menopausal symptoms, such as the Kupperman Menopause Index and the Greene Menopause Score. These scales attempt to quantify symptoms of menopause and incorporate measures of vasomotor vasomotor /vaso·mo·tor/ (-mo´tor) 1. affecting the caliber of blood vessels. 2. a vasomotor agent or nerve. va·so·mo·tor adj. (hot flushes), somatic somatic /so·mat·ic/ (so-mat´ik) 1. pertaining to or characteristic of the soma or body. 2. pertaining to the body wall in contrast to the viscera. so·mat·ic adj. and psychological symptoms. (15,16) Results and discussion The review of the literature identified two lines of evidence pertaining per·tain intr.v. per·tained, per·tain·ing, per·tains 1. To have reference; relate: evidence that pertains to the accident. 2. to NPS for treatment of menopausal symptoms. The first approach included investigation of the mechanism of action to explain the use of the NPS, most commonly the ability to bind to to contract; as, to bind one's self to a wife s>. See also: Bind oestrogen receptors and exert an oestrogenic response. The second line of inquiry was through clinical intervention studies involving symptomatic women, and examined the effects of NPS on hot flushes. As few clinical studies specifically addressed safety issues of NPS, additional information was located in the literature and included in a separate section. The strengths and limitations of the studies are discussed, enabling evaluation of the evidence regarding the efficacy of a particular NPS for treatment of hot flushes. Black cohosh Black cohosh (Cimicifuga racemosa Cimicifuga racemosa, n See cohosh, black; black snakeroot. ) was one of the more extensively studied menopausal NPS. Traditionally used in North America North America, third largest continent (1990 est. pop. 365,000,000), c.9,400,000 sq mi (24,346,000 sq km), the northern of the two continents of the Western Hemisphere. , Europe and China for gynaecological adj. 1. Of or pertaining to gynecology; same as gynecological. Adj. 1. gynaecological - of or relating to or practicing gynecology; "gynecological examination" gynecologic, gynecological conditions, black cohosh has been used in Germany since the 1940s to treat disorders of menstruation menstruation, periodic flow of blood and cells from the lining of the uterus in humans and most other primates, occurring about every 28 days in women. Menstruation commences at puberty (usually between age 10 and 17). and menopausal symptoms. Biological activity is attributed to the presence of triterpene triterpene plant toxins, e.g. lantadenes A, B, found in Lantana camara, icterogenins A, B, C, found in Lippia spp. Called also triterpene acids. triterpene acids see triterpene (above). glycosides, including actein, cimicifugoside, deoxyacetylacteol and 27-deoxyactein. (17) The mechanism proposed to explain the effect of black cohosh has been the possession of oestrogenic components, (18-20) although this has not been supported by in vitro studies investigating the ability of the triterpenes to bind to the oestrogen receptor and exert an oestrogenic response. (21-23) Authors have postulated pos·tu·late tr.v. pos·tu·lat·ed, pos·tu·lat·ing, pos·tu·lates 1. To make claim for; demand. 2. To assume or assert the truth, reality, or necessity of, especially as a basis of an argument. 3. that black cohosh may possess alternative mechanisms of action by activating receptors for pituitary hormones pituitary hormones, n.pl the hormones of the anterior lobe of the pituitary gland controlled by hypothalamic releasing factors; they include growth hormone (somatotropin) prolactin, thyroid-luteinizing hormone, adrenocorticotropic hormone, and that regulate oestrogen synthesis, such as luteinising hormone or follicle stimulating hormone Follicle stimulating hormone (FSH) A hormone that stimulates the growth and maturation of mature eggs in the ovary. Mentioned in: Polycystic Ovary Syndrome, Premature Menopause , or that black cohosh components influence enzymes required in the synthesis of endogenous endogenous /en·dog·e·nous/ (en-doj´e-nus) produced within or caused by factors within the organism. en·dog·e·nous adj. 1. Originating or produced within an organism, tissue, or cell. oestrogen. (20,21,23) However, these possibilities have not been tested. Seven clinical trials between 1982 and the present have investigated the efficacy of black cohosh for relief of symptoms in menopausal women (Table 1); two of these trials were placebo-controlled. (27,30) The majority used Remifemin, a standardised extract of Cimicifuga racemosa root containing 1 mg of the triterpene 27-deoxyacetein per tablet. (17) The current recommended dose of Remifemin is two tablets/day (40 mg black cohosh extract/day). This is lower than the dose of four tablets/day (or 80 drops of liquid extract/day) used in trials prior to 1996, because of an improvement in the extraction process; however, the quantity of active constituent was not altered. (17) Of the seven clinical trials, two were conducted after 1996, using the current recommended dose; (29,30) there was no observed difference in efficacy between studies conducted either before or after introduction of the new formulation. In a placebo-controlled trial with 80 women, Stoll reported that Remifemin reduced mean overall symptom scores by 59% compared with baseline and responses were significantly greater than the reduction by 29% with placebo. (27) Similar results were obtained in a second placebo-controlled trial by Wuttke et al. (30) Both studies were conducted over 12-week periods among German women with moderately severe symptoms of at least three hot flushes/day. They featured a parallel design that compared the effect of black cohosh with conjugated conjugated adj. Conjugate. estrogens, conjugated Warning - Hazardous drug! C.E.S. oestrogen (0.625 mg/day) or placebo on a measure of overall menopausal symptom scores. Although both studies reported a decrease in overall menopausal symptom scores, the effect on the hot flush component was not described (27) or was not significant. (30) Remifemin compared with placebo also resulted in a significant increase in the degree of proliferation of vaginal epithelial cells Epithelial cells Cells that form a thin surface coating on the outside of a body structure. Mentioned in: Corneal Transplantation , suggestive of suggestive of Decision making adjective Referring to a pattern by LM or imaging, that the interpreter associates with a particular–usually malignant lesion. See Aunt Millie approach, Defensive medicine. an oestrogenic effect. (27) Five uncontrolled trials have also reported consistently significant improvements in overall menopausal symptoms compared with baseline after 12-24 weeks of treatment with Remifemin. (24-26,28,29) None of the studies reported separately on the frequency of hot flushes. In one study the improvement in symptoms was accompanied by increased proliferation of vaginal epithelial cells, (26) although another study found no changes in vaginal epithelium. (29) However, in the absence of a placebo control, the results of these studies are not definitive. Dong quai Extracted from the root of Angelica angelica (ănjĕl`ĭkə), any species of the genus Angelica, plants of the family Umbelliferae (parsley family), native to the Northern Hemisphere and New Zealand, valued for their potency as a medicament and protection against sinesis, dong quai or tang-kuei has been used in Chinese herbal medicine Chinese herbal medicine see herbal medicine. to treat disorders of menstruation and menopausal symptoms. Dong quai contains various coumarins and a phenolic phe·no·lic adj. Of, relating to, containing, or derived from phenol. n. Any of various synthetic thermosetting resins, obtained by the reaction of phenols with simple aldehydes and used as adhesives. constituent, ferulic acid fe·ru·lic acid n. A compound, C10H10O4, related to vanillin and obtained from certain plants. [From New Latin Ferula, plant genus, from Latin ferula . The mechanism of action is uncertain, although it has been proposed that the ferulic acid could provide oestrogenic activity. (31) However, results of in vitro studies investigating the ability of dong quai extracts to activate the oestrogen receptor are inconsistent, with findings of no oestrogenic activity, (20,21) an antagonist antagonist /an·tag·o·nist/ (an-tag´o-nist) 1. a substance that tends to nullify the action of another, as a drug that binds to a cell receptor without eliciting a biological response, blocking binding of substances that could effect, (22) or a weak oestrogenic effect. (23) One randomised placebo-controlled trial has investigated the use of dong quai root in 71 symptomatic postmenopausal post·men·o·paus·al adj. Of or occurring in the time following menopause. postmenopausal Change of life Gynecology adjective Referring to the time in ♀ when menstrual periods stop for ≥ 1 yr American women (Table 2). (31) Following a 24-week intervention, no significant differences between treatment and placebo groups were observed in frequency of hot flushes or overall menopausal symptom scores. A power-based estimate of sample size indicated that subject numbers were adequate to detect a difference of 11 hot flushes per week. Although dong quai root given alone did not demonstrate an effect in this group of women, practitioners of Chinese medicine who have reported positive outcomes typically use dong quai in combination with at least four other herbs, including Radix The base value in a numbering system. For example, in the decimal numbering system, the radix is 10. (mathematics) radix - The ratio, R, between the weights of adjacent digits in positional representation of numbers. paeoniae lactiflorae, Rhizoma ligustici, Rhizoma atractylodes, Rhizoma alismatis, Sclerotium sclerotium /scle·ro·ti·um/ (skle-ro´she-um) a structure formed by fungi and certain protozoa in response to adverse environmental conditions, which will germinate under favorable conditions; in fungi, it is a hard mass of intertwined poriae. (31) These herbs could potentially affect hot flushes either alone or in combination with dong quai but these possibilities have not been tested in placebo-controlled studies. Evening primrose oil Evening primrose oil has been perceived by many women to be effective for the control of acute menopausal symptoms. (32) Gamma-linolenic acid gamma-Linolenic acid (GLA) is an omega-6 essential fatty acid found primarily in vegetable oils. It is sold as a dietary supplement for treating problems with inflammation and auto-immune diseases. The efficacy of such use is disputed. , an omega-6 polyunsaturated fatty acid Noun 1. polyunsaturated fatty acid - an unsaturated fatty acid whose carbon chain has more than one double or triple valence bond per molecule; found chiefly in fish and corn and soybean oil and safflower oil , is considered to be the active component. (35) Gamma-linolenic acid is the precursor of other omega-6 fatty acids Noun 1. omega-6 fatty acid - a polyunsaturated fatty acid whose carbon chain has its first double valence bond six carbons from the beginning omega-6 including dihomogamma-linolenic acid and prostaglandins Prostaglandins Prostaglandins are produced by the body and are responsible for inflammation features, such as swelling, pain, stiffness, redness and warmth. of the '1' series, which possess anti-inflammatory and antithrombotic properties. (36,37) Evening primrose oil also contains arachidonic acid arachidonic acid /arach·i·don·ic acid/ (ah-rak?i-don´ik) a polyunsaturated 20-carbon essential fatty acid occurring in animal fats and formed by biosynthesis from linoleic acid; it is a precursor to leukotrienes, prostaglandins, and , which gives rise to the '2' series of prostaglandins, which are pro-inflammatory. (38) On the basis of anti-inflammatory and antithrombotic properties, evening primrose oil has been promoted for treatment of a range of health problems including cardiovascular disease and arthritis, although there is no scientific rationale to support the use of evening primrose oil for treatment of hot flushes. One placebo-controlled trial has investigated the effect of evening primrose oil on hot flushes in 56 English women (Table 2) and reported no significant differences between treatment and placebo groups. (32) The sample size was adequate to detect a 13% treatment difference in hot flush frequency; however, one limitation was the high withdrawal rate, with only 63% of women completing the trial, attributed to a lack of efficacy of the treatment. Based on the lack of observed efficacy and a plausible rationale, authors of the study concluded that evening primrose oil should not be promoted for treatment of hot flushes. Ginseng Ginseng (Panex ginseng), a traditional herbal medicine herbal medicine, use of natural plant substances (botanicals) to treat and prevent illness. The practice has existed since prehistoric times and flourishes today as the primary form of medicine for perhaps as much as 80% of the world's population. used in China, Japan and Korea, is widely valued as a stimulant stimulant, any substance that causes an increase in activity in various parts of the nervous system or directly increases muscle activity. Cerebral, or psychic, stimulants act on the central nervous system and provide a temporary sense of alertness and well-being as . (39) The biologically active ingredients are considered to be a series of saponin saponin: see soap plant. glycosides known as ginsenosides or panoxosides. (40) Oestrogenic activity of the ginseng saponins saponins, n.pl glycosides from plants that foam in aqueous solutions. They contain adaptogenic, antiinflammatory, mucoprotective characteristics and can induce hemolysis. Also called sapogenins. has been suggested as a mechanism of action to support the use of ginseng in treatment of menopausal symptoms. (39) In one study, which used a methanolic extract of ginseng, significant binding to oestrogen receptors in a human myometrial tissue assay was observed; (39) however, two assays reported no significant oestrogen receptor binding affinity. (22,23) One randomised placebo-controlled trial has been conducted to test the efficacy of ginseng in 384 postmenopausal Swedish women (Table 2). (33) After 16 weeks, ginseng, compared with the placebo, had no significant effect on the frequency of hot flushes, with similar reductions in frequency observed in both treatment (30%) and placebo (24%) groups. The placebo response of 24% was typical for studies of hot flush frequency. The sample size was calculated to detect a change in five units of the Patient Generated Wellbeing Index, rather than the frequency of hot flushes. However, the large sample, with approximately 190 women per group, and high completion rate of 98%. suggest that the numbers would have been sufficient to detect possible changes in hot flush frequency. Results of that study indicate that ginseng is not useful for the treatment of hot flushes. Sage Sage (Salvia salvia: see sage. salvia Any of about 700 species of herbaceous and woody plants that make up the genus Salvia, in the mint family. Some members (e.g., sage) are important as sources of flavouring. officinalis) contains the phenolic constituent ferulic acid, which has the potential to bind to the oestrogen receptor, (41) although the specific binding affinity of sage has not been tested. De Leo Leo, in astronomy Leo [Lat.,=the lion], northern constellation lying S of Ursa Major and on the ecliptic (apparent path of the sun through the heavens) between Cancer and Virgo; it is one of the constellations of the zodiac. et al. undertook a study to test the efficacy of a product based on an extract of sage and alfalfa in a group of 30 Italian women with an average of 14 hot flushes/day (Table 2). (34) Following 12 weeks of therapy the occurrence of hot flushes ceased in 20 women (67%); was reduced in frequency to between one and three flushes/day in four women (13%), and to between four and six flushes/day in six women (20%). The mean reduction by 85% in the frequency of hot flushes in the treatment group was significantly greater than the reduction by 25% in the placebo group, and comparable in magnitude to the effect of HT. (42) De Leo et al. concluded that the product was an effective agent for treatment of hot flushes and without side-effects. (34) However, the mechanism is not clear and it cannot be assumed that sage alone was the effective component because alfalfa (Medicago sativa) is a significant source of the isoflavonoid, coumestrol, which could have contributed to the observed efficacy. (43) Further studies using sage and/or alfalfa in treatment of menopausal symptoms are required to confirm findings of that study and to clarify a mechanism. Phytoestrogens Phytoestrogens were the most extensively studied NPS for the treatment of acute menopausal symptoms. The main supplemental sources of phytoestrogens used in the clinical trials were isoflavonoids derived from either red clover or soy. These are discussed separately as their isoflavonoid profiles differ. Red clover (Trifolium pratense Trifolium pratense, n See red clover. ), a forage forage Vegetable food, including corn and hay, of wild or domestic animals. Harvested, processed, and stored forage is called silage. Forage should be harvested in early maturity to avoid a decrease in protein and fibre content as crops mature. legume legume (lĕ`gy m, lĭgy , contains genistein, daidzein and their methylated meth·yl·ate n. An organic compound in which the hydrogen of the hydroxyl group of methyl alcohol is replaced by a metal. tr.v. meth·yl·at·ed, meth·yl·at·ing, meth·yl·ates 1. precursors, biochanin A biochanin A the 4-methyl ether of genistein, an estrogenic substance found in rye grasses and clovers. and formononetin, respectively. Soybean soybean, soya bean, or soy pea, leguminous plant (Glycine max, G. soja, or Soja max) of the family Leguminosae (pulse family), native to tropical and warm temperate regions of Asia, where it has been (Glycine max Glycine max, n See soy. Glycine max see soybean. ) contains predominantly genistein and daidzein, with smaller quantities of glycitein. (44,45) The primary mechanism proposed to explain the effect of isoflavonoids in the treatment of hot flushes pertains to weak oestrogen agonist agonist /ag·o·nist/ (ag´ah-nist) 1. one involved in a struggle or competition. 2. agonistic muscle. 3. effects. Isoflavonoids are structurally similar to the mammalian oestrogen, 17-[beta] oestradiol Noun 1. oestradiol - the most powerful female hormone that occurs naturally; synthesized and used to treat estrogen deficiency and breast cancer estradiol Loestrin - trade name for an oral contraceptive containing estradiol and norethindrone , and in vitro studies using tissue assays have demonstrated their capacity to bind to oestrogen receptors (ER). (22,23,43,46-48) Although molar molar /mo·lar/ (mo´lar) 1. pertaining to a mole of a substance. 2. a measure of the concentration of a solute, expressed as the number of moles of solute per liter of solution. Symbol M, , or mol/L. binding affinities for isoflavonoids to the classic ER-[alpha] are 100- to 1000-fold weaker than that of oestradiol, certain isoflavonoids, notably genistein and coumestrol, have a relatively high binding affinity for the ER-[beta] subtype (programming) subtype - If S is a subtype of T then an expression of type S may be used anywhere that one of type T can and an implicit type conversion will be applied to convert it to type T. . For example, the binding affinity of genistein compared with oestradiol is 4% for ER-[alpha] and 87% for ER-[beta]. (48) Isoflavonoids can also stimulate transcriptional activity in both ER-[alpha] and ER-[beta] subtypes at physiological concentrations, suggesting they have the potential to exert an oestrogenic response. (48,49) These data support a potential mechanism for the possible efficacy of phytoestrogens in the treatment of hot flushes. Isoflavonoids from red clover Four randomised placebo-controlled trials have been conducted to assess the efficacy of red clover isoflavonoids in the treatment of hot flushes (Table 3). (50-53) Following adjustment for the placebo, the effect of isoflavonoids remained significant in one study, which reported a 44% decrease in the frequency of hot flushes. (52) The report of a significant 44% reduction compared with the placebo in the frequency of hot flushes in the study by van de Weijer and Barentsen supports a role for red clover in the treatment of hot flushes. (52) However, this conclusion is disputed by the results of the three other trials, (50,51,53) including a study by Tice et al. with a larger sample size (252 women with 84 per group), high response rate (98%), equally stringent selection criteria in terms of symptom severity (>five flushes/day), and the same duration, dose and form of supplement (80 mg isoflavonoids/day for 12 weeks). (53) Notably, both studies showed a similar reduction in the frequency of symptoms, by 41% (53) or 44% (52) compared with baseline. However, a major difference was the magnitude of the placebo response compared with baseline, with a 36% decrease in the Tice study (53) compared with a 0% decrease in the van de Weijer and Barentsen study, (52) which allowed a significant treatment effect to emerge in the latter but not the former study. In a power-based estimate of the sample size, Tice et al. designed their study to detect at least a 15% greater reduction in hot flush frequency in the treatment compared with the placebo arms, and assumed a placebo response of 25% compared with the baseline. Therefore, the higher than expected placebo response (36%) would have contributed to the lack of overall treatment effect. (53) Interestingly, although these investigators reported no effect of isoflavonoids in the treatment group as a whole, they did observe a greater reduction of hot flushes in women above the median body mass index (BMI BMI body mass index. BMI abbr. body mass index Body mass index (BMI) A measurement that has replaced weight as the preferred determinant of obesity. ) (>25.1 kg/[m.sup.2]) compared with those below the median BMI (<25.1 kg/[m.sup.2]); the BMI trends were seen within the two isoflavonoid treatment groups but not within the placebo group (Table 3). Further studies are required to investigate the effect of BMI and adiposity adiposity /ad·i·pos·i·ty/ (ad?i-pos´i-te) obesity. cerebral adiposity fatness due to cerebral disease, especially of the hypothalamus. adiposity obesity. on individual responsiveness to isoflavonoid treatment. Isoflavonoids in the soy protein matrix or purified soy isoflavonoids Nine randomised placebo-controlled trials have been conducted to investigate isoflavonoids within a soy protein matrix (54,55,60,61) or in purified form (56-59,62) (Table 3). Taken together, the reduction in the number or severity of hot flushes ranged from 28% to 61% (median 45%) in treatment groups compared with baseline and 18-77% (median 30%) in the placebo groups. After accounting for the placebo, the effect of isoflavonoids was significant in five of the nine studies. (54,55,57-59) Power-based estimates of the sample size in two of the studies indicated that 30-35 subjects per group were required to detect a treatment difference of three hot flushes per day. (54,58) The majority of studies had a sample sizes between 27 and 89 women per group, although two studies had smaller numbers of 17 (55) or 20 per group, (59) which could limit the interpretation of their findings. Inclusion criteria
Inclusion criteria are a set of conditions that must be met in order to participate in a clinical trial. for the frequency of hot flushes varied from low, more than one or two hot flushes/day (55,60,61) to moderate, more than five hot flushes/day (57) or high, more than seven to 10 hot flushes/day. (54,58,62) With the exception of one study, (62) significant improvements compared with the placebo were demonstrated only in studies that selected women with at least moderate to high flushing frequency; (54,57,58) no significant effects were observed in women with milder symptoms of one to two flushes/day; (56-59,60-62) one study did not specify the frequency of hot flushes in the inclusion criteria. (59) There were no apparent dose-dependent effects, although in one study, a split dose designed to provide more consistent blood levels during the day was more effective than a single daily dose. (55) Efficacy was reported at isoflavonoid doses between 34 and 76 mg/day, (54,55,57-59) whereas in studies with no significant improvements, doses ranged from 42 to 118 mg/day. (56,60-62) The effective doses were within the physiological range of intakes achievable by regular consumption of phytoestrogen-rich foods, for example, mean isoflavonoid intakes obtained in communities with traditional consumption of soy foods have ranged from 15 to 54 mg isoflavonoids/day. (63-65) Another possible source of variation relates to the reproducibility of the isoflavonoid content of supplements. An analysis of the isoflavonoid content of commercially available supplements, reported that Promensil (Novogen, Sydney, NSW NSW New South Wales Noun 1. NSW - the agency that provides units to conduct unconventional and counter-guerilla warfare Naval Special Warfare , Australia), the supplement used in all studies with red clover isoflavonoids, provides a reproducible dose of isoflavonoids. (66) However, the accuracy of the isoflavonoid content of soy supplements cannot be confirmed from the data provided. There was no clear preference between the provision of isoflavonoids in a soy protein matrix and as a purified supplement, with significant effects reported in two of four studies using soy protein (54,55) and three of five studies using purified soy isoflavonoids. (57-59) Efficacy was not consistently related to the duration of the study, with improvements noted in trials ranging from 6 to 16 weeks (54,55,57-59) and no improvements in studies from 12 to 104 weeks. (56,60-62) A striking source of variation in the studies with either red clover or soy isoflavonoids was the placebo response, which ranged in magnitude from 0 to 70% compared with the baseline. The larger placebo responses in some studies could reflect the high motivation of the participants and belief in the benefits of isoflavonoids or inadvertent consumption of isoflavonoid-containing foods, such as soy and other legumes Legumes A family of plants that bear edible seeds in pods, including beans and peas. Mentioned in: Cholesterol, High legumes (l , during the study, as confirmed by increased isoflavonoid excretion in the placebo groups in two of the clinical trials. (50,51) This highlights the challenge of conducting such studies alongside growing community awareness of the possible benefits of soy and isoflavonoids and ready availability of products in pharmacies and supermarkets. The study that showed the greatest reduction in hot flushes, by 44% with treatment compared with placebo, implemented procedures to minimise the placebo effect placebo effect n. A beneficial effect in a patient following a particular treatment that arises from the patient's expectations concerning the treatment rather than from the treatment itself. by using a four-week observation period prior to intervention to identify susceptible individuals. (52) That study also involved Dutch participants whose diets are traditionally low in isoflavonoids, and participants were further instructed not to increase their intake of isoflavonoid-rich foods during the study. Responsiveness to treatment could also depend on the individual's capacity to convert the isoflavonoid daidzein to equol, a secondary metabolite Secondary metabolites are organic compounds that are not directly involved in the normal growth, development or reproduction of organisms. Unlike primary metabolites, absence of secondary metabolities results not in immediate death, but in long-term impairment of the organism's , which has greater oestrogenic potency than the original isoflavonoid. Not all individuals have the capacity to produce equol, with observed prevalence rates from 20% to 36% in different studies. (67) This factor could contribute to some of the unexplained variation in responses to the same supplement, with greater efficacy in equol producers. Differences in dietary macronutrient macronutrient /mac·ro·nu·tri·ent/ (-noo´tre-ent) an essential nutrient required in relatively large amounts, such as carbohydrates, fats, proteins, or water; sometimes certain minerals are included, such as calcium, chloride, or sodium. intake could also influence the absorption and hence efficacy of isoflavonoids. (68) None of the studies reviewed specifically addressed these issues. Isoflavonoids from Kudzu Kudzu (Pueraria lobata Pueraria lobata, n See kudzu. Pueraria lobata a coarse, perennial leguminous vine. Has woody stems but very palatable and nutritious foliage equal in value to alfalfa. Called also kudzu. ), or Japanese arrowroot arrowroot, any plant of the genus Maranta, usually large perennial herbs, of the family Marantaceae, found chiefly in warm, swampy forest habitats of the Americas and sometimes cultivated for their ornamental leaves. , is used as a herb in traditional Chinese medicine Traditional Chinese Medicine Definition Traditional Chinese medicine (TCM) is an ancient and still very vital holistic system of health and healing, based on the notion of harmony and balance, and employing the ideas of moderation and prevention. . It has a unique profile of isoflavonoids with high concentrations of daidzein, exceeding those found in the soybean, and small quantities of genistein, formononetin, biochanin A and coumestrol. (44) No clinical trials were located on the efficacy of this herb in treatment of menopausal hot flushes. Safety Although NPS are considered to represent a lower risk than pharmaceutical goods, a range of safety concerns have been identified in the literature. The studies detailed in Tables 1-3 focused on the efficacy rather than the safety of supplements. Although mild adverse events were reported in trials of black cohosh, dong quai, evening primrose oil, red clover, sage and soy, these did not differ significantly between placebo and intervention groups. (30-32,34,52,54,56-58) Of the studies that specified the nature of adverse events, the most common symptoms related to gastrointestinal effects, such as bloating bloating Vox populi A lay term for post-prandial abdominal fullness or swelling , nausea and constipation. (54,56-58) However, as the duration of the clinical trials was 12-24 weeks in most studies, long-term safety cannot be assumed and interactions with pharmaceutical drugs may be possible. Additional information on the safety of NPS was identified in the literature, although many reports of adverse events were isolated and the dose responsible was not specified. Other adverse effects included an association between dong quai and increased skin photosensitivity Photosensitivity Definition Photosensitivity refers to any increase in the reactivity of the skin to sunlight. Description The skin is a carefully designed interface between our bodies and the outside world. ; (41) and between ginseng and increased hypertension, jitteriness jit·ter·y adj. jit·ter·i·er, jit·ter·i·est 1. Having or feeling nervous unease: a jittery vigil in the dark. 2. , confusion, depression and insomnia insomnia, abnormal wakefulness or inability to sleep. The condition may result from illness or physical discomfort, or it may be caused by stimulants such as coffee or drugs. However, frequently some psychological factor, such as worry or tension, is the cause. , and risk of hypotension hypotension or low blood pressure Condition in which blood pressure is abnormally low. It may result from reduced blood volume (e.g., from heavy bleeding or plasma loss after severe burns) or increased blood-vessel capacity (e.g., in syncope). on withdrawal. (69) Dong quai contains coumarins and ferulic acid that can exert antithrombotic effects, which could potentiate po·ten·ti·ate v. 1. To make potent or powerful. 2. To enhance or increase the effect of a drug. 3. To promote or strengthen a biochemical or physiological action or effect. the effect of anticoagulant anticoagulant (ăn'tēkōăg`yələnt), any of several substances that inhibit blood clot formation (see blood clotting). drugs such as warfarin warfarin (wôr`fərĭn), anticoagulant used to treat blood clots. In large doses it causes bleeding. Warfarin, mixed with bait, is used in rodent control. warfarin Anticoagulant drug, marketed as Coumadin. and increase the risk of bleeding in susceptible individuals; (70) increased prothrombin time Prothrombin Time Definition The prothrombin time test belongs to a group of blood tests that assess the clotting ability of blood. The test is also known as the pro time or PT test. was observed in a patient who had taken a 565 mg tablet of dong quai one to two times/day for 4 weeks. (71) Consequently, women with clotting clotting /clot·ting/ (klot´ing) coagulation (1). clotting the formation of a jellylike substance over the ends or within the walls of a blood vessel, with resultant stoppage of the blood flow. disorders or on anticoagulant therapy anticoagulant therapy Hematology The use of anticoagulants to prevent intravascular clot formation, or dissolve clots that have already formed Indications DVT/thrombophlebitis, CAD, TIA/stroke, dysrhythmia, prosthetic heart valve, cancer Monitoring Serial should not use dong quai. Conclusions Results from two randomised placebo-controlled trials suggested that black cohosh compared with the placebo was beneficial for relief of overall symptoms of menopause; (27,30) however, further trials are required to specifically measure the frequency and severity of hot flushes. One preliminary placebo-controlled trial reported that an extract of sage and alfalfa significantly reduced the frequency of severe hot flushes by 60% compared with the placebo. (34) To date, placebo-controlled trials do not support the use of dong quai, (31) evening primrose oil (32) or ginseng (33) for treatment of hot flushes. There was no conclusive evidence CONCLUSIVE EVIDENCE. That which cannot be contradicted by any other evidence,; for example, a record, unless impeached for fraud, is conclusive evidence between the parties. 3 Bouv. Inst. n. 3061-62. for the presence of oestrogenic components in any of these supplements. The findings from 13 randomised placebo-controlled trials using isoflavonoids from red clover or soy, demonstrated significant efficacy in six studies (46%), with reductions in moderate to severe hot flushes by 10-44% compared with placebo; (52,54,55,57-59) seven studies (54%) reported no significant improvements. (50,51,53,56,60-62) If there was no relationship between isoflavonoids and hot flushes, the chance of a statistically significant treatment effect would be less than one in 20, or 5% of studies. The fact that significant findings were reported by one in two studies (46%), conducted by 13 independent investigators independent investigator Independent research investigator NIHspeak A well-established scientist whose research accomplishments have resulted in the bestowal of "tenure", ie, long-term commitment of salary, personnel and research resources , suggests that these findings may not have arisen by chance. Therefore, it is recommended that further studies are conducted with appropriate design, including an adequate sample size, attention given to minimise inadvertent consumption of isoflavonoids by the placebo group, and evaluation of possible differences in individual responsiveness to treatment, including equol-producer status, (67,68) background diet (67,68) and BMI. (53) In vitro studies have demonstrated that isoflavonoids can bind to oestrogen receptors and exert an oestrogenic response, (20,22,23,46) providing a mechanism to support their use. The present review provides evidence for health professionals that can be used to inform their advice to women regarding the efficacy of NPS for treatment of acute menopausal symptoms. Studies on the use of dong quai, evening primrose oil and ginseng suggest that they are unlikely to be useful for treatment of hot flushes. Evidence from a small number of short-term, randomised control trials of 12- to 24-week duration indicates that further research is warranted on black cohosh, red clover, soy, sage and alfalfa, involving studies with appropriate design and outcome measures, to establish any evidence of efficacy and evaluate optimal dosage, elucidate precise mechanisms of action and identify any long-term adverse effects. References 1. Walsh B, Schiff I. Vasomotor flushes. 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Soy intake related to menopausal symptoms, serum lipids, and bone mineral density bone mineral density n. See bone density. bone mineral density A measurement of bone mass, expressed as the amount of mineral–in grams divided by the area scanned in cm2. See Bone densitometry. in postmenopausal Japanese Women. Obstet Gynaecol 2001; 97: 109-15. 65. Arai Y, Uehara M, Sato Y et al. Comparison of isoflavones among dietary intake, plasma concentration and urinary excretion for accurate estimation of phytoestrogen intake. J Epidemiol 2000; 10: 127-35. 66. Setchell K, Brown N, Desai P, Zimmer-Nechemias L. Bioavailability bioavailability /bio·avail·a·bil·i·ty/ (bi?o-ah-val?ah-bil´i-te) the degree to which a drug or other substance becomes available to the target tissue after administration. bi·o·a·vail·a·bil·i·ty n. of pure isoflavones in healthy humans and analysis of commercial soy isoflavone supplements. J Nutr 2001; 131: 1362S-75S. 67. Duncan A, Merz-Demlow B, Xu X, Phipps W, Kurzer M. Premenopausal pre·me·no·paus·al adj. Of or relating to the years or the stage of life immediately before the onset of menopause. premenopausal adjective equol excretors show plasma profiles associated with lowered risk of breast cancer. Cancer Epidemiol Biomarkers Prev 2000; 9: 581-6. 68. Blakesmith S, Lyons-Wall P, Joannou G, Petocz P, Samman S. Urinary isoflavonoid excretion is inversely associated with the ratio of protein to dietary fibre dietary fibre Noun the roughage in fruits and vegetables that aid digestion intake in young women. Eur J Clin Nutr 2005; 59: 284-90. 69. Sheehan D. Herbal medicines, phytoestrogens and toxicity: risk: benefit considerations. Proc Soc Exp Biol Med 1998; 217: 379-85. 70. Fugh-Berman A. Herb-drug interactions herb-drug interactions, n.pl See drug interactions. . Lancet 2000; 355: 134-8. 71. Page R, Lawrence J. Potentiation potentiation /po·ten·ti·a·tion/ (po-ten?she-a´shun) 1. enhancement of one agent by another so that the combined effect is greater than the sum of the effects of each one alone. 2. posttetanic p. of warfarin by dong quai. Pharmacotherapy pharmacotherapy /phar·ma·co·ther·a·py/ (-ther´ah-pe) treatment of disease with medicines. phar·ma·co·ther·a·py n. Treatment of disease through the use of drugs. 1999; 19: 870-76. School of Public Health, Queensland University of Technology, Brisbane K. Hanna, BHealthSci (NutrDiet) A. Day, BMedSci, MNutrDiet C. Patterson, PhD, MSc, GradDipBusAdmin P. Lyons-Wall, PhD, GradDipNutrDiet Betty Byrne Henderson Centre, Royal Brisbane and Women's Hospital The Royal Brisbane and Women's Hospital is a hospital located in the suburb of Herston in Brisbane, Queensland, Australia. The hospital currently has a total of 948 beds. It is estimated that 65% of the patients served come from 15 kilometres of the hospital. and The University of Queensland The University of Queensland (UQ) is the longest-established university in the state of Queensland, Australia, a member of Australia's Group of Eight, and the Sandstone Universities. It is also a founding member of the international Universitas 21 organisation. , Brisbane S. O'Neill, MBBCh, BAO bao (pä·ö), n preciousness, one of the five virtues in Chinese medicine, for which po is responsible. See also po. BAO Basal Acid Output, see there Correspondence: P. Lyons-Wall, School of Public Health, Queensland University of Technology, Victoria Park Road, Kelvin Grove Kelvin Grove is the name of various places:
Table 1. Clinical intervention studies with black cohosh for treatment
of acute menopausal symptoms
Study Subjects Intervention
Daiber (24) 36 German women with Uncontrolled trial,
climacteric symptoms, 45-62 parallel: Remifemin twice/
years day
Vorberg (25) 50 German women with Uncontrolled trial,
climacteric symptoms, 45-60 parallel: Remifemin 40
years drops twice/day (liquid
extract). No control group
Warnecke (26) 60 German women with Uncontrolled trial,
climacteric symptoms, 45-60 parallel:
years 1. Remifemin 40 drops
twice/day (liquid extract)
2. Conjugated oestrogen
0.625 mg/day
3. Diazepam 2 mg/day
Stoll (27) 80 German women with Placebo-controlled trial,
[greater than or equal to]3 randomised double-blind,
hot flushes/day and parallel:
psychological symptoms (e.g. 1. Remifemin 8 mg/day (4
anxiety, vaginal symptoms), tablets/day)
46-58 years. Power estimate 2. Conjugated oestrogen
of sample size not reported 0.625 mg/day
3. Placebo
Lehmann- 60 German women, Uncontrolled trial,
Willenbrock hysterectomised with at randomised, parallel:
and least one intact ovary and 1. Oestriol 1 mg/day
Riedel (28) climacteric symptoms, <40 2. Oestrogen 1.25 mg/day
years 3. Oestrogen/gestagen
4. Remifemin 8 mg/day (4
tablets/day)
Liske 150 Polish perimenopausal Uncontrolled trial,
et al. (29) and postmenopausal women randomised double-blind,
with KMI score parallel:
[greater than or equal to]20 1. Remifemin standard dose
(moderate severity), 42-60 39 mg extract/day (no. of
years. Sample size tablets not stated)
calculated to detect 2. Remifemin high dose 127
standardised difference of mg extract/day
0.5 units, [alpha] = 0.05.
Power not stated
Wuttke 62 German women with =3 hot Placebo-controlled trial,
et al. (30) flushes/day, 40-60 years. randomised, double-blind,
Power estimate of sample parallel:
size not reported 1. Black cohosh ((a)) 40 mg
extract/day (2 capsules/
day)
2. Conjugated oestrogen 0.6
mg/day
3. Placebo
Duration
Study (weeks) Results
Daiber (24) 12 * [down arrow] KMI (P < 0.001)
Vorberg (25) 12 Remifemin at 12 weeks compared with
baseline:
* [down arrow] KMI (P < 0.001)
Warnecke (26) 12 Remifemin at 12 weeks compared with
baseline:
* [down arrow] KMI
Stoll (27) 12 Remifemin at 4, 8 and 12 weeks compared with
oestrogen or placebo:
* [down arrow] KMI (P < 0.001)
Lehmann- 24 All groups at 8, 12 and 24 weeks compared
Willenbrock with baseline:
and * [down arrow] KMI (P < 0.01)
Riedel (28)
Liske 12 Standard or high-dose Remifemin at 12 and 24
et al. (29) extended to weeks compared with baseline:
24 * [down arrow] KMI (change from moderate to
normal range symptoms) in 70-72% of subjects
Wuttke 12 Black cohosh compared with placebo at 12
et al. (30) weeks:
* [down arrow] MRS (P = 0.05)
* NS change in hot flush scale of MRS
Study Comments
Daiber (24) Mean KMI improved from moderate-severe to light-moderate
symptoms at 12 weeks
Vorberg (25) Mean KMI improved from moderate to light symptoms at 12
weeks
Warnecke (26) P-values not cited
Stoll (27) [down arrow] 48-59% in KMI scales with Remifemin,
[down arrow] 24-29% with placebo and low-dose oestrogen,
compared with baseline. Oestrogen dose was too low for
efficacy. 86% completed trial
Lehmann- [down arrow] 43% in KMI with Remifemin, [down arrow]
Willenbrock 47-62% with oestrogen groups, compared with baseline
and
Riedel (28)
Liske No difference between standard and high dose. NS
et al. (29) side-effects at either dose of Remifemin. 82% completed
12-week trial. 77% completed 24-week trial
Wuttke [down arrow] 1.8 MRS points with black cohosh versus
et al. (30) [down arrow] 1.5 MRS points with placebo, compared with
baseline. Specific values not presented. 97% completed
trial
(a) Cimicifuga racemosa preparation CR BNO 1055 (Klimadynon/Menofem).
KMI = Kupperman Menopause Index; MRS = Menopause Rating Scale; NS =
non-significant.
Table 2. Clinical intervention studies with dong quai, evening primrose
oil, ginseng and sage for treatment of acute menopausal symptoms
Study Subjects Intervention
Hirata 71 US postmenopausal women Placebo-controlled trial,
et al. (31) with >14 hot flushes any randomised, double-blind,
severity/week or >5 hot parallel:
flushes moderate to 1. Dong quai root 1.5 g (3
severe/week, mean age; capsules/day)
placebo group, 52.6 2. Placebo
[+ or -] 6 years; treatment
group, 52.2 [+ or -] 4
years. Sample size
calculated to detect
difference of 11 vasomotor
episodes/week, 90% power,
[alpha] = 0.05
Chenoy 56 UK menopausal women with Placebo-controlled trial,
et al. (32) [greater than or equal to]3 randomised, double-blind,
hot flushes/day, 45-67 parallel:
years. Sample size to 1. Evening primrose oil 500 mg
detect 13% difference in /day + Vit E (8 capsules/day)
hot flush frequency, 90% 2. Placebo
power, [alpha] = 0.05
Wiklund 384 Swedish postmenopausal Placebo-controlled trial,
et al. (33) women with =6 hot flushes, randomised, double-blind:
at least 3/7 days, 45-65 1. 100 mg ginseng extract (2
years. Sample size to capsules/day)
detect difference of 5 2. Placebo
units in Patient Generated
Wellbeing Index, 80% power,
[alpha] = 0.05
De Leo 30 Italian postmenopausal Placebo-controlled trial:
et al. (34) women, with 1. 120 mg sage + 60 mg alfalfa
[greater than or equal to] n = 30 (tablet no. not stated)
10 hot flushes/day, 46-52 2. Placebo, n = 12
years. Power estimate of
sample size not reported
Study Duration Results Comments
Hirata 24 weeks Dong quai compared [down arrow] 35% in hot flush
et al. (31) with placebo at 24 frequency with treatment,
weeks: [down arrow] 19% in hot flush
* NS change in hot frequency with placebo,
flush frequency compared with baseline. 86%
* NS change in completed trial
Kupperman
Menopausal Index
Chenoy 24 weeks Evening primrose [down arrow] 11% in day
et al. (32) oil compared with frequency and [down arrow]
placebo at 24 19% in night frequency in
weeks: treatment versus [down arrow]
* NS change in hot 37% in day frequency and
flush frequency [down arrow] 29% in night
or intensity frequency in placebo,
compared with baseline.
63% completed trial
Wiklund 2 weeks Ginseng group [down arrow] 30% in hot flush
et al. (33) run in compared with frequency with treatment,
16 weeks placebo at 16 [down arrow] 24% in placebo,
weeks: compared with baseline.
* NS change in hot 99% completed trial
flush frequency
De Leo 3 months Sage and alfalfa [down arrow] 85% in hot flush
et al. (34) compared with frequency with treatment,
placebo at 3 [down arrow] 25% in placebo,
months: compared with baseline
* [down arrow] 60%
in hot flush
frequency (P <
0.01). Sage and
alfalfa compared
with baseline at 3
months
NS = non-significant.
Table 3. Clinical intervention studies with phytoestrogens for treatment
of acute menopausal symptoms
Study Subjects Intervention
Red clover
Baber 51 Australian Placebo-controlled trial,
et al. (50) postmenopausal women, randomised, double-blind,
[greater than or equal to] crossover:
3 hot flushes/day, 45-65 1. Promensil 40 mg
years. Power estimate of isoflavonoids (1 tablet/
sample size not reported day)
2. Placebo
Knight 37 Australian Placebo-controlled trial,
et al. (51) postmenopausal women with randomised, double-blind,
[greater than or equal to] parallel:
3 hot flushes/day, 40-65 1. Promensil 40 mg
years. Power estimate of isoflavonoids/day (1 tablet
sample size not reported /day)
2. Promensil 160 mg
isoflavonoids/day (4
tablets/day)
3. Placebo
Van de 30 Dutch postmenopausal Placebo-controlled trial,
Weijer and women with >5 hot randomised, double-blind,
Barentsen (52) flushes/day, mean age: parallel:
52.5 [+ or -] 5.2 years 1. Promensil isoflavonoids
(placebo), 54.2 [+ or -] 80 mg/day (2 tablets/day)
7.4 years (treatment). 2. Placebo
Power-based estimate of
sample size not reported
Tice 252 US menopausal women, Placebo-controlled trial,
et al. (53) [greater than or equal to] randomised double-blind,
35 hot flushes/week, 45-60 parallel:
years. Sample size to 1. Promensil ((a))
detect 15% decrease in hot isoflavonoids 82 mg/day (2
flush frequency, 90% power, tablets/day)
[alpha] = 0.05 2. Rimostil ((a))
isoflavonoids 57 mg/day (2
tablets/day)
3. Placebo
Soy isoflavonoids and soy protein
Albertazzi 104 Italian Placebo-controlled trial,
et al. (54) postmenopausal women, randomised, double-blind,
[greater than or equal to] parallel:
7 hot flushes/day, 48-61 1. Soy protein ~76 mg
years. Sample size to aglycone isoflavonoids
detect difference of 3 hot (powder)
flushes/day, 90% power, 2. Placebo
[alpha] = 0.05
Washburn 51 US perimenopausal women, Placebo-controlled trial,
et al. (55) [greater than or equal to] randomised, double-blind,
1 hot flush/night sweats/ crossover:
day, 45-55 years. Power 1. Soy protein 34 mg
estimate of sample size not isoflavonoids single dose
reported (powder)
2. Soy protein 34 mg
isoflavonoids, split dose
3. Placebo
Kotsopoulos 94 Australian Placebo-controlled trial,
et al. (56) postmenopausal women with randomised, double-blind,
mild menopausal symptoms, parallel:
hot flush number not 1. Soy isoflavonoids 118 mg
specified, 50-75 years. /day (soy powder beverage)
Power estimate of sample 2. Placebo
size not reported
Upmalis 177 US postmenopausal Placebo-controlled trial,
et al. (57) women, randomised, double-blind,
[greater than or equal to] parallel:
5 hot flushes/day, (mean 1. Soy isoflavonoid extract
age 55 years). Power 50 mg isoflavonoids/day (2
estimate of sample size tablets/day)
not reported 2. Placebo
Scambia 39 Italian postmenopausal Placebo-controlled trial,
et al. (59) women, hot flush number randomised, double-blind,
not specified, 29-63 years. parallel:
Power estimate of sample 1. Soy isoflavonoids 50 mg/
size not reported day (tablet no. not
reported)
2. Placebo Conjugated
equine oestrogens (CEE)
give to all participants
after week 6
St Germain 69 US perimenopausal women, Placebo-controlled trial,
et al. (60) [greater than or equal to] randomised, double-blind,
10 hot flushes/night parallel:
sweats/week. Power estimate 1. Soy protein
of sample size not reported isoflavonoids 80.4 mg/day
(aglycone) (powder +
muffin)
2. Soy protein
isoflavonoids 4.4 mg/day
(powder + muffin)
3. Placebo
Faure 75 French Placebo-controlled trial,
et al. (58) postmenopausal women, randomised, double-blind,
[greater than or equal to] parallel:
7 hot flushes/day, mean age 1. Soy isoflavonoids 70 mg
53 years. Sample size glycones (4 capsules/day)
calculated to detect 2. Placebo
difference of 3 hot
flushes/day, 90% power,
[alpha] = 0.05
Burke 241 US perimenopausal Placebo-controlled trial,
et al. (61) women, mild symptoms randomised, double-blind,
[greater than or equal to] parallel:
1 hot flush/day, 45-55 1. Soy protein 42 mg/day
years. Power estimate of isoflavonoids (SP ((b))
sample size not reported beverage)
2. Soy protein 58 mg/day
isoflavonoids (SP beverage)
3. Soy protein
[greater than or equal to]
4 mg/day isoflavonoids
Penotti 62 Italian Placebo-controlled trial,
et al. (62) postmenopausal women, randomised, double-blind,
[greater than or equal to] parallel:
7 hot flushes/day, 49-58 1. Soy isoflavonoids 72 mg/
years. Power estimate of day (2 tablets/day)
sample size not reported 2. Placebo (2 tablets/day)
Duration
Study (weeks) Results
Red clover
Baber 2 X 12 4 Promensil compared with placebo at 12 weeks
et al. (50) wash out (combined data):
* NS change in Greene Menopause Score
* NS change in hot flush frequency
Knight 12 Promensil compared with placebo at 12 weeks:
et al. (51) * NS change Greene Menopause Score
* NS change in hot flush frequency
Van de 12 plus 4 Promensil compared with placebo at 12 weeks:
Weijer and run in * [down arrow] 44% hot flush frequency
Barentsen (52) (P = 0.02)
* NS change in Greene Menopause Score
Tice 12 At 12 weeks:
et al. (53) Promensil/Rimostil compared with placebo:
* NS change in Greene Menopause Score
* NS change in hot flush frequency
Subgroup with BMI > 25.1 versus subgroup
with BMI <25 kg/[m.sup.2];
* [down arrow] 19% in hot flush frequency
(Promensil) (P = 0.09)
* [down arrow] 23% in hot flush frequency
(Rimostil) (P < 0.02)
Soy isoflavonoids and soy protein
Albertazzi 12 Soy protein group compared with placebo at
et al. (54) 12 weeks:
* [down arrow] 15% in hot flush frequency
(P = 0.01)
Washburn 6 per Soy protein split-dose group compared with
et al. (55) treatment, placebo:
18 total * [down arrow] 23% in hot flush severity
(P < 0.05)
* [down arrow] 11% in night sweat severity
(NS)
* [up arrow] 4% in hot flush frequency (NS)
* [up arrow] 4% in night sweat frequency
(NS)
Kotsopoulos 12 Soy isoflavonoids compared with placebo at
et al. (56) week 12:
* NS change in menopause questionnaire
* NS change in hot flush component of
menopausal symptoms questionnaire
Upmalis 12 Soy extract group compared with placebo at
et al. (57) 12 weeks:
* [down arrow] 10% in hot flush severity
score (P = 0.01)
* [down arrow] 9% in hot flush frequency
(trend, P = 0.08)
* [down arrow] 28% in night sweat frequency
(P = 0.04 at 6 weeks, NS at 12 weeks)
Scambia 12 Soy isoflavonoids compared with placebo at
et al. (59) treatment week 6:
and * [down arrow] 20% in hot flush frequency
placebo (P < 0.01) Soy isoflavonoids compared with
given to placebo at week 12 (both groups taking CEE):
week 10 * NS change hot flush frequency
only
St Germain 24 High isoflavonoid soy compared with
et al. (60) placebo at 24 weeks
* NS change in hot flush frequency
* NS change in night sweat frequency
Faure 16 Soy isoflavonoids compared with placebo at
et al. (58) 16 weeks:
* [down arrow] 40% in hot flush frequency
(P = 0.01)
Burke 104 Soy isoflavonoids compared with placebo at
et al. (61) 12 or 104 weeks:
* NS change in hot flush frequency
Penotti 24 Soy isoflavonoids compared with placebo at
et al. (62) 12 or 24 weeks:
* NS change in hot flush frequency
Study Comments
Red clover
Baber [down arrow] 22% in hot flush frequency with Promensil,
et al. (50) [down arrow] 32% with placebo, compared with baseline.
84% completed trial
Knight [down arrow] 29% in hot flush frequency with 40 mg dose,
et al. (51) [down arrow] 34% with 160 mg dose, [down arrow] 33% with
placebo, compared with baseline. 95% completed trial
Van de [down arrow] 44% in hot flush frequency with Promensil,
Weijer and [down arrow] 0% with placebo, compared with baseline.
Barentsen (52) 87% completed trial
Tice Hot flush frequency compared with baseline: whole group:
et al. (53) [down arrow] 41% with Promensil, [down arrow] 34% with
Rimostil, [down arrow] 36% with placebo. Subgroup BMI >
25.1 versus BMI <25 kg/[m.sup.2]:
Promensil: [down arrow] 49% versus [down arrow] 30%;
Rimostil: [down arrow] 45% versus [down arrow] 22%;
Placebo: [down arrow] 32% versus [down arrow] 40%.
98% completed trial
Soy isoflavonoids and soy protein
Albertazzi [down arrow] 45% in hot flush frequency with soy
et al. (54) protein, [down arrow] 30% with placebo, compared with
baseline. 76% completed trial
Washburn Original scores compared with baseline not reported. No
et al. (55) significant changes in soy protein single-dose group,
compared with placebo. 82% completed trial
Kotsopoulos Hot flush scores not reported. 80% completed trial
et al. (56)
Upmalis [down arrow] 28% in hot flush severity with soy versus
et al. (57) [down arrow] 18% in placebo; [down arrow] 28% hot flush
frequency with soy, [down arrow] 19% in placebo;
[down arrow] 62% in night sweat frequency with soy,
[down arrow] 34% in placebo, compared with baseline. 69%
completed trial
Scambia [down arrow] 45% hot flush frequency with isoflavonoids,
et al. (59) [down arrow] 25% with placebo, compared with baseline.
Withdrawal rate not specified
St Germain [down arrow] 45% in hot flush frequency with 80.4 mg
et al. (60) isoflavonoids, [up arrow] 3% with 4.4 mg isoflavonoids,
[down arrow] 45% with placebo, compared with baseline.
99% completed trial
Faure [down arrow] 61% in hot flush frequency with soy
et al. (58) isoflavonoids, [down arrow] 21% with placebo, compared
with baseline. 84% completed trial in soy group. 60%
completed trial in placebo group
Burke Hot flush frequency at 12 or 104 weeks compared with
et al. (61) baseline, in whole group:
1. [down arrow] 19/42%, (42 mg isoflavonoids)
2. [down arrow] 50/59% (58 mg isoflavonoids)
3. [down arrow] 51/77% with placebo.
88% completed trial
Penotti Hot flush frequency at 12 or 24 weeks, compared with
et al. (62) baseline:
1. [down arrow] 44/53% with soy isoflavonoids
2. [down arrow] 53/53% with placebo.
79% completed study
(a) Promensil contains a higher proportion of biochanin A and genistein;
Rimostil contains a higher proportion of formononetin and daidzein.
(b) Soy protein.
BMI = body mass index; NS = non-significant.
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