Fredi Kronenberg

Hot Flashes: Epidemiology and Physiologya

A review of the literature illustrates the many questions about hot flashes that remain unanswered. My survey addresses some of these questions. The prospective and retrospective descriptions of hot flashes provide a more detailed profile of the hot flash than has previously been available. Further, data from this survey demonstrate that while the patterns of hot flashes may be varied, there are commonalities in hot flash physiology and subjective manifestation. The data indicate that hot flashes may start much earlier and continue far longer than is commonly recognized by physicians or acknowledged in textbooks of gynecology. Studies of hot flash duration must control for age or age at hot flash onset, since the older the subjects, the more potential years of hot flashes and the greater the probability of encompassing the entire period of hot flashes. Hot flashes are not static; patterns may change with time. For some women, hot flashes become less frequent and less intense; for others, hot flashes may continue at hourly intervals well into old age. How common these experiences are for women of all ages still needs to be discovered. As expounded by Kaufert, McKinlay, Goodman, and many others, a greater effort must be made to standardize definitions and question formats as well as to improve methodology in epidemiologic investigations to facilitate comparability between studies and insure that proffered conclusions indeed reflect the questions being asked. Physiological studies are critical counterparts to the epidemiology; yet such studies have been too few. My work, by examining the physiology and psychophysiology of hot flashes, has raised additional questions about central and peripheral inputs that may affect the subjective experience of hot flashes. A more complete understanding of the thermoregulatory, cardiovascular, and psychophysiology of women with hot flashes are compared to women without will facilitate the prediction of who is most likely to be affected and the identification of additional approaches to the management of hot flashes.

Complementary and Alternative Medicine for Menopausal Symptoms: A Review of Randomized, Controlled Trials

Women are frequent users of complementary and alternative medicine (CAM) therapies in many countries (1-5), including the United States, where women use CAM therapies more often than men (48.9% vs. 37.8%) (6). Many women report using these therapies for menopausal symptoms (7, 8). A national magazine received more than 15 000 responses to a survey of alternative treatments for menopausal women (7). Primary symptoms included hot flashes, joint pain, sleep problems, forgetfulness, and fatigue; hot flashes (the most common menopausal symptom for women in the United States) (9) were most commonly treated. Therapies of choice were herbal remedies, chiropractic, and meditation. Recently, dietary supplements and foods containing phytoestrogens have become increasingly popular, despite the lack of data from clinical trials. The science of CAM therapies is still inadequate to sufficiently inform clinicians and the public of the benefits or potential risks of CAM therapies. To provide information for clinicians, we reviewed randomized, controlled clinical trials of CAM therapies for menopausal symptoms. Methods Study Selection We searched MEDLINE from January 1966 to December 2002, the Alternative and Complementary Database (AMED) of the British Library from January 1985 to December 2000, and our own extensive files. Databases were searched under the terms hot flash/flush, menopause, and climacteric, combined with phytoestrogens, alternative medicine, herbal medicine, traditional medicine, Traditional Chinese Medicine (TCM), Ayurveda, naturopathy, chiropractic, osteopathy, massage, yoga, relaxation therapy, homeopathy, aromatherapy, and therapeutic touch. We did not limit the search to English-language literature. Studies that examined single symptoms or conditions that are not clearly associated with menopause (for example, anxiety and lipids) were excluded. All other randomized, controlled trials, regardless of their quality, were included. A total of 29 studies were identified. Each author extracted information on the number of patients, study design, outcome measures, and results for half the studies; the other author then checked results. Role of the Funding Source The funding source had no role in the design, conduct, analyses, or reporting of the study or the decision to submit the manuscript for publication. CAM Therapies Herbal Remedies Herbs used in the United States for menopausal problems include black cohosh (Cimicifuga racemosa), chaste tree berry (Vitex agnus-castus), dong quai (Angelica sinensis), ginseng (Panax ginseng and other Panax species), evening primrose oil (Oenethera biennis), motherwort (Leonurus cardiaca), red clover (Trifolium pratense), and licorice (Glycyrrhiza glabra). We identified 10 trials of herbs (Table 1) (10-19). Most studies found no significant changes in primary outcome measures. However, these studies were small, of short duration, and far from sufficient to yield definitive conclusions. Table 1. Herbs for Menopausal Symptoms The most studied and perhaps most popular herb is black cohosh, traditionally used by Native Americans for gynecologic and other conditions. Almost all clinical studies of black cohosh have used the standardized product Remifemin (GlaxoSmithKline, Pittsburgh, Pennsylvania); however, the formulation and the dosage have changed over time. One of four randomized, controlled trials of black cohosh for hot flashes was placebo controlled (10), one used both a treatment and placebo control (12), and two were treatment controlled (11, 13). Three of the four trials found black cohosh to be beneficial for treating hot flashes. Neither the identity of active compounds nor the mechanism of action of black cohosh is known. Although formononetin, an estrogenic isoflavone, was reported to have been isolated from black cohosh extract (20), another study found no formononetin in black cohosh extract (21). In addition, a recent systematic examination of extracts of black cohosh collected from 13 locations in the eastern United States as well as Remifemin also found no formononetin in any sample (22). Thus, other compounds must be responsible for its biological activity. Small amounts of biochanin, another isoflavone, have been isolated from C. racemosa roots (23). Other candidates for the biological activity of black cohosh include triterpene glycosides, organic acids, and esters. Black cohosh is not usually used on a long-term basis, and no clinical trials have lasted for more than 6 months. This is of concern because women using this product for natural hormone replacement therapy may take it for years. There are no published data from human trials about long-term safety, particularly regarding endometrial or breast stimulation. Effects on vaginal epithelium are inconclusive; two of five randomized, controlled trials that examined estrogenic effect on vaginal epithelium reported a stimulatory effect (11, 12). In vitro and in vivo studies are not consistent or sufficient. Although black cohosh may be useful for menopausal symptoms, long-term use cannot be presumed to be safe until appropriate safety studies are conducted. Red clover contains the phytoestrogens formononetin, biochanin A, daidzein, and genistein (24). Two small, 3-month clinical trials conducted in Australia reported no significant benefit of red clover extract for hot flashes (14, 15) (Table 1). Several larger trials are in progress. Red clover, a Native American herb, has not been traditionally used on a long-term basis for hot flashes, and it is unknown whether long-term use would have an estrogenic effect on the breast or endometrium. Dong quai, a Chinese herb traditionally prescribed as a tonic for women, is most commonly used as part of a mixture. It is sold in the United States for use alone or as part of newly formulated, nontraditional herbal combinations. One trial of dong quai found no benefit for hot flashes (16) (Table 1). It would be valuable to study Traditional Chinese Medicine (TCM) formulas, prescribed in accordance with TCM diagnostic methods. Dong quai does not contain the typically reported phytoestrogens, and the data on stimulation of estrogen receptorpositive breast cancer cells or binding to estrogen receptors (25, 26) are conflicting. Dong quai contains coumarins and can cause bleeding when administered concurrently with warfarin (27); the furocoumarins contained in dong quai can cause photosensitization (24). Oil of evening primrose, a good source of the prostaglandin E1 precursor -linolenic acid, was evaluated for hot flashes in one trial; no differences were found between a group of patients using evening primrose oil and a placebo group (17). Single-dose studies are difficult to evaluate when optimum dose and duration of treatments are unknown. Evening primrose oil is a benign treatment. Ginseng has been used as a tonic for centuries in Asia. One trial found no benefit of ginseng over placebo for menopausal symptoms and quality-of-life measures, although there were positive effects on mood (18). Case reports link ingestion of ginseng with postmenopausal bleeding (28, 29); one case of postmenopausal bleeding occurred after topical use of a ginseng-containing face cream (30). Ginseng also reduced the international normalized ratio in one patient receiving warfarin therapy (27). In summary, of the herbs that have been tested for hot flashes, only black cohosh has shown a beneficial effect. Questions remain about the long-term safety of most herbs. Dietary Phytoestrogens Many food plants contain phytoestrogens, primarily phenolic (rather than steroidal) compounds that include isoflavones, lignans, and coumestans. Isoflavone precursors are found in soy and other types of beans, clover, and alfalfa. Lignan precursors are found in whole grains, seeds (especially flaxseed [linseed]), fruits, vegetables, rye, millet, and legumes (31). Intestinal bacteria convert plant lignans to mammalian lignans (enterolactone and enterodiol) and convert conjugated isoflavones to unconjugated active isoflavones (genistein, daidzein, and equol). Phytoestrogens are estrogenic, and, thus, diet may modulate endocrine actions in the body. High dietary intake of soy products in Japan, China, and Korea has been proposed as one reason for the lower prevalence of menopausal symptoms reported in those countries (32, 33). Soy foods have become popular in the United States for treating hot flashes, despite few strong supporting clinical studies. We identified 11 clinical trials that examined soy or isoflavone supplementation for hot flashes (Table 2) (34-44); one additional study of soy for menopausal women examined vaginal epithelium rather than hot flashes (45). Products studied ranged from soy foods to purified isoflavone preparations. Only 3 of 8 studies with treatment phases that lasted for more than 6 weeks showed significant improvement in hot flashes at the end of the study (35, 41, 43). The longest study to date showed no benefit for hot flashes (or other symptoms) at 24 weeks (36). Comparisons are difficult because of variations in product, dosage, scoring systems for symptoms of hot flashes, and the menopausal status of patients. Published data show only modest effects (primarily on the severity of hot flashes), and most benefits disappeared after 6 weeks (for hot flashes, even 3 months is barely adequate to appropriately assess efficacy). It is of interest that in most of these studies, symptoms decreased in all groupsoften as much as 50% to 60% in placebo as well as treatment groups. Studies of longer duration must be done to determine whether this placebo effect would have declined over time in any or all groups. Additional studies of menopausal symptoms are warranted to differentiate among whole foods, soy protein, and isoflavone extracts. Soy foods have been a staple in Asian cuisine for thousands of years and are presumed safe. Supplementing the diet with beans or bean products is a benign interve

A public health agenda for traditional, complementary, and alternative medicine

Traditional medicine (a term used here to denote the indigenous health traditions of the world) and complementary and alternative medicine (T/CAM) have, in the past 10 years, claimed an increasing share of the publics awareness and the agenda of medical researchers. Studies have documented that about half the population of many industrialized countries now use T/CAM, and the proportion is as high as 80% in many developing countries. Most research has focused on clinical and experimental medicine (safety, efficacy, and mechanism of action) and regulatory issues, to the general neglect of public health dimensions. Public health research must consider social, cultural, political, and economic contexts to maximize the contribution of T/CAM to health care systems globally.

Hot flashes: phenomenology, quality of life, and search for treatment options.

Menopausal hot flashes are a significant problem for women. Hot flashes can impact on daily functioning, particularly when they disrupt sleep, leading to fatigue and irritability during the day. However, our knowledge about this primary complaint of menopausal women is far from complete. It is known that a hot flash is associated with thermoregulatory, cardiovascular, and endocrine changes. However, much is unknown about the phenomenology of hot flashes, such as the range of variability in the pattern and longitudinal course of hot flashes. Although estrogen plays a role in the etiology of hot flashes, the mechanism by which its withdrawal precipitates hot flashes and its replacement relieves them is not understood. Nor do we know what it is that triggers individual hot flash episodes. We are beginning to learn about factors, such as ambient temperature, that modulate the frequency of severity of hot flashes. And very new data suggest that the ingestion of certain foods may influence hot flashes via estrogenic substances present in the food plants. Although there is much anecdotal information about herbs and other nonconventional remedies, little or no research had been done to assess the efficacy or safety of these methods for the treatment of hot flashes. An immediate focus on some of the most promising of these therapies could broaden the available treatment options and should provide new insights into the mechanism underlying hot flashes.

Menopausal hot flashes: thermoregulatory, cardiovascular, and circulating catecholamine and LH changes.

Thermoregulatory, cardiovascular and endocrine changes were simultaneously monitored in 11 post-menopausal women with frequent hot flashes (catecholamine and LH levels were measured in 5 and 6 subjects respectively). Plasma samples were obtained at 1- and 5-min intervals. Hot flashes were accompanied by abrupt increases in plasma epinephrine (about 150%) and concomitant decreases in norepinephrine (about 40%). Increased luteinizing hormone was associated with most hot flashes. A detailed sequence of hot flash-associated changes was established. An aura preceded the onset of the hot flash by several seconds. HR and FBF increased just before the onset of the flash and reached peak levels of 10-20 beats/min and 30-fold respectively. Coincident with vasodilation and sweating, finger temperature increased an average of 3.9 degrees C and esophageal temperature fell 0.2-0.6 degrees C. Flashes of both discrete and prolonged intervals were observed. Sensation was a reliable index of flash occurrence and intensity as measured physiologically. Our observations are consistent with the hypothesis that hot flashes are due to a change in the thermoregulatory set point. Furthermore, the changes in catecholamine levels are consistent with the cardiovascular changes accompanying hot flashes.

Medicinal plants used by Latino healers for women's health conditions in New York City

This paper examines the use of medicinal plants by Latino healers in New York City to treat various women’s illnesses. Eight Latino healers collaborated on the study through consultations with female patients who had one of the following conditions as diagnosed by biomedically trained physicians: uterine fibroids, hot flashes, menorrhagia, or endometriosis. The study identified a total of 67 plant species prescribed by the healers in the form of mixtures or as individual plants. Voucher specimens were collected from local botánicas and identified by specialists at The New York Botanical Garden. Studies of immigrant traditional healers and the plants they use in an urban setting can provide interesting ethnobotanical data and information to assist in diagnosing conditions and contributing to treatment of patients from Latino as well as non-Latino communities.ResumenEste documento examina el uso de plantas medicinales por curanderos Latinos en la ciudad de Nueva York en el tratamiento de varias enfermedades en mujeres. Ocho curanderos Latinos colaboraron en el estudio a través de consultas con pacientes mujeres que tenían una de las siguentes condiciones de salud diagnosticadas por médicos: fibroma del útero, incrementos de temperatura repentinos, menorrea o endometriosis. El estudio identificó un total de 67 especies de plantas presentas por los curanderos ya sea en mezclas o individualmente. Muestras de los especímenes fueron colectadas en botánicas locales e identificadas por especialistas en El Jardín Botánico de Nueva York. Estudios de curanderos tradicionales inmigrantes y sus plantas en un área urbana pueden proveer datos etnobotánicos interesantes e información que asista en el diagnóstico del estado de salud y contribuya al tratamiento de pacientes tanto de comunidades Latinos, como no Latinos.

Race/Ethnicity and Women’s Use of Complementary and Alternative Medicine in the United States: Results of a National Survey

OBJECTIVES We studied the use of complementary and alternative medicine (CAM) among women in 4 racial/ethnic groups: non-Hispanic Whites, African Americans, Mexican Americans, and Chinese Americans. METHODS We obtained a nationally representative sample of women aged 18 years and older living in the United States in 2001. Oversampling obtained 800 interviews in each group, resulting in a sample of 3068 women. RESULTS Between one third and one half of the members of all groups reported using at least 1 CAM modality in the year preceding the survey. In bivariate analyses, overall CAM use among Whites surpassed that of other groups; however, when CAM use was adjusted for socioeconomic factors, use by Whites and Mexican Americans were equivalent. Despite the socioeconomic disadvantage of African American women, socioeconomic factors did not account for differences in CAM use between Whites and African Americans. CONCLUSIONS CAM use among racial/ethnic groups is complex and nuanced. Patterns of CAM use domains differ among groups, and multivariate models of CAM use indicate that ethnicity plays an independent role in the use of CAM modalities, the use of CAM practitioners, and the health problems for which CAM is used.

Colonial thermoregulation in honey bees (Apis mellifera)

Summary1.Populations of honey bees held at a constant temperature for 24–48 h exhibited diurnal rhythms of metabolic rate (MR) and locomotor activity with peaks during the day and lows at night. The amplitude of the metabolic rhythm decreased as air temperature (Tin) increased.2.Thermoregulatory behaviors including clustering and fanning occurred in cycles which correlated with the diurnal rhythms of MR and activity.3.At cold air temperature (10°C), a high rate of thermoregulatory heat production was independent of visible activity, and conversely, at high air temperatures (40°C), MR was low despite increased locomotor activity.4.Decreasing air temperature from 30 to 10°C day and night resulted in clustering, and metabolic increases proportional to the degree of cooling. Raising air temperature from 30 to 40°C day and night caused a drop in metabolic rate, an increase in locomotor activity, and fanning.5.Day/night differences in thermoregulatory responses to cooling included a nocturnal reduction of the threshold air temperature for thermogenesis and a decrease in the slopes of the metabolic response curves below this threshold. At 10°C there was more clustering at night than during the day.6.The presence of capped brood moderates these responses in a quantitative manner, as indicated by the greater metabolic rate when the bee/brood ratio is small and the greater amount of clustering on brood comb than on broodless comb.7.At cold air temperatures (10°C), capped brood temperature is maintained above 30°C through the combined effects of clustering and thermogenesis. The metabolic responses are inversely correlated with the degree of clustering.

Research on Complementary/Alternative Medicine for Patients With Breast Cancer: A Review of the Biomedical Literature

PURPOSE This article reviews English-language articles published in the biomedical literature from 1980 to 1997 that reported results of clinical research on complementary and alternative medical treatments (CAM) of interest to patients with breast cancer. METHODS We searched 12 electronic databases and the bibliographies of the retrieved papers, review articles, and books on CAM and breast cancer. The retrieved articles were grouped by end point: breast cancer (eg, tumor size, survival), disease-related symptoms, side effects of treatment, and immune function. Within each end point, we organized the articles by modality and assessed study design, findings, and qualitative aspects. RESULTS Of the more than 1,000 citations retrieved, 51 fit our criteria for review. Of the articles reviewed, 17 were randomized clinical trials; three of these were trials of cancer-directed interventions, two of which involved the same treatment (melatonin). Seven articles described observational studies, and the remainder were reports of phase I or II trials. Relatively few CAM modalities reportedly used by many breast cancer patients were mentioned in articles retrieved by this process. Most articles had shortcomings. CONCLUSION Although many studies had encouraging results, none showed definitively that a CAM treatment altered disease progression in patients with breast cancer. Several modalities seemed to improve other outcomes (eg, acupuncture for nausea, pressure treatments for lymphedema). If CAM studies are well-founded, well-designed, and meticulously conducted, and their hypotheses, methods, and results are reported clearly and candidly, research in this controversial area should acquire credibility both in the scientific community and among advocates of unconventional medicine.

Extracted or synthesized soybean isoflavones reduce menopausal hot flash frequency and severity: systematic review and meta-analysis of randomized controlled trials

Objective This analysis was conducted to determine the efficacy of extracted or synthesized soybean isoflavones in the alleviation of hot flashes in perimenopausal and postmenopausal women. Methods PubMed and The Cochrane Controlled Clinical Trials Register Database were searched for relevant articles reporting double-blinded randomized controlled trials through December 14, 2010. References within identified articles, as well as peer-reviewed articles that had come to the attention of the authors through other means, were also examined for suitability. This systematic review and meta-analysis, which evaluated the effects of isoflavones on the frequency, severity, or composite score (frequency × severity) of hot flashes compared with placebo was conducted according to Cochrane Handbook guidelines. Results From 277 potentially relevant publications, 19 trials (reported in 20 articles) were included in the systematic review (13 included hot flash frequency; 10, severity; and 3, composite scores), and 17 trials were selected for meta-analyses to clarify the effect of soybean isoflavones on hot flash frequency (13 trials) and severity (9 trials). Meta-analysis revealed that ingestion of soy isoflavones (median, 54 mg; aglycone equivalents) for 6 weeks to 12 months significantly reduced the frequency (combined fixed-effect and random effects model) of hot flashes by 20.6% (95% CI, −28.38 to −12.86; P < 0.00001) compared with placebo (heterogeneity P = 0.0003, I 2 = 67%; random effects model). Meta-analysis also revealed that isoflavones significantly reduced hot flash severity by 26.2% (95% CI: −42.23 to −10.15, P = 0.001) compared with placebo (heterogeneity, P < 0.00001, I 2 = 86%; random effects model). Isoflavone supplements providing more than 18.8 mg of genistein (the median for all studies) were more than twice as potent at reducing hot flash frequency than lower genistein supplements. Conclusions Soy isoflavone supplements, derived by extraction or chemical synthesis, are significantly more effective than placebo in reducing the frequency and severity of hot flashes. Additional studies are needed to further address the complex array of factors that may affect efficacy, such as dose, isoflavone form, baseline hot flash frequency, and treatment duration.