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Menopause: The Journal of The North American Menopause SocietyVol. 11, No. 1, pp. 11-33DOI: 10.1097/01.GME.0000108177.85442.71 2004 The North American Menopause Society POSITION STATEMENT
Treatment of menopause-associated vasomotor symptoms:position statement of The North American Menopause Society ABSTRACT
Objective: To create an evidence-based position statement regarding the treatment of vasomotor
Design: The North American Menopause Society (NAMS) enlisted clinicians and researchers
acknowledged to be experts in the field of menopause-associated vasomotor symptoms to reviewthe evidence obtained from the medical literature and develop a document for final approval by theNAMS Board of Trustees.
Results: For mild hot flashes, lifestyle-related strategies such as keeping the core body tempera-
ture cool, participating in regular exercise, and using paced respiration have shown some efficacywithout adverse effects. Among nonprescription remedies, clinical trial results are insufficient toeither support or refute efficacy for soy foods and isoflavone supplements (from either soy or redclover), black cohosh, or vitamin E; however, no serious side effects have been associated withshort-term use of these therapies. Single clinical trials have found no benefit for dong quai, eveningprimrose oil, ginseng, a Chinese herbal mixture, acupuncture, or magnet therapy. Few data supportthe efficacy of topical progesterone cream; safety concerns should be the same as for other proges-togen preparations. No clinical trials have been conducted on the use of licorice for hot flashes.
Among nonhormonal prescription options, the antidepressants venlafaxine, paroxetine, and fluox-etine and the anticonvulsant gabapentin have demonstrated some efficacy for treating hot flashesand were well tolerated. Two antihypertensive agents, clonidine and methyldopa, have shownmodest efficacy but with a relatively high rate of adverse effects. For moderate to severe hot flashes,systemic estrogen therapy, either alone (ET) or combined with progestogen (EPT) or in the form ofestrogen-progestin oral contraceptives, has been shown to significantly reduce hot flash frequencyand severity. Clinical trials have associated ET/EPT with adverse effects, including breast cancer,stroke, and thromboembolism. Several progestogens (both oral and intramuscular formulations)have shown efficacy in treating hot flashes, including women with a history of breast cancer, although no definitive data are available on long-term safety in these women.
Conclusions: In women who need relief for mild vasomotor symptoms, NAMS recommends
first considering lifestyle changes, either alone or combined with a nonprescription remedy, such asdietary isoflavones, black cohosh, or vitamin E. Prescription systemic estrogen-containing prod-ucts remain the therapeutic standard for moderate to severe menopause-related hot flashes. Rec-ommended options for women with concerns or contraindications relating to estrogen-containingtreatments include prescription progestogens, venlafaxine, paroxetine, fluoxetine, or gabapentin.
Clinicians are advised to enlist women's participation in decision making when weighing the ben-efits, harms, and scientific uncertainties of therapeutic options. Regardless of the management Charles L. Loprinzi, MD; and Nancy King Reame, MSN, PhD, FAAN.
Edited, modified, and subsequently approved by the NAMS Board of The Board of Trustees of The North American Menopause Society (NAMS) developed this manuscript with assistance from an EditorialBoard composed of Nanette F. Santoro, MD (Chair); Thomas B. Clark- Address correspondence and reprint requests to NAMS, PO Box 94527, son, DVM; Robert R. Freedman, PhD; Adriane J. Fugh-Berman, MD; strategy adopted, treatment should be periodically reassessed as menopause-related vasomotorsymptoms will abate over time without any intervention in most women.
Key Words: Menopause - Vasomotor symptoms - Hot flashes - Estrogen - Progestogen - Hor-
mone therapy - Antidepressants - Isoflavones - Black cohosh - Vitamin E - Gabapentin.
Inresponsetotheneedtodefinestandardsofclini- cancer.Althoughtheirvasomotorsymptomsmaybe cal practice in North America, The North Ameri- related to breast cancer treatment (eg, tamoxifen), it is can Menopause Society (NAMS) has created this reasonable to assume that the therapeutic results may evidence-based position statement on the treat- be applicable to naturally postmenopausal women, ment of menopause-associated vasomotor symptoms.
even though the physiologic mechanisms can differ. Fi-nally, although the information is relevant internation- METHODOLGY
ally, the focus is limited to therapies available in clini-cal practice in the United States and Canada.
An Editorial Board composed of experts from both clinical practice and research was enlisted to review the OVERVIEW
published data, compile supporting statements andconclusions, and reach consensus on which recommen- The symptoms of vasomotor instability associated dations to endorse. If the evidence was contradictory or with menopause are commonly termed hot flashes. Hot inadequate to form a conclusion, a consensus-based flashes are recurrent, transient episodes of flushing, opinion was established. (Practice parameter standards perspiration, and a sensation ranging from warmth to related to NAMS position statements were described in intense heat on the upper body and face, sometimes fol- lowed by chills.5 Hot flashes that occur with perspira- For this position statement, a search was conducted tion during sleep are termed night sweats.
of the medical literature for clinical trials that presented The terms hot flash, hot flush, and vasomotor symp- data specific to the treatment of vasomotor symptoms toms are often used to describe the same phenomenon.
using the database MEDLINE. Priority was given to NAMS defines vasomotor symptoms as a global term evidence from randomized, controlled clinical trials as that encompasses both hot flashes and night sweats.
well as systematic reviews and meta-analyses of such NAMS prefers the term hot flash rather than hot flush.
trials, using criteria described elsewhere for evaluating Hot flashes are considered one of the hallmark signs the evidence levels.2-4 Conclusions from other evi- of perimenopause. The exact cause of hot flashes has dence-based guidelines also were reviewed. The not been determined, although it seems that the chang- NAMS Board of Trustees was responsible for the final ing endogenous estrogen concentrations associated review and approval of this document. Updates to this with menopause may play a role. However, endog- enous estrogen concentrations alone are not predictive in scientific research occur that substantially alter the Most hot flashes are mild to moderate in intensity The overall objective of this position statement is to and typically stop over time without therapy, but the provide a review of clinical data relating to treatment of exact timing cannot be predicted. Nevertheless, many peri- and postmenopausal vasomotor symptoms and to North American women experience hot flashes severe recommend the most effective treatments. Research of- enough to seek treatment. Although the available thera- ten does not distinguish between vasomotor symptoms pies do not "cure" hot flashes, they can provide signifi- resulting from spontaneous menopause and those from induced menopause, although anecdotal reports sug- The main focus of this paper is on treatment options gest that induced menopause may result in more fre- for hot flash symptoms; however, it first presents some quent and/or severe symptoms. This position statement background information on epidemiologic, etiologic, will not specifically address vasomotor symptoms as- sociated with causes other than menopause, such as EPIDEMIOLOGIC CONSIDERATIONS
hypogonadism, low serum gonadotropin levels, orgonadotropin-releasing hormone agonist therapy.
Hot flashes are an early, readily apparent sign of ap- However, it will include research conducted among proaching menopause. A review5 found that the inci- peri- and postmenopausal women who have had breast dence of hot flashes typically increases during peri- menopause, reaches its highest rate during the first 2 compared with 32% of women without a history (odds years postmenopause, then declines over time. In a pro- spective, longitudinal study of 436 community-based Various lifestyle and social factors also seem to be US women aged 35 to 47,6 31% experienced hot flashes before noting any observable irregularity in • Warm ambient air temperatures increase a wom- menstrual cycles or changes in serum estrogen levels.
an's core body temperature and make her more Most women experience hot flashes for 6 months to likely to reach the sweating threshold. Cooler air 2 years, although some women have them for 10 years temperatures are associated with a lower incidence or longer.5 A Swedish study found that about 9% of • Previously, it was believed that hot flash risk was During perimenopause, hot flashes can occur infre- inversely related to BMI, as estradiol is elevated as quently (monthly, weekly) or frequently (hourly), but a result of aromatization in adipose tissue. How- there is usually a consistent within-woman pattern. A ever, in SWAN, which enrolled women aged 40 to circadian rhythm has been observed, with hot flash fre- 55, a high BMI (Ն 27 kg/m2) was found to be a quency peaking in the early evening hours, about 3 h predictor of hot flash frequency (OR, 1.15-1.18; after the peak in core body temperature.8 95% CI, 1.04-1.32).15 A cross-sectional study Reports of the incidence of hot flashes vary widely.
among 1,087 women aged 40 to 60 found that a In the United States, the Massachusetts Women's high BMI (> 30 kg/m2) was associated with an in- Health Study,9 a longitudinal, population-based study creased risk for moderate to severe hot flashes com- of 454 women, found that about 75% of the women pared with a low BMI (< 24.9 kg/m2) among pre- or experienced hot flashes during the transition from peri- perimenopausal women; an increased risk between menopause to postmenopause, which lasted a median hot flashes and BMI was not found in postmeno- of 3.8 years. Other US studies report different figures.
pausal women.21 It has been postulated that, at least Outside the United States, the reported hot flash rates in pre- and perimenopausal women, any increase in vary even more widely, from about 10% in Hong estradiol is offset by increased insulation from body Kong10 to 62% in Australia,11 68% in Canada,12 and up fat, resulting in a higher core body temperature and to 83% in the United Kingdom.13,14 Reasons for these • In SWAN,15 cigarette smoking (past and current) In the United States, prevalence rates also differ increased the relative risk of hot flashes (OR, 1.24- among racial/ethnic groups. According to a multiethnic 1.68; 95% CI, 1.12-1.94), perhaps because of its ef- cross-sectional survey of 16,065 women aged 40 to 55in the Study of Women's Health Across the Nation fect on estrogen metabolism. This finding has also (SWAN), African American women report hot flashes been observed in other studies.21,22 The Whiteman most frequently (45.6%), followed by Hispanics et al study21 found that current smokers were at an increased risk for both moderate and severe hot Japanese (17.6%).15 More recent data from SWAN in- flashes and for daily hot flashes; among current dicate that differences in body mass index (BMI) may smokers, hot flash risk increased with greater be a more important predictor of hot flashes than ethnic • SWAN also found that less physical activity in- After bilateral oophorectomy, acute symptomatol- creased the relative risk of hot flashes (OR, 1.33- ogy may be worse than for women experiencing spon- 1.71; 95% CI, 1.16-2.07).15 Another study, how- taneous menopause. In US women who undergo bilat- ever, found that exercise could trigger hot flashes in eral oophorectomy, hot flash rates of up to 90% have symptomatic women.23 Although strenuous exer- been reported.17,18 Over time, symptom rates become cise may elicit hot flashes in unconditioned women, similar to those for women who have reached meno- daily exercise is associated with an overall de- A history of premenstrual complaints is significantly • Low socioeconomic status was identified in SWAN associated with hot flashes in perimenopausal women, as another factor associated with an increased rela- according to data from the Melbourne Women's tive risk for hot flashes (OR, 1.22-1.85).15 Midlife Health Project.11 Approximately 47% of peri- • No clinical trial evidence supports a relationship menopausal women with a history of moderate to se- between the frequency and severity of hot flashes vere premenstrual complaints experienced hot flashes and certain triggers, such as emotional stress and consuming particular types of foods (eg, thermally els of MHPG are associated with increased whole-body hot or spicy food) or drinks (eg, caffeine, alcohol), sympathetic activation.34 In contrast, plasma levels of although this has been reported anecdotally. The the peripheral metabolite of norepinephrine, vanillyl- Melbourne Women's Midlife Health Project11 mandelic acid, do not change with hot flashes.35 This found no significant association between alcohol lends support to the hypothesis that central norepineph- rine levels are involved in the initiation of hot flashes.
Furthermore, hot flashes are known to be affected by ETIOLOGIC CONSIDERATIONS
drugs that influence sympathetic activation. In clinicaltrials, the ␣ -adrenergic agonist clonidine reduced cen- The precise cause of hot flashes is not known, al- tral noradrenergic activation and hot flash fre- though they seem to have a hypothalamic origin.
quency.36,37 Conversely, the ␣ -adrenergic antagonist Menopause, however, is not the only condition associ- yohimbine increased central noradrenergic activation ated with hot flashes. Other conditions that have the potential to result in hot flashes include thyroid disease, Gonadotropins and opiates have also been investi- epilepsy, infection, insulinoma, pheochromocytoma, gated for a possible role in hot flash onset, but no link carcinoid syndromes, leukemia, pancreatic tumors, au- has been substantiated. Elevations of gonadotropin toimmune disorders, and mast-cell disorders. Drugs concentrations at menopause, primarily luteinizing such as tamoxifen and raloxifene also are known to hormone, led to studies evaluating a potential link with hot flashes. Although some temporal associations wereshown,38,39 subsequent studies with more specific end- Endocrinology
points found no causative connection.40-43 Thus, acute Estrogen plays a role in the genesis of hot flashes as increases in luteinizing hormone levels have been ruled these symptoms are encountered by most women expe- riencing spontaneous menopause, when estrogen levels An opioidergic system link to hot flashes was inves- are known to fluctuate, and induced menopause, when tigated after a small study reported that naloxone, an estrogen levels decline abruptly. Hot flashes are more opioid antagonist, significantly reduced the frequency likely to occur after a relatively acute decrease in en- of hot flashes.44 However, a subsequent randomized, dogenous plasma estrogen concentrations or the with- placebo-controlled trial in postmenopausal women drawal of estrogen therapy, rather than low levels per found no causal connection between naloxone and se. In studies of postmenopausal women in whom en- hot flashes.45 Furthermore, two studies evaluating dogenous estrogen concentrations were measured, am- hot flash occurrence and ␤-endorphin plasma concen- bient estradiol levels did not predict the presence or ab- trations found no conclusive evidence of a causative Several other factors are thought to mediate the es- Thermoregulation
Recent evidence suggests that control of the core body temperature (T ) has a role in initiating hot phenomenon of hot flashes. Considerable evidencesupports the hypothesis that ␣ -adrenergic receptors flashes. Around the time of menopause, whether natu- and that norepinephrine levels, which play an impor- ral or induced, increased sensitivity to heat (ie, a nar- tant role in thermoregulation, at least partly regulate rowed thermoneutral zone) often occurs. One study23 this process.30 Additionally, one study showed that hot found that women who suffer hot flashes have a signifi- flash frequency was significantly reduced through cantly smaller thermoneutral zone than women without therapy with oral clonidine, an ␣ -adrenergic agonist, hot flashes (0.0°C v 0.4°C, respectively). Small eleva- even though circulating estrogen levels were not tions in T have been shown to precede most hot flashes changed.31 There is also considerable evidence that go- in postmenopausal women.8,35,48 This indicates that Tc nadal steroids modulate central noradrenergic activity.32 elevations, acting within a narrowed thermoneutral Compared with asymptomatic postmenopausal zone, trigger hot flashes. However, T elevations alone women, symptomatic postmenopausal women have do not explain the entire triggering mechanism, be- higher levels of plasma 3-methoxy-4-hydroxyphenyl- cause they have been observed in asymptomatic glycol (MHPG), the main metabolite of norepineph- rine, and these levels further increase significantly with Animal studies have shown that increased brain nor- the occurrence of each hot flash.33 Higher plasma lev- epinephrine narrows the width of the thermoneutral zone.30 Clonidine reduces norepinephrine release, tion remedies, and prescription therapies. This section raises the sweating threshold, and reduces hot flashes in reviews their efficacy and safety evidence. It bears not- symptomatic women.50 Thus, it is proposed that el- ing that the placebo effect is higher in trials of hot evated brain norepinephrine narrows the thermoregu- flashes than for many other conditions. In well- latory zone in symptomatic postmenopausal women, controlled, randomized clinical trials, placebo treat- and that small elevations in T trigger hot flashes when ment has reduced hot flashes by approximately 51%.57 Clinical trials for hot flashes are also affected by thefluctuations in symptoms among perimenopausal women PHYSIOLOGIC CHANGES
and by the abatement of hot flashes seen over time.
It is important to note that for moderate to severe hot Thermoregulatory and cardiovascular system flashes, the US Food and Drug Administration (FDA) changes that accompany a hot flash have been well stipulates that a woman must have seven to eight hot documented. Measurable increases have been observed flashes per day or at least 60 per week. Most nonhor- in T , skin temperature, skin conductance, perspiration monal efficacy studies presented herein enrolled rate, and the respiratory exchange ratio (metabolic rate women with lower rates of hot flashes.
In the 5 to 60 seconds before a hot flash occurs, skin temperature, cutaneous blood flow, and heart rate begin Lifestyle modification
to increase.51,52 Increases in T of approximately 0.1°C One potential approach for mild menopause- have been shown to occur before a hot flash.35 associated hot flashes is modification of lifestyle, in- An individual hot flash generally lasts 1 to 5 min; cluding manipulating the environment and changing about 7% are longer, and about 17% are shorter.53 Dur- behaviors. The following reviews some of these options.
ing a hot flash, skin temperatures rise as a result ofperipheral vasodilation.35,51,52,54,55 This change is par- ticularly marked in the fingers and toes, where skin Because hot flashes can be triggered by small core temperature can increase 1°C to 7°C. Most women ex- body temperature elevations in symptomatic perience a sudden wave of heat sensation that spreads women,8,35,48 it is rational to assume that practices that over the body, particularly on the upper body and face.
lower the core body temperature may be beneficial.
Sweating begins, primarily on the upper body, and it Observational studies have shown that lowering air corresponds closely in time with the increase in skin temperature reduces hot flashes.19,20 Anecdotally, conductance.35 Sweating has been observed in women women report that using a fan, keeping cool by dressing during 90% of hot flashes.35 Modest heart rate in- in layers, and consuming cool or cold food and drinks creases of about 7 to 15 beats per min occur at approxi- may help prevent hot flashes. Conversely, thermally mately the same time as the peripheral vasodilation and hot foods or drinks that may raise the core body tem- sweating.54,56 Heart rate and skin RETIRED peak within 3 min of the onset of a hot flash. Significantelevations in metabolic rate occur simultaneously withsweating and peripheral vasodilation.35 However, be- cause increased metabolic rate and peripheral vasocon- In observational studies,24,25 physically active striction do not precede the T elevations, they do not women reported fewer and less severe hot flashes than an age-matched control group with sedentary lifestyles; Skin temperature returns to normal gradually, possi- significant decreases of more than 50% were noted. In bly taking 30 min or longer. Decreases in T of 0.1°C to SWAN, less physically active women experienced sig- 0.9°C occurring approximately 5 to 9 min after the hot nificantly more hot flashes.15 However, exercise, espe- flash begins have been observed,52,54,55 probably due cially strenuous exercise that causes perspiration, may to heat loss via perspiration and increased peripheral trigger hot flashes in symptomatic women.23 No ran- vasodilation. If the heat loss is significant, the woman domized, controlled trials have examined the efficacy of exercise in managing hot flashes.
TREATMENT EVIDENCE
Various treatments have been used to relieve hot Evidence from community-based, cross-sectional flashes, including lifestyle modification, nonprescrip- studies15,21 indicates that a high BMI predisposes women to more frequent or severe hot flashes. How- Although not evaluated in controlled clinical trials, ever, whether losing excess weight reduces hot flash some women report that they have fewer hot flashes when they engage in activities to enhance relaxation,such as meditation, yoga, massage, or even just a lei- Women who do not smoke cigarettes generally ex- perience fewer hot flashes than do smokers,15,21,22 andthe risk of experiencing hot flashes increases with the Nonprescription remedies
amount smoked.21 Stopping smoking may lower the In the United States and Canada, many women use hot flash risk, but no study has specifically tested the nonprescription remedies to treat hot flashes, including effects of smoking cessation on the severity and rate of isoflavones, black cohosh, and topical hormone creams containing progesterone. Less commonly used are dong quai, evening primrose oil, ginseng, licorice, mix-tures of Chinese herbs, and other options.
Paced respiration-slow, controlled, diaphragmatic Evidence is generally lacking regarding efficacy and breathing-has shown some efficacy in reducing hot long-term safety of these remedies. Most nonprescrip- flashes when performed as a hot flash begins. In three tion remedies for hot flashes are categorized as dietary randomized, prospective clinical trials,58-60 paced res- supplements and, therefore, are not government regu- piration lowered hot flash frequency by approximately lated as drugs. Demonstrating efficacy and safety is not 50% more than the controls, a significant difference required before marketing. Also, data regarding the in- from baseline. Hot flashes were objectively measured teraction of many of these therapies with each other and by ambulatory monitoring of sternal skin conductance with prescription drugs are limited. Interactions will be In the earliest study,58 14 postmenopausal women with hot flashes used either a combination of paced res-piration plus muscle relaxation exercises or a control procedure using alpha-wave electroencephalographic(EEG) biofeedback. In a second study,59 33 postmeno- These are plant-derived diphenolic compounds that pausal women experiencing frequent hot flashes were exhibit both hormonal and nonhormonal properties.
randomly assigned to one of two interventions: paced Isoflavones are often called phytoestrogens because respiration or muscle relaxation. The control group par- they bind to estrogen receptors, with greater affinity to ticipated in alpha-wave EEG biofeedback. Only the estrogen receptor-␤ than to estrogen receptor-␣, and paced respiration group had a significant decline in hot possess both estrogen agonist and antagonist proper- flashes from baseline. In a third study,60 24 postmeno- ties.63 Isoflavones are found in whole foods and com- pausal women experiencing at least RETIRED mercial preparations, such as purified isoflavone day were randomly assigned to use either paced respi- supplements, mixed preparations containing isofla- ration or as a control, alpha-wave EEG biofeedback.
vones, and fortified foods. Two common sources of Hot flash frequency declined significantly in the paced- isoflavones are soy and red clover. No toxicity or ad- respiration group; no significant decline was noted in verse effects have been found for whole-food isofla- vones, although some people with soy allergies may Another randomized, prospective study61 also sup- ports the efficacy of behavioral relaxation, including Soy-Derived Isoflavones. Randomized, controlled paced respiration. In this trial, 33 women experiencing clinical trials have shown that, in general, hot flashes hot flashes were randomly assigned to one of three are only slightly reduced in women who consume soy- groups: behavioral relaxation, reading, or a control.
derived isoflavones when compared with controls Only the relaxation group had a significant reduction in (Table 1). Comparing studies is difficult because dif- ferent products and amounts of isoflavones were used.
Foot reflexology has been evaluated for relief of Symptom indices used to measure efficacy also differed.
menopausal symptoms. In a randomized, parallel- Between 30% and 50% of women convert daidzein, group study comparing this technique with foot mas- one of the isoflavones found in soy, to a metabolite sage (control group), no significant difference was known as equol (ie, "equol producers").78 Equol is a found regarding hot flash declines from baseline.62 nonsteroidal estrogen with estrogenic effects.79 In a re- TABLE 1. Efficacy of soy-derived isoflavones in hot flash treatment: controlled clinical trials
Superscript numbers refer to citations in the reference list. Tx, treatment; R, randomized; DB, double-blind; PC, placebo-controlled; OL, open label;CO, crossover; iso, isoflavones; S, statistically significant vs control; NS, not statistically significant vs control.
aNS v baseline; no between-group comparison.
bS v baseline; no between-group comparison.
cent study of 180 Japanese women,80 equol producers 252,81 51,82 and 3783 peri- and postmenopausal derived the most hot flash relief from their soy con- women. One randomized, double-blind, placebo- sumption. In a randomized, controlled trial of soy iso- controlled trial in 30 women aged 49 to 65 years re- flavones in 62 postmenopausal women,73 no difference ported that, after a 4-week placebo run-in, Promensil at in hot flash efficacy was found between women in the 80 mg/day for 8 weeks reduced hot flashes.84 However, the placebo response was lower than expected (16.7%), between production of equol and hot flash control has which may have affected the results.
not been disproved, it seems less likely given the recent The adverse effects reported with red clover isofla- vones seem minimal, although the long-term safety of Most hot flash studies used isoflavone amounts of 40 to 80 mg/day. The potential for adverse effects fromisoflavones and soy foods in these amounts seems minimal. Data are inconclusive regarding the estroge- Preparations made from the rhizomes of black co- hosh (Cimicifuga racemosa syn. Actaea racemosa) Red Clover-Derived Isoflavones. Red clover (Trifo- have been studied for relieving hot flashes, although lium pratense) contains several phytoestrogen com- the precise mechanism of action in humans is un- pounds, including a rich supply of the isoflavones daid- known. Among the substances in black cohosh thought to have an active therapeutic role are the triterpene Three randomized, double-blind, placebo-controlled glycosides, including actein, 27-deoxyactein, and clinical trials of the red clover supplements Rimostil cimifugoside. Almost all studies used the commercial (57 mg/day isoflavones) or Promensil (40 mg/day iso- preparation Remifemin. The currently available tablet flavones) found no benefit for hot flash treatment at one form is standardized to the 27-deoxyactein content tablet per day for 3 months using study populations of (1 mg per 20 mg tablet), although the formulation and dose have changed over time, making it difficult to This herb is commonly used in traditional Chinese Three randomized, double-blind, placebo-controlled medicine (TCM) for treating gynecologic conditions.
clinical trials have compared black cohosh with estro- TCM practitioners traditionally do not use dong quai gens for treating hot flashes.85-87 A recent 3-month (Angelica sinensis) alone, but as part of an individually trial85 tested BNO 1055 (Klimadynon, Menofem), a standardized black cohosh preparation, against conju- The only randomized, double-blind, placebo- gated equine estrogens (CEE) or placebo in 62 post- controlled study of dong quai for hot flashes evaluated menopausal women aged 40 to 60 years. Black cohosh, 71 postmenopausal women (mean age, 52 years) using at a dose equivalent to 40 mg/day, had no significant 4.5 g/day dong quai root for 6 months. During the effect on hot flashes compared with placebo; only CEE study, the hot flash incidence decreased by approxi- increased endometrial thickness. The other two trials mately 25% to 30% from baseline in the dong quai used Remifemin. One of these trials86 evaluated black group; this was not significantly different from placebo.94 cohosh at a dose of 40 mg/day for 2 months in 85 breast Data are inconclusive regarding the estrogenicity of cancer survivors older than 18 years (44 were aged 50- dong quai.90,94 Dong quai is contraindicated in women 60 years), 59 of whom were taking tamoxifen. In this trial, black cohosh provided no benefit over placebo,although the study did report a substantially lower in- cidence of sweating. In the other trial, a study of 80 Preparations made from the oil of evening primrose women aged 45 to 58 years (41 postmenopausal),87 (Oenothera biennis) seeds have been used for meno- treatment with an earlier formulation of Remifemin (4- pause-associated hot flashes. However, the only ran- mg tablets twice daily for 3 months) was more effective domized, double-blind, placebo-controlled clinical than either CEE (0.625 mg/day) or placebo in improv- trial conducted95 found no benefit over placebo from ing the Kupperman menopausal symptom index scores using evening primrose oil (2,000 mg gamma-linolenic acid plus 40 mg vitamin E twice daily for 6 months) for In 60 women aged 45 to 60 years with menopause- treating hot flashes (daily mean 7.2-7.6) in 56 women related symptoms, a Remifemin liquid extract (40 aged 45 to 67 years. No significant improvement in the drops twice daily), CEE (0.625 mg/day), and diazepam number of hot flashes from baseline was found for the (2 mg/day) all reduced Kupperman menopausal index treated group, whereas the placebo group had signifi- scores.88 Another randomized, treatment-controlled cant improvement. Reported side effects include nau- trial89 of 60 symptomatic women aged 40 years or older found similar improvement with Remifemin tablets(standardized to 4 mg triterpene glycosides), estriol A commonly used TCM ingredient is ginseng root mg/day, or an estrogen/progestogen combination (Panax ginseng and other Panax species). A random- product (Trisequens). Neither trial was placebo ized, double-blind, placebo-controlled clinical trial in 384 postmenopausal women aged 45 to 65 years found Previous reports, including the 1989 monograph that P. ginseng (Ginsana brand containing 100 mg of from the German government's Commission E (which standardized extract G115) for 14 weeks had no benefit regulates herb efficacy and safety), postulated that black cohosh has estrogenic effects. However, more re- Case reports have associated ginseng with uterine cent reports suggest that it is not estrogenic.90-92 Be- bleeding.97,98 These reports, however, did not examine cause currently available data are contradictory, cau- the ginseng products for adulterants. Mastalgia with tion dictates that the use of black cohosh not be diffuse breast nodularity also has been reported. Gin- presumed safe in women with breast cancer.
seng should not be used with monoamine oxidase There are no known reports of serious adverse ef- (MAO) inhibitors, anticoagulants, or stimulants. Data fects or drug interactions with black cohosh. Moderate are inconclusive regarding the estrogenicity of ginseng.
side effects are rare and include gastrointestinal up-set.93 The effects of long-term use are unknown as no clinical trial has lasted longer than 6 months. However, The root of the licorice plant (Glycyrrhiza glabra) is used in many TCM preparations, including those used for menopause-related symptoms. However, there are no clinical data regarding its safety or efficacy for treat- The use of nonprescription progesterone creams for the treatment of hot flashes is growing among US and Large chronic doses of licorice may result in pseu- Canadian women. So-called "natural" progesterone is doprimary aldosteronism, with symptoms that may synthesized commercially by a chemical process using include edema, hypertension, and hypokalemia. Car- plants such as soybeans and wild yam (Dioscorea vil- diac arrhythmias and cardiac arrest have occurred in losa), and it is identical to endogenous progesterone.
users of massive amounts of licorice. Licorice should However, diosgenin, the precursor of progesterone not be used with diuretics. Reports differ as to the found in these plants, cannot be converted to progester- estrogenic effect of licorice root.90 (Note: Most lico- rice candy in the United States is not made from real Commercial topical progesterone preparations vary widely in dosages, formulations, additional ingredi-ents, and recommended application sites. Many products labeled as wild yam cream contain only pro- In the only randomized, double-blind, placebo- gesterone precursors; however, some of these creams controlled clinical trial of a Chinese herb mixture, 55 may be adulterated with progesterone. Progesterone postmenopausal women aged 45 to 70 years found that creams are regulated as dietary supplements, not the herb mixture taken for 3 months provided less ben- efit than placebo in treating hot flashes.99 However, A 1-year randomized, double-blind, placebo- this study did not represent a typical use of TCM in that controlled study found that topical progesterone mixed all women in the treatment group received the same with vitamin E and aloe vera (Pro-Gest), at 20 mg/day, mixture, not individualized preparations.
significantly reduced hot flashes (a secondary end-point) in 102 healthy postmenopausal women (mean age, 52 years).104 Hot flash incidence was reduced in The first well-controlled trial of vitamin E was a 83% of the active treatment group as compared with double-blind, 3-year study reported in 1953100 that 19% of the placebo group, a significant between-group found vitamin E (50-100 IU/day) was no more effective than placebo in 658 women in relieving an 11-symptom A 12-week randomized, double-blind, placebo- menopause index (hot flashes were not analyzed sepa- controlled study of 80 postmenopausal women having hot flashes evaluated 32 mg/day of progesterone in Vitamin E therapy has also been evaluated in women a topical formulation containing vitamin E and other with breast cancer. A randomized, double-blind, pla- oils (Pro-Feme).105 Among the 72 participants who cebo-controlled crossover study tested 400 IU vitamin completed the study (mean age, 54 years; range, 43- 69), no detectable changes in hot flashes were ob- with hot flashes.101 After two 4-week periods (vitamin served, despite a slight elevation of serum progesterone E followed by placebo or vice versa), results with vita- min E were statistically superior to placebo only in A randomized, double-blind, placebo-controlled, women who received placebo followed by vitamin E crossover trial106 found that a topical cream contain- rather than vitamin E followed by placebo. However, ing wild yam extract, vitamin E, and other oils the difference between groups was small (one hot flash (BioGest) had no significant effects, when com- pared with either baseline or placebo, on hot flashes No acute adverse effects have been noted with vita- or night sweats in 23 postmenopausal women min E use at doses of up to 1,200 IU/day. Individuals (average age, 53.3 years) treated for 3 months.
with vitamin K deficiency may experience increased Participants applied 1 teaspoonful to the skin twice bleeding with high doses of vitamin E. This may have led to the common misperception that vitamin E in- No adverse effects associated with progesterone creases bleeding risk. However, a generalized increase creams have been reported in the medical literature.
in bleeding risk has not been observed in studies de- Whether they are safe for women with a history of a signed to assess bleeding risk,102 even with vitamin E hormone-dependent neoplasm is unknown. Although dosages up to 1,200 IU/day for 1 month in individuals some topical progesterone preparations may increase serum levels of progesterone, there is little evidence that any of these creams can prevent estrogen-induced als enrolling 2,511 women found that systemic ET/EPT significantly reduced both hot flash frequency and se-verity compared with placebo. Overall, hot flash fre- quency was reduced by 77% relative to placebo,whereas symptom severity was reduced by 87% (95% Several other nonprescription approaches have been CI, 0.08-0.22). Among placebo recipients, a significant used to treat hot flashes. Two such approaches, acu- reduction in hot flashes of 51% from baseline to end of puncture and magnet therapy, are discussed.
study also was reported. Trial durations ranged from 3 Acupuncture. A study of acupuncture for hot flashes randomized 24 postmenopausal women to either elec- There are many government-approved systemic ET troacupuncture (electrical stimulation of acupuncture and EPT preparations, routes of administration, regi- needles) or control (shallow acupuncture needle inser- mens, and doses. No evidence indicates that one prod- tion) at standardized points.107 Both groups improved, uct or regimen is superior to another for symptom with no statistical difference between groups.
Magnet Therapy. In the only randomized, placebo- Among ET products, conjugated equine estrogens, controlled trial,108 a crossover study in 15 postmeno- synthetic conjugated estrogens, 17␤-estradiol, ethinyl pausal breast cancer survivors, investigators found no estradiol, estradiol acetate, esterified estrogens, estro- significant hot flash relief using magnetic devices pipate (piperazine estrone sulfate), and estriol have all placed on acupuncture points commonly used to treat been shown to be effective treatments for hot flashes.
The most commonly used ET product in the United States and Canada is oral conjugated equine estrogens Prescription therapies: hormonal options
(CEE) dosed at 0.625 mg/day. Another commonly used Many women suffer persistent hot flashes that re- estrogen therapy is 17␤-estradiol at 0.5-1.0 mg/day spond only to prescription medications. Hormones are (oral) or 0.025-0.075 mg/day (patch).
often prescribed, although their mechanism of action is The vaginal ring that delivers either 0.05 or 0.1 unclear. The most commonly prescribed hormone is es- mg/day of estradiol acetate over a 3-month period is the trogen, either alone or with a progestogen for women only vaginal estrogen preparation that has been shown with a uterus. Other hormones that have been used in- to effectively treat hot flashes.110,111 Other vaginal es- clude progestogens alone, oral contraceptives (OCs), trogen preparations at doses used to treat atrophic vag- androgen-estrogen, and custom hormonal preparations.
initis have not been found to deliver ample estrogen tothe circulatory system to relieve hot flashes.
Because of the increased risk of endometrial hyper- plasia and adenocarcinoma with ET alone, all women Over the past few decades, dozens of randomized, with an intact uterus should receive systemic progesto- gen with estrogen.112 Medroxyprogesterone acetate ing the clinical efficacy of both estrogen therapy (ET) (MPA), 2.5 mg/day, is the most commonly used pro- and estrogen plus progestogen therapy (EPT) in reliev- gestogen for EPT. Other oral progestogens used for ing menopause-related hot flashes, although 4 weeks or EPT include norethindrone (also known as norethister- longer may be required to get the full effect. All oral one, 0.35 mg/day), norethindrone acetate (5 mg/day), and transdermal estrogen formulations and one vaginal norgestrel (0.075 mg/day), and micronized progester- estrogen product are government approved for this in- dication. (In this manuscript, "government approved" An oral tablet of CEE (0.625 mg/day) with MPA (2.5 indicates approval for marketing by US and/or Cana- mg/day) is the most commonly used combined EPT in dian institutions responsible for regulating therapies.) hot flash trials; lower doses (0.45 mg/day CEE with 1.5 Most clinicians consider systemic ET/EPT to be the mg/day MPA) have been found to be effective for hot therapeutic standard for the treatment of hot flashes.
flashes, but long-term endometrial safety is un- According to NAMS recommendations, treatment of known.113 Other oral tablets offering combined EPT moderate to severe menopause symptoms (including include ethinyl estradiol (0.05 mg/day) with norethin- hot flashes) is the primary indication for systemic ET drone acetate (1 mg/day), 17␤-estradiol (1 mg/day) with norethindrone acetate (0.5 mg/day), and 17␤- A meta-analysis conducted by the Cochrane Group57 estradiol (1 mg/day) with norgestimate (0.09 mg inter- of 21 randomized, double-blind, placebo-controlled tri- mittently for 3 days every 3 days). Combined EPT is also available transdermally as 17␤-estradiol (0.05 terone). Although each progestogen has unique proper- mg/day) with norethindrone acetate (0.14 mg/day), ap- ties, studies have found that several progestogens ef- plied twice weekly and either used continuously for 28 fectively treat hot flashes, leading to the conclusion days or used for 2 weeks on and 2 weeks off, as well as that, as with estrogens, it is a drug class effect.
17␤-estradiol (0.45 mg/day) with levonorgestrel (0.15 In women with a history of breast or endometrial car- mg/day), applied once a week for 28 days.
cinoma, there are no data demonstrating safety of pro- A dose-response relationship between hot flash effi- gestogen on the breast, although progestogen seems to cacy and systemic ET/EPT has been observed.114,115 contribute substantially to the increased breast cancer Individual responses vary widely, with some women risk seen with EPT use.112 Mammographic density, responding to very low doses of estrogen and others linked in some studies to greater breast cancer risk, is increased with progestogen use, although this effect Current data from the Women's Health Initiative will reverse with discontinuation of use.123-125 (WHI) and the Heart and Estrogen/progestin Replace- Medroxyprogesterone Acetate (MPA). This proges- ment Study (HERS) support a link between EPT and tin has been shown in several double-blind, placebo- increased risks for breast cancer, coronary heart dis- controlled trials to relieve menopause-associated hot ease, thromboembolism, stroke, and dementia.116-121 flashes in healthy women, as well as in women with Data from these studies should be extrapolated only breast or endometrial cancer. Both intramuscular and with caution to women younger than 50 years of age oral forms have demonstrated efficacy.
who initiate ET/EPT. WHI and HERS involved womenaged 50 and over (with mean ages of 63 and 67, respec- • Intramuscular MPA. In a double-blind, placebo-
tively), and HERS was conducted solely in women controlled trial in 69 women, the contraceptive with known coronary artery disease. The data should depot-medroxyprogesterone acetate (DMPA), in- not be extrapolated to women experiencing premature jected intramuscularly at a dose of 150 mg/month, menopause (< 40 years of age) and initiating HT at reduced hot flashes by 90%, as compared with a that time. Breast cancer risk is increased with ET 25% reduction for placebo.126 Uterine bleeding and, to a greater extent, EPT use beyond 5 years.121,122 was the major side effect, observed in 43% of par- Progestogen may contribute substantially to that ad- ticipants. In a randomized, double-blind, placebo- verse effect. EPT and, to a lesser extent, ET increase controlled trial of 36 postmenopausal women, breast cell proliferation, breast pain, and mammographic DMPA (50, 100, and 150 mg) exhibited a dose- response relationship.127 By week 4, hot flashes ET/EPT is contraindicated in women with a history were reduced by 75%, 90%, and 100% versus pla- of hormone-sensitive cancer, liver disease (oral estro- cebo on doses of 50 mg, 100 mg, and 150 mg, gen is of particular concern), history of blood-clotting respectively. Only two participants had uterine disorders, and confirmed cardiovascular disease.
Hot flash treatment with DMPA was compared ing, breast tenderness, nausea, abdominal bloating, with CEE in a randomized trial of 42 women who fluid retention in extremities, headache, dizziness, and had reached menopause spontaneously or surgi- hair loss. Additional adverse effects when progestogen cally.128 Women received either DMPA (150 mg) is added to estrogen (EPT) include mood changes and or CEE (0.625 mg) for 25 days each month for 3 the potential for more uterine bleeding than with estro- months. Hot flashes decreased significantly from baseline in both groups; no between-group differ-ence was noted. Among women who benefitedfrom treatment (82% of women in each group), hot flashes were reduced by 62% with CEE and by 69% NAMS has determined that the primary menopause- with DMPA. During the treatment period, no hot related indication for progestogen use is endometrial flashes were reported by 18% of those using CEE protection from unopposed ET.112 Progestogen alone, and by 33% of those using DMPA. Side effects however, may be considered as a treatment for hot were similar between the two treatment groups.
flashes if the benefit-risk profile is acceptable to the In women with a history of breast cancer, a ran- woman. Two chemical types of progestogens are avail- domized trial129 of 71 postmenopausal women able: progesterone (identical to the hormone secreted compared DMPA (500 mg on days 1, 14, and 28) by the human ovary) and progestin (synthetic proges- with oral megestrol acetate (40 mg/day). After the 6-week treatment period, 67% of DMPA recipients megestrol acetate for periods of up to 3 years or longer had at least a 50% reduction in hot flashes, which with continued control of hot flashes and a minimum of was statistically similar to the megestrol acetate side effects.139 In a randomized trial comparing meges- group. An observational study of 15 women with a trol acetate with DMPA in 71 postmenopausal women history of breast cancer found that DMPA (3 bi- with a history of breast cancer,129 no between-group weekly injections of 500 mg) reduced hot flashes by 90%.130 Improvement remained for months af- The full efficacy of megestrol acetate on reducing ter discontinuing DMPA in many of the women.
hot flashes may not be observed until after 3 or 4 weeks Contraindications of DMPA are the same as for of therapy. In women receiving concurrent tamoxifen, estrogen. Adverse effects include weight gain, ir- there seems to be an increase in hot flashes for a few regular uterine bleeding, amenorrhea, and nervous- days after starting megestrol acetate therapy, before ness. Evidence is inconclusive regarding associating DMPA therapy with a decrease in bone loss.131-134 Despite the use of higher doses of megestrol acetate • Oral MPA. In clinical trials, oral MPA has shown
to treat metastatic breast cancer, a government- efficacy similar to DMPA in relieving hot flashes; approved indication, concerns exist regarding the ad- however, oral MPA is associated with less uterine verse effects of low doses of any progestational agent bleeding and has been associated with no adverse on breast cancer. No definitive data are available re- effect on BMD. Contraindications are the same as garding the long-term safety of megestrol acetate for treatment of hot flashes in women with breast cancer.
Side effects include increased appetite (one of the A double-blind, crossover trial of 27 postmeno- drug's approved indications is for treating unwanted pausal women found that MPA, 20 mg/day, was weight loss, but at much higher doses, in the 160- to significantly more effective than placebo in re- 800-mg/day range) and, possibly, exacerbation of pre- lieving hot flashes.135 A randomized, placebo- existing diabetes and an increase in thromboembolic controlled, crossover trial in six postmenopausal women determined that MPA at 20 mg/day signifi-cantly reduced both the subjectively noted hotflashes and the frequency of recorded temperature A commonly prescribed therapy for women needing One randomized, double-blind, crossover trial137 both contraception and hot flash therapy is a low-dose evaluated the efficacy of MPA in endometrial can- OC. A randomized, double-blind, placebo-controlled cer survivors. In 21 women treated for endometrial Canadian study of 132 healthy, nonsmoking perimeno- carcinoma who had severe menopausal symptoms, pausal women (aged 40-55) experiencing hot flashes MPA (100 mg twice daily) for 12 weeks was sig- found that an OC containing 0.02 mg ethinyl estradiol and 1 mg norethindrone acetate (Minestrin 1/20, hot flashes. On average, the maximal effect was equivalent to Loestrin 1/20) substantially reduced both the number and severity of hot flashes, but it was sta- Megestrol Acetate. Another oral progestin, meges- tistically no more effective than placebo.140 A 3-year trol acetate, has also been studied for treating hot randomized study of a low-dose triphasic OC in 200 flashes. The only well-controlled clinical trial was in perimenopausal women found significant reductions in women with a history of breast cancer. In this trial-a hot flashes compared with controls.141 The relatively randomized, placebo-controlled, double-blind cross- high estrogen and progestin doses found in OCs, com- over trial138-97 postmenopausal women received 4 pared with menopausal HT, increase the likelihood that weeks of relatively low doses of megestrol acetate (20 mg twice daily). At the end of the study, hot flashes Contraindications to the use of OCs include a history were reduced by about 85% in the megestrol acetate of blood clots, cardiovascular disease, migraine, hor- group compared with 21% in the placebo group, a sig- mone-sensitive carcinoma, jaundice, or liver disease.
nificant between-group difference. The primary ad- Smokers over age 35 should not use OCs. The most verse effect was withdrawal uterine bleeding, generally common adverse effects of OCs include nausea, vom- occurring 1 to 2 weeks after discontinuation of therapy.
iting, abdominal bloating, breakthrough uterine bleed- A follow-up telephone survey of study participants de- ing, change in menstrual flow, edema, melasma, and termined that 18 (31%) of 58 women continued to use from alterations of central serotonin or norepinephrine One androgen-estrogen product, a combination of concentrations. Serotonin, injected into the hypothala- 0.625 or 1.25 mg esterified estrogens and 1.25 or 2.5 mus, widens the thermoneutral zone in rats and guinea mg methyltestosterone, respectively, is marketed for pigs; no human data are available.30 A review of the the treatment of moderate to severe vasomotor symp- data for three antidepressants follows. However, these toms that are not improved by estrogen alone. Pub- studies enrolled women with lower hot flash rates than lished clinical trial data are lacking to support this those required by the FDA to prove efficacy with mod- Contraindications and adverse effects are the same Venlafaxine. One antidepressant investigated for as for estrogen therapy, along with side effects associ- treating menopause-related hot flashes is venlafaxine ated with androgen treatment (including alopecia, acne, HCl, a combined serotonin and norepinephrine reup- deepening of the voice, and hirsutism). However, these effects are infrequent at doses currently available for A randomized, double-blind, placebo-controlled women. Long-term effects of low-dose testosterone clinical trial144 enrolled 229 women who were experi- treatment in women are not known. Higher endogenous encing at least 14 hot flashes per week (69% were tak- testosterone concentrations have been linked to in- ing tamoxifen) and either had a history of breast cancer creased breast cancer, premature atherosclerosis, and or chose not to take ET/EPT. Women were randomized to 4 weeks of treatment with either placebo or one ofthree venlafaxine doses: 37.5, 75, or 150 mg/day. At theend of the study, venlafaxine recipients had hot flash score reductions from baseline of 37% for the 37.5- In addition to patented formulations, custom-made mg/day dosage and 60% for both higher doses, as com- formulations prepared by a compounding pharmacist pared with a 27% reduction for placebo recipients. The from a prescription are also available. These prepara- effect on reducing hot flashes was relatively rapid, with tions, although not government approved, offer dif- full effect noted within 1 to 2 weeks. An uncontrolled ferent types and amounts of estrogen (usually estriol, pilot trial also supports this finding.145 estrone, or estradiol) and progestogen (usually micron- In the clinical trial, venlafaxine was relatively well ized progesterone) as well as ways to administer these tolerated at doses of up to 150 mg/day. (Doses used to hormones (eg, capsule, skin cream/gel, subdermal im- treat depression start at 75 mg/day and increase to 150 plant, sublingual tablet, rectal suppository, nasal to 225 mg/day.) The most problematic side effect was spray). Custom preparations have not been adequately nausea or vomiting, which led to drug discontinuation studied for any indication, including hot flash efficacy.
in 5% to 10% of women, depending on the dose. In Neither side effects nor other safety issues have been women who developed nausea but continued therapy, determined. No data support claims that these prepara- nausea largely dissipated over the following 1 to 2 weeks. In addition, those taking venlafaxine had moredry mouth and a decreased appetite. Only the highest Prescription therapies: nonhormonal options
dose arm had more constipation than the placebo arm.
Contraindications to using venlafaxine include con- In women with hot flashes for whom hormones are comitant use with MAO inhibitors. Other adverse ef- not an option, other prescription drugs that are govern- fects observed in venlafaxine trials for depression in- ment approved for different indications have shown clude somnolence, dizziness, constipation, and sexual some effectiveness in relieving hot flashes. Some of dysfunction. There is also a dose-related risk of in- these drugs were studied in women with a history of creased blood pressure with the use of venlafaxine, af- breast cancer. Available evidence suggests that data fecting about 3% of those using less than 100 obtained from cancer survivors can be extrapolated to other populations of women. These data are included in Paroxetine. A selective serotonin-reuptake inhibitor (SSRI), paroxetine HCl has also been associated withdecreased hot flash rates. The only randomized, double-blind, placebo-controlled trial used controlled- Certain prescription antidepressants may decrease release paroxetine in 165 women without a history of hot flashes in women, including those with a history of breast cancer and experiencing 2 or 3 hot flashes per breast cancer. This effect on hot flashes likely results day.147 At doses of either 12.5 or 25.0 mg/day for 6 weeks, paroxetine significantly decreased hot flash Although higher doses of gabapentin are commonly composite scores by 62.2% (12.5 mg/day) and 64.6% used for treatment of seizures or neuropathies (up to (25.0 mg/day), compared with a 37.8% decrease for 3,000-3,600 mg/day), doses as low as 100 mg/day are placebo recipients. Results from two uncontrolled pilot typically used as starting doses for hot flashes, particu- Contraindications to using paroxetine include con- Hypersensitivity to the drug is the only contraindica- comitant use of MAO inhibitors or thioridazine. Cau- tion to gabapentin use. Adverse effects observed in sei- tion is advised with concomitant administration of war- zure trials include somnolence, dizziness, ataxia, fa- farin. Adverse effects observed in trials for depression include asthenia, sweating, nausea, decreased appetite,somnolence, insomnia, and dizziness. The recom- mended initial dose for treating depression is 20 mg/day.
Two older antihypertensive drugs, clonidine HCl Fluoxetine. Another SSRI, fluoxetine HCl, is gov- and methyldopa HCl, have been studied for treating hot ernment approved to treat depression and premenstrual dysphoric disorder, but it also has been studied for hot Clonidine. Two randomized, placebo-controlled tri- flashes at the same dose (20 mg/day) recommended as als (N = 10 and N = 29) found that the ␣ -adrenergic the initial dose to treat depression.
agonist clonidine, given either orally or transdermally, In a double-blind, placebo-controlled, crossover reduced hot flash frequency by 46% (for 0.4 mg/day) trial,150 81 healthy women with a history of breast can- and 80%, respectively, in healthy women.36,37 How- cer or a perceived risk of breast cancer and at least 14 ever, in one of these studies,36 four women in the clo- hot flashes per week were randomized to fluoxetine (20 nidine group withdrew because of drug-related side ef- mg/day) or placebo for a 4-week period, with the alter- fects, which included nausea, fatigue, headaches, native treatment given for an additional 4 weeks. The crossover analysis found additional reductions in hot In breast cancer survivors using tamoxifen, two ran- flash frequency of about 20% for fluoxetine recipients domized, placebo-controlled clinical trials also found compared with placebo recipients (no difference in results clonidine effective in relieving hot flashes.154,155 An based on age). The magnitude of benefit in this study, 8-week trial154 found that oral clonidine (0.1 mg/day) however, did not seem to be as great as was seen with significantly reduced hot flashes in 194 postmeno- venlafaxine. Fluoxetine was well tolerated in this trial.
pausal women (by 38% v 20% for placebo), although Contraindications and side effects with fluoxetine the clonidine group reported more difficulty sleeping than those receiving placebo (41% v 21%, respec-tively). In 110 women (median age, 54),155 transdermal clonidine (equivalent to 0.1 mg/day) for 4 weeks sig- This anticonvulsant has been studied for treating hot nificantly improved hot flash frequency and severity compared with placebo. However, clonidine was asso- known, although it has been speculated that gabapentin ciated with more side effects than the placebo, includ- ing dry mouth, drowsiness, constipation, and itchiness A randomized, double-blind, placebo-controlled trial performed in 59 postmenopausal women averaging Contraindications include cardiac sinus node func- seven or more hot flashes per day found that, after 12 tion impairment. Clonidine lowers blood pressure, weeks of gabapentin therapy (900 mg/day, adminis- heart rate, and pulse rate; arrhythmias have been ob- tered in three divided doses), hot flash frequency was served at high doses. Adverse effects observed in hy- reduced by 45%, with a 54% reduction in a hot flash pertension trials include dry mouth, drowsiness, dizzi- composite score.151 The differences were statistically significant compared with placebo recipients, who had Methyldopa. Two randomized, double-blind, placebo- reductions of 29% and 31%, respectively. Gabapentin controlled, crossover trials reported that methyldopa, was relatively well tolerated in this clinical trial, with in daily oral doses of 500 to 1,000 mg, decreased dizziness and lightheadedness (especially at initiation menopause-related hot flashes, although improvement of therapy) and peripheral edema being the major ob- was modest.156,157 Nesheim et al156 reported a median served adverse effects. Results from a prospective, reduction in hot flashes of 65% with methyldopa (250 single-arm study152 and an open-case series153 also mg/day) compared with 38% for placebo, a significant between-group difference. Hammond et al157 found significant reductions in hot flashes in a trial involving The decision to undertake treatment should be based on the severity of the symptoms, an assessment of treat- Contraindications include active hepatic disease and ment-related risks, and the woman's personal attitudes use of MAO inhibitors. Methyldopa lowers blood pres- about menopause and medication. The clinical goal is sure. A positive Coombs test, hemolytic anemia, and to tailor therapy to each individual woman's needs, us- liver disorders may occur with methyldopa therapy.
ing the various options. Clinicians are advised to enlist Side effects observed in hypertension trials include se- women's participation in decision making when dation, headache, asthenia, edema, and weight gain.
weighing the benefits, harms, and scientific uncertain-ties of options.
No therapy is government approved in either the United States or Canada for treating hot flashes in There are limited data to support the efficacy of this women who are at high risk for or have been diagnosed older sedative, a combination tablet of low-dose phe- with breast cancer or other hormone-dependent neopla- nobarbital (a barbiturate), ergotamine tartrate, and le- sias. However, a variety of nonprescription and non- vorotatory alkaloids of belladonna, in treating meno- hormonal treatments have been used to relieve hot pause-related hot flashes. Its specific mechanism of flashes in these populations. Caution is advised when recommending therapies to these women, as some A randomized, double-blind, placebo-controlled therapies may have estrogenic activity.
study in 72 women found that Bellergal significantly Data are inadequate to determine if the physiologic reduced hot flashes compared with placebo (60% v mechanisms for hot flashes in breast cancer survivors 22%, respectively) after 12 weeks of treatment.158 In a using tamoxifen are different from hot flashes in randomized, placebo-controlled, double-blind trial of women experiencing menopause-related hot flashes.
66 women,159 significant decreases in hot flashes from At this time, it is reasonable to assume that the thera- baseline were reported after 8 weeks for both the Bel- peutic results seen with hot flashes may be applicable to lergal (75%) and placebo (68%) groups. However, the between-group difference was not significant.
In most women, hot flashes will abate over time Contraindications include cardiovascular or hepatic without any intervention. When therapy is desired, disease and glaucoma. Adverse effects include visual various nonpharmacologic and pharmacologic options disturbances, dry mouth, flushing, dizziness, and som- are available. The recommended clinical management nolence. Bellergal reduces the efficacy of certain drugs, approach includes lifestyle modification followed by including anticoagulants and OCs. Bellergal intoxica- nonprescription and/or prescription therapies, when tion can lead to death. Barbiturates are addictive and should not be recommended for long-term use.
Most of the clinical recommendations in this section are based on medical evidence, and they represent areas in which the Editorial Board reached consensus. If the Additional prescription therapies RETIRED evidence was inconclusive, recommendations were hot flashes are available in many countries but not in made based on expert opinion and clinical judgments; North America. Other options can be expected in the readers should be aware that these opinions might not be shared by all healthcare clinicians. In some cases, anintervention is recommended, or not discouraged, if itseems to have a harmless side effect profile. In other CLINICAL MANAGEMENT
cases, interventions are not recommended if they have The treatment of menopause-associated vasomotor symptoms is a common clinical challenge. Beforetreatment begins, a detailed patient history of hotflashes is needed, including frequency and severity as Lifestyle changes
well as the effect they have on activities of daily living.
In women who need relief from mild menopause- Women differ in their attitude toward hot flashes. No related hot flashes, NAMS recommends first consider- treatment is needed unless the hot flashes are bother- ing lifestyle changes, which include environmental ma- some to the woman. Some women seek only to reduce nipulations and behavioral changes, such as keeping their symptoms slightly, whereas others request more the core body temperature as cool as possible, partici- pating in regular exercise, and avoiding hot flash trig- gers. Use of paced respiration is another option to con- though older trials found no benefit for vitamin E over sider, based on its effectiveness in studies, ease of use, placebo. Because vitamin E seems to be nontoxic at and lack of side effects. Because both obesity and a low doses, inexpensive, and available without a pre- sedentary lifestyle are linked to increased hot flashes, a scription, it is a reasonable option for a trial. Effects, if strategy to maintain a healthy weight and to exercise Scientific data are lacking regarding the efficacy and safety of topical progesterone creams for relief of hot Nonprescription remedies
flashes. Contents and concentrations vary widely in When lifestyle changes are not adequate to achieve different brands of nonprescription progesterone the desired level of relief from mild hot flashes, adding creams. Additionally, safety concerns regarding sys- a nonprescription remedy may be considered. A trial of temic progestogen preparations may also apply to topi- dietary isoflavones or supplements containing black cal progesterone preparations. Therefore, NAMS does cohosh or vitamin E may be an option, primarily be- not recommend use of progesterone creams for hot cause these remedies are not associated with serious side effects. However, because of inconclusive efficacy Given the lack of efficacy data, NAMS also does not data, this is not a consensus recommendation.
recommend dong quai, evening primrose oil, ginseng, Efficacy in clinical trials of both soy foods and iso- licorice, Chinese herb mixtures, acupuncture, or mag- flavone supplements (from either soy or red clover) has been mixed, possibly because it is limited to the subsetof women who are equol producers. Nevertheless, for Prescription therapies: hormonal options
women with frequent hot flashes, clinicians may con- When lifestyle changes and nonprescription ap- sider recommending soy foods or soy isoflavone proaches do not provide the desired relief, prescription supplements. Most hot flash studies used isoflavone options are available. Hormonal approaches, primarily amounts of 40 to 80 mg/day. Whole foods may be a systemic ET/EPT, are most often prescribed and are the better choice than isoflavone supplements or fortified only government-approved therapies in the United foods, based on lack of potential isoflavone "overdose" States and Canada for treating moderate to severe hot with soy foods.160 Effects, if any, may take several flashes. During perimenopause, follicle-stimulating weeks. Isoflavones exhibit a low incidence of side ef- hormone and estradiol levels fluctuate. Dosing estro- fects, although caution is advised when estrogenicity is gen at this time provides uncertain results. After meno- a concern. Whether these foods or supplements can pause is reached and ovarian activity ceases, response treat hot flashes effectively and safely in women who to estrogen therapy will be more predictable.
have had or are at risk for breast cancer is unknown.
NAMS considers treatment for moderate to severe Additional studies are needed to determine whether menopause-related hot flashes to be a primary indica- there are differences among whole food, soy protein, tion for systemic ET and EPT. Use of ET and EPT should be limited to the shortest duration consistent consumed for thousands of years and are presumed with treatment goals, benefits, and risks for the indi- safe, but supplements and fortified foods may contain high levels of isolated isoflavones, the long-term ef- standard doses of ET and EPT (ie, daily doses of In the most recent trials of black cohosh, the results 0.3-mg conjugated estrogens tablet, 0.25-0.5-mg 17␤- have been negative. However, some older and smaller estradiol tablet, 0.025-mg 17␤-estradiol patch, or the trials from Germany have shown some efficacy for hot equivalent). Many studies have demonstrated that flashes. With its low incidence of side effects, a black these doses provide similar vasomotor symptom relief.
cohosh supplement (two 20-mg tablets daily of a 27- Lower EPT doses are better tolerated and may or deoxyactein standardized preparation) taken for fewer may not have a more positive safety profile than stan- than 6 months is likely to do no harm and may provide dard doses; however, lower doses have not been tested for outcomes (including endometrial safety) in Vitamin E, 800 IU/day, is another nonprescription option to try for hot flash relief, although clinical evi- For all women with an intact uterus who are using dence is mixed. A statistically significant but not clini- estrogen therapy, NAMS recommends that they re- cally significant decrease in hot flashes among breast ceive adequate progestogen, either in a continuous- cancer survivors was noted in one clinical trial, al- combined or continuous-sequential EPT regimen.
However, there is insufficient evidence regarding long- Prescription progestogen alone can be used to treat term endometrial safety to recommend use of long- hot flashes of varying severity. In clinical trials, cycle progestogen (ie, progestogen every 3-6 months DMPA, MPA, and megestrol acetate have demon- for 12-14 days), a progestin-containing intrauterine de- strated efficacy. Short-term use of these drugs seems vice, or low-dose estrogen without progestogen as an reasonable in women without contraindications who do alternative to standard EPT regimens. If utilizing any of not wish to try estrogen but who are not opposed to these approaches, close surveillance of the endometri- trying another hormone, although progestogens have um is recommended, pending more definitive re- been linked to breast cancer risk in some studies.
search.109 Some women with an intact uterus who Perimenopausal women who need both hot flash re- choose EPT may experience undesirable side effects lief and contraception may achieve both goals with low-dose, combined estrogen-progestin OCs. NAMS If the initial ET/EPT dose is not effective, it may be supports this use for otherwise healthy women who do increased. For women who are not obtaining symptom not smoke or have other contraindications. The poten- relief with once-daily dosing of oral ET due to the pos- tial side effects of nausea, mood swings, and headaches sibility of their metabolizing the hormone more rap- can usually be decreased or eliminated by altering the idly, twice-daily dosing with half doses may be advised regimen or dose. Relief of hot flashes should be or they may be switched to transdermal ET. There is achieved within 2 to 3 months of starting therapy. If hot often no need to increase the total daily oral dose in flashes occur during the placebo week, adding a low women suspected of having rapid or irregular metabo- dose of supplemental estrogen or shortening or elimi- lism of exogenous estrogen. In such women, stability of nating the placebo interval may provide relief. DMPA the circulating estrogen level may be more important offers another option for hot flash relief and contracep- than attainment of an absolute level. The route of ad- tion, although adverse effects are greater than with ministration can also be switched. Transdermal ET OCs. Standard menopausal doses of ET/EPT have not may provide more stable levels of circulating estrogen been well studied with respect to protection from an than oral therapies. Another option is the vaginal estro- unwanted pregnancy and, thus, should not be relied on gen ring (Femring) that is FDA-approved for treating If EPT is needed postmenopause, transitioning from There are few clinical trial data on custom hormone a combination OC to EPT should be done as soon as preparations. For most women, NAMS does not recom- appropriate. Even OCs with very low hormone doses mend these preparations for hot flash relief, due to lack still provide significantly more hormone than in stan- of efficacy and safety data on the specific compounded dard EPT, which may increase exposure to unnecessary With cyclic ET regimens (ie, estrogen-only for 3 weeks followed by 1 week off therapy), hot flashes mayreturn by the end of the Prescription therapies: nonhormonal options
especially true with 17␤-estradiol, due to its rapid In women with hot flashes for whom hormones are clearance from the body. Thus, NAMS recommends not an option, nonhormonal prescription drugs have using continuous ET regimens before cyclic regimens shown some effectiveness in relieving hot flashes.
However, there are no comparative trials in similar pa- If hot flashes persist after an adequate trial (ie, 2-3 tient populations to guide clinicians in selecting a par- months) of HT, other conditions associated with hot flashes should be considered in the differential diagnosis.
If there are no contraindications, NAMS recom- When ET/EPT is discontinued abruptly, hot flashes mends the antidepressants venlafaxine (at dosages of often return within several days, depending on the type 37.5-75 mg/day), paroxetine (12.5-25 mg/day), or and route of estrogen therapy. No specific protocols fluoxetine (20 mg/day) as options for women with hot can be recommended for discontinuing therapy to flashes who are not candidates for HT, including breast avoid rebound hot flashes. Some clinicians gradually cancer survivors. The additional antidepressant effect decrease the dose, whereas others lengthen the time be- may benefit some women who suffer from mood dis- tween doses. There are no data to suggest that one method is better than the other. If hot flashes recur, Hot flash relief, if any, is almost immediate with ET/EPT may be reinstituted then discontinued at a later these therapies, whereas for depression, effects often are not observed for 6 to 8 weeks. This rapid onset of action can be a powerful reinforcement for women who Given their toxicity, NAMS does not recommend do not find relief from other, simpler methods. A brief methyldopa or Bellergal as hot flash treatments for trial of 1 week may determine if these agents are going Any hot flash treatment may need to change over Side effects, especially nausea and sexual dysfunc- time because of gradually lowering levels of ovarian tion, should be monitored. Women who experience hormones through perimenopause and the possible ap- drowsiness should take the drug at night. Venlafaxine pearance of medical conditions unrelated to menopause is the most likely in its class to promote weight loss (by or menopause treatments. New research and changing causing anorexia), and may be preferred by overweight ideas about treatments may have an impact on health women. Paroxetine has similar side effects, although decisions. Before switching from one therapy to an- less nausea and anorexia. It can also cause blurred vi- other, a wash-out period may be required.
sion, although this is rare. Fluoxetine is less likely tocause acute withdrawal side effects because of its For mild vasomotor symptoms, lifestyle changes To minimize side effects, very low doses of these alone or combined with a nonprescription remedy, such antidepressants can be used when starting therapy. If as dietary isoflavones, black cohosh, or vitamin E, can not effective, the dose can be increased after 1 week.
be considered. Although there is insufficient clinical Higher doses than those used in trials do not seem ap- trial evidence to support the efficacy of these options, propriate, given the lack of additional efficacy and the they are reasonable approaches to consider given their potential for increased toxicity. Taking the drugs with lack of potential short-term adverse effects. It is not known whether isoflavone supplements can be safely These antidepressant medications should not be consumed by women with breast cancer.
stopped abruptly, as sudden withdrawal has been asso- Prescription systemic ET/EPT remains the gold stan- ciated with headaches and anxiety. Women who have dard for treating moderate to severe menopause-related been using an antidepressant for at least 1 week should hot flashes in women without contraindications. Oral taper off the drug. Tapering may require up to 2 weeks, contraceptives are an option for perimenopausal women, especially those needing contraception.
Gabapentin is another nonhormonal option recom- Options for women with concerns relating to estro- mended by NAMS for treating hot flashes. Therapy can gen-containing treatments include lifestyle modifica- be initiated at a daily dose of 300 mg (although starting tion combined with one of the following, provided at 100 mg/day may be advisable in women older than there are no contraindications: the antidepressants ven- age 65). Bedtime administration is advised, given the lafaxine, paroxetine, or fluoxetine, or gabapentin. Pro- initial side effect of dizziness. In women who continue gestogens may be considered, although no definitive to have hot flashes, the dose can be RETIRED data are available on long-term safety in women with a twice daily and then to three times daily, at 3- to 4-day history of breast cancer. Clonidine and methyldopa intervals. Increased efficacy may be seen at even higher may be an option for some women, but they are limited doses, although this has not been well studied. Antacids by only moderate efficacy combined with a relatively may reduce the bioavailability of gabapentin; the drug should be taken at least 2 h after antacid use.
Regardless of the management option utilized, treat- Clonidine is sometimes used to treat mild hot ment should be periodically evaluated to determine if it flashes, although it is less effective than the newer an- is still necessary, as in almost all women, menopause- tidepressants or gabapentin. In addition, clonidine has a related vasomotor symptoms will abate over time with-out any intervention.
side effect profile that limits its use in many women.
The initial oral dose for hot flash treatment is 0.05 mg Acknowledgments: NAMS appreciates the contributions of the
twice daily, but women may require at least 0.1 mg following reviewers: Nanette F. Santoro, MD (Chair), Professor twice daily. The clonidine patch, delivering 0.1 and Director, Division of Reproductive Endocrinology, Depart- mg/day, can also be considered. When discontinuing ment of Obstetrics and Gynecology and Women's Health, Al- higher-dose therapy, the dose should be gradually ta- bert Einstein College of Medicine, Bronx, NY; Thomas B.
Clarkson, DVM, Professor of Comparative Medicine, Compara- pered to avoid adverse side effects, including nervous- tive Medicine Clinical Research Center, Wake Forest University ness, headache, agitation, confusion, and a rapid rise in School of Medicine, Winston-Salem, NC; Robert R. Freedman, PhD, Professor, Department of Psychiatry, Department of Ob- stetrics and Gynecology, Wayne State University School of Health Science Center, Jacksonville, FL; Ian Graham, PhD, Se- Medicine, Detroit, MI; Adriane J. Fugh-Berman, MD, Associate nior Social Scientist and Associate Director, Clinical Epidemi- Clinical Professor of Medicine, George Washington University ology Program, Ottawa Health Research Institute, University of School of Medicine, Washington, DC; Charles L. Loprinzi, MD, Ottawa, Ottawa, ON, Canada; Alastair H. MacLennan, MD, De- Professor of Oncology, Mayo Clinic, Rochester, MN; and Nancy partment of Obstetrics and Gynaecology, University of Ad- King Reame, MSN, PhD, FAAN, Rhetaugh Dumas Professor of elaide, Adelaide, Australia; as well as Philip K. Lammers, Nursing and Research Scientist, Reproductive Sciences Pro- NAMS Medical Editor, and Pamela P. Boggs, MBA, NAMS Di- gram, Department of Obstetrics and Gynecology, University of rector of Education and Development.
Final review and approval was conducted by the 2002-2003 The development of this manuscript was supported by an unre-stricted educational grant from Duramed Pharmaceuticals, Inc, a NAMS Board of Trustees: Margery L.S. Gass, MD (President), subsidiary of Barr Laboratories, Inc.
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