HM Medical Clinic

 

Doi:10.1016/s0140-6736(08)60346-3

Menopause
Heidi D Nelson Lancet 2008; 371: 760–70
Menopause is the time of life when menstrual cycles cease, and is caused by reduced secretion of the ovarian
Oregon Evidence-based
hormones oestrogen and progesterone. Although menopause is a normal event for women, individual experiences
Practice Center, Department of
vary, and some women seek medical advice for the management of symptoms. Many symptoms have been attributed
Medical Informatics and
to menopause, but only vasomotor dysfunction and vaginal dryness are consistently associated with this time of life
Clinical Epidemiology and
in epidemiological studies. Other common symptoms such as mood changes, sleep disturbances, urinary incontinence,
Department of Medicine,
Oregon Health and Science
cognitive changes, somatic complaints, sexual dysfunction, and reduced quality of life may be secondary to other
University, OR, USA; and the
symptoms, or related to other causes. Trials of therapies for vasomotor dysfunction have shown improvements with
Women and Children's Health
oestrogen, gabapentin, paroxetine, and clonidine, but little or no benefi t with other agents; adverse eff ects of these
Research Center, Providence
treatments must also be considered. Many questions about menopausal transition and its eff ects on health have not
Health and Services, Portland,
OR, USA (H D Nelson MD)
been adequately addressed.
Correspondence to: Dr Heidi D Nelson , Oregon of ovarian hormones. As the menopausal transition Health and Science University, The transition to menopause is a complex physiological progresses, menstrual cycles are missed and ultimately Mailcode BICC, 3181 SW Sam process, often accompanied by the additional eff ects of stop, as does ovulation. For some women, 3 consecutive Jackson Park Road, Portland, ageing and social adjustment. Historically, much medical months of amenorrhoea, or mean cycle lengths longer knowledge of menopause drew on convention rather than 42 days, are predictors of impending menopause.2,3 than on rigorously designed studies, which led to Several terms have been used to describe the events that inappropriate care. Moreover, at times serious symptoms take place during the menopausal transition. A model were regarded as normal concomitants of the time of life developed at the Stages of Reproductive Aging and not addressed further, and mild symptoms were Workshop (STRAW)4 described seven stages of reproductive overmedicalised.
ageing (fi gure 1), which were subdivided into reproductive Menopause results from reduced secretion of the stages, characterised by regular menstrual cycles; ovarian hormones oestrogen and progesterone, which menopausal transition stages, with variable menstrual takes place as the fi nite store of ovarian follicles is depleted. cycles and high FSH values; and postmenopause stages, Natural menopause is diagnosed after 12 months of beginning with the fi nal menstrual period, and lasting amenorrhoea not associated with a pathological cause. until the end of life. Defi nitions and models continue to be Menopause can also be induced by surgery, chemotherapy, assessed and refi ned for clinical and research applications.5–7 or radiation. Initially, the menstrual cycle lengths become Although models are useful to describe the general irregular, and follicle-stimulating hormone (FSH) progression of events leading to menopause, substantial concentrations rise in response to decreased concentrations individual variation exists, including skipping stages and moving back and forth between stages.8 The menopausal transition usually begins when women Search strategy and selection criteria
are in their mid-to-late 40s, and can last several years, most commonly 4–5 years.9 The fi nal menstrual period generally Relevant studies were identifi ed from comprehensive searches of MedLine (1966 to happens when women are between 40 and 58 years old,9 December, 2006) and the Cochrane database of systematic reviews and controlled trials (last and a fi nal menstrual period before 40 years of age is accessed December, 2006). Search strategies focused on menopausal symptoms and regarded as premature. Population studies suggest that therapies for symptoms using the terms climacteric and menopause with terms depression, smoking and low socioeconomic status are associated depressive disorder, aff ect, mood disorders, quality of life, sex disorders or dysfunction, sleep with premature fi nal menstrual periods.10 Other factors disorder, urination disorder, vasomotor symptom, somatic symptom, and vaginal dryness, can aff ect the age at which women have their fi nal and with specifi c terms for treatments such as, estrogen, androgen, progestin, tibolone, menstrual period, including age at menarche, parity, antidepressants, gabapentin, etc. Specifi c searches are described in a previous publication1 previous oral contraceptive use, body-mass index, ethnic and were updated for this Seminar. Additional articles were obtained by searching recent origin, and family history.11 The age at which women have systematic reviews, reference lists of related articles, and websites, and by consulting their fi nal menstrual period varies across large surveys experts. Non-English studies were included if they were suffi ciently described in English- done in diff erent countries. Mean ages of 50–51 years were language abstracts. For symptoms, prospective cohort studies of the menopause, examining reported in Italy, Iran, Slovenia,11 and the USA;12 and of at least one potential menopausal symptom, were included; cross-sectional studies with 47–50 years in Korea, Lebanon, Singapore, Greece, similar criteria were examined for contributory data, such as prevalence rates of symptoms. Morocco, Mexico, Taiwan, and Turkey.11 For therapies, randomised, double-blind, placebo-controlled trials, providing data on the treatment of menopausal symptoms with one or more therapies, were included, as were meta-analyses of relevant trials. Trials without a placebo group, comparing therapies, were Many clinical manifestations have been attributed to excluded, because of diffi culty in interpreting their results. Studies were included whether menopause. Vasomotor episodes manifest as spon- the women were recruited from health-care settings, or the general population. taneous sensations of warmth, usually felt on the chest, www.thelancet.com Vol 371 March 1, 2008
Final menstrual period (FMP) Menopausal transition Menopausal transition Duration of stage ≥2 skipped cycles Variable cycle length and an interval of (>7 days different Figure 1: Stages of normal reproductive ageing in women
Reproduced with permission from Soules and colleagues.4 FSH=follicle-stimulating hormone.
neck and face, and often associated with pers pir ation, inconsistencies and limitations. Many methods have been palpitations, and anxiety. These episodes are described developed to assess menopausal symptoms, but only a as hot fl ushes, hot fl ashes, and night sweats. The term few are standardised, valid, and reliable. Some methods "hot fl ush" indicates the sensation of heat; "hot fl ash" are based on self-reports of the presence, severity, and describes episodes with sweating, sometimes followed frequency of individual symptoms, such as hot fl ashes. by a chill; however, the terms are often used Others use cumulative scores, based on lists or scales of interchangeably. Vasomotor episodes are variable in symptoms that are thought to be associated with the frequency, duration, and severity, are sometimes menopause, such as changes of mood, cognition, quality recurrent, and usually last less than 5 min. They can be of life, sexual function, and somatic symptoms. The Green triggered by warm environments, hot food or drinks, climacteric scale,17 Kupperman index,18 and menopause-and stress. For some women, these episodes interfere specifi c quality of life questionnaire19 are examples of with activities or sleep to such a degree that medical commonly used scores of menopausal symptoms. The advice is needed. The mechanisms causing vasomotor multitude of symptoms studied and methods used often symptoms are not fully understood. One theory is that does not allow comparisons between studies, and the reduced oestrogen concentrations cause decreased populations they represent. Most studies fail to adjust or endorphin concentrations in the hypothalamus, which stratify for potentially important variables such as age, increases the release of norepinephrine and serotonin; these neurotransmitters lower the set point in the thermoregulatory nucleus, and trigger inappropriate heat loss.13–15 Urogenital problems, such as vaginal dryness, itching, and dyspareunia, are caused by physiological responses to low concentrations of oestrogen and androgens. These responses include reduced vaginal blood fl ow and secretions, tissue changes, and a change in the pH of Urinary complaints uid, from acidic to neutral. Additional symptoms, such as anxiety, depression, and mood changes, urinary incontinence and leakage, sleep Sleep disturbance disturbances, cognitive changes, somatic complaints, and sexual dysfunction have been associated with the menopausal transition. Some of these symptoms are secondary to vasomotor and urogenital symptoms, and others are related to other causes. Factor analysis studies Vasomotor symptoms showed that menopausal status is more consistently associated with vasomotor than with psychological or physical symptoms, arguing against a universal Prevalence rate (%) menopausal syndrome that includes all of them.16 Distinction between clinical signs related specifi cally to Figure 2: Prevalence rates of symptoms
the menopausal transition, and those related to ageing in 51 population studies showed wide ranges of prevalence rates. Rates of vasomotor symptoms, vaginal dryness, and sleep disturbances are higher for general, is diffi cult. Studies of menopausal dysfunctions women in menopausal transition and postmenopause than for women in need to be carefully interpreted, because of methodological www.thelancet.com Vol 371 March 1, 2008
pre-existing disorders, and the use of hormone therapy. menopausal transition (table 1). Vasomotor dysfunctions, In epidemiological studies, the reproductive stages are including hot fl ashes (odds ratio [OR] 1∙3–13) and night often defi ned by terms that predate the STRAW model.4 sweats (OR 2∙4–4∙3), substantially increase in frequency In general, premenopause corresponds to the STRAW and severity during the menopausal transition:20–22 these reproductive stages; perimenopause corresponds to the symptoms are experienced by more than 50% of STRAW menopausal transition stages; and postmenopause menopausal women.1 Although most symptoms resolve begins at the time of the fi nal menstrual period. However, within a few months for many women, they can persist studies vary in: how these terms are used; the data used to for several years after the fi nal menstrual period. About assess menopausal status;6 which stages are compared; 29% of 60-year-old women report persistent hot fl ashes.23 and when and how frequently symptoms are measured. Studies of factors that might aff ect vasomotor Most studies, including those from prospective cohorts, dysfunction are inconclusive, but suggest that body-report cross-sectional data and compare results for mass index, exercise, age of onset of menopausal premenopausal, perimenopausal, and postmenopausal transition, surgical menopause, smoking, and groups of women, whereas others provide serial measures depression might all be implicated.1 from individuals as they progress through stages. Vaginal dryness is also associated with the menopausal Prevalence rates of symptoms, such as vasomotor transition22 and is reported by up to a third of menopausal dysfunctions, vaginal dryness, sleep disturbance, urinary women.1 Additionally, menopausal women have more complaints, and mood changes, vary greatly (fi gure 2).1 sleep disturbances than non-menopausal women erences between studies might result from (OR 1∙3–1∙5),20,22 sometimes because of vasomotor symp- inconsistencies in methods, or from true diff erences toms.23 About 40–60% of women have sleep dis turbances between populations. during menopause and postmenopause stages.
Cohort studies have shown that only a few clinical Several symptoms are inconsistently associated with manifestations are signifi cantly associated with the menopause. Some studies have reported no correlation Description (length of
Transition from premenopause Perimenopause stage
Transition from perimenopause Postmenopause stage
follow-up in studies)
to perimenopause
8236 women (45–50 years Increased hot fl ashes, night Increased hot fl ashes, night Increased night sweats and Increased night sweats, Longitudinal Study on of age) enrolled in 1996 in sweats, sleeping disturbances, sweats, sleeping disturbances, sleeping disturbances. No decreased general mental Australia (2 years) severe tiredness, and stiff painful severe tiredness, stiff painful associations with hot fl ashes, health. No associations with joints. No associations with back joints, back pain, body pain, somatic symptoms (severe hot fl ashes, diffi culty sleeping, pain, body pain, headache, urinary leakage, worse general tiredness, stiff painful joints, back somatic symptoms (severe urinary leakage, general health health perception, and quality of pain, body pain, headache), tiredness, stiff painful joints, perception, general mental life. No associations with general urinary leakage, general health back pain, body pain, health, quality of life, or mental health, headache, or perception, general mental headache), urinary leakage, health, quality of life, or general health perception, quality of life, or constipation No association with depression No association with depression Increased depression based on 1941 and 1947 recruited on the basis of responses to an osteoporosis screening study in Eindhoven, Netherlands (5 years) 899 women (38–60 years No associations with development of mental disorder of age) randomly selected in 1968–1969 and followed up for more than 25 years in Gothenburg, Sweden (6 years) Manitoba Project on 469 women (40–59 years No associations with depression (based on CES-D score 16 and over) of age) from Manitoba, Health in the Middle 231 premenopausal No associations with depression (based on CES-D score 16 and over) Women's Health Study women (45–55 years of age) from Massachusetts, USA (8 years) Medical Research 1572 women identifi ed No associations with vasomotor Increased vasomotor symptoms; No associations with vasomotor Council (MRC) National from a socially stratifi ed symptoms, anxiety, or no associations with anxiety or symptoms, anxiety, or Survey for Health and sample of all births in March 1943 in Britain (52 years) (Continues on next page) www.thelancet.com Vol 371 March 1, 2008
Description (length of
Transition from premenopause Perimenopause stage
Transition from perimenopause Postmenopause stage
follow-up in studies)
to perimenopause
(Continued from previous page) Melbourne Women's 494 women (45–55 years Increased sleeping disturbances, Increased hot fl ashes and Midlife Health Project of age) from Melbourne, decreased quality of life. No night sweats, vaginal dryness, Australia enrolled in 1991 association with hot fl ashes, sleeping disturbances, and vaginal dryness, mood, somatic general wellbeing; decreased symptoms, urinary symptoms, breast soreness, and quality incontinence, or sexual dysfunction of life. No association with mood changes, somatic Increased hot fl ashes and night symptoms, urinary sweats, vaginal dryness, sleeping symptoms, or incontinence disturbances, sexual dysfunction, and general wellbeing; decreased breast soreness, and quality of life. No association with mood changes, somatic symptoms, urinary symptoms, or incontinence (late perimenopause) 3049 women (40–60 years No associations with depression or quality of life Examination Follow- of age) from the US National Health and Nutrition Examination Survey (NHANES) (10 years) Ohio Midlife Women's 208 women (40–60 years of No associations with anxiety or depression age) from a community in Ohio, USA, including 57% white and 43% African-American women (2 years) Pennsylvania Ovarian 436 women (35–47 years Increased depression (CES-D score No increase in depression score of age) from Pennsylvania, 16 or higher) (transition from USA, including 50% white premenopause to early and 50% African-American and late perimenopause) 11 222 premenopausal and No associations with vasomotor symptoms, insomnia, dysphoric or depressed mood, or neuromuscular or somatic symptoms Women's Health Study perimenopausal women (35–55 years of age) from Seattle, USA, census tracts, including diff erent ethnic groups (2–3 years) Study of Women's 3306 women (40–55 years Increased vasomotor symptoms Increased depressive symptoms Increased depressive Health Across the of age), from diff erent (based on CES-D score 16 or higher) symptoms (based on CES-D community sites in the score 16 or higher) USA, followed up since 1995 (6 years) EDS=Edinburgh depression scale. CES-D=center for epidemiologic studies depression scale. PRIME-MD=primary care evaluation of mental disorders. *Summarised from reference 1.
Table 1: Associations of symptoms with menopausal stages* reported in cohort studies
between menopausal transition and mood changes, responsivity, libido, and frequency of sexual activity with development of mental disorders, or general mental menopause;40,41 depression and vaginal dryness were health;21,24,–34 others—including the Pennsylvania Ovarian reliable predictors of low sexual desire. Although decreased Aging Study,35 the Study of Women's health Across the oestradiol concentrations were associated with low sexual Nation (SWAN),36 and the Eindhoven Perimenopausal function in an Australian cohort, previous sexual and Osteoporosis study37—have shown associations. The partner issues have more substantial eff ects than hormonal inconsistent results probably indicate methodological factors.42 Studies of quality of life during menopause are diff erences, especially in how symptoms are measured.38 icting: some have indicated decline, others an No associations have been reported between cognitive improvement, and others no association.1change and menopause, in the few studies that have been Large cohorts provide useful information about the done;1 increased somatic symptoms are sometimes menopausal transition. However, individual experience reported.1 can be aff ected by many additional factors; ethnic origin Urinary complaints, including incontinence and leakage, and culture are important, but whether biological or were related to menopause in some,20 but not all,22,39 sociocultural factors have the biggest eff ect is unclear. investigations. Women reported decreased sexual Genetics, dietary practices, parity, body-mass index, www.thelancet.com Vol 371 March 1, 2008
and their association with menopause is crucial. Number of
Number of hot flashes per day
Number of hot flashes per day
Symptoms should be assessed and treated individually (mean difference 95% CI)
(mean difference 95% CI)
and specifi cally. If treatments for menopausal symptoms are prescribed, understanding their eff ectiveness and Transdermal oestradiol50 –3·2 (–5·1 to –1·5) safety is essential. Oral oestrogen51 –2·6 (–3·3 to –1·9) Many investigators have reported on the treatment of –2·8 (–3·8 to –1·8) Oestrogen+progestagen51 symptoms associated with the menopausal transition. –2·1 (–2·9 to –1·2) Oestrogen alone51 Most randomised, placebo-controlled trials focus on the –2·05 (–2·80 to –1·30) –1·13 (–1·70 to –0·57) treatment of vasomotor symptoms. These trials provide SSRI/SNRI antidepressants52 –1·66 (–2·43 to –0·89) useful information for the management of highly –1·37 (–3·03 to 0·29) symptomatic women, although not all proposed therapies –0·49 (–2·40 to 1·41) ciently assessed. Eff ectiveness varies –0·20 (–1·45 to 1·05) between therapies; evidence of substantial clinical benefi t –0·95 (–1·44 to –0·47) exists only for a few (fi gure 3). So y-extract isoflavones52 –1·15 (–2·33 to 0·03) Red-clover isoflavones52 –0·44 (–1·47 to 0·58) –8 –6 –4 –2 6 Oestrogen has been used for many years as a hormonal supplement to treat menopausal symptoms, and is the most eff ective treatment for vasomotor dysfunction in Figure 3: Results of trials of therapies for hot fl ashes
most women. This hormone is no longer recommended Hot fl ashes were reduced by two to three fl ashes per day with oestrogen, two with gabapentin, about one with paroxetine, and one with clonidine in double-blind, randomised, placebo-controlled trials. Isofl avones had slight or for prevention of chronic conditions,53 although it is no eff ect.
eff ective and approved for osteoporosis prevention.1 Oestrogen is provided in several formulations, and is physical activity, and environmental exposures diff er with most commonly given by oral, transdermal, or vaginal ethnic origin and culture, and are likely to aff ect the routes. Women with an intact uterus are prescribed the menopausal transition as they do other phases of "combined" or "opposed" regimen, in which oestrogen is reproductive life,11 and health in general. Additionally, the combined with progestagen: this is intended to avoid the perception and description of symptoms vary with development of endometrial hyperplasia and endometrial cultural context and language. Some women might cancer. The combined regimen can be administered on a interpret a vasomotor symptom as a warm sensation, cyclical basis, in which components are provided on whereas others might describe dizziness or other specifi c days of the month, or on a continuous schedule, sensation because it is more culturally meaningful to in which women take both hormones daily. Women them.43 without a uterus can take a daily dose of oestrogen In SWAN,36 done in the USA, African-American without progestagen (the "unopposed" regimen). Doses women reported more frequent vasomotor dysfunctions vary by formulation, but present recommendations than did white women, who in turn reported more than suggest the use of the lowest possible dose, for the did Hispanic, Chinese, and Japanese women.44,45 White shortest duration needed to relieve symptoms.1 Periodic and Hispanic women had sleep diffi culties more often attempts to taper and discontinue oestrogen treatment than did African-American, Chinese, and Japanese are encouraged, to reduce to a minimum potential women.46 Hispanic women reported body pain more adverse events, although the best method of discontinuing frequently than did white women.47 In surveys done in oestrogen is not known. The interruption of oestrogen Asia, most Asian women had body or joint pain rather therapy can be diffi cult for many women, who experience than vasomotor symptoms, although proportions varied a recurrence of symptoms.54 with ethnic group.48 The use of oestrogen to treat hot fl ashes has been studied in many randomised controlled trials; the results Management and treatment
are summarised in recent systematic reviews and Many questions about the menopausal transition and its meta-analyses.50,51,55,56 Most trials were done in the USA or eff ects on health have not yet been adequately answered. western Europe, and assessed forms of oestrogen that Considerable diff erences exist between individuals from are common in these countries, especially oestradiol and diff erent countries. Even in homogeneous populations, conjugated equine oestrogen. Trials often recruited individual experiences of menopause vary, as do participants from primary care or gynaecology practices, experiences of pregnancy. The best possible approach to focusing on healthy menopausal women in their the management of menopausal symptoms is to address early 50s; the baseline symptoms varied from study to each woman's unique needs. Surveys in the USA indicate that physicians A Cochrane meta-analysis of randomised controlled underestimate their patients' concerns about menopausal trials found that symptomatic women treated with symptoms.49 A correct diagnosis of clinical manifestations various forms of oral oestrogen had 2·6 fewer hot fl ashes www.thelancet.com Vol 371 March 1, 2008
Number Number of trials
Diff erence in number of daily
Diff erence in severity or
Potential adverse eff ects (selected)†
of trials
including women
hot fl ashes (95% CI)
composite score (%)*
with breast cancer
100–300 mg three times a day −2·05 (−2·80 to −1·30); Improved 17–30% Somnolence, fatigue, nausea, vomiting, and dizziness 10–20 and 12·5–25 controlled −1·66 (−2·43 to −0·89); Improved 25–35% Headache, nausea, drowsiness, and −1·37 (−3·03 to 0·29); two trials‡ Improved 25% Nausea and dry mouth −0·20 (−1·45 to 1·05) Nausea and dry mouth Reduced by <1 per day in 2 trials Improved in 2 trials Headache, nausea, drowsiness, dry mouth, and dizziness 37·5–150 extended release −0·49 (−2·40 to 1·41); 2 trials‡ Improved 10–35% Dry mouth, nausea, decreased appetite, constipation, and insomnia Improved 45% in 2 trials Mastodynia and galactorrhea Oral 0·025–0·075 mg twice a −0·95 (−1·44 to −0·47); 4 trials Improved 13–26% in 4 of Dry mouth, nausea, constipation, day; transdermal 0·1 insomnia, drowsiness, skin irritation −1·63 (−2·76, to −0·05); 2 trials with transdermal form Improved in 1 of 2 trials Dry mouth, nausea, and fatigue Bellergal Retard81 One tablet twice a day Dry mouth, dizziness, and sleepiness (0·6 mg ergotamine, 40 mg phenobarbital, 0·2 mg levorotatory alkaloids) SSRI/SNRI=selective serotonin reuptake inhibitor/selective noradrenergic reuptake inhibitor. *Frequency and severity. †Additional adverse eff ects are described in other sources. ‡Based on meta-analysis of trials.52 §Between-group diff erences not reported. Data presented in graphs.
Table 2: Effi
cacy of non-hormonal prescribed therapies in placebo-controlled trials
per day (95% CI 1·9–3·3) than did women given placebo.51 cholecystitis, and liver disorders.50 Oestrogen users have This eff ect was equivalent to a 75% reduction in frequency increased breast density, leading to higher rates of biopsy (0∙64–0∙82).51 Oestrogen users also had signifi cantly of lesions detected by mammography.57 Results of the reduced hot-fl ash severity, compared with placebo users. Women's Health Initiative (WHI), a large trial of The decrease in frequency of hot fl ashes was similar in conjugated equine oestrogen alone or combined with women treated with opposed and unopposed oestrogen medroxyprogesterone acetate versus placebo, reported regimens, than in those treated with placebo, although increased risks of stroke and venous thromboembolic severity decreased slightly more in women treated with events with both regimens.58,59 Risks of coronary heart the opposed regimen. disease and invasive breast cancer were also higher for In a systematic review, hot-fl ash frequency, severity, or those treated with conjugated equine oestrogen and both, improved with oral and transdermal forms of medroxyprogesterone acetate than for those treated with oestradiol more than it did with placebo.50 Oral oestradiol placebo,58 but not for those treated with conjugated reduced hot fl ashes by 2∙4 per day (1∙5–3∙2), and equine oestrogen alone.59 Secondary analysis of WHI transdermal oestradiol by 3∙2 per day (1∙5–5∙1); and data suggested that women starting hormone therapy results were similar for opposed and unopposed within 10 years from the onset of menopause had a regimens.50 Trials of oral conjugated equine oestrogen reduced risk of coronary heart disease, compared with reported similar improvements in hot-fl ash frequency, those who started later.60 Oestrogen should not be severity, or both. Trials comparing oestrogen agents prescribed to women with cardiovascular disease, a head-to-head (conjugated equine oestrogen vs oral or history of thromboembolic events, breast or uterine transdermal oestradiol) showed reduced number and cancer, or liver disease. The eff ects of other forms of severity of hot fl ashes for all treatment groups, with no oestrogen, including customised and bioidentical substantial diff erences between them.50 formulations, have not been well studied and are not Adverse eff ects of oestrogen have been well studied. known.
Breast tenderness and uterine bleeding are the most Few trials of progestagen or progesterone have common side-eff ects from short-duration treatment described their eff ectiveness as single agents for the trials.50 Others include nausea and vomiting, headache, treatment of hot fl ashes; these trials have confl icting61,62 weight change, dizziness, venous thromboembolic or inconclusive results.63–65 In a trial of women with events, cardiovascular events, rash and pruritus, breast cancer, the use of megestrol reduced hot fl ashes www.thelancet.com Vol 371 March 1, 2008
by 73% compared with 26% with placebo (p<0∙001).66 50% of trials of clonidine, a centrally active antihyper- Few trials have reported comparisons of testosterone tensive α-adrenergic agonist, showed substantially and oestrogen combinations versus oestrogen alone or reduced hot-fl ash frequency or severity, and the other placebo. One trial showed no diff erences between 50% did not.52 In combination, results from all trials treatment with testosterone and oestrogen versus suggest a reduction of about one hot fl ash per day treatment with oestrogen alone for hot-fl ash severity.67 (table 2).52 Clonidine might relieve hot fl ashes by Tibolone is a synthetic steroid with progestogenic, decreasing peripheral vascular reactivity. Trials comparing androgenic, and oestrogenic eff ects. Some trials methyldopa, an α-adrenergic antihypertensive agonist, comparing the eff ect of tibolone with that of placebo with placebo showed no signifi cant diff erences in showed decreased severity of hot fl ashes68,69 and a hot-fl ash frequency.52decreased score on Kupperman's scale;70 other trials did not.1 Common adverse eff ects of tibolone include uterine bleeding, body pain, weight gain, and headache.1 Trials of non-prescribed therapies are often diffi interpret because of variability of components and doses. Non-hormonal agents
Adverse eff ects, especially long-term eff ects, are not as Concerns about the adverse eff ects of oestrogen, after the well known as those of prescribed medications. Clinicians results of the WHI trial were published in 2002,58 have should access reliable sources to assess potential benefi ts led to increased interest in non-hormonal therapies for and harms of individual agents (for an example, see US menopausal symptoms. These agents have not been National Institutes of Health Offi approved by drug-regulating agencies for menopause; Supplements). moreover, they are associated with adverse eff ects that Phyto-oestrogens are plant-based substances that bind are well described (see US Food and Drug Administration). to oestrogen receptors, and have weak oestrogenic and Several trials of non-hormonal therapies enrolled women anti-oestrogenic activities. Soy isofl avone extracts, with vasomotor symptoms who have breast cancer, for containing predominantly daidzein, genistein, and their whom oestrogen is contraindicated. Whether women glucoconjugates, show mixed eff ects on hot fl ashes in with breast cancer have responses to these agents that placebo-controlled trials (table 3).52 In combination, are diff erent from those of women without cancer is not results indicated about one hot fl ash less per day clear, because of the small number of trials. Trials that compared with placebo, although some estimates were compare tamoxifen users and non-users showed similar not signifi cant.52 Other systematic reviews drew similar results;71 however, whether vasomotor symptoms of conclusions.113–115 Few trials of dietary forms of soy—women with breast cancer are induced mainly by including soy in beverages, powder, fl our, protein, cereal, menopause or by use of tamoxifen is not known. ns—reported improvements in frequency or Use of gabapentin, a γ-aminobutyric acid analogue for other hot-fl ash measures (table 3).1,83,84 treatment of seizures, reduced hot-fl ash frequency72,73 and Red-clover isofl avones, containing genistein, daidzein, severity72–74 compared with placebo in three trials (table 2). formononetin, and biochanin, did not improve frequency This reduction is equivalent to about two fewer hot or severity of hot fl ashes in placebo-controlled trials fl ashes per day.52 Women reported improvement when (table 3).52,85,116–121 Similarly, phyto-oestrogens from hop treated with 900 mg per day gabapentin,73,74 but not with extract,85 fl ax,84,87 and in topical forms,88,89 did not show 300 mg per day.73 benefi t in the treatment of hot fl ashes.
Two trials of paroxetine,75,76 a selective serotonin Black cohosh is a herbal therapy (Cimicifuga racemosa) reuptake inhibitor (SSRI), and two of venlafaxine,79,80 a believed to have oestrogenic properties. Black cohosh serotonin norepinephrine reuptake inhibitor (SNRI), does not reduce the frequency of hot fl ashes, and showed a reduction in hot-fl ash frequency of at least one although some trials showed improvement of other hot fl ash per day (table 2).52 This eff ect was not signifi cant hot-fl ash measures,90–92 others did not93–96 (table 3). Results in other trials of SSRIs and SNRIs. Although some trials are also ambiguous when black cohosh is added to soy of sertraline suggest potential benefi ts in reducing hot isofl avones97,98 or St John's wort.99 Black cohosh has been fl ashes,77,78 others do not.82 It has been postulated that hot associated with liver damage.122 fl ashes are linked to an overloading of serotonin-receptor Several trials assessing Chinese herbs showed no sites in the hypothalamus, which are then blocked by diff erences in hot fl ashes compared with placebo.1,83 SSRIs or SNRIs.75 In treatment trials, hot fl ashes Single trials of other supplements, such as evening improved earlier than did psychiatric symptoms, and primrose oil,100 phospholipid liposomes,101 and pollen irrespective of coexisting depression and anxiety.76 For extract102 reported some improvements in hot-fl ash some women, treatment of underlying depression might measures, but most did not (table 3).103–107 One small trial improve their ability to cope with their hot fl ashes. Trials of osteopathic manipulations reported improved hot of other antidepressants, veralipride and moclobemide, fl ashes and night sweats.108 Trials of refl exology,109 have been inconclusive because of methodological magnets,110 and aerobic exercise111 showed no limitations.52 improvement in hot-fl ash measures compared with www.thelancet.com Vol 371 March 1, 2008
Types and doses (mg/day)
Number of trials
Diff erence in number of daily hot fl ashes
Improvement in severity, composite
(including women
score,* or other measures†
with breast cancer)
Soy isofl avone extract52 Various components and doses −1·15 (−2·33 to 0·03); 5 trials at 4–6 weeks‡ Improved in 4 of 9 trials −0·97 (−1·82 to −0·12); 4 trials at 12–16 weeks‡ −1·22 (−2·02 to −0·42); 2 trials at 6 months‡ Soy beverage, powder, fl our, protein, cereal, Improved in 1 of 7 trials Improved in 2 of 10 trials Red-clover extract52,85 Promensil (40–160); rimostil (57) −0·44 (−1·47 to 0·58); 6 trials‡ Improved in 1 of 6 trials Hop-derived fl avonoids Lignans (20– 50) Topical agents88,89 Phyto-oestrogen cream, wild yam cream Black cohosh90–96 Improved in 3 of 7 trials Dietary combinations97–99 Soy isofl avones and black cohosh; St John's Improved in 2 of 3 trials Wort and black cohosh Ginseng, ginkgo, dong quai, pueraria lobata, Vitamin E, kava, phospholipid liposomes, Improved in 3 of 8 trials evening primrose oil, botanical formulas, guar gum, pollen extract, DHEA Manual therapies108 Improved hot fl ashes and night sweats Energy therapies109,110 Refl exology, magnets Improved with placebo vs magnets Behavioural interventions111 Aerobic exercise Various treatments DHEA=dehydroepiandrosterone. *Frequency and severity. †Additional measures of hot fl ashes are included in this column because few trials of non-prescribed therapies provided severity and composite measures comparable to trials of prescribed therapies. ‡Based on meta-analysis of trials.52 §Between-group diff erences not reported.
Table 3: Effi
cacy of non-prescribed therapies in placebo-controlled trials
placebo. A pilot study of acupuncture reduced night-time through the menopausal transition; the placebo eff ect; or hot fl ashes,112 but other trials of acupuncture did not diff erent eff ects in diff erent groups of women (for show benefi t.1,83 instance, a positive eff ect only in women with the most severe symptoms, or comorbidities). Some symptoms Therapies for non-vasomotor symptoms
could be secondary to others and improve as the primary Vaginal dryness and dyspareunia improved in trials of symptom is treated, such as sleep disturbances arising oral and vaginal forms of oestrogen.123 For vaginal from night sweats. As the epidemiological evidence symptoms, the intravaginal oestradiol ring, oestradiol indicates, some symptoms might not be related to tablet, and conjugated equine oestrogen vaginal cream menopause; if so, they would not be expected to improve are similarly eff ective for relief of vaginal dryness, with menopause-specifi c therapies such as oestrogen. dyspareunia, reso lution of atrophic signs, improvement in vaginal mucosal maturation indices, and reduction in vaginal pH.123 Some women report reduced vaginal Menopause is an expected life event for midlife women. dryness with non-oestrogen moisturisers. Oestrogen Most women have transient symptoms that are does not improve urinary frequency and incontinence.1 A manageable with self-care approaches, such as wearing few trials comparing oestrogen plus testosterone with layers of clothing, and lowering stress. Some women oestrogen alone, or placebo, showed improved scores on ask health providers for help to manage menopausal sexual questionnaires addressing sexual interest and symptoms, especially frequent and severe vasomotor desire, responsiveness, and frequency of sexual activity, symptoms and vaginal dryness, that interfere with among other topics.1 Tibolone could improve sexual healthy living. Coexistent health concerns can complicate interest and performance.1 the presentation, and require independent assessment. Treatment of other symptoms, including sleep Social changes that are common in midlife, such as disturbances, mood changes, somatic complaints, and children leaving home, parents becoming ill or disabled, quality of life, have been assessed in trials for most and the patient's changing role in society, can also aff ect therapies,1 but results are inconclusive. This ambiguity the experience of menopause. Studies of menopause might be due to the insensitivity and non-comparability are vast in number, but incomplete in what they of various measures and outcomes considered; the uncover.124 Nonetheless, these results inform the eventual resolution of symptoms as women progress recommendations of medical professional organisations, www.thelancet.com Vol 371 March 1, 2008
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