Jersey Alcohol Profile Health Intelligence Unit, November 2015 HIU INFORMATION READER Document purpose Report on Alcohol indicators for Jersey in 2015 Jersey Alcohol Profile 2015 Health Intelligence Unit Publication date 17 November 2015 States of Jersey Statistics Unit, States of Jersey Police, Social Circulation list Security, HSSD, Superintendent Registrar Biennial report on alcohol use and its consequences for Islanders in Jersey for 2015. Information on consumption and patterns of
Therefore, it is necessary to see your doctor about any defects cialis australia but also by those who experience temporary dip in sexual activeness.
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
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)
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)
(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)†
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
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
and inﬂ uence standards of practice.125,126 Improved 22 Dennerstein L, Dudley EC, Hopper JL, Guthrie JR, Burger HG. understanding of the menopausal transition, its A prospective population-based study of menopausal symptoms.
Obstet Gynecol 2000; 96: 351–58.
symptoms, and therapies will permit a better response 23 Koster A, Eplov LF, Garde K. Anticipations and experiences of to the needs of patients.
menopause in a Danish female general population cohort born
in 1936. Arch Womens Ment Health 2002; 5: 9–13.
Conﬂ ict of interest statement
24 Kaufert PA, Gilbert P, Tate R. The Manitoba Project: I declare that I have no conﬂ ict of interest.
a re-examination of the link between menopause and depression. Maturitas 1992; 14: 143–55.
I would like to thank Sydney Edlund-Jermain for collecting articles and 25 Avis NE, Brambilla D, McKinlay SM, Vass K. A longitudinal managing references, Andrew Hamilton for undertaking literature analysis of the association between menopause and depression. searches, and collaborators of previous reviews on menopause and its Results from the Massachusetts Women's Health Study. therapies at the Oregon Evidence-based Practice Center. This study was Ann Epidemiol 1994; 4: 214–20.
supported by Providence Women and Children's Health Research Center.
26 McKinlay SM, McKinlay JB. The impact of menopause and social factors on health. In: Hammond CB, Haseltine FP, Schiﬀ I, eds. References
Menopause: evaluation, treatment, and health concerns. New York: Nelson H, Haney E, Humphrey L, et al. Management of Alan R Liss, 1989: 137–61.
menopause-related symptoms. Evidence Report/Technology 27 Mitchell ES, Woods NF. Symptom experiences of midlife women: Assessment 120. Rockville, MD: Agency for Healthcare Research observations from the Seattle Midlife Women's Health Study. and Quality, 2005.
Maturitas 1996; 25: 1–10.
Dudley EC, Hopper JL, Taﬀ e J, Guthrie JR, Burger HG, 28 Woods NF, Mitchell ES. Pathways to depressed mood for midlife Dennerstein L. Using longitudinal data to deﬁ ne the perimenopause women: observations from the Seattle Midlife Women's Health by menstrual cycle characteristics. Climacteric 1998; 1: 18–25.
Study. Res Nurs Health 1997; 20: 119–29.
3 Taﬀ e JR, Dennerstein L. Menstrual patterns leading to the ﬁ nal 29 Glazer G, Zeller R, Delumba L, et al. The Ohio Midlife Women's menstrual period. Menopause 2002; 9: 32–40.
Study. Health Care Women Int 2002; 23: 612–30.
Soules MR, Sherman S, Parrott E, et al. Executive Summary: stages 30 Busch CM, Zonderman AB, Costa PT. Menopausal transition and of reproductive aging workshop (STRAW), Park City, Utah, July psychological distress in a nationally representative sample: is 2001. Menopause 2001; 8: 402–07.
menopause associated with psychological distress? J Aging Health Johnston JM, Colvin A, Johnson BD, et al. Comparison of SWAN 1994; 6: 209–28.
and WISE Menopausal Status Classiﬁ cation Algorithms. 31 Hallstrom T, Samuelsson S. Mental health in the climacteric. The J Women Health 2006; 15: 1184–94.
longitudinal study of women in Gothenburg. Harlow SD, Cain K, Crawford S, et al. Evaluation of four proposed Acta Obstet Gynecol Scand Suppl 1985; 130: 13–18.
bleeding criteria for the onset of late menopausal transition. 32 Mishra GD, Brown WJ, Dobson AJ. Physical and mental health: J Clin Endocrinol Metab 2006; 91: 3432–38.
changes during menopause transition. Qual Life Res 2003; 12: 405–12.
Randolph JF Jr, Crawford S, Dennerstein L, et al. The value of 33 Dennerstein L, Lehert P, Burger H, Dudley E. Mood and the follicle-stimulating hormone concentration and clinical ﬁ ndings as menopausal transition. J Nerv Ment Dis 1999; 187: 685–91.
markers of the late menopausal transition. J Clin Endocrinol Metab 34 Dennerstein L, Lehert P, Dudley E, Guthrie J. Factors contributing 2006; 91: 3034–40.
to positive mood during the menopausal transition. J Nerv Ment Dis 8 Mansﬁ eld PK, Carey M, Anderson A, Barsom SH, Koch PB. Staging 2001; 189: 84–89.
the menopausal transition: data from the TREMIN Research Program 35 Freeman EW, Sammel MD, Lin H, Nelson DB. Associations of on Women's Health. Womens Health Issues 2004; 14: 220–26.
hormones and menopausal status with depressed mood in women North American Menopause Society. Menopause Guidebook, 6th edn. with no history of depression. Arch Gen Psychiatry 2006; http://www.menopause.org/MGI.pdf (accessed April 6, 2007).
10 Gold EB, Bromberger J, Crawford S, et al. Factors associated with 36 Bromberger J, Matthews KA, Brockwell S, et al. Depressive age at natural menopause in a multiethnic sample of midlife symptoms during the menopausal transition: The Study of women. Am J Epidemiol 2001; 153: 865–74.
Women's Health Across the Nation (SWAN) J Aﬀ ect Disord 2007. 11 Melby MK, Lock M, Kaufert P. Culture and symptom reporting at DOI: 10.1016/j.jad.2007.01.034. menopause. Hum Reprod Update; 11: 495–512.
37 Maartens LW, Knottnerus JA, Pop VJ. Menopausal transition and 12 North American Menopause Society. http://www.menopause.org increased depressive symptomatology: a community based (accessed Dec 13, 2004).
prospective study. Maturitas 2002; 42: 195–200.
13 Casper RF, Yen SS. Neuroendocrinology of menopausal ﬂ ushes: a 38 Vesco KK, Haney EM, Humphrey L, Fu R, Nelson HD. Inﬂ uences hypothesis of ﬂ ush mechanism. Clin Endocrinol (Oxf) 1985; of menopause on mood: a systematic review of cohort studies. Climacteric 2007; 10: 448–65.
14 Freedman RR, Norton D, Woodward S, Cornelissen G. Core body 39 Sherburn M, Guthrie JR, Dudley EC, O'Connell HE, Dennerstein L. temperature and circadian rhythm of hot ﬂ ashes in menopausal Is incontinence associated with menopause? Obstet Gynecol 2001; women. J Clin Endocrinol Metab 1995; 80: 2354–58.
15 Freedman RR, Krell W. Reduced thermoregulatory null zone in 40 Dennerstein L, Dudley E, Burger H. Are changes in sexual postmenopausal women with hot ﬂ ashes. Am J Obstet Gynecol 1999; functioning during midlife due to aging or menopause? Fertil Steril 2001; 76: 456–60.
16 Avis NE, Brockwell S, Colvin A. A universal menopausal syndrome? 41 Dennerstein L, Randolph J, Taﬀ e J, Dudley E, Burger H. Hormones, Am J Med 2005; 118 (suppl 2): 37–46.
mood, sexuality, and the menopausal transition. Fertil Steril 2002; 17 Greene JG. A factor analytic study of climacteric symptoms. 77 (suppl 4): S42–48.
J Psychosom Res 1976; 20: 425–30.
42 Dennerstein L, Lehert P, Burger H, Guthrie J. Sexuality. Am J Med 18 National Institutes of Health. Assessing and improving measures of 2005; 118 (suppl 2): 59–63.
hot ﬂ ashes: summary of an NIH workshop. Bethesda, MD: Rose Li 43 Boulet MJ, Oddens BJ, Lehert P, Vemer HM, Visser A. Climacteric and Associates, Jan 20, 2004.
and menopause in seven South-east Asian countries. Maturitas 19 Hilditch JR, Lewis J, Peter A, et al. A menopause-speciﬁ c quality of 1994; 19: 157–76.
life questionnaire: development and psychometric properties. 44 Avis NE, Stellato R, Crawford S, et al. Is there a menopausal Maturitas 1996; 24: 161–75.
syndrome? Menopausal status and symptoms across racial/ethnic 20 Brown WJ, Mishra GD, Dobson A. Changes in physical symptoms groups. Soc Sci Med 2001; 52: 345–56.
during the menopause transition. Int J Behav Med 2002; 9: 53–67.
45 Gold EB, Sternfeld B, Kelsey JL, et al. Relation of demographic 21 Hardy R, Kuh D. Change in psychological and vasomotor and lifestyle factors to symptoms in a multi-racial/ethnic symptom reporting during the menopause. Soc Sci Med 2002; 55:
population of women 40–55 years of age. Am J Epidemiol 2000; www.thelancet.com Vol 371 March 1, 2008
46 Kravitz HM, Ganz PA, Bromberger J, Powell LH, Sutton-Tyrrell K, 68 Meeuwsen IB, Samson MM, Duursma SA, Verhaar HJ. The Meyer PM. Sleep diﬃ culty in women at midlife: a community inﬂ uence of tibolone on quality of life in postmenopausal women. survey of sleep and the menopausal transition. Menopause 2003; Maturitas 2002; 41: 35–43.
69 Landgren MB, Helmond FA, Engelen S. Tibolone relieves 47 Avis NE, Ory M, Matthews KA, Schocken M, Bromberger J, climacteric symptoms in highly symptomatic women with at least Colvin A. Health-related quality of life in a multiethnic sample of seven hot ﬂ ushes and sweats per day. Maturitas 2005; 50: 222–30.
middle-aged women: Study of Women's Health Across the Nation 70 Baksu A, Ayas B, Citak S, Kalan A, Baksu B, Goker N. Eﬃ (SWAN). Med Care 2003; 41: 1262–76.
tibolone and transdermal estrogen therapy on psychological 48 Haines CJ, Xing S-M, Park K-H, Holinka CF, Ausmanas MK. symptoms in women following surgical menopause. Prevalence of menopausal symptoms in diﬀ erent ethnic groups of Int J Gynaecol Obstet 2005; 91: 58–62.
Asian women and responsiveness to therapy with three doses of 71 Sloan JA, Loprinzi CL, Novotny PJ, Barton DL, LaVasseur BI, conjugated estrogens/medroxyprogesterone acetate: the Pan-Asia Windschitl HE. Methodological lessons learned from hot ﬂ ash Menopause (PAM) study. Maturitas 2005; 52: 264–76.
studies. J Clin Oncol 2001; 19: 4280–90.
49 Ghali WA, Freund KM, Boss RD, Ryan CA, Moskowitz MA. 72 Guttuso T, Jr., Kurlan R, McDermott MP, Kieburtz K. Gabapentin's Menopausal hormone therapy: physician awareness of patient eﬀ ects on hot ﬂ ashes in postmenopausal women: a randomized attitudes. Am J Med 1997; 103: 3.
controlled trial. Obstet Gynecol 2003; 101: 337–45.
50 Nelson HD. Commonly used types of postmenopausal estrogen 73 Pandya KJ, Morrow GR, Roscoe JA, et al. Gabapentin for hot ﬂ ashes for treatment of hot ﬂ ashes: scientiﬁ c review. JAMA 2004; in 420 women with breast cancer: a randomised double-blind placebo-controlled trial. Lancet 2005; 366: 818–24.
51 MacLennan AH, Broadbent JL, Lester S, Moore V. Oral oestrogen 74 Reddy SY, Warner H, Guttuso T Jr, et al. Gabapentin, estrogen, and and combined oestrogen/progestogen therapy versus placebo for placebo for treating hot ﬂ ushes: a randomized controlled trial. hot ﬂ ushes. Cochrane Database Syst Rev 2004. CD002978.
Obstet Gynecol 2006; 108: 41–48.
52 Nelson HD, Vesco KK, Haney E, et al. Nonhormonal therapies for 75 Stearns V, Beebe KL, Iyengar M, Dube E. Paroxetine controlled menopausal hot ﬂ ashes: systematic review and meta-analysis. release in the treatment of menopausal hot ﬂ ashes: a randomized JAMA 2006; 295: 2057–71.
controlled trial. JAMA 2003; 289: 2827–34.
53 US Preventive Services Task Force. Hormone replacement therapy 76 Stearns V, Slack R, Greep N, et al. Paroxetine is an eﬀ ective for the prevention of chronic conditions in postmenopausal treatment for hot ﬂ ashes: results from a prospective randomized clinical trial. J Clin Oncol 2005; 23: 6919–30.
(accessed April 6, 2007).
77 Gordon PR, Kerwin JP, Boesen KG, Senf J. Sertraline to treat hot 54 Grady D, Sawaya GF. Discontinuation of postmenopausal hormone ﬂ ashes: a randomized controlled, double-blind, crossover trial in a therapy. Am J Med 2005; 118 (suppl 2): 163–65.
general population. Menopause 2006; 13: 568–75.
55 MacLennan A, Lester S, Moore V. Oral estrogen replacement 78 Kimmick GG, Lovato J, McQuellon R, Robinson E, Muss HB. therapy versus placebo for hot ﬂ ushes: a systematic review. Randomized, double-blind, placebo-controlled, crossover study of Climacteric 2001; 4: 58–74.
sertraline (Zoloft) for the treatment of hotﬂ ashes in women with 56 Nelson HD. Postmenopausal estrogen for treatment of hot ﬂ ashes: early stage breast cancer taking tamoxifen. Breast J 2006; clinical applications. JAMA 2004; 291: 1621–25.
57 Chlebowski RT, Hendrix SL, Langer RD, et al. Inﬂ uence of estrogen 79 Loprinzi CL, Kugler JW, Sloan JA, et al. Venlafaxine in management plus progestin on breast cancer and mammography in healthy of hot ﬂ ashes in survivors of breast cancer: a randomised controlled postmenopausal women: the Women's Health Initiative trial. Lancet 2000; 356: 2059–63.
Randomized Trial. JAMA 2003; 289: 3243–53.
80 Carpenter JS, Storniolo AM, Johns S, et al. Randomized, 58 Rossouw JE, Anderson GL, Prentice RL, et al. Risks and beneﬁ ts of double-blind, placebo-controlled crossover trials of venlafaxine for estrogen plus progestin in healthy postmenopausal women: hot ﬂ ashes after breast cancer. Oncologist 2007; 12: 124–35.
principal results from the Women's Health Initiative randomized 81 Bergmans MG, Merkus JM, Corbey RS, Schellekens LA, controlled trial. JAMA 2002; 288: 321–33.
Ubachs JM. Eﬀ ect of Bellergal Retard on climacteric complaints: 59 The Women's Health Initiative Steering Committee. eﬀ ects of a double-blind, placebo-controlled study. Maturitas 1987; conjugated equine estrogen in postmenopausal women with 9: 227–34.
hysterectomy: the Women's Health Initiative Randomized 82 Grady D, Cohen B, Tice J, Kristof M, Olyaie A, Sawaya GF. Controlled Trial. JAMA 2004; 291: 1701–12.
Ineﬀ ectiveness of sertraline for treatment of menopausal hot 60 Rossouw JE, Prentice RL, Manson JE, et al. Postmenopausal ﬂ ushes. Obstet Gynecol 2007; 109: 823–30.
hormone therapy and risk of cardiovascular disease by age and 83 Nedrow A, Miller J, Walker M, Nygren P, Huﬀ man LH, Nelson HD. years since menopause. JAMA 2007; 297: 1465–77.
Complementary and alternative therapies for the management of 61 Wren BG, Champion SM, Willetts K, Manga RZ, Eden JA. menopause-related symptoms: a systematic evidence review. Transdermal progesterone and its eﬀ ect on vasomotor symptoms, Arch Intern Med 2006; 166: 1453–65.
blood lipid levels, bone metabolic markers, moods, and quality of 84 Lewis JE, Nickell LA, Thompson LU, Szalai JP, Kiss A, Hilditch JR. life for postmenopausal women. Menopause 2003; 10: 13–18.
A randomized controlled trial of the eﬀ ect of dietary soy and 62 Leonetti HB, Longo S, Anasti JN. Transdermal progesterone cream ns on quality of life and hot ﬂ ashes during for vasomotor symptoms and postmenopausal bone loss. menopause. Menopause 2006; 13: 631–42.
Obstet Gynecol 1999; 94: 225–28.
85 Hidalgo LA, Chedraui PA, Morocho N, Ross S, San Miguel G. The 63 de Wit H, Schmitt L, Purdy R, Hauger R. Eﬀ ects of acute eﬀ ect of red clover isoﬂ avones on menopausal symptoms, lipids and progesterone administration in healthy postmenopausal women vaginal cytology in menopausal women: a randomized, double-blind, and normally-cycling women. Psychoneuroendocrinology 2001; placebo-controlled study. Gynecol Endocrinol 2005; 21: 257–64.
86 Heyerick A, Vervarcke S, Depypere H, Bracke M, De Keukeleire D. 64 Morrison JC, Martin DC, Blair RA, et al. The use of A ﬁ rst prospective, randomized, double-blind, placebo-controlled medroxyprogesterone acetate for relief of climacteric symptoms. study on the use of a standardized hop extract to alleviate Am J Obstet Gynecol 1980; 138: 99–104.
menopausal discomforts. Maturitas 2006; 54: 164–75.
65 Schiﬀ I, Tulchinsky D, Cramer D, Ryan KJ. Oral 87 Dodin S, Lemay A, Jacques H, Legare F, Forest JC, Masse B. The medroxyprogesterone in the treatment of postmenopausal eﬀ ects of ﬂ axseed dietary supplement on lipid proﬁ le, bone mineral symptoms. JAMA 1980; 244: 1443–45.
density, and symptoms in menopausal women: a randomized, 66 Loprinzi CL, Michalak JC, Quella SK, et al. Megestrol acetate for the double-blind, wheat germ placebo-controlled clinical trial. prevention of hot ﬂ ashes. N Engl J Med 1994; 331: 347–52.
J Clin Endocrinol Metab 2005; 90: 1390–97.
67 Hickok LR, Toomey C, Speroﬀ L. A comparison of esteriﬁ ed 88 Carranza-Lira S, Barahona OF, Ramos D, et al. Changes in estrogens with and without methyltestosterone: eﬀ ects on symptoms, lipid and hormone levels after the administration of a endometrial histology and serum lipoproteins in postmenopausal cream with phytoestrogens in the climacteric—preliminary report. women. Obstet Gynecol 1993; 82: 919–24.
Int J Fertil Womens Med 2001; 46: 296–99.
www.thelancet.com Vol 371 March 1, 2008
89 Komesaroﬀ PA, Black CV, Cable V, Sudhir K. Eﬀ ects of wild yam 107 Barton DL, Loprinzi CL, Quella SK, et al. Prospective evaluation of extract on menopausal symptoms, lipids and sex hormones in vitamin E for hot ﬂ ashes in breast cancer survivors. J Clin Oncol healthy menopausal women. Climacteric 2001; 4: 144–50.
1998; 16: 495–500.
90 Osmers R, Friede M, Liske E, Schnitker J, Freudenstein J, 108 Cleary C, Fox JP. Menopausal symptoms: an osteopathic Henneicke-von Zepelin H-H. Eﬃ cacy and safety of isopropanolic investigation. Complement Ther Med 1994; 2: 181–86.
black cohosh extract for climacteric symptoms. Obstet Gynecol 2005; 109 Williamson J, White A, Hart A, Ernst E. Randomised controlled trial of reﬂ exology for menopausal symptoms. BJOG 2002; 91 Jacobson JS, Troxel AB, Evans J, et al. Randomized trial of black cohosh for the treatment of hot ﬂ ashes among women with a history 110 Carpenter JS, Johnson D, Wagner L, Andrykowski M. Hot ﬂ ashes of breast cancer. J Clin Oncol 2001; 19: 2739–45.
and related outcomes in breast cancer survivors and matched 92 Hernandez Munoz G, Pluchino S. Cimicifuga racemosa for the comparison women. Oncol Nurs Forum Online 2002; 29: E16–25.
treatment of hot ﬂ ushes in women surviving breast cancer. 111 Aiello EJ, Yasui Y, Tworoger SS, et al. Eﬀ ect of a yearlong, Maturitas 2003; 44 (suppl 1): S59–65.
moderate-intensity exercise intervention on the occurrence and 93 Wuttke W, Seidlova-Wuttke D, Gorkow C. The Cimicifuga severity of menopause symptoms in postmenopausal women. preparation BNO 1055 vs conjugated estrogens in a double-blind Menopause 2004; 11: 382–88.
placebo-controlled study: eﬀ ects on menopause symptoms and 112 Huang MI, Nir Y, Chen B, Schnyer R, Manber R. A randomized bone markers. Maturitas 2003; 44 (suppl 1): S67–77.
controlled pilot study of acupuncture for postmenopausal hot 94 Newton KM, Reed SD, LaCroix AZ, Grothaus LC, Ehrlich K, ﬂ ashes: eﬀ ect on nocturnal hot ﬂ ashes and sleep quality. Fertil Steril Guiltinan J. Treatment of vasomotor symptoms of menopause with 2006; 86: 700–10.
black cohosh, multibotanicals, soy, hormone therapy, or placebo. 113 Krebs EE, Ensrud KE, MacDonald R, Wilt TJ. Phytoestrogens for Ann Intern Med 2006; 145: 869–79.
treatment of menopausal symptoms: a systematic review. 95 Frei-Kleiner S, Schaﬀ ner W, Rahlfs VW, Bodmer C, Birkhauser M. Obstet Gynecol 2004; 104: 824–36.
Cimicifuga racemosa dried ethanolic extract in menopausal disorders: 114 Balk E, Chung M, Chew P, et al. Eﬀ ects of soy on health outcomes. a double-blind placebo-controlled clinical trial. Maturitas 2005; Summary, Evidence Report/Technology Assessment 126. Rockville, MD: AHRQ, 2005.
96 Pockaj BA, Gallagher JG, Loprinzi CL, et al. Phase III double-blind, 115 Cassidy A, Albertazzi P, Lise Nielsen I, et al. Critical review of randomized, placebo-controlled crossover trial of black cohosh in health eﬀ ects of soyabean phyto-oestrogens in post-menopausal the management of hot ﬂ ashes: NCCTG Trial N01CC1. J Clin Oncol women. Proc Nutr Soc 2006; 65: 76–92.
2006; 24: 2836–41.
116 Atkinson C, Warren RM, Sala E, et al. Red-clover-derived isoﬂ avones 97 Russo R, Corosu R. The clinical use of a preparation based on and mammographic breast density: a double-blind, randomized, phyto-oestrogens in the treatment of menopausal disorders. placebo-controlled trial. Breast Cancer Res 2004; 6: R170–79.
Acta Biomed Ateneo Parmense 2003; 74: 137–43.
117 Baber RJ, Templeman C, Morton T, Kelly GE, West L. Randomized 98 Uebelhack R, Blohmer J-U, Graubaum H-J, Busch R, Gruenwald J, placebo-controlled trial of an isoﬂ avone supplement and Wernecke K-D. Black cohosh and St. John's wort for climacteric menopausal symptoms in women. Climacteric 1999; 2: 85–92.
complaints: a randomized trial. Obstet Gynecol 2006; 107: 247–55.
118 Jeri AR. The use of an isoﬂ avone supplement to relieve hot ﬂ ashes. 99 Verhoeven MO, van der Mooren MJ, van de Weijer PHM, et al. Female Patient 2002; 27: 35–37.
Eﬀ ect of a combination of isoﬂ avones and Actaea racemosa Linnaeus 119 Knight DC, Howes JB, Eden JA. The eﬀ ect of Promensil, an on climacteric symptoms in healthy symptomatic perimenopausal isoﬂ avone extract, on menopausal symptoms. Climacteric 1999; women: a 12-week randomized, placebo-controlled, double-blind 2: 79–84.
study. Menopause 2005; 12: 412–20.
120 Tice JA, Ettinger B, Ensrud K, Wallace R, Blackwell T, Cummings 100 Chenoy R, Hussain S, Tayob Y, O'Brien PM, Moss MY, Morse PF. SR. Phytoestrogen supplements for the treatment of hot ﬂ ashes: the Eﬀ ect of oral gamolenic acid from evening primrose oil on Isoﬂ avone Clover Extract (ICE) study: a randomized controlled trial. menopausal ﬂ ushing. BMJ 1994; 308: 501–03.
JAMA 2003; 290: 207–14.
101 Rachev E, Nalbansky B, Kolarov G, Agrosi M. Eﬃ cacy and safety of 121 van de Weijer PH, Barentsen R. Isoﬂ avones from red clover phospholipid liposomes in the treatment of neuropsychological (Promensil) signiﬁ cantly reduce menopausal hot ﬂ ush symptoms disorders associated with the menopause: a double-blind, randomised, compared with placebo. Maturitas 2002; 42: 187–93.
placebo-controlled study. Curr Med Res Opin 2001; 17: 105–10.
122 Whiting PW, Clouston A, Kerlin P. Black cohosh and other herbal 102 Winther K, Rein E, Hedman C. Femal, a herbal remedy made from remedies associated with acute hepatitis. Med J Australia 2002; pollen extracts, reduces hot ﬂ ushes and improves quality of life in menopausal women: a randomized, placebo-controlled, parallel 123 Nelson HD, Nygren P, Freeman M, Benjamin K. Drug Class study. Climacteric 2005; 8: 162–70.
Review on Estrogens. http://www.ohsu.edu/drugeﬀ ectiveness/ 103 Barnhart KT, Freeman E, Grisso JA, et al. The eﬀ ect of dehydroepiandrosterone supplementation to symptomatic (accessed April 6, 2007).
perimenopausal women on serum endocrine proﬁ les, lipid 124 National Institutes of Health. National Institutes of Health parameters, and health-related quality of life. State-of-the-Science Conference statement: management of J Clin Endocrinol Metab 1999; 84: 3896–902.
menopause-related symptoms. Ann Intern Med 2005; 142: 1003–13.
104 Hudson TS, Standish L, Breed C, et al. Clinical and 125 Stephenson J. FDA orders estrogen safety warnings: agency oﬀ ers endocrinological eﬀ ects of a menopausal botanical formula. guidance for HRT use. JAMA 2003; 289: 537–38.
J Med Issue 1998; 7: 73–77.
126 North American Menopause Society. Recommendations for 105 Cagnacci A, Arangino S, Renzi A, Zanni AL, Malmusi S, Volpe A. estrogen and progestogen use in peri-and postmenopausal women: Kava-Kava administration reduces anxiety in perimenopausal October 2004 position statement of The North American women. Maturitas 2003; 44: 103–09.
Menopause Society. Menopause 2004; 11: 589–600.
106 Makkonen M, Simpanen AL, Saarikoski S, et al. Endocrine and metabolic eﬀ ects of guar gum in menopausal women.
Gynecol Endocrinology 1993; 7: 135–41.
www.thelancet.com Vol 371 March 1, 2008
BURN WOUND CARE WITH Skin acts as a barrier against infection. CLEANING AND DRESSING YOUR Once you lose your skin, it increases your BURN WOUNDS chance for infection to occur. Taking careof your burn is very important. The • Take pain medication about 30 minutes before following are ways to prevent infection and