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Page 1

HAPTER

3: S

YMPTOMS AND THE

ENOPAUSE

1. Conflicting findings regarding which symptoms are related to hormonal

changes of menopause reflect different research methodologies and their

limitations.

2. When symptom checklists are used, middle-aged women are highly

symptomatic.

3. Age related symptoms may be differentiated from those related to the

menopausal phase.

4. Only vasomotor symptoms, vaginal atrophic symptoms, and breast tender-

ness consistently vary with the phase of the menopause transition and are

significantly affected by the administration of hormones in double blind

RCTs [A].

5. Other symptoms, such as insomnia and mood, may be affected by the

presence of bothersome vasomotor symptoms.

6. Symptoms are influenced by psychosocial and lifestyle factors.

Lorraine Dennerstein, A.O., M.B.B.S., Ph.D., F.R.A.N.Z.C.P., D.P.M.;* Janet Guthrie, M.Sc., Dip. Ed. Ph.D.;

†

Martin

Birkhäuser, M.D.;

‡

Sherry Sherman, Ph.D.

OINTS

* From the Office for Gender and Health, Department of Psychiatry, University of Melbourne, Royal Melbourne Hospital, Australia.

†

From the Office for Gender and Health, Department of Psychiatry, Faculty of Medicine, Dentistry, and Health Sciences, University of Melbourne,

Australia.

‡

From the Division of Gynaecological Endocrinology, Department of Obstetrics and Gynaecology, University of Bern, Switzerland.

From the Clinical Endocrinology and Osteoporosis Research Branch, National Institute on Aging, NIH, Bethesda, MD U.S.A.

Evidence categories are given in square brackets. A = randomized controlled trials (rich body of data); B = randomized controlled trials (limited data);

C = nonrandomized trials and observational epidemiologic studies; D = Panel expert judgement. (See also table 1–1).

Conflicting findings

regarding which

symptoms are related

to hormonal changes

of menopause reflect

different research

methodologies and

their limitations.

Page 2

1. I

NTRODUCTION

A large number of symptoms have been variously

linked with the menopause transition. Important

clinical questions include the following:

1. What are the most frequent symptoms experi-

enced by middle-aged women?

2. Which of these are related to the hormonal

events reflected in the different phases of the

menopausal transition, and which relate to aging?

3. What is the role of other psychosocial and

lifestyle factors in determining women’s experi-

ence of symptoms?

4. What evidence is there for the effectiveness of

treatment interventions for symptoms linked to

the transition to menopause?

2. Q

UALITY OF

IFE AND

YMPTOMS

The term “quality of life” refers to

a subjective perception on the part

of both researcher and subject.

Areas covered range from health

status (SF–36),

life satisfaction,

coping,

and depression (Center

for Epidemiologic Studies

Depression scale)

to scales mea-

suring symptoms thought to be characteristic of

specific states, such as menopause. This breadth of

coverage and absence of a single, widely accepted

definition may be a limiting feature of the concept

of quality of life.

There are two different types of

measures: global quality of life or aspects specific

to a particular disease (such as osteoporosis) or a

physiological state such as the hormonal changes

underlying the menopause transition. Scales

designed to measure the latter make the assump-

tion that the more symptoms are present and the

more severe those symptoms are, the lower is the

ensuing quality of life. Yet there has been surpris-

ingly little research linking symptom presence with

the other more global aspects of quality of life

described above.

There is debate as to whether the term “sign” or

“symptom” should be used when referring to the

events of the menopausal transition. The term

“sign” is often used to refer to objective clinical

manifestation of a disease, such as a lump or a

bruit, whereas the term “symptoms” is used to

refer to those bodily perceptions presented as

complaints by the individual. This chapter uses the

term “symptom” in this context.

3. M

ETHODOLOGICAL

SPECTS OF

EASURING

YMPTOMS

Conflicting findings as to the etiology of symp-

toms in midlife reflect some of the methodological

difficulties inherent in menopause research as well

as specific issues pertaining to the measurement of

symptoms, such as sample selection, validity of

symptom measures, age at baseline and length of

followup, separation of the effects of the natural

menopausal transition from that of induced

menopause, statistical and experimental design.

The most obvious methodological issue is the

potential to confuse studies evaluating the effects

of estrogen or differences between estrogen users

and nonusers on various outcomes as “studies of

menopause.” In order to distinguish menopause-

related changes (due to changes from altered levels

of estrogen and/or other sex hormones) from those

of aging or disease, it is necessary to elucidate the

processes of the transition from premenopause to

postmenopause. Although there is an abundance

of studies and findings on the effects of ERT on

various physiological and psychological outcomes,

the actual processes and mechanisms of follicular

depletion which underlie the transition to

menopause are poorly understood.

3.1 Study Type

Clearly a number of different research modes can

be used to explore whether the menopause transi-

tion affects quality of life, varying from studies of

primates (often involving extirpative surgery and

then hormonal intervention), to clinical trials of

Symptoms are

influenced by

psychosocial and

lifestyle factors.

Page 3

women who may have reached natural menopause

or had menopause induced. However, clinical

experience is based on a small proportion of self-

selecting, predominantly ill women and may not

be representative of most women’s experience of

the menopause.

6,7

Population-based studies have

demonstrated that women who seek treatment

differ in systematic ways from those who do not.

6,7

Patient-based samples are biased in terms of

education, socioeconomic status, other health

problems, and incidence of general depression.

Clinical trial samples often included women who

had undergone surgical menopause, and the hor-

mones administered were usually synthetic, so

these studies do not inform us of the relationship

of symptoms to the natural menopause transition.

Only studies of women derived randomly from

the general population provide findings which

can be confidently generalized to be the experience

of most women of that particular culture and

geographic location. Reliable transcultural compar-

isons are rare because rating scales and question-

naires cannot be easily translated to other languages:

a specific term may not exist in the target language

or may have a slightly different meaning. This

problem exists even for translations within the

group of western languages and points to the

importance of validation.

There are intercultural and intracultural differences

in symptom reporting. Kaufert and Syrotuik

describe how stereotypes held by differing social

and cultural groups act as a framework within which

an individual can select and organize and label

experience. Moreover, in menopause research there

is a risk that stereotypes will become operative

whenever subjects know the topic of the research.

3.2 Rating Scales

Health outcomes and their determinants can be

measured by validated rating scales. The failure to

use adequately validated scales has been a major

problem in menopause research. In the classical

Kuppermann Menopausal Index,

a numerical

summation of 11 menopausal complaints derived

from clinical experience in New York in the 1950s,

as well as in other rating scales, the importance of

“neurovegetative symptoms” is overestimated,

whereas other changes are neglected. This particu-

larly applies to the measurement of sexuality and

of symptom experience. For example, with regard

to sexuality, relatively few of the population-based

studies of the menopause transition have made any

inquiry about sexual functioning. Differing mea-

sures of sexual functioning have been used but

studies often fail to offer any data on the validity

or reliability of these measures in their local popu-

lation. The research process itself may result in

response bias. This includes interviewer bias in the

phrasing of questions and specification bias if the

variable under study is not well specified to the full

understanding of the subject.

3.3 Symptom Measure

A major methodological issue is that of the symp-

tom measure utilized and its validity and reliability

for the cultural group studied. The standard

method used for collecting information on the

prevalence and severity of symptoms has been a

checklist of symptoms. But the checklist in itself

introduces a number of biases, including the prob-

lem of elicitation. For example, Wright,

inter-

viewing women of the Navajo tribe, found that vir-

tually all respondents reported no bodily changes

since menopause in relation to open-ended ques-

tions, but most responded positively to symptoms

in the checklist. Holte

noted that the sounder the

methodology, the lower the prevalence of symp-

toms. When frequency or bothersomeness of com-

plaint are included, the reporting rate goes down

further: irritability was reported by 57 percent of

premenopausal women as being present occasion-

ally, but only 10 percent of the same women

reported that it was there frequently.

The presence

of symptoms “occasionally” does not indicate their

impact on the woman and may not be clinically

relevant or indicative of treatment needs. Porter et

al.

assessed the impact and prevalence of symp-

Page 4

toms in a Scottish postal survey of 6,096 women

aged 45–54. Fifty-seven percent of the cohort had

experienced a hot flush, but only 22 percent said

that it had been a problem. Similar disparity exist-

ed for night sweats (55 percent and 24 percent)

and dry vagina (34 percent and 14 percent). Only

4 percent had experienced none of the symptoms.

The most frequently used checklist has been based

on a numerical summation of 11 menopausal com-

plaints, the Kupperman Menopausal Index, derived

from clinical experience in New York in the 1950s.

The index was a combination of self-report and

physician ratings. The index included 11 symp-

toms (vasomotor, paraesthesia, insomnia, nervous-

ness, melancholia, vertigo, weakness (fatigue),

arthralgia and myalgia, headaches, palpitations and

formication) rated on a 4-point scale. In a critical

review, Alder

noted that terms were ill defined,

categories included overlapping scores, and scores

were summed without being based on independent

factors. Symptoms seemed to be arbitrarily select-

ed; omitted were measures of vaginal dryness, dys-

pareunia, and breast tenderness. The following

year Kupperman and coworkers, including Blatt,

described a modification, which allowed for some

symptoms to be weighted more than others.

Weighting was used without statistical justifica-

tion. Later, investigators, such as Neugarten and

Kraines,

extended the list to 28 symptoms but

found that only 9 of these distinguished

menopausal women from those at other develop-

mental phases. These authors, and many since,

arbitrarily categorized groups of symptoms.

Greene

was the first to use factor analysis as the

basis for categorizing symptoms into three factors,

vasomotor, somatic, and psychological. But

Greene’s study contained a number of flaws.

Although his 30-symptom list was constructed

from the scale of Neugarten and Kraines,

failed to include breast pain, somewhat curiously

as Neugarten and Kraines had found this symptom

to be associated with menopausal women. Nor did

he include symptoms of vaginal atrophy. These

symptoms (mastalgia and atrophy) were still not

included in a later amended 20-item list.

Whether psychological complaints vary with the

menopause transition has been a key concept, yet

the capacity of most symptom checklists to ade-

quately measure psychological morbidity is

unknown.

In their Manitoba study, symptoms

measuring psychological morbidity had to conform

to scales used by psychological epidemiologists,

and concurrent validity was sought. The symptom

checklist was not restricted to items with an asso-

ciation with menopause but was embedded in an

18-item general symptom list adapted from one

used in a community health survey. The 11 symp-

toms forming the menopausal index were derived

from the International Health Foundation studies

(hot flush, night sweats, dizziness, rapid heart beat,

pins and needles in hands and feet, tiredness, irri-

tability, headaches, depression, nervous tension,

and insomnia). Interestingly, the list did not

include vaginal atrophy symptoms, yet the

International Health Foundation list was supposed-

ly chosen as a “succinct summary of the core

symptoms as described in the clinical literature.”

Four factors were found. Hot flushes and night

sweats group together as a separate factor, and five

symptoms burdened on a psychological factor.

These were five of the six symptoms in the

International Health Foundation arbitrary classifi-

cation of “symptoms of the nervous system.” A

strong association was found between the five psy-

chological symptoms and the two standardized

measures of psychological morbidity used for con-

current validity.

Greene

compared the findings of seven factor

analytic studies. Despite different methodologies

and sampling, he found that vasomotor symptoms

(hot flushes, night sweats) always formed a sepa-

rate cluster, totally independent of other symptoms.

There was also agreement that a number of symp-

toms cluster together to form a general somatic or

perhaps psychosomatic factor: pressure or tight-

ness in head or body, muscle and joint pains,

Page 5

numb-tingling feelings, headaches, feeling dizzy or

faint, breathing difficulties, and loss of feeling in

hands or feet. A further group of symptoms cluster

together to form a psychological factor, which in

some studies can be subdivided into anxiety and

depression.

3.4 Cross-Sectional Versus

Longitudinal Design

As indicated above, observational studies of popu-

lation-based samples are the best way to determine

the symptom experience of women in relationship

to the phases of the natural menopause transition.

However, they often suffer from being cross-sec-

tional in design

rather than having the power of

longitudinal analysis of the same women through

the menopause transition.

Cross-sectional studies

can only indicate whether associations exist and

are unable to determine causality. Cross-sectional

studies have certain advantages. They are more

convenient and less expensive to carry out.

Subjects are only asked to participate on one occa-

sion so that the response rate is likely to be higher

than when subjects are asked to contribute time for

assessments on a regular basis. Those who accept

to participate in a longitudinal study may differ in

certain systematic ways from those who decline

and this may introduce bias into the sample.

Thus, the sample participating in a cross-sectional

study may be more similar to a general population

sample than that of a longitudinal study sample.

Splintering of the study population can continue

for other reasons during the accrual process.

From the target group, only those persons available

to the investigator are potentially eligible for study.

Further splintering occurs after applying inclusion

and exclusion criteria. After being admitted to the

study, the subject’s records must be properly filled

in: missing data on some variables can lead to

exclusion of the subject with some analytic tech-

niques. If the reason for drop-out or premature

early termination of the study is related to the stud-

ied endpoint, this can induce further bias. Another

source of error is that of confounding, which

necessitates the need for multivariate analytic

methods to control for the influence of the various

factors that can affect an outcome. The majority of

community-based studies have been cross-sectional

and thus limit researchers to inferring apparent

associations. Cross-sectional studies cannot control

for premenopausal characteristics nor separate the

effects of aging from those of menopause.

These studies are less satisfactory than longitudinal

studies in which the same women are followed

over time with the same instruments, so that what

is being observed is change in the same population

with time. Longitudinal cohort designs facilitate

the identification of causal pathways and allow the

effects of aging to be disentangled from those of

menopause.

However, most longitudinal studies

have used inadequate statistical methods, often

resorting to a cross-sectional approach to data,

which, as repeated measures, are no longer inde-

pendent in nature.

Longitudinal collection of

data reduces reliance on memory for long recall

periods. The length of the recall period in cross-

sectional studies can lead to further inaccuracy of

data. This is not only true for the studied end-

points, but also for possible covariates at the time

of occurrence. In longitudinal studies, there is the

opportunity for measures to be made prospectively

(such as menstrual diaries) rather than relying on

self-recall, which may be substantially less accu-

rate. When change over time is the key concern, a

prospective design is mandatory.

3.5 Statistical Analysis

Most studies have only utilized univariate analysis

and thus been unable to take into account the role

of confounding or interacting factors. The findings

of these studies are thus often contradictory. A

major problem in the longitudinal studies has been

the lack of a sensitive enough statistical analysis,

which would use a within-subject-repeated-measures

method, allowing for the various factors which

may affect the quality-of-life measure, changes in

those factors, and interactions with the menopausal

transition to be identified.

Page 6

The analysis of longitudinal studies becomes more

complex as the temporal dimension is added to the

other possible components of the study. Many sta-

tistical approaches are possible. A simple and pow-

erful technique is to calculate mean values prior to

and following an event such as the FMP. To allow

for the influence of multiple factors, linear regres-

sion is preferred to logistic regression where con-

tinuous data are available. For more information

about evolution in time, more complex techniques

are needed. A suitable technique is repeated

measures multivariate analysis of variance using

a number of contrasts to estimate various effects.

Simple split plot or randomized block designs

cannot be recommended as they often violate com-

pound symmetry assumptions. For series involving

more than 100 observations for each subject, time

series and spectral analysis techniques should be

considered. Structural equation modeling is recom-

mended for examination in detail of a range of

factors that may influence the studied endpoint, the

presence of feedback and of latent or nonmeasur-

able variables.

In reviewing the extensive observational literature

in this field accessible in Medline, we will concen-

trate on those studies which use adequate study

design.

These include random sampling; describ-

ing the study as a general health survey, so that

bias caused by emotional response to menopause is

lessened; collecting information on current symp-

tomatology, so that the problem of recall bias is

minimized; utilizing an age range that encompasses

the menopause transition, for example, 45–55

years for cross-sectional studies or a younger

(mean) age group for longitudinal studies of the

menopause transition, to ensure that women are

premenopausal at outset; longer followup in longi-

tudinal studies; and collection of data on menstrual

status, hormone usage, and induced menopause, so

that the phase of the menopause transition can be

adequately determined. Where there are method-

ological problems such as poor response rate, these

are outlined.

4. P

REVALENCE OF

YMPTOMS IN

IDDLE

-A

GED

OMEN

: R

ELATIONSHIP

ORMONAL

VENTS OF THE

ENOPAUSE

RANSITION AND

GING

A few studies have tried to address this question by

examining different symptom experiences for women

of different age groups and menopausal status.

Two studies compared symptom checklist results

for men and women of different age groups using

lists from general practices. Results were presented

by age groups rather than by menopausal status.

Bungay et al.,

in a United Kingdom postal survey,

found that four different patterns occurred by age

and sex. Peaks of prevalence of flushing and

sweating were closely associated with the mean

age of the menopause. Less impressive peaks of

minor mental symptoms were associated with an

age just preceding the mean age of menopause.

Complaints about aching breasts, irritability, and

low backache diminished after menopause. Male

and female curves were parallel for loss of

appetite, crawling or tingling sensations on skin,

headaches, difficulty with intercourse, indigestion,

constipation, diarrhea, shortness of breath, cold-

ness of hands and feet, dryness of skin, dryness

of hair, aching muscles, aching joints, feelings of

panic, feelings of depression, and stinging on

passing urine.

A Dutch national study

of the symptoms in the

Kupperman index experienced by men and women

aged over 25 years, reported female/male ratios for

each symptom. Only transpiration (excessive

sweating) showed a significant increase at age

45–54, compared to younger age groups and then

remained raised. No other symptom showed a signif-

icant increase in the age group 45–54, including the

General Health Questionnaire score of mental health.

Most observational studies using symptom check-

lists find that middle-aged women are highly

symptomatic. An Australian study

of women aged

45–54 found the symptoms most commonly expe-

rienced in the prior 2 weeks to be very dry skin

(68 percent), backache (49 percent), forgetfulness

Page 7

(47 percent), problems sleeping (39 percent), irri-

tability (37 percent), and mood swings (36 percent).

Hot flushes were reported by 25 percent of women

(rank order 10) and sweating attacks by 13 percent

(rank order 19). Vaginal dryness and discomfort

was reported by 16 percent (rank order 17).

As noted earlier, there is consensus about the

marked temporal relationship of vasomotor symp-

toms to menopause.

These begin to increase in

perimenopause, reach a peak within 1–2 years of

the FMP,

and remain elevated for up to 10

years.

29–31

McKinlay et al.,

in a followup study

over 4 years of 1,178 premenopausal women,

found increasing hot flushes—10 percent in early

premenopause, 30 percent in early perimenopause

increasing to 50 percent of women 1 year prior to

the FMP—coinciding with late perimenopause,

with reports of hot flushes starting to decline sig-

nificantly 2 years after FMP and reaching 20 per-

cent of women 4 years after FMP. Thus, hot flush-

es are not the most frequent symptoms reported,

nor are they pathognomonic of menopause, being

reported by younger menstruating women. A num-

ber of studies have shown an association between

hot flushes and night sweats,

and some show an

association between these vasomotor symptoms

and insomnia.

Women who had an artificially

induced menopause were more likely to still report

flushing than were naturally menopausal women

and to report more symptoms.

Only a few studies

included any reported measure of dryness of the

vagina. Oldenhave reports that dry vagina

increased in the perimenopause to postmenopause,

with a slight decrease > 10 years postmenopause,

which may be explained by lack of a partner.

This

complaint is related to hot flush reporting. There

was less consistency regarding other symptoms.

A number of cross-sectional studies, including the

two Ede studies,

29,31

report a small but transient

increase in nonvasomotor symptoms in peri-

menopause. There was no attempt to differentiate

whether any increase in such symptoms is due to

distress caused by vasomotor symptoms. A

Norwegian 5-year prospective study found that

vasomotor symptoms, vaginal dryness, heart palpi-

tations, and social dysfunction increased with the

menopausal transition, but that headache and

breast tenderness decreased.

However, these

results were based on only 59 of the 200 pre-

menopausal women selected for the study. The

author notes that the finding of heart palpitations

must be treated with caution since it differs from

all previous factor analytic studies.

Recently

released results from the cross-sectional phase of

the Study of Women’s Health Across the Nation

(SWAN) study have also found an increase in

vasomotor symptoms and in psychological and

psychosomatic symptoms related to menopause.

Analyses of data from 14,906 women aged 40 to

55 years found vasomotor symptoms burden on a

different factor to psychosomatic symptoms.

Perimenopausal and postmenopausal women, HRT

users, and women who had a surgical menopause

were all significantly more likely to report vaso-

motor symptoms compared to premenopausal

women, with postmenopausal women having the

higher OR. Psychosomatic symptoms (tense,

depressed, irritable, forgetful, headaches) were

reported more often by perimenopausal women,

hormone users, and women with a surgical

menopause than by premenopuase or post-

menopausal women. A number of other studies,

including recent longitudinal studies using validat-

ed mood scales, have not found an association

between mood and menopausal status.

The Melbourne Women’s Midlife Health Project

reported on the analysis of those women who after

7 years of followup had progressed through the

menopause transition. Annual measures included a

33-item symptom checklist. Increasing significantly

from early to late perimenopause were the total

number of symptoms, hot flushes, night sweats, and

dry vagina. Breast soreness/tenderness (mastalgia)

decreased significantly with the menopause transi-

tion. Trouble sleeping showed a smaller increase,

which was found to in part reflect bothersome hot

Page 8

flushes.

(See figs. 3–1 to 3–5.) The onset of hot

flushes was found to be related to decreased estra-

diol levels (p < 0.01), and the onset of night sweats

was related to the change

in estradiol level (p <

0.05).

Interestingly, breast

tenderness was not includ-

ed in the SWAN study

reported above. The

SWAN study found that

vaginal dryness was related

to vasomotor symptoms

but did not reach the crite-

ria for inclusion in the fac-

tor analysis, and results

were not reported by

menopausal status.

Longcope et al.

also report a significant negative

association of hot flushes with estrone and

estradiol levels amongst their sample of 241

Massachusetts women followed for 3 years. Thus,

a number of epidemiological studies have found

that only vasomotor and vaginal atrophic symp-

toms significantly increase as women pass through

the natural menopause transition.

Although many theories have been suggested to

explain the mechanism of menopausal flushing,

none provide a satisfactory explanation.

Core

body temperature elevations precede the

menopausal hot flush and serve as one trigger of

this heat loss phenomenon.

What is responsible

for the core temperature elevation is a matter of

speculation. Although vasomotor symptoms are

associated with increasing FSH and decreasing

estradiol levels,

38,42

it may be that vasomotor symp-

toms relate to the activity of another substance, in

whose absence the activity of the thermoregulatory

center is disturbed.

This substance may be com-

mon to both ovaries and testes and explain the fact

that the male flushes after orchidectomy and the

woman after ovarian failure. Each hot flush is

accompanied by a gonadotrophin-releasing hor-

mone (GnRH) pulse with a consecutive episode of

FSH and LH secretion.

Because hypophysec-

Epidemiological studies

have found that only

vasomotor and vaginal

atrophic symptoms

significantly increase

as women pass through

the natural menopause

transition.

IGURE

3–1

Proportion of Women Bothered by Hot Flushes by Menopausal Status

1.00

0.75

0.5

0.25

Pre

Early

Peri

Late

Peri

Post

+1 yr

Post

+2 yr

Post

+3 yr

Proportion

pre = premenopausal

early peri = change in menstrual frequency

late peri = 3–11 months amenorrhoea

post 1 year = 12–23 months amenorrhoea

post 2 years = 24–35 months amenorrhoea

post 3 years ≥ 36 months amenorrhoea

Page 9

IGURE

3–2

Proportion of Women Bothered by Night Sweats by Menopausal Status

1.00

0.75

0.5

0.25

Pre

Early

Peri

Late

Peri

Post

+1 yr

Post

+2 yr

Post

+3 yr

Proportion

pre = premenopausal

early peri = change in menstrual frequency

late peri = 3–11 months amenorrhoea

post 1 year = 12–23 months amenorrhoea

post 2 years = 24–35 months amenorrhoea

post 3 years ≥ 36 months amenorrhoea

IGURE

3–3

Proportion of Women Bothered by Dryness of Vagina by Menopausal Status

1.00

0.75

0.5

0.25

Pre

Early

Peri

Late

Peri

Post

+1 yr

Post

+2 yr

Post

+3 yr

Proportion

pre = premenopausal

early peri = change in menstrual frequency

late peri = 3–11 months amenorrhoea

post 1 year = 12–23 months amenorrhoea

post 2 years = 24–35 months amenorrhoea

post 3 years ≥ 36 months amenorrhoea

Page 10

IGURE

3–4

Proportion of Women Bothered by Breast Soreness by Menopausal Status

1.00

0.75

0.5

0.25

Pre

Early

Peri

Late

Peri

Post

+1 yr

Post

+2 yr

Post

+3 yr

Proportion

pre = premenopausal

early peri = change in menstrual frequency

late peri = 3–11 months amenorrhoea

post 1 year = 12–23 months amenorrhoea

post 2 years = 24–35 months amenorrhoea

post 3 years ≥ 36 months amenorrhoea

IGURE

3–5

Proportion of Women Bothered by Trouble Sleeping by Menopausal Status

1.00

0.75

0.5

0.25

Pre

Early

Peri

Late

Peri

Post

+1 yr

Post

+2 yr

Post

+3 yr

Proportion

pre = premenopausal

early peri = change in menstrual frequency

late peri = 3–11 months amenorrhoea

post 1 year = 12–23 months amenorrhoea

post 2 years = 24–35 months amenorrhoea

post 3 years ≥ 36 months amenorrhoea

Page 11

tomized hypogonadotropic women experience hot

flushes in the same way as women with an intact

pituitary, vasomotor instability is induced by a

common higher cerebral center and not by the

gonadotropin-pulse. The vasodilatation occurring

during hot flushes leads to an increase of skin tem-

perature and finger volume and to an augmented

oxygen consumption.

Due to peripheral vasodi-

latation, there is an increase of the pulse rate by

about 15 percent. Body core temperature then

decreases. The increase of finger perfusion starts

1.5 min before the start of the hot flush and lasts

for several minutes after its subjective end. Serum

LH levels increase only after the beginning of

peripheral vasodilatation and reach their maximal

value approximately 12 minutes later. Most likely

as a consequence of the cooling down of the body

core temperature, an elevation of adrenocoticotropic

hormone (ACTH) and of human growth hormone

(hGH) occurs respectively 5 and 30 minutes after

the rise of skin temperature. Because hot flushes

occur not only after menopause, but also during

the down-regulation by GnRH analogues, the pri-

mary decrease of serum estradiol is essential for

vasomotor symptoms. Anorexia nervosa or other

conditions of hypothalamic amenorrhea do not

provoke hot flushes. Furthermore, hot flushes are

only observed in women previously exposed to

endogenous or exogenous estrogen activity. The

pathophysiological mechanism provoking hot

flushes involves catecholamines, catecholestrogens,

serotonin, histamine, endorphins, and prostaglandins.

The endorphin neurons are inactivated by low

estrogen levels, a phenomenon that is reversible.

5. R

OLE OF

SYCHOSOCIAL

AND

IFESTYLE

ACTORS IN

ETERMINING

OMEN

’

XPERIENCE OF

YMPTOMS

Cross-sectional studies have explored associations

between symptom experience and a large range of

other factors. In keeping with other studies from

Australia, North America, Scandinavia, and

Europe, an Australian study found lower symptom

experience in the midlife years to be associated

with increasing years of education, better self-rated

health, the use of fewer nonprescription medica-

tions, absence of chronic conditions, a low level of

interpersonal stress, not currently smoking, exer-

cise at least once per week, and positive attitudes

to aging and to menopause.

A previous history of premenstrual complaints was

reported to be associated with the occurrence of

vasomotor symptoms during menopause in cross-

sectional analyses of this population-based sample

of midlife women.

42,46

Longitudinal analysis of the

same cohort found that a prior history of both

physical and psychological premenstrual com-

plaints was associated with a more symptomatic

perimenopause characterized by dysphoria, skele-

tal, digestive, and respiratory symptoms.

The cross-sectional phase of the SWAN study

found that reports of vasomotor symptoms were

negatively associated with educational level and

self-assessed health and positively associated with

difficulty in paying for basics. Psychosomatic

symptoms decreased with age and were reported

less often by those with better self-reported health

and with less difficulty in paying for basics.

Longitudinal population-

based studies are best able

to establish the likely rela-

tionship between experience

of symptoms, psychosocial

and lifestyle factors. The

Massachusetts Women’s

Health Study found that

prior physical and psycho-

logical symptoms explained

physical symptoms, while

psychological symptoms were explained by low

education and perceived health.

A further analysis

of the 454 women from this sample who were pre-

menopausal at baseline and postmenopausal by the

Cross-sectional

studies have

explored associations

between symptom

experience and a large

range of other factors.

Page 12

6th followup found that variables related to greater

frequency of vasomotor reporting included a

longer perimenopause, more symptoms reported

prior to menopause, lower education, and more

negative attitudes to menopause prior to

menopause.

Symptom bothersomeness was relat-

ed to a greater frequency of vasomotor symptom

reporting, smoking, and being divorced. Variables

that predicted consultations were greater frequency

and bothersomeness of symptoms, higher educa-

tion, and greater health care utilization.

Women

with negative attitudes to menopause were more

likely to subsequently experience bothersome

symptoms.

A British study

found that women who had expe-

rienced an early natural menopause had a strongly

increased risk of vasomotor symptoms (hot flushes

or night sweats), sexual difficulties (vaginal dry-

ness or difficulties with intercourse), and trouble

sleeping. However, there was little or no excess

risk of the other somatic or psychological symp-

toms studied. In contrast, all types of symptoms

were more common among women who had had a

hysterectomy or were users of HRT. Using

prospective data collected when the women were

36, symptom reporting was predicted by low edu-

cation, stressful lives, or a previous history of poor

physical and psychological health. Adjustment for

these factors in a logistic regression model did not

affect the relationship between symptoms and cur-

rent menopausal status. For vasomotor symptoms,

postmenopausal women had an adjusted OR of 4.7

(95 percent confidence internval (CI) 2.6–8.5), and

perimenopausal women had an adjusted OR of 2.6

(95 percent CI 1.9–3.5) compared with pre-

menopausal women. Corresponding adjusted ORs

for sexual difficulties were 3.9 (95 percent CI

2.1–7.1) and 2.2 (95 percent CI 1.4–3.2) and for

trouble sleeping were 3.4 (95 percent CI 1.9–6.2)

and 1.5 (95 percent CI 1.1–2.0).

A postal survey of men and women aged between

49–55 years and registered with a London general

practice

found no gender differences in reporting

of self-rated health, life satisfaction, and health-

related quality of life, although women reported

more physical problems. Menopausal status was

not significantly related to life satisfaction or to

health-related quality of life. Significant predictors

of health-related quality of life were serious ill-

ness, employment, and marital status. Sample size

was relatively small in this study (n = 189),

response rate was only 47 percent, and the age

range may have meant that most women were

already in the menopausal transition.

Using structural modeling of data from the first 6

years of followup of the Melbourne Women’s

Midlife Health Project, the presence of bothersome

symptoms was found to adversely affect well-

being.

Repeated measures multivariate analysis of

covariance also found that bothersome symptoms

adversely impacted negative mood.

Greene

suggested a vulnerability model to explain

the role of psychosocial factors in symptom expe-

rience during the menopausal transition. The Greene

vulnerability model hypothesizes that adverse

psychosocial factors render women vulnerable to

develop nonspecific physical and psychological

symptoms at this time. Response to stress interacts

with personality and sensitivity to biological changes

to determine the actual symptoms experienced.

Hot beverages can cause flushing through counter

current heat exchange mediated through the ther-

moregulation center of the anterior hypothalamus.

Foods containing nitrites and sulphites and spicy

foods, such as those containing the active agent in

red pepper or capsaicin, may also provoke severe

flushing. Alcohol intake is also associated with

flushing reactions, although there are no controlled

trials examining the effect of alcohol intake on the

severity of menopausal symptoms, in particular

vasomotor symptoms. The mechanism of alcohol-

provoked flushing is complex but is probably related

to the fact that fermented alcoholic beverages con-

tain tyramine or histamine, which induces flushing.

Page 13

5.1 Exercise

It has been suggested that physical activity may

have a beneficial effect on reducing vasomotor

symptoms in menopausal women. Physical exer-

cise involving increased energy expenditure

increases hypothalamic β-endorphin production,

and β-endorphins are reported to stabilize ther-

moregulation.

However, conflicting evidence

exists as to whether exercise has an effect on

menopausal symptoms.

In a cross-sectional study of a population-based

sample of 728 Australian-born women,

physical

activity had no significant effect on women’s expe-

rience of troubling symptoms, including those

symptoms associated with their menopausal status,

such as vasomotor symptoms. Hammar et al.

reported that women who participated in organized

physical exercise on a regular basis had a lower

prevalence of moderate to severe vasomotor symp-

toms compared with women of the same

menopausal status from the population. A further

study by these researchers

reported that from a

population of 793 women, only 5 percent of highly

physically active women experienced severe vaso-

motor symptoms as compared with 14–16 percent

of women who had little or no weekly exercise.

The latter study collected data on physical habits

and on current and previous experience of vasomo-

tor symptoms. There is the risk of women overesti-

mating the time spent in physical activities as well

as the problems of retrospective reporting of vaso-

motor symptoms. A prospective or intervention

study would avoid these problems. However, the

fluctuating nature of the experience of vasomotor

symptoms and the expectations of participants

could affect such studies. A case-control study

(82 cases and 89 controls) found that habitual

exercise prior to the FMP did not reduce the likeli-

hood of experiencing vasomotor symptoms during

the perimenopause.

6. E

FFECTIVEMESS OF

REATMENT

NTERVENTIONS FOR

YMPTOMS

INKED TO THE

RANSITION

ENOPAUSE

Available treatments aimed at reducing symptoms

related to the menopausal transition include HRT,

phytoestrogens, and natural therapies, which have

been shown to possess different degrees of efficacy.

6.1 Hormone Replacement Therapies (HRT)

Most RCTs of HRT have been carried out on post-

menopausal women, many of whom have already

received HRT and may have undergone a surgical

menopause. Nevertheless, there is considerable

consensus in findings that the symptoms which

consistently respond to HRT are the vasomotor and

vaginal atrophic symptoms. These beneficial

effects of HRT persisted after adjusting for base-

line symptom level and uterine status.

There is a substantial body of

evidence showing that HRT is

effective in reducing hot flushes.

Randomized double-blind place-

bo controlled trials have report-

ed that CEE at dosages of 0.3,

0.625, and 1.25 mg/day signifi-

cantly reduced hot flushes com-

pared with placebo.

59–61

Similarly, other preparations of

estrogen, administered either orally or by transder-

mal patch, have also shown effectiveness in the

relief of vasomotor symptoms.

62–70

Gordon et al.

compared the efficacy of estradiol patches and oral

conjugated estrogen and found no statistically sig-

nificant difference between the preparations with

regard to their effect on the reduction of hot flush-

es. The response to the 0.1 mg estradiol patch was

greater, and the response to the 0.05 mg estradiol

patch was less than the response to conjugated

estrogens, although these differences were not sta-

tistically different. Percutaneous estradiol delivered

in an alcohol-water gel has been reported to be

effective in treating vasomotor symptoms.

The

Conflicting

evidence exists as

to whether exercise

has an effect

on menopausal

symptoms.

Page 14

use of either continuous or sequential progestins

with estrogen does not reduce the efficacy of the

preparation in the reduction of hot flushes.

58,65,72

Recently, an intranasal 17β-estradiol spray has

been shown to be significantly better than placebo

and similar to oral estradiol in reducing hot flushes

and is also well tolerated.

Vaginal symptoms

related to atrophy

have been reported

to be alleviated by

ERT. Local low-dose

treatment with a

small vaginal tablet

of 25 micrograms

of 17β-estradiol

was shown to significantly relieve postmenopausal

symptoms related to vaginal atrophy when com-

pared to placebo.

Preparations of estradiol vaginal

cream have a similar effect

and also result in an

increase in plasma levels of estradiol. Percutaneous,

transdermal, and oral estradiol treatments have all

been reported to improve the vaginal cytology pro-

file in comparison with placebo therapy.

67,71,76

Sleep

disturbances do not appear to be helped by trans-

dermal or oral ERT.

69,77

The benefits and risks of

HRTs are discussed in other chapters.

A number of nonestrogen preparations have been

evaluated for their effects on menopausal symp-

toms with varying results. The progestational agent

megestrol acetate (20 mg twice daily) has been

reported to significantly decrease the frequency of

hot flushes in women with a history of breast can-

cer.

Veralipride, an antidopaminergic treatment,

reduced vasomotor symptoms and was significant-

ly more effective than placebo in three trials.

79–81

Other dopamine agonists and antagonists have also

been found to be more effective than placebo in

alleviating hot flushes.

In one trial, opipramol

treatment was reported as being significantly better

than placebo in reducing hot flushes.

Trials with

clonidine,

propranolol,

and dong quai

have

shown these treatments to be no more effective

than placebo in controlling hot flushes. Dong quai

did not have any effect on vaginal cell matura-

tion.

More promising results for non-hormonal

treatment of hot flushes have come from trials of

antidepressants, particularly the selective serotonin

reuptake inhibitors (SSRIs) and related drugs such

as venlafaxine. Pilot studies presented at confer-

ences have found significant reduction in hot flush

frequency and severity, but evidence from larger

double-blind randomized trials is needed.

Studies of the effects of HRT on mood, cognitive

and sexual functioning are discussed elsewhere.

The symptom of breast soreness/tenderness

(mastalgia) has been shown in clinical trials to be

related to estrogen/progestin balance.

The

Postmenopause Estrogen/Progestin Intervention

(PEPI) trial

found a significant reduction in mus-

cle and joint pain in women who adhered to estro-

gen- and progestin-containing regimes. This bene-

ficial effect on muscle and joint pain was not evi-

dent in intention-to-treat analyses. Aches or stiff

joints were reported by over 40 percent of women

in the Melbourne Women’s Midlife Health Project

at each phase of the menopause transition,

although there was no demonstrable variation with

the menopause transition. Given the prevalence

of these symptoms among middle-aged women,

further research is needed.

6.2 Phytoestrogens

Phytoestrogens are plant compounds that have a

close similarity in structure to estrogens. Evidence

for the effects of phytoestrogens on reducing

menopausal symptoms, hot flushes, and vaginal

dryness come from two main sources—observa-

tional studies and clinical trials. The first source is

from epidemiological data of populations who

have high dietary intakes of phytoestrogen com-

pounds and who have a very low rate of hot flushes

(for example, 5–10 percent of Japanese women

report hot flushes compared with 70–80 percent of

Western women).

Japanese women are reported

Considerable consensus in

findings that the symptoms

which consistently respond to

HRT are the vasomotor and

vaginal atrophic symptoms.

Page 15

to consume 20–150 mg/day of isoflavones

com-

pared to Western women, where less than

5 mg/day is consumed.

The second source is from placebo-controlled clin-

ical trials. Five studies

90–94

have reported improve-

ment in hot flushes after dietary supplementation

with phytoestrogens. In three of these studies,

90,93,94

there was no significant improvement in these

symptoms in subjects in the treatment compared to

the placebo group. In one study,

there was an

increase in urinary isoflavone excretion in the

placebo group. There was a strong negative corre-

lation between the level of urinary isoflavone

excretion and the incidence of vasomotor symptoms

in both treatment and placebo groups. This further

emphasises the problem with intervention studies

using naturally occurring dietary compounds.

There are problems with both sources of informa-

tion. Whether Japanese women do in fact experi-

ence a significantly lower frequency of hot flushes

has been challenged,

and there is no data from

this population on the prevalence of vaginal dry-

ness. Evidence from controlled trials is limited by

several problems—finding an effective control

group, as phytoestrogens are present in so many

foods that it is difficult to eliminate them from the

diet, and the fact that natural improvement of

menopausal symptoms occurs with time. Of five

studies that looked at changes in vaginal cytology

with and without phytoestrogen supplementation,

there was a significant improvement in three

instances

91,96,97

but not in two.

90,98

The variations in

response may depend on populations studied,

source of phytoestrogen, and study design, particu-

larly with respect to duration of exposure.

6.3 Natural Therapies

Evening primrose oil, containing gamma-linolenic

acid, has been evaluated as a therapy for treating

hot flushes and sweating associated with

menopause in a randomized, double-blind, place-

bo-controlled trial.

Although there is no good

scientific rationale for the use of this preparation in

treating hot flushes and although neither clinicians

nor the pharmaceutical industry have ever promot-

ed evening primrose oil for this purpose, there is a

current view among the lay public that it is effective

in the control of menopausal symptoms. Chenoy

and colleagues

reported that gamma-linolenic acid

provided by evening primrose oil offers no benefit

over placebo in treating menopausal flushing.

7. F

UTURE

EEDS

Clearly there has been a great deal of research

documenting the relationship of symptoms of the

menopause transition. In this section, we expand

on those areas that require further detailed studies.

In the field of observational studies, there is a

need for better documentation of the processes of

the natural menopause transition using prospective

investigations to distinguish menopause-related

changes from those of aging or disease. Design

features needed in these longitudinal epidemiologi-

cal studies are:

• Randomized population sampling including

minority women of the country concerned

• Baseline age 45 or less, so that women are more

likely to be premenopausal

• Symptom checklists which include all symp-

toms shown to vary directly (vasomotor, vaginal

atrophic, breast tenderness) or indirectly

(insomnia, mood) with hormonal change

• Validated measures of psychosocial and lifestyle

factors which may mediate hormonal effects

• Prospectively kept menstrual calendars so that

phase of the menopause transition can be deter-

mined without bias of retrospective recall

• Regular hormonal measures

• Power analysis for sample size, so that effects

of hormones and other factors can be delineated

Page 16

• Long-term followup until women are at least 10

years postmenopausal, so that longer term

effects can be studied, including the natural his-

tory of untreated symptoms

• Studies of different populations worldwide, rep-

resenting women from a broader array of racial-

ethnic and socioeconomic backgrounds

In the field of treatment interventions, there have

been many RCTs of different forms of HRT on

symptoms, and larger studies are in progress. On

the other hand, there is a need for—

• Questionnaires validating phytoestrogen intake

against metabolic measures of metabolites in

different cultural settings before either RCTs or

observational studies of the role of phytoestro-

gens can proceed

• A larger RCT of phytoestrogen supplementa-

tions, including metabolic measures of metabo-

lite levels

Page 17

Stewart AL, Hays RD, Ware JE Jr. The MOS short-

form general health survey Reliability and validity

in a patient population. Med Care

1988;26(7):724–35.

Neugarten BL, Havighurst RJ, Tobin SS. The measure-

ment of life satisfaction. J Gerontol

1961;16:134–43.

Folkman S, Lazarus RS. An analysis of coping in a

middle-aged community sample. J Health Soc

Behav 1980;21(3):219–39.

Radloff LS. The Center for Epidemiologic

Studies–Depression scale: A self-report depression

scale for research in the general population. Appl

Psychol Mea 1977;1:385–401.

Dennerstein L, Helmes E. The menopausal transition

and quality of life: Methodologic issues. Qual Life

Res 2000;9(Suppl S):721–31.

McKinlay JB, McKinlay SM, Brambilla DJ. Health

status and utilization behavior associated with

menopause. Am J Epidemiol 1987;125(1):110–21.

Morse CA, Smith A, Dennerstein L, Green A, Hopper

J, Burger H. The treatment-seeking woman at

menopause. Maturitas 1994;18(3):161–73.

Avis NE, McKinlay SM. The Massachusetts Women’s

Health Study: an epidemiologic investigation of the

menopause. J Am Med Womens Assoc

1995;50(2):45–9, 63.

Kaufert P, Syrotuik J. Symptom reporting at the

menopause. Soc Sci Med – [E] 1981;15(3):173–84.

Kupperman H, Blatt M, Wiesbader H, Togashi S. Use

of the amenorrhoea and menopausal index in the

clinical evaluation of estrogenic compounds. Fed

Proc 1952;11:365.

Wright AL. On the calculation of climacteric symp-

toms. Maturitas 1981;3(1):55–63.

Holte A. Prevalence of climacteric complaints in a

representative sample of middle-aged women in

Oslo, Norway. J Psychosom Obst Gyn

1991;12:303–17.

Porter M, Penney GC, Russell D, Russell E,

Templeton A. A population based survey of

women’s experience of the menopause. Br J Obstet

Gynaecol 1996;103(10):1025–8.

Alder E. The Blatt-Kupperman menopausal index: a

critique. Maturitas 1998;29(1):19–24.

Blatt M, Wiesbader H, Kuppermann HS. Vitamin E

and climacteric syndrome. AMA Arch Intern Med

1953:792–9.

Neugarten BL, Kraines RJ. Menopausal symptoms in

women of various ages. Pyschosom Med

1965;27:266–73.

Greene JG. A factor analytic study of climacteric

symptoms. J Psychosom Res 1976;20(5):425–30.

Greene JG. Constructing a standard climacteric scale.

Maturitas 1998;29(1):25–31.

Van Keep Pam, Kellerhals, JM. The ageing woman.

About the influence of some social and cultural

factors on the changes in attitude and behaviour

that occur during and after the menopause. Acta

Obstet Gynecol Scand Suppl 1976;51:17–27.

McCoy NL, Davidson JM. A longitudinal study of the

effects of menopause on sexuality. Maturitas

1985;7(3):203–10.

Burger HG, Dudley EC, Hopper JL, Shelly JM, Green

A, Smith A, Dennerstein L, Morse C. The

endocrinology of the menopausal transition: a

cross-sectional study of a population-based sample.

J Clin Endocrinol Metab 1995;80(12):3537–45.

Wheeler JM. A multivariate look at the menopause.

J Clin Epidemiol 1989;42(11):1029-30.

EFERENCES

Page 18

Lehert P, Dennerstein L. Statistical Techniques for the

Analysis of Change in Longitudinal Studies of the

Menopause. Acta Obstet Gynecol Scand, 2000.

Dennerstein L. Well-being, symptoms and the

menopausal transition (review). Maturitas

1996;23(2):147–57.

Bungay GT, Vessey MP, McPherson CK. Study of

symptoms in middle life with special reference to

the menopause. Br Med J 1980;281(6234):181–3.

van Hall E, Verdel M, van der Velden J.

“Perimenopausal” complaints in women and men:

a comparative study. J Womens Health

1994;3:45–9.

O’Connor VM, Del Mar CB, Sheehan M, Siskind V,

Fox-Young S, Cragg C. Do psycho-social factors

contribute more to symptom reporting by middle-

aged women than hormonal status? Maturitas

1994;20(2–3):63–9.

Greene JG. The cross-sectional legacy: an introduc-

tion to longitudinal studies of the climacteric.

Maturitas 1992;14(2):95–101.

Jaszmann L, van Lith ND, Zaat JC. The peri-

menopausal symptoms: the statistical analysis of a

survey. part A. Med Gynecol Sociol 1969;4:268–77.

Ballinger CB. Psychiatric morbidity and the

menopause; screening of general population sam-

ple. Br Med J 1975;3(5979):344–6.

Oldenhave A, Jaszmann L. The climacteric: absence

or presence of hot flushes and their relation to

other complaints. In: Schonbaum E, ed. The cli-

macteric hot flush. Prog Basic Clin Pharmacol,

Basel Karger 1991;6:6–39.

McKinlay SM, Brambilla DJ, Posner JG. The normal

menopause transition. Maturitas

1992;14(2):103–15

McKinlay SM, Jefferys M. The menopausal syn-

drome. Br J Prev Soc Med 1974;28(2):108–15.

Thompson B, Hart SA, Durno D. Menopausal age and

symptomatology in a general practice. J Biosoc Sci

1973;5(1):71–82.

Holte A. Influences of natural menopause on health

complaints: a prospective study of healthy

Norwegian women. Maturitas 1992;14(2):127–41.

Avis NE, Stellato R, Crawford S, Bromberger J, Ganz

P, Cain V, Kagawa-Singer M. Is there a

menopausal syndrome? Menopausal status and

symptoms across racial/ethnic groups. Soc Sci Med

2001;52(3):345–56.

Dennerstein L, Lehert P, Burger H, Dudley E. Mood

and the menopausal transition. J Nerv Ment Dis

1999;187(11):685–91.

Dennerstein L, Dudley EC, Hopper JL, Guthrie JR,

Burger HG. A prospective population-based study

of menopausal symptoms. Obstet Gynecol

2000;96(3):351–8.

Longcope C, Crawford S, McKinlay S. Endogenous

estrogens: relationships between estrone, estradiol,

non-protein bound estradiol, and hot flashes and

lipids. Menopause 1996;3:77–84.

Ginsburg J, Hardiman P. The menopausal hot flush:

facts and fancies. In: Berg G, Hammar M, eds. The

modern management of the menopause.

International Congress, Symposium & Seminar

Series. The Parthenon Publishing Group

1993;8:123–35.

Freedman RR, Woodward S. Core body temperature

during menopausal hot flushes. Fertil Steril

1996;65(6):1141–4.

Guthrie JR, Dennerstein L, Hopper JL, Burger HG.

Hot flushes, menstrual status, and hormone levels

in a population-based sample of midlife women.

Obstet Gynecol 1996;88(3):437–42.

Kronenberg F. Hot flashes: epidemiology and physiol-

ogy (review). In: Flint M, Kronenberg F, Utian W,

eds. Multidisciplinary perspectives on menopause.

Ann NY Acad Sci 1990;592:52–86; discussion

123–33.

Lock M. Ambiguities of aging: Japanese experience

and perceptions of menopause. Cult Med

Psychiatry 1986;10(1):23–46.

Freedman RR. Biochemical, metabolic, and vascular

mechanisms in menopausal hot flashes. Fertil Steril

1998;70(2):332–7.

Dennerstein L, Smith AM, Morse C, Burger H, Green

A, Hopper J, Ryan M. Menopausal symptoms in

Australian women. Med J Aust 1993;159(4):232–6.

Morse CA, Dudley E, Guthrie J, Dennerstein L.

Relationships between premenstrual complaints

and perimenopausal experiences. J Psychosom

Obstet Gynaecol 1998;19(4):182–91.

Page 19

Avis NE, Crawford SL, McKinlay SM. Psychosocial,

behavioral, and health factors related to menopause

symptomatology. Womens Health

1997;3(2):103–20.

Avis NE, McKinlay SM. A longitudinal analysis of

women’s attitudes toward the menopause: results

from the Massachusetts Women’s Health Study.

Maturitas 1991;13(1):65–79.

Kuh DL, Wadsworth M, Hardy R. Women’s health in

midlife: the influence of the menopause, social fac-

tors and health in earlier life. Br J Obstet Gynaecol

1997;104(8):923–33.

O’Dea I, Hunter MS, Anjos S. Life satisfaction and

health-related quality of life (SF-36) of middle-

aged men and women. Climacteric 1999;2:131–40.

Dennerstein L, Lehert P, Burger H, Dudley E. Factors

affecting sexual functioning of women in the mid-

life years. Climacteric 1999;2:254–62.

Guthrie JR. Diet and exercise: do they influence

health outcomes during the menopausal transition.

In: Aso T, ed. The menopause at the millennium.

Proceedings of the 9th International Menopause

Society World Congress of the Menopause;

Yokohama, Japan. Parthenon Publishing

2000:204–11.

Ivarsson T, Spetz AC, Hammar M. Physical exercise

and vasomotor symptoms in postmenopausal

women. Maturitas 1998;29(2):139–46.

Guthrie JR, Smith AM, Dennerstein L, Morse C.

Physical activity and the menopause experience: a

cross-sectional study. Maturitas 1994;20(2–3):71–80.

Hammar M, Berg G, Lindgren R. Does physical exer-

cise influence the frequency of postmenopausal hot

flushes? Acta Obstet Gynecol Scand

1990;69(5):409–12.

Sternfeld B, Quesenberry CP Jr, Husson G. Habitual

physical activity and menopausal symptoms: a

case-control study. J Womens Health

1999;8(1):115–23.

Greendale GA, Reboussin BA, Hogan P, Barnabei

VM, Shumaker S, Johnson S, Barrett-Connor E.

Symptom relief and side effects of postmenopausal

hormones: results from the Postmenopausal

Estrogen/Progestin Interventions Trial. Obstet

Gynecol 1998;92(6):982–8.

Coope J, Thomson JM, Poller L. Effects of “natural

oestrogen” replacement therapy on menopausal

symptoms and blood clotting. Br Med J

1975;4(5989):139–43.

Sherwin BB, Gelfand MM. A prospective one-year

study of estrogen and progestin in postmenopausal

women: effects on clinical symptoms and lipopro-

tein lipids. Obstet Gynecol 1989;73(5 Pt 1):759–66.

Agnusdei D, Gennari C, Bufalino L. Prevention of

early postmenopausal bone loss using low doses of

conjugated estrogens and the non-hormonal, bone-

active drug ipriflavone. Osteoporos Int

1995;5(6):462–6.

Kicovic PM, Cortes-Prieto J, Luisi M, Milojevic S,

Franchi F. Placebo-controlled cross-over study of

effects of Org OD 14 in menopausal women.

Reproduction 1982;6(2):81–91.

Paterson ME. A randomised, double-blind, cross-over

study into the effect of sequential mestranol and

norethisterone on climacteric symptoms and bio-

chemical parameters. Maturitas 1982;4(2):83–94.

Nevinny-Stickel J. Double-blind cross-over study

with Org OD 14 and placebo in postmenopausal

patients. Arch Gynecol 1983;234(1):27–31.

Marslew U, Riis BJ, Christiansen C. Desogestrel in

hormone replacement therapy: long-term effects on

bone, calcium and lipid metabolism, climacteric

symptoms, and bleeding. Eur J Clin Invest

1991;21(6):601–7.

Marslew U, Overgaard K, Riis BJ, Christiansen C.

Two new combinations of estrogen and progesto-

gen for prevention of postmenopausal bone loss:

long-term effects on bone, calcium and lipid

metabolism, climacteric symptoms, and bleeding.

Obstet Gynecol 1992;79(2):202–10.

Gordon SF, Thompson KA, Ruoff GE, Imig JR, Lane

PJ, Schwenker CE. Efficacy and safety of a seven-

day, transdermal estradiol drug-delivery system:

comparison with conjugated estrogens and placebo.

The Transdermal Estradiol Patch Study Group. Int

J Fertil Menopausal Stud 1995;40(3):126–34.

Good WR, John VA, Ramirez M, Higgins JE. Double-

masked, multicenter study of an estradiol matrix

transdermal delivery system (Alora) versus placebo

in postmenopausal women experiencing

menopausal symptoms. Alora Study Group. Clin

Ther 1996;18(6):1093–105.

Page 20

Polo-Kantola P, Erkkola R, Irjala K, Pullinen S,

Virtanen I, Polo O. Effect of short-term transdermal

estrogen replacement therapy on sleep: a

randomized, double-blind crossover trial in

postmenopausal women. Fertil Steril

1999;71(5):873–80.

Utian WH, Burry KA, Archer DF, Gallagher JC,

Boyett RL, Guy MP. Tachon GJ. Chadha-Boreham

HK, Bouvet AA. Efficacy and safety of low, stan-

dard, and high dosages of an estradiol transdermal

system (Esclim) compared with placebo on vaso-

motor symptoms in highly symptomatic

menopausal patients. The Esclim Study Group. Am

J Obstet Gynecol 1999;181(1):71–9.

Kornafel KL, March CM. Estradiol gel in the treat-

ment of menopausal symptoms: a placebo-con-

trolled double-blind case study of efficacy and

safety. South Med J 1992;85(3):270–3.

Dennerstein L, Burrows GD, Hyman G, Wood C.

Menopausal hot flushes: a double blind comparison

of placebo, ethinyl oestradiol and norgestrel. Br J

Obstet Gynaecol 1978;85(11):852–6.

Studd J, Pornel B, Marton I, Bringer J, Varin C,

Tsouderos Y, Christiansen C. Efficacy and accept-

ability of intranasal 17 beta-oestradiol for

menopausal symptoms: randomised dose-response

study [published erratum appears in Lancet

1999;354:780]. Aerodiol Study Group. Lancet

1999;353(9164):1574–8.

Eriksen PS, Rasmussen H. Low-dose 17 beta-estradi-

ol vaginal tablets in the treatment of atrophic

vaginitis: a double-blind placebo controlled study.

Eur J Obstet Gynecol Reprod Biol

1992;44(2):137–44.

Dickerson J, Bressler R, Christian CD, Hermann HW.

Efficacy of estradiol vaginal cream in post-

menopausal women. Clin Pharmacol Ther

1979;26(4):502–7.

Campbell S, Whitehead M. Oestrogen therapy and the

menopausal syndrome. Clin Obstet Gynaecol

1977;4(1):31–47.

Thomson J, Oswald I. Effect of oestrogen on the

sleep, mood, and anxiety of menopausal women.

Br Med J 1977;2(6098):1317–9.

Loprinzi CL, Michalak JC, Quella SK, et al.

Megestrol acetate for the prevention of hot flashes.

N Engl J Med 1995;331(6):347–52.

Zichella L, Falaschi P, Fioretti P, et al. Effects of

different dopamine agonists and antagonists on

post-menopausal hot flushes. Maturitas

1986;8(3):229–37.

David A, Don R, Tajchner G, Weissglas L.

Veralipride: alternative antidopaminergic treatment

for menopausal symptoms. Am J Obstet Gynecol

1988;158(5):1107–15.

Melis GB, Gambacciani M, Cagnacci A, Paoletti AM,

Mais V, Fioretti P. Effects of the dopamine antago-

nist veralipride on hot flushes and luteinizing hor-

mone secretion in postmenopausal women. Obstet

Gynecol 1988;72(5):688–92.

van Lith ND, Motke JC. Opipramol in the climacteric

syndrome. A double-blind, placebo-controlled trial.

Maturitas 1983;5(1):17–23.

Salmi T, Punnonen R. Clonidine in the treatment of

menopausal symptoms. Int J Gynaecol Obstet

1979;16(5):422–6.

Coope J, Williams S, Patterson JS. A study of the

effectiveness of propranolol in menopausal hot

flushes. Br J Obstet Gynaecol 1978;85(6):472–5.

Hirata JD, Swiersz LM, Zell B, Small R, Ettinger B.

Does dong quai have estrogenic effects in post-

menopausal women? A double-blind, placebo-

controlled trial. Fertil Steril 1997;68(6):981–6.

Gottlieb N. Nonhormonal agents show promise

against hot flashes. J Natl Cancer Inst

2000;92(14):1118–20.

Avis NE, Kaufert PA, Lock M, McKinlay SM, Vass

K. The evolution of menopausal symptoms.

Bailleres Clin Endocrinol Metab 1993;7(1):17–32.

Murkies AL, Wilcox G, Davis SR. Clinical review 92:

Phytoestrogens. J Clin Endocrinol Metab

1998;83(2):297–303.

Coward L, Setchell K, Barnes S. The antitumor

isoflavones, genistein and daidzein, in soybean

foods of American and Asian diets. J Agric Biol

Chem 1993;41:1961–7.

Murkies AL, Lombard C, Strauss BJ, Wilcox G,

Burger HG, Morton MS. Dietary flour supplemen-

tation decreases post-menopausal hot flushes:

effect of soy and wheat. Maturitas

1995;21(3):189–95.

Brezezinski A, Aldercreutz H, Shoul R. Short-term

effects of phytoestrogen-rich diet on post-

menopausal women. Menopause 1997;4:89–94.

Page 21

Albertazzi P, Pansini F, Bonaccorsi G, Zanotti L,

Forini E, De Aloysio D. The effect of dietary soy

supplementation on hot flushes. Obstet Gynecol

1998;91(1):6–11.

Baber RJ, Templeman C, Morton T, Kelly GE, West

L. Randomized placebo-controlled trial of an

isoflavone supplement and menopausal symptoms

in women [published erratum appears in

Climacteric 1999;2:vi]. Climacteric 1999;2:85–92.

Knight DC, Howes JB, Eden JA. The effect of

Promensil, an isoflavone extract, on menopausal

symptoms. Climacteric 1999;2:79–84.

Albery N. The menopause in Japan – Konenki Jigoku

(editorial). Climacteric 1999;2:160–1.

Wilcox G, Wahlqvist ML, Burger HG, Medley G.

Oestrogenic effects of plant foods in post-

menopausal women. Br Med J

1990;301(6757):905–6.

Dalais F, Wahlqvist M, Grehan M, Murkies A,

Medley G, Ayton R, Strauss B. Effects of dietary

phytoestrogens in postmenopausal women.

Climacteric 1998;1:124–9.

Baird DD, Umbach DM, Lansdell L, et al. Dietary

intervention study to assess estrogenicity of dietary

soy among postmenopausal women. J Clin

Endocrinol Metab 1995;80(5):1685–90.

Chenoy R, Hussain S, Tayob Y, O’Brien PM, Moss

MY, Morse PF. Effect of oral gamolenic acid from

evening primrose oil on menopausal flushing. Br

Med J 1994;308(6927): 501–3.

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