A Longitudinal Analysis of the Association between

Menopause and Depression

Results from the Massachusetts Women’s Health Study

NANCY E. AVIS, PHD, DONALD BRAMBILLA, PHD, SONJA M. McKINLAY, PHD,

AND KERSTIN VASS, BA

7% present article prospectively examines the effect of change in menopause status on depression,
while controlling for prior depression. This is Q longitudinal follow-up of previous moss-sectional
analyses reported by M&inlay, M&inlay, and Brambilla who examined the relative contribution
of menopause to depression. The data derive from the Massachusetts Women’s Health Study, a S-year
longitudinal study ofa cohort of 2565 women aged 45 to 55 years at baseline (1981 to 1982). Results
show that prior depression is the variable most predictive of subsequent depression, as measured by
the Center for Epidemiologic Studies-Depression (CES-D) scale. Onset of natural menopause was
not associated with increased risk of depression. Experiencing a long perimenopausal period (at least
27 months), howewer, was associated with increased risk of depression. The association between a
long perimenopause and depression appeared to be explained by increased menopausal symptoms
rather than by the menopause status itself. The observed increase in depression during u lengthy
perimenopause appears to be transitory. Ann Epidemiol 1994;4:214-220.

KEY WORDS: Menopause, depression, cohort study, women.

the vasomotor symptoms associated with changing estrogen

INTRODUCTION
Despite evidence to the contrary (l-6), the notion persists
that menopausal women are likely to experience increased
depression. This presumption prevails among women in
general (7) as well as among clinicians (8, 9). Estrogen re-
placement therapy (ERT) is touted as a mental tonic (IO,
11) and in general surveys, high percentages of women agree
with the statement that “many women become depressed
or irritable during the menopause ” (7). Much of the research
that gives rise to this perceived relationship is derived from
clinic or patient populations of women who self-select into
treatment (12). While more recent research has been based
on community- or population-based samples, this research
continues to suffer from methodologic limitations. Much
of the research is based on cross-sectional data (3, 13-16)
that can neither control for premenopausal depression nor
characterize the transition through menopause.
Four hypotheses are generally offered to explain apparent
associations between menopause and depression. The first
two hypotheses are related to declining estrogen levels but
differ in the direction of the effect. The first is the symptom
hypothesis, which posits that depressed mood is explained by
From the New England Research Institute, Watertown, MA.
Address reprint requests to: Nancy E. Avis, PhD, New England Re-
search Institute, 9 Galen Street, Watertown, MA 02172.
Received March 25, 1993; revised September 15, 1993.
levels (17,18). Second, is the biochemical hypothesis that asso-
ciates a decline in estrogen directly with biochemical changes
in the brain that lead to depression. Three mechanisms
involving decreased neurotransmitter activity have been
suggested as possible explanations: decreased production,
increased metabolism, and interference with the neurohu-
moral response at the synaptic level (19,20). The biochemi-
cal hypothesis differs from the symptom hypothesis in that
it posits a direct association between estrogen decline and
depression. According to the symptom hypothesis, vasomo-
tor symptoms mediate the association between decreased
hormonal levels and depression. The third hypothesis is the
psychoanalytic eriew, which posits that onset of menopause is
a critical event in the life of a mid-aged woman and is a
threat to her adjustment and self-concept (21). Finally, the
social circumstances perspective states that menopause per se
is not associated with depression, but rather it is various
life events and circumstances coincidental with menopause
that are related to depression (6, 22).
To adequately address these hypotheses, longitudinal
data are necessary to study women as they proceed through
menopause, as well as to control for premenopausal depres-
sion. Cross-sectional data cannot examine the effect of be-
coming menopausal or control for premenopausal depres-
sion. The present article reports prospective data that address
the effect of change in menopause status on depression (as
measured by self-reported depressive symptoms), while con-

1047.2797/94/$07.00
AEP Vol. 4, No. 3 Avis et al. 215
May 1994: 214-220 MENOPAUSE AND DEPRESSION

trolling for prior depression, with special emphasis on the ments once. Women were randomly assigned to one of the
different stages of menopause. three possible orderings of instruments. The group of
This article is a longitudinal follow-up of previous cross- women assigned to each rotation did not differ in terms of
sectional analyses reported by McKinlay, McKinlay, and either education or age. The same sequence was used for
Brambilla (1) who examined the relative contribution of interviews four through six. Thus, during the course of the
menopause to depression among women participating in study, each respondent completed each supplemental in-
the Massachusetts Women’s Health Study (MWHS). The strument twice, 27 months apart.
MWHS was a 5-year longitudinal study designed to observe
women as they approached and experienced menopause,
Description of Variables
in order to identify which health changes were clearly re-
lated to the physiologic changes of menopause and which Depression. Depression was measured by the CES-D scale
were attributable to other independent life events and cir- (23) that was included on one of the rotated instruments.
cumstances. In their cross-sectional analyses, McKinlay and The CES-D is a well-established scale developed by the Cen-
colleagues (1) did not find an association between meno- ter for Epidemiologic Studies and often used in epidemio-
pause status and depression. logic research. It consists of 20 self-report items concerning
This article addresses two questions: (a) Controlling for depressed mood that were all selected from previously de-
prior depression, how are changes in natural menopause scribed scales to represent major symptoms in the clinical
status related to depression? (b) How are symptoms com- syndrome of depression as identified by clinical judgment,
monly attributed to the menopause transition associated frequency of use in other questionnaires for depression, and
with depression? factor analytic studies (24). It has been shown to be a valid,
reliable, and useful instrument for measuring depressive
symptoms in both the general community and psychiatric
populations. The CES-D has been shown to have high inter-
METHODS
nal consistency and adequate test-retest repeatability (23).
Sample It discriminates well between psychiatric inpatients and the
The MWHS was a 5-year longitudinal study of a cohort of general population. Scores range from 0 to 60, with those
2565 mid-aged women. The cohort was identified in 1981 scoring 16 and above generally being classified as at high
to 1982 from a baseline survey conducted on 8050 women risk for clinical depression (25).
aged 45 to 55 years, randomly sampled from the Common- Because the scores on the CES-D scale are highly skewed,
wealth of Massachusetts from annually compiled census with the mode being 0, it is generally recommended that
lists. Baseline survey information was gathered through linear models that assume normally distributed errors should
brief mailed questionnaires or in telephone interviews, if not be used for analysis of this scale. A widely used alterna-
no response to two mailings was obtained, to yield an overall tive is to dichotomize the scale and use methods such as
response rate of 77%. From this cross-sectional sample, a logistic regression for analysis. A cutpoint of 16 for identi-
cohort of 2565 women was identified; it consisted of women fying a “case” was established through several studies that
who had menstruated in the preceding 3 months and who compared the use of this cutpoint to clinical diagnoses of
had a uterus and at least one ovary intact. Prospective study depression, and has been found to provide the best discrimi-
of the cohort consisted of six telephone contacts that were nation (26-30). This dichotomous measure was used in the
9 months apart in the period of 1982 to 1987. Retention present analyses. Those women with scores less than 16
of the cohort was excellent, with response rates ranging were classified as “not depressed,” and those with scores of
from 94 to 99% over the six contacts, among those who 16 or higher were classified as “depressed.”
responded at the previous contact. The response rate at the In the analyses presented in this article, T1 refers to the
sixth interview was 91.5% of the original cohort. first completion of the CES-D scale and Tr refers to the
To limit interview length to approximately 30 minutes, second completion, 27 months later.
questions were divided into four instruments. A core instru- Menopause status. Each respondent’s menstrual status
ment (administered at each interview) included questions was determined from a combination of questions on current
related to menstrual status, physical health, health care utili- menstrual status at each contact and changes in the prior
zation, and sociodemographic characteristics. The remain- 9 months. Women were considered “premenopausal” if they
ing three instruments, covering social support networks, had reported regular menses in the last 3 months. Women
life-style (including depression), and help-seeking behavior, were classified as “perimenopausal” if menses had been expe-
were administered in rotation, so that respondents com- rienced in the past 12 months, but with periods of amenor-
pleted one of these three instruments at each interview. rhea and/or changes in regularity or flow. This definition is
Assignments were rotated so that after three interviews each consistent with prior research (3 l-33). “Natural menopause”
woman had been administered each of these three instru- was considered to have occurred if no menses were reported
216 Avis et al. AEP Vol. 4, No. 3
MENOPAUSE AND DEPRESSION May 1994: 214-220

for 12 consecutive months, in the absence of surgery that TABLE 1. Characteristics of study sample (N = 2356)
would terminate menstruation. Twelve months of amenor- included in analyses“
rhea is the widely accepted definition used in European TI T2
studies since the 1950s (32) and is recommended by Treloar
Variable N % N %
on the basis of his prospective study of normal menstrual
Menopause status
patterns (33). Women were classified as having a “surgical
Pre 485 20.6 235 10.0
menopause” if menses were stopped either by a hysterectomy
Peri 1549 65.9 1077 45.8
(with or without removal of the ovaries) or by a bilateral Post 240 10.2 894 38.0
oophorectomy. Surgical 78 3.3 146b 6.2
Menopause transition. To study change in menopause Menopausal transition
status, a menopause transition variable that took into ac- Pre-pre 235 10.7
count a woman’s menopausal status at both Tr and Tz was Pre-peri 291 13.2
Peri-peri 785 35.6
created. Women were classified into five categories: pre-
Pre/peri-post 652 29.6
menopausal at both Tr and Tz (pre-pre), premenopausal at
Post-post 240 10.9
Tr and perimenopausal at T2 (pre-peri), perimenopausal at
CES-D scale
both Tr and Tr (peri-peri), pre- or perimenopausal at Tr and
< 16 1913 90.4 1974 91.2
postmenopausal at Tr (pre/peri-post), and postmenopausal >, 16 203 9.6 190 8.8
at both T1 and Tz (post-post). Because Tr, for these analyses,
Hormone replacement therapy
could take place 18 months after entry into the study, it No 2097 94.9
was possible for women to be postmenopausal at both T1 Yes 113 5.1
and Tr. Women who had a surgical menopause are excluded Hot flashes or night sweats
from this categorization and from analyses for this article. No 1487 67.3 1276 57.7
Health variables. At each interview, respondents were Yes 722 32.7 934 42.3
asked to indicate whether or not they had experienced symp- Menstrual problems
toms commonly associated with menopause: hot flashes, night No 1965 88.9 2062 93.3
Yes 245 11.1 148 6.7
sweats, and menstrual problems. Hot flashes (or flushes) has
been found to be the primary symptom commonly associ- ’Numbers do not always add to same total because of missing data.
* These 146 wmnen are excluded from all other frequency distributions.
ated with menopause (5, 15). Women were also asked if
during the previous 2 weeks they had taken any hormones
for aging or menopause. These questions were embedded figures, Tr refers to the first completion of the CES-D scale,
in more general questions concerning symptomatology and which occurred at follow-up 1, 2, or 3 (depending on rota-
medication, respectively. tion group), and Tz refers to the second completion, which
Sociodemographic variables. The sociodemographic occurred at follow-up 4,5, or 6. Analyses reported here are
variables included in analyses were age, education (< 12 based on a sample of 2352 women for whom we had both
years, 12 years, and > 12 years of schooling), and marital menstrual status and depression measures at both Tr and
status. Tz and who had not had a surgical menopause before Tz.
Characteristics of the study sample for each of these vari- Because depression was treated as a dichotomous vari-
ables are shown in Table 1. Hormone replacement therapy able, logistic regression analyses were used. To determine
(HRT) use was low in this data set as more than half the if becoming menopausal was related to depression, a logistic
users in the cohort had a surgical menopause. However, regression of Tz CES-D on menopause transition was per-
the overall low rates of use observed in the MWHS also formed. The five menopause transition groups were repre-
reflect low use in New England (34-36). sented by a set of four indicator variables with the pre-pre
group treated as the reference group. We controlled for Tl
depression and use of hormone therapy by including these
Analysis Plan variables in the model as covariates. To determine if Tz
For analyses presented here, data on each woman’s meno- depression could be attributed to symptoms associated with
pause status, symptoms, and use of HRT (all of which were menopause (i.e., hot flashes, night sweats, menstrual prob-
measured at every follow-up) were selected from the fol- lems), menopausal symptoms were added to the logistic re-
low-up at which she completed the CES-D measure. Less gression of Tz depression on menopausal transition. We
than half of the women using exogenous hormones reported were unable to include each symptom in the model sepa-
taking combined estrogen and progestin (43.2%), and then rately because the number of women reporting specific
only from 1984 onward. The small number of women using symptoms in some of the transition categories was small.
exogenous hormones does not allow for type of hormone For example, none of the women in the pre/peri-post and
therapy to be included as a variable. For all tables and post-post groups reported menstrual problems. A single
AJZP Vol. 4, No. 3 Avis et al. 217
May1994: 214-220 MENOPAUSE AND DEPRESSION

TABLE 2. Results of logistic regression of TZ CES-D on for differences among the five menopause transition groups
TI CES-D and menopausal transition with respect to depression before examination of departures
Odds ratio of individual transition groups from the reference group.
Independent variable (95% confidence interval) P” Analyses revealed that the significant effect was primarily
< 0.001 due to the peri-peri group, which significantly differed from
T, CES-D
< 16 1.00 the pre-pre group (OR = 2.05). The peri-peri group also
B 16 9.62 (6.78, 13.7) differed significantly from the post-post group (OR = 2.70)
Hormone replacement therapy 0.95 (0.46, 1.95) NS when the latter was used as the comparison group, sug-
Ti-Tz menopausal transition < 0.03b gesting that the increased rate of depression is transitory.
Pre-pre 1.00 The interaction between prior depression and menopausal
Pre-peri 1.56 (0.72, 3.40) NS transition was not significant. Neither the main effect of
Peri-peri 2.05 (1.05, 4.02) < 0.05
hormone therapy nor its interaction with prior depression
Pre/peri-post 1.62 (0.81, 3.24) NS
Post-post 0.82 (0.33, 2.03) NS or menopause transition were significant in this model.
The rate of depression according to transition pattern
’Likelihood ratio statistic.
’4df. and premenopausal depression is graphically shown in Fig-
NS = not significant.
ure 1: For all menopause transitions, those women who were
classified as depressed at Ti had higher rates of depression at
variable, menopausal symptoms, was thus created and in- Tl. For women who were not depressed at Ti, the rate of
cluded reports of any of the three symptoms. This variable depression at Tz increased slightly as women moved from
was dichotomized so that women reporting at least hot pre-pre (4%) to pre-peri, and was highest for women who
flashes, night sweats, or menstrual problems received a score remained perimenopausal for at least 27 months (7%). The
of 1. Women who reported none of these symptoms received rate of depression began to decrease as women moved from
a score of 0. The models were tested for goodness of fit using peri- to postmenopause, and was lowest for those women
the Hosmer-Lemeshow (37) statistic. who were postmenopausal for at least 27 months. While
these results show that depression is associated with the
perimenopause status, they also show that this depression
RESULTS is transitory; as women become postmenopausal, their rates
To examine how change in menopause status is associated of depression decline, irrespective of premenopausal depres-
with depression, we used the menopause transition variable. sion.
In the logistic regression of Tz depression on T1 depression, While these results suggest that women who experience
menopause transition, and HRT (Table 2), prior depression a long perimenopause have increased rates of depression,
was clearly the variable most predictive of subsequent de- it is not clear whether this is due to prolonged experience
pression (P < 0.0001) with an odds ratio (OR) of 9.6. There of physical symptoms rather than to a biologic transition
was also a significant effect of menopausal transition (P < itself. In the same cohort, McKinlay, Brambilla, and Posner
0.03). A likelihood ratio test with 4 dfwas employed to test (38) showed that reports of hot flashes and night sweats

MENOPAUSAL STATUSTRANSITION,T, +T2:

??
Pre-Pre ??
Pre+Peri Peri-bPeri ??Pre/Peri+Post ??PoshPost
50

TT

FIGURE 1. Percent ofwomen clas-

sified as depressed at T2 by depres-
sion status at T1 and menopausal
NOT DEPRESSED ATT, DEPRESSED ATT, transition.
218 Avis et al. AEP Vol. 4, No. 3
MENOPAUSE AND DEPRESSION May 1994: 214-220

increase as the perimenopause progresses. They also showed MENOPAUSAL SYMPTOMS AT T2:

that perimenopausal and newly menopausal women are ON” m YES

“1 -r
more likely to report hot flashes, night sweats, and insom-
nia, as well as other physical symptoms, than are women
at other menopausal transition stages. DEPRESSED 40-
at T2 6)
The results of the logistic regression in which the variable
menopausal symptoms are added to the model (Table 3) 20-

show that again, T1 depression was the variable most pre-

dictive of TZ depression. The menopausal symptom variable,
however, was also a significant contributor, with an OR of 0
J-1
I

3.55. With menopausal symptoms in the model, menopausal NOT DEPRESSED ATT, DEPRESSED ATT,

transition was no longer statistically significant. The inter-

FIGURE 2. Percent of women classified as depressed at Tz, by
action term for TI CES-D by menopausal symptoms was not
depression status at TI and menopausal symptoms at Tz.
significant. Although we were unable to separately analyze
each menopausal symptom, descriptive data suggest that
menstrual problems may be more associated with depression
than vasomotor symptoms. Combining over early transi- DISCUSSION
tion categories (pre-pre, pre-peri, and peri-peri), we found
The data reported here provide for the first time, reliable
that of those women who reported hot flashes or night
estimates of depressive symptoms in a large, randomly sam-
sweats at Tz, 16.3% (78/479 women) were classified as de-
pled cohort of women as they proceed through menopause.
pressed, while of those who reported menstrual problems,
These longitudinal data are unique because the large sample
24.6% (34/138) were classified as depressed. provides the opportunity to measure depression across
The rate of depression at T2 according to depression at menopause transitions, controlling for prior depression, as
T1 is graphically shown in Figure 2. Regardless of prior well as taking into account menopausal symptoms and hor-
depression, those women who reported experiencing hot mone use.
flashes, night sweats, and/or menstrual problems showed Results from this large community-based cohort of
higher rates of depression. The differences between those women do not confirm evidence that onset of menopause
who reported symptoms and those who did not are even is significantly associated with increased risk of depression.
more striking than the differences across menopause transi- Experiencing a long perimenopausal period (at least 27
tions (see Figure 1). months), however, is moderately associated with increased,
but transitory depression. This increased depression is
partly explained by menopausal symptoms. We should
point out that menopausal symptoms are associated with
depression regardless of whether the multinomial variable
TABLE 3. Results of logistic regression of T2 CES-D on
menopause transition is in the model. Menopause transi-
TI CES-D and menopausal transition
tion, however, is significant only when symptoms are not
Odds ratio
included. This suggests that reported menopausal symptom-
Independent variable (95% confidence interval) P”
atology carries more information than menopause transi-
T, CES-D < 0.0001 tion in explaining depression. From these results we con-
< 16 1.00 clude that while perimenopause is associated with a slight
2 16 9.12 (6.35, 13.10)
increase in depression, this association can be explained by
Hormone replacement therapy 0.93 (0.45, 1.92) NS
increased symptom reporting and appears to be transitory.
T2 menopausal symptomsb < 0.cOO1 One caveat we should acknowledge is that symptoms and
1.00
No depression were both measured by self-report and may well
Yes 3.55 (2.45, 5.13)
be manifestations of the same underlying process. It may be
T,-T2 menopausal transition < 0.16’
difficult, even with a clinical interview, to clearly distinguish
Pre-pre 1.00
these variables.
Pre-peri 1.28 (0.58, 2.81)
Peri-peri 1.34 (0.67, 2.66) The hypotheses linking depression and menopause listed
Pre/peri-post 1.03 (0.51, 2.10) in the introduction are considered here in light of the find-
Post-post 0.59 (0.23, 1.49) ings presented. These results do not provide conclusive sup-
a Likelihood ratio statistic. port for the psychoanalytic view (hypothesis 3) that onset
b Includes hot flashes, night sweats, and/or menstrual problems. of menopause is associated with depression. The increase
c 4 df.
NS = not significant. in depression is transitory, is associated with a prolonged
AEP Vol. 4, No. 3 Avis et al. 219
May 1994: 214-220 MENOPAUSE AND DEPRESSION

perimenopause, and is overwhelmingly associated with the

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