Judith K. Ockene, David H. Barad, Barbara B. Cochrane, Joseph C. Larson, Margery Gass, Sylvia Wassertheil-Smoller, JoAnn E. Manson, Vanessa M. Barnabei, Dorothy S. Lane, Robert G. Brzyski, Milagros C. Rosal, Judy Wylie-Rosett, Jennifer Hays. Symptom Experience After Discontinuing Use of Estrogen Plus Progestin. JAMA. 2005;294(2):183–193. doi:10.1001/jama.294.2.183
Author Affiliations: Division of Preventive
and Behavioral Medicine, University of Massachusetts Medical School, Worcester
(Drs Ockene and Rosal); Departments of Obstetrics and Gynecology and Women’s
Health (Dr Barad) and Epidemiology and Population Health (Drs Wassertheil-Smoller
and Wylie-Rosett), Albert Einstein College of Medicine, Bronx, NY; Division
of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle,
Wash (Dr Cochrane and Mr Larson); Department of Obstetrics and Gynecology,
University of Cincinnati College of Medicine, Cincinnati, Ohio (Dr Gass);
Division of Preventive Medicine, Brigham and Women's Hospital, Harvard Medical
School, Boston, Mass (Dr Manson); Department of Obstetrics and Gynecology,
Medical College of Wisconsin, Milwaukee (Dr Barnabei); Department of Preventive
Medicine, State University of New York, Stony Brook (Dr Lane); Department
of Obstetrics and Gynecology, University of Texas Health Science Center, San
Antonio (Dr Brzyski); and Department of Medicine, Baylor College of Medicine,
Houston, Tex (Dr Hays).
Context Little is known about women’s experiences after stopping menopausal
Objective To describe women’s symptoms and management strategies after stopping
the intervention in a large estrogen plus progestin trial.
Design, Setting, and Participants Cross-sectional survey of 8405 women (89.9%; N = 9351) at 40 clinical
centers who were still taking study pills (conjugated equine estrogens plus
medroxyprogesterone [CEE + MPA] or placebo) when the estrogen plus progestin
intervention (Women's Health Initiative) was stopped. Surveys were mailed
8 to 12 months after the stop date. Logistic regression was used to model
vasomotor symptoms and pain or stiffness symptoms as functions of former treatment
and baseline symptoms, adjusted for appropriate covariates.
Main Outcome Measures Symptoms (vasomotor or pain and stiffness) and management strategies.
Results Respondents’ mean (SD) age at trial stop date was 69.1 (6.7) years.
They averaged 5.7 years of taking study pills. Moderate or severe vasomotor
symptoms after discontinuing study pill use were reported by 21.2% of former
CEE + MPA and 4.8% of placebo group respondents overall and by 55.5% and 21.3%,
respectively, with these symptoms at baseline (randomization). Compared with
respondents in the former placebo group, moderate or severe vasomotor symptoms
(adjusted odds ratio [AOR] 5.82; 95% confidence interval [CI], 4.92-6.89)
and pain or stiffness symptoms (AOR, 2.16; 95% CI, 1.95-2.40) were more likely
in respondents in the former CEE + MPA group. Both vasomotor symptoms (AOR,
5.36; 95% CI, 4.51-6.38) and pain or stiffness symptoms (AOR, 3.21; 95% CI,
2.90-3.56) also were more likely in women with these symptoms at baseline.
Women reported a wide range of strategies to manage symptoms.
Conclusions More than half of the women with vasomotor symptoms at randomization
to active CEE + MPA also reported these symptoms after discontinuing use of
the study pills. However, these participants did not include women who were
unwilling to be randomized or who had stopped taking the study pills earlier.
These findings should be considered when advising women to treat menopausal
symptoms with hormone therapy for as short duration as possible. Investigation
of alternative strategies to manage menopausal symptoms is warranted.
Recommended guidelines and prescribing practices for menopausal hormone
therapy (MHT) have changed significantly1,2 since
publication of the Women's Health Initiative (WHI) estrogen plus progestin
(E + P) trial findings that the overall health risks of taking conjugated
equine estrogens and medroxyprogesterone acetate for disease prevention exceed
the benefits.3 Management of vasomotor and
vaginal dryness symptoms remains the cornerstone of opinion in favor of MHT
use. Women frequently cite relief from vasomotor symptoms4,5 and
improvement in well-being as reasons for starting or continuing MHT.6,7
Current recommendations for MHT focus on treatment of symptoms at the
lowest effective dosage for the shortest duration possible,8- 10 yet
there is little information about the effects of stopping MHT on either symptoms
or health-related quality of life. Many possible alternative but largely untested
strategies have been proposed for symptom relief after stopping MHT.11 Newton et al12 found
that women generally view such alternative strategies as helpful. Unfortunately
there is little information about the efficacy of many of these proposed alternatives.
The WHI E + P trial participants represent a large, unique cohort of
women who have undergone sudden withdrawal from active combined hormone therapy
or placebo. This article reports on vasomotor (hot flashes or night sweats)
and other symptoms, use of alternative strategies for managing symptoms, and
the perceived effectiveness of these strategies in those E + P trial participants
who responded to a survey mailed 8 to 12 months after they were instructed
to stop taking their study pills. These data are compared with baseline and
year 1 postrandomization data from the same participants.
Details of the E + P trial design, recruitment, screening, randomization,
baseline characteristics, and comparison of participants receiving active
treatment with those receiving placebo are described elsewhere.3,13- 15 Relevant
to the current analysis, participants with menopausal symptoms at baseline
were generally not excluded from participating. Women who were taking hormones
at screening were required to undergo a 3-month washout. Those women who completed
the washout were asked if they were having postmenopausal symptoms, such as
hot flashes or night sweats. Women who reported that they were having mild
or moderate symptoms during the washout were cautioned that they could be
randomized to placebo and that their symptoms could continue for the rest
of the study. Women who reported that they were having severe menopausal symptoms
during the washout were ineligible for the study. Participants who had not
had a hysterectomy at baseline and were still interested in and eligible for
the E + P trial provided written informed consent and were assigned to 0.625
mg/d of conjugated equine estrogens plus 2.5 mg/d of medroxyprogesterone acetate
(CEE + MPA) or placebo at 40 clinical centers across the United States. All
participants completed self-administered questionnaires that included health-related
quality of life and symptom items at baseline (before randomization) and at
1-year postrandomization.13,14,16,17 Some
of the participants who were taking hormones at screening may have completed
these questionnaires before washout. Race/ethnicity was self-reported by participants
who were given choices on a form.
In May 2002, the WHI data and safety monitoring board concluded that
the risks of CEE + MPA treatment outweighed the benefits and recommended early
stopping of the E + P trial.3,18 The
National Heart, Lung, and Blood Institute concurred, and in a centralized
mailing timed to be received by participants on July 8, 2002 (average intervention
duration was 5.6 years), E + P participants were informed of the findings
and instructed to stop taking their study pills. The WHI clinical center staff
subsequently met with each E + P participant, confirmed that she had stopped
taking the study pills, obtained a medical history update, informed her of
her treatment assignment, and discussed the findings of the study.
Participants who were still taking study pills on July 8, 2002, when
the E + P trial intervention was stopped (n = 9351 or 56% of the
16 608 women randomized in the E + P trial) were eligible to complete
a survey mailed 8 to 12 months after the stop date. For women who stopped
taking the study pills earlier, their recall of symptoms may have been distorted
by time. Therefore, the remaining 7257 participants (44%), who had permanently
discontinued use of the study pills before the stop date or were deceased,
were excluded from this analysis.
The E + P survey instrument was designed to collect self-report data
after the WHI E + P trial intervention was stopped. The survey was pretested
at 4 WHI clinical centers using cognitive interviewing techniques19,20 with 56 age-eligible women who had
not been enrolled in the WHI. Survey items were based on previously standardized
scales, expert clinician input, and a review of the relevant literature.12,21- 23 Some
items have been described previously, including the depression and symptom
checklist,10,23 which had 8 items
appended to capture additional menopausal symptoms and treatment effects.
Anxiety was measured using the 7-item Anxiety Disorder subscale of the
Patient Health Questionnaire.24 For each symptom
of anxiety, respondents rated on a 3-point scale (“not at all”
to “more than half the days”) the extent to which they had experienced
the symptom during the last 4 weeks. Panic attacks were assessed similarly
by a single item from the Patient Health Questionnaire that asked if the participant
had “an anxiety attack, suddenly feeling fear or panic.”
Symptom management strategies included a checklist of 25 items reported
by or recommended for women to cope with symptoms.12,22,23 For
each strategy, the respondent noted whether she had tried the strategy, and
if so, how helpful she perceived it to be on a 3-point scale (from “helped”
to “made things worse”).
Hormone use items were based on questions included on other WHI surveys.
Respondents also were asked about reasons for starting or continuing to take
hormone medications since the intervention stop date.
Following review and approval by the institutional review boards for
the clinical coordinating center and the local clinical centers, a cover letter,
E + P survey, and prepaid return envelope were mailed out to all eligible
E + P participants who had been taking study pills, either active or placebo,
as of July 8, 2002. A subsequent follow-up mailing and telephone call were
used to enhance response rates. The current analysis represents all eligible
responses received and entered into the WHI database between the first mailing
on March 15, 2003, and August 31, 2003.
To characterize survey respondents more fully and improve the generalizability
of study findings, we examined baseline demographic and health characteristics
of survey respondents, eligible nonrespondents, and E + P participants who
were not eligible to complete the survey because they had stopped taking the
study pills before July 8, 2002. Participants who reported moderate or severe
vasomotor symptoms (hot flashes or night sweats) within the 4 weeks before
their screening visit were considered to have vasomotor symptoms at baseline
(randomization or study entry).
The percentage of study pills taken was calculated from the actual weight
of returned pills or the participant’s estimate of remaining pills if
they were not returned. Adherence was defined as taking 80% or more of the
standard study pill regimen. The last adherence rate was based on the last
actual or estimated pill collection before a participant stopped taking her
Symptoms were selected for analysis from the 42-item checklist based
on previous research on symptoms of menopause, adverse effects of treatment,
other treatment effects attributed to exogenous hormones, and symptoms identified
in the earlier E + P trial analyses of health-related quality of life and
symptoms.16,17 Descriptive statistics
and graphic displays of symptoms and symptom management strategies were reviewed.
Logistic regression was used to model the occurrence of selected symptoms
since discontinuing study pill use as a function of both the baseline report
of the same symptom and treatment group. These models were run separately
for individual symptoms, including moderate or severe vasomotor symptoms and
pain or stiffness. With the symptom of interest after discontinuing study
pill use as the response, the models were adjusted for the baseline variables
of age, race/ethnicity, prior hormone use, smoking, alcohol use, and body
mass index (calculated as weight in kilograms divided by the square of height
in meters). Receiver operating characteristic curves were checked graphically
and used in conjunction with the Hosmer-Lemeshow χ2 test25 to assess the model fit. Collinearity was checked
by examining correlation tables of the variables involved in the model, and
overfitting was evaluated by looking at reduced models and checking for similar
In addition to these models, logistic models stratified by vasomotor
symptom history (present at baseline vs not present at baseline) were run
to assess the interaction between baseline vasomotor symptoms and treatment
assignment with the presence of moderate or severe symptoms after stopping.
Parameter estimates for all models were tested with a 2-tailed Wald test from
a χ2 statistic. For all testing, P <.05 was
identified as significant. All analyses were conducted with SAS version 9.0
(SAS Institute Inc, Cary, NC).
A total of 9351 participants (4558 in the CEE + MPA group and 4793 in
the placebo group), representing 56.3% of all participants in the E + P trial,
were still taking study pills when the E + P trial was stopped and were, therefore,
eligible to receive the survey (Figure).
Of these participants, 8405 (representing 89.6% of those formerly assigned
to CEE + MPA and 90.1% to placebo) returned their surveys and are included
in this data set.
Mean (SD) age at the time participants discontinued study pill use was
69.1 (6.7) years. Table 1 shows baseline
characteristics of survey respondents, eligible nonrespondents, and ineligible
participants who discontinued use of study pills prior to the stop date of
the E + P trial. Respondents compared with eligible nonrespondents were older
and more likely to be white, high school or college graduates, or married;
have past or current MHT use at baseline; drink alcohol; and were former smokers.
Respondents also were more likely to be adherent at their last pill collection
before the stop date, to have longer follow-up, and were less likely to have
had a history of hypertension, cardiovascular disease, or treated diabetes
at baseline. Comparisons of survey respondents with E + P participants ineligible
for this survey indicate differences similar to those described above. However,
survey respondents were younger than women who were ineligible to receive
the survey, and there was no significant difference in cardiovascular disease
prevalence at baseline.
Women who were taking hormones at baseline represented 7.2% of survey
respondents compared with 4.6% of eligible nonrespondents (P = .009) and 5.4% of E + P trial participants ineligible to receive
the survey (P<.001). The percentage of respondents
who had moderate or severe vasomotor symptoms at baseline (11.3% overall;
12.3% of CEE + MPA group and 10.4% of placebo group) was significantly lower
(P<.001) than the percentage of eligible nonrespondents
(15.4% overall; 16.1% of CEE + MPA group and 14.8% of placebo group) and the
percentage of women ineligible to receive the survey (13.1% overall; 12.5%
of CEE + MPA group and 13.8% of placebo group; P =
.008) with these symptoms.
Among those participants ineligible to receive the survey because they
had discontinued study pill use prior to July 8, 2002, only 10 reported vasomotor
symptoms as a reason for stopping study pill use (0.1% of CEE + MPA group
and 0.2% of placebo group). More survey-ineligible participants reported discontinuing
study pill use because of vaginal bleeding (14.1% of CEE + MPA group and 0.9%
of placebo group) or breast tenderness (6.8% of CEE + MPA group and 1.2% of
placebo group) than because of vasomotor symptoms.
Survey respondents reported a wide array of symptoms after discontinuing
study pill use. Respondents formerly randomized to the CEE + MPA group had
a higher prevalence of each symptom since discontinuing study pill use than
those randomized to placebo (Table 2).
In addition, the total number of moderate or severe symptoms reported by women
after discontinuing use of CEE + MPA was greater than the number of symptoms
reported by women after discontinuing use of placebo, with 36.7% and 59.5%,
respectively, reporting no symptoms.
Symptoms reported by more than 10% of respondents after discontinuing
use of CEE + MPA included (in descending frequency) pain or stiffness, feeling
tired, vasomotor symptoms, difficulty sleeping, and bloating or gas. Symptoms
reported by more than 10% of respondents after stopping placebo were pain
or stiffness and feeling tired. The percentage of respondents with scores
on the Center for Epidemiologic Studies Depression Scale above the cut point
for depression was greater for women after discontinuing use of CEE + MPA
(10.5%) than placebo (7.2%) (P <.001). Younger women reported
more frequent emotional or neurological symptoms, headaches, breast tenderness,
vaginal symptoms, and vasomotor symptoms.
Table 3 shows moderate or severe
symptoms in participants after discontinuing study pill use stratified by
whether or not women had these symptoms at baseline. Women who reported having
moderate or severe symptoms at baseline were more likely to report these symptoms
after discontinuing study pill use regardless of treatment group. Overall,
91.1% of women in the former CEE + MPA group who reported vasomotor symptoms
after discontinuing MHT had also experienced them in the past.
Table 4 shows the adjusted odds
ratios for specific moderate or severe vasomotor symptoms and pain or stiffness
after discontinuing study pill use. The strongest determinant of these symptoms
after discontinuing study pill use was their presence at baseline even after
adjusting for former treatment assignment, age at stop date, baseline MHT
use, body mass index, alcohol use, and smoking status. After adjusting for
all other variables, respondents formerly assigned to CEE + MPA compared with
those formerly assigned to placebo were also more likely to have these symptoms
after discontinuing study pill use. Other factors that increased the likelihood
of experiencing vasomotor symptoms after discontinuing study pill use in these
adjusted models were taking hormones prior to study enrollment and current
smoking. Higher body mass index, past or current alcohol use, and current
smoking increased the likelihood of pain or stiffness after discontinuing
study pill use in these adjusted models.
An additional model was run to evaluate an interaction between the effects
of treatment assignment and history of vasomotor symptoms. This model included
all of the covariates presented in Table 4 with
the addition of an interaction term. The interaction between treatment assignment
and baseline vasomotor symptoms proved to be significant (P = .02). To determine the nature of this interaction, separate
models were created for the subgroups of participants based on vasomotor symptom
status at baseline. Among respondents in both former treatment groups who
reported vasomotor symptoms at baseline, those women previously assigned to
CEE + MPA were 4.4 times more likely than those assigned to placebo to have
vasomotor symptoms after discontinuing study pill use. Among respondents in
both former treatment groups who reported none or only mild vasomotor symptoms
at baseline, those women previously assigned to CEE + MPA were 7 times more
likely than those assigned to placebo to have these symptoms after discontinuing
study pill use.
Among survey respondents reporting any mild, moderate, or severe symptoms
after discontinuing study pill use, the percentage that reported specific
lifestyle and medical strategies to manage their symptoms are included in Table 5. More than half of the respondents with
symptoms in either treatment group reported use of at least 1 management strategy.
However, many of the management strategies were tried by 10% or fewer of the
respondents. More respondents who had been assigned to CEE + MPA than those
assigned to placebo tried at least 1 of any management strategy and, specifically,
at least 1 lifestyle (49.1% vs 41.2%, respectively; P<.001)
or 1 medical (48.0% vs 37.1%, respectively; P<.001)
management strategy. Among women who reported only mild symptoms, 42% had
tried 1 or more management strategies as opposed to 68% of women with any
moderate or severe symptoms.
The most frequent lifestyle management strategies that women reported
trying were drinking more fluids and starting or increasing exercising, which
were reported by more than 20% of women in each treatment group. More than
86% of the women in each treatment group who tried these strategies reported
that they helped to reduce symptoms.
The most frequent medical management strategy that women reported trying
was talking to a clinician, which was used by 23.2% of the CEE + MPA group
and 17.0% of the placebo group. Use of prescription MHT was not common in
either the CEE + MPA group (4.3%) or the placebo group (1.2%). Among women
in each treatment group who tried prescription hormones, 87% reported that
A separate question asked women whether they started taking prescription
hormones (not necessarily as a management strategy) after discontinuing study
pill use. A total of 5% of all respondents chose to start MHT after stopping
their study pills for any reason, with CEE + MPA participants more likely
to report starting MHT compared with placebo participants (7.6% vs 2.6%, respectively; P<.001). Table 6 lists
the reasons these women gave for starting MHT after discontinuing study pill
use. The most frequent reasons for starting MHT were symptom management (55.2%
of CEE + MPA group) and physician advice (59.5% of placebo group). Compared
with women who reported none or only mild vasomotor symptoms at baseline,
a higher percentage of women with moderate or severe baseline symptoms also
reported that they started MHT after discontinuing study pill use to deal
with symptoms. This difference was greater for women in the former CEE + MPA
group (77.8% of those with moderate or severe vasomotor symptoms vs 49.4%
of those who reported none or only mild symptoms) than for women in the former
placebo group (26.7% and 25.0%, respectively).
This article provides the first published data on symptoms and management
strategies reported by a large and diverse sample of relatively healthy postmenopausal
women after discontinuing CEE + MPA or placebo. These findings offer preliminary
insights about the symptom experience women might anticipate after discontinuing
MHT and are timely in light of recent recommendations to limit MHT primarily
to the treatment of moderate to severe menopausal symptoms at the lowest effective
dose for the shortest duration possible.9,10
Respondents who reported moderate or severe menopausal symptoms at study
entry are somewhat comparable with women who might take prescription hormones
to treat vasomotor symptoms. Our finding that respondents were more likely
to report such symptoms after discontinuing hormone use even after more than
5 years of treatment is consistent with results from a recent cross-sectional
survey of postmenopausal women in which troublesome symptoms after discontinuing
hormone use were more prevalent among women who had started MHT for symptoms
than in those who started MHT to prevent disease.26 Although
discontinuing CEE + MPA may be associated with a recurrence or persistence
of vasomotor symptoms, we also noted this same phenomenon in a smaller percentage
of respondents formerly assigned to the placebo group.
For women who do not have vasomotor symptoms before they start MHT,
it appears that discontinuing use does not induce these symptoms. Among women
formerly receiving active treatment in our study who reported none or only
mild vasomotor symptoms at baseline, few reported these symptoms after discontinuing
study pill use. These findings are consistent with the only clinical trial
to date that looked at symptoms after discontinuing MHT and found that abruptly
stopping a sequential regimen of combined hormone therapy after 14 weeks was
not associated with an induction of vasomotor symptoms in women who had never
had these symptoms.27
We presume that moderate or severe symptoms that occur after stopping
CEE + MPA eventually diminish. In fact, the symptoms reported by the WHI participants
since stopping use may have disappeared by the time respondents actually completed
the survey 8 to 12 months after discontinuing study pill use. A recent study
examining the occurrence of vasomotor symptoms in 266 blinded women transitioning
from CEE + MPA to either placebo or raloxifene or continuing CEE + MPA found
that vasomotor symptoms reported by 50% to 70% of those women transitioning
off CEE + MPA were generally reported to be mild to moderate and peaked at
8 weeks into the transition.28 That study followed
up participants for only 12 weeks and did not report symptoms after discontinuing
study pill use as a function of baseline symptoms. Grady et al26 reported
that symptoms were still troublesome in 73% of their study participants who
discontinued MHT several months before. Additional research on the timing
of onset and duration of symptoms after discontinuing use of MHT is warranted.
The higher prevalence of pain or stiffness in former CEE + MPA respondents
compared with placebo respondents after discontinuing study pill use suggests
an additional beneficial effect of CEE + MPA or a rebound symptom response
to discontinuing use. These findings are consistent with WHI data reported
by Barnabei et al,16 which suggest that CEE
+ MPA may decrease or prevent musculoskeletal symptoms in postmenopausal women.
The high rate of this withdrawal symptom rivals the report of vasomotor symptoms
and has not been well documented in the past. Other MHT trials have not shown
a beneficial effect of hormones on musculoskeletal symptoms,29,30 except
in a separate analysis of adherent participants. The presence of estrogen
receptors in cartilage is generally acknowledged,31 and
animal models suggest that estradiol and progesterone influence pain latency
as a factor contributing to an analgesic effect of these hormones.32 However, a recent review of MHT effects on osteoarthritis
by the American College of Obstetricians and Gynecologists noted that research
in this area is limited and conflicting. These reviewers concluded that there
is no beneficial role of combined hormone therapy or estrogen alone in the
prevention or treatment of osteoarthritis or rheumatoid arthritis.33 The current finding of an increase in pain or stiffness
after discontinuing active study pill use may be an effect of aging. However,
it is intriguing and warrants further research because the common wisdom has
held that vasomotor symptoms are more strongly linked to hormonal effects
of menopause despite increased reporting of joint stiffness or soreness in
middle-aged women across racial/ethnic groups.34
Current hormone prescribing guidelines to limit MHT to the treatment
of moderate to severe vasomotor symptoms is supported by our finding that
few women with only mild symptoms regardless of treatment group sought treatment
for managing these symptoms. In fact, the number of former CEE + MPA participants
who obtained prescription hormones to manage symptoms is considerably smaller
than the 21.2% of patients surveyed by Grady et al.26 Also
consistent with current MHT prescribing guidelines is that most respondents
regardless of treatment group started taking prescription hormones to deal
with symptoms. Our rates correspond to those found by Grady et al,26 who found that 57% of women reported that they restarted
MHT for relief of symptoms.
Similar to findings reported in a telephone survey of alternative therapies
for managing menopausal symptoms,21 most commonly
recommended medical and self-help strategies for controlling menopausal symptoms
were viewed as helpful in both treatment groups. Although a higher percentage
of placebo group respondents identified that the strategies they tried actually
helped, this finding may be due to the fact that the symptoms reported by
former placebo group respondents were more often mild or absent after discontinuing
study pill use.
Complementary and alternative treatments for MHT have gained increasing
attention since the release of the WHI E + P trial results, but the use of
herbal or natural hormones by respondents in the current study was reported
as one of the least effective strategies. Scientific data about the efficacy
of many of these kinds of treatments are limited and women often receive information
about alternative strategies from lay sources.35 In
prior qualitative research, menopausal women reported limited discussion with
clinicians on lifestyle or self-care alternatives and a lack of knowledge
and support for such alternatives.36 Although
the effectiveness women attributed to any strategies they tried may be related
to a potential placebo effect,12 the differences
seen in the therapies tried and the relative effectiveness of each are important
discussion points in clinical practice. Further studies on alternative therapies
The generalizability of these findings is limited in several ways. Despite
the high response rate of almost 90% in both treatment groups, there were
significant differences between the baseline characteristics of respondents
and eligible nonrespondents. These differences may have influenced the results.
An important study limitation is that the survey was sent only to those
participants who were still taking study pills when the intervention was stopped.
More than 40% of trial participants had already discontinued study pill use
for personal or protocol-related reasons and were not included in this survey.
These excluded women may have had different symptom experiences before, during,
and after discontinuing study pill use compared with the survey respondents
who took study pills for a longer period. Although there were no significant
differences in the proportions of survey-ineligible participants and respondents
who had moderate or severe hot flashes at baseline, a significantly greater
proportion of survey-ineligible participants than respondents did have moderate
or severe night sweats at baseline. It may be that night sweats, more than
hot flashes, were disruptive to participants’ daily lives during follow-up
and therefore prompted more women with these symptoms to discontinue study
pill use before the stop date. During follow-up, survey-ineligible participants,
particularly those assigned to active CEE + MPA, more often identified symptoms
associated with MHT (eg, breast changes and vaginal bleeding) rather than
menopausal symptoms as reasons for discontinuing study pill use. Although
vasomotor symptoms and vaginal changes were given as reasons for discontinuing
study pill use early by similarly low numbers of both CEE + MPA and placebo
participants, the experience of stopping study pills in these survey-ineligible
participants may have been different from the experience of survey respondents.
Participants who enrolled in the E + P trial and continued taking study
pills until July 2002 undoubtedly do not represent the full spectrum of symptom
severity. The WHI clinical trial protocol excluded the randomization of women
who were unable to tolerate discontinuing MHT. The mean age of women in this
study was considerably older than the age at which women typically begin MHT
to treat menopausal symptoms. Less than 7% of all E + P participants reported
current MHT use at baseline, but these participants represented a higher proportion
of survey respondents than survey-ineligible participants in both treatment
groups, and significantly more CEE + MPA than placebo respondents were taking
hormones at baseline. Participants were unblinded to their former treatment
assignment well before they completed these surveys, which also may have influenced
their recall of symptoms since discontinuing study pill use.
Most of these limitations would argue against survey respondents reporting
a heightened symptom experience after stopping study pills compared with survey-ineligible
participants or the typical woman who starts MHT to treat menopausal symptoms.
However, nearly 13% of respondents overall (21.2% of those formerly assigned
to CEE + MPA) reported moderate or severe vasomotor symptoms after stopping
study pill use. More than half of the youngest age group of CEE + MPA respondents
who had these symptoms at baseline—those most comparable with the typical
woman who begins MHT for symptom management—also experienced these symptoms
after discontinuing use.
Participants in a randomized clinical trial of CEE + MPA and placebo,
who had been taking study pills an average of 5.7 years, reported a range
of symptoms experienced and strategies for managing symptoms after the intervention
was stopped. While most respondents regardless of treatment assignment did
not experience moderate to severe vasomotor symptoms after discontinuing study
pill use, a history of vasomotor symptoms greatly increased the likelihood
of experiencing symptoms after discontinuing use and participants randomized
to active CEE + MPA were more likely to report recurrence or persistence of
these symptoms after discontinuing study pill use. Short-term use of CEE +
MPA may only alleviate symptoms temporarily for many women, including older
women, who may experience a return of menopausal symptoms after stopping MHT.
A wide range of lifestyle and medical strategies to manage symptoms may help.
Further testing of the efficacy of these management strategies for women whose
symptoms recur after discontinuing short-term MHT is warranted.
Corresponding Author: Judith K. Ockene,
PhD, MEd, University of Massachusetts Medical School, Division of Preventive
and Behavioral Medicine, 55 Lake Ave N, Worcester, MA 01655 (Judith.Ockene@umassmed.edu).
Author Contributions: Dr Ockene had full access
to all of the data in the study and takes responsibility for the integrity
of the data and the accuracy of the data analysis.
Study concept and design: Ockene, Barad, Cochrane,
Larson, Gass, Wassertheil-Smoller, Manson, Barnabei, Lane, Rosal, Wylie-Rosett,
Acquisition of data: Ockene, Barad, Gass, Wassertheil-Smoller,
Manson, Lane, Brzyski.
Analysis and interpretation of data: Ockene,
Barad, Cochrane, Larson, Gass, Wassertheil-Smoller, Manson, Barnabei, Lane,
Brzyski, Rosal, Hays.
Drafting of the manuscript: Ockene, Barad,
Cochrane, Larson, Barnabei, Lane.
Critical revision of the manuscript for important
intellectual content: Ockene, Barad, Cochrane, Larson, Gass, Wassertheil-Smoller,
Manson, Barnabei, Lane, Brzyski, Rosal, Wylie-Rosett, Hays.
Statistical analysis: Barad, Larson, Wassertheil-Smoller.
Obtained funding: Ockene, Wassertheil-Smoller,
Manson, Lane, Brzyski, Hays.
Administrative, technical, or material support:
Ockene, Cochrane, Manson, Lane, Brzyski, Hays.
Study supervision: Ockene, Gass, Wassertheil-Smoller,
Manson, Barnabei, Lane, Brzyski, Hays.
Financial Disclosures: Dr Gass has received
research grants and contracts from Eli Lilly & Co, GlaxoSmithKline, Merck
& Co, Pfizer Inc, Procter & Gamble Pharmaceuticals, and Wyeth-Ayerst
Laboratories; has received honoraria or consultation fees from Aventis, GlaxoSmithKline,
Merck & Co, and Procter & Gamble Pharmaceuticals; and has served on
advisory boards for Eli Lilly & Co, Merck & Co, Procter & Gamble
Pharmaceuticals, and Solvay Pharmaceuticals. No other authors reported disclosures.
WHI Program Office: National Heart, Lung, and
Blood Institute, Bethesda, Md (Barbara Alving, Jacques Rossouw, Linda Pottern).
Clinical Coordinating Centers: Fred Hutchinson
Cancer Research Center, Seattle, Wash (Ross Prentice, Garnet Anderson, Andrea
LaCroix, Ruth E. Patterson, Anne McTiernan); Wake Forest University School
of Medicine, Winston-Salem, NC (Sally Shumaker, Pentti Rautaharju); Medical
Research Labs, Highland Heights, Ky (Evan Stein); University of California,
San Francisco (Steven Cummings); University of Minnesota, Minneapolis (John
Himes); University of Washington, Seattle (Bruce Psaty).
Clinical Centers: Albert Einstein College of
Medicine, Bronx, NY (Sylvia Wassertheil-Smoller); Baylor College of Medicine,
Houston, Tex (Jennifer Hays); Brigham and Women's Hospital, Harvard Medical
School, Boston, Mass (JoAnn Manson); Brown University, Providence, RI (Annlouise
R. Assaf); Emory University, Atlanta, Ga (Lawrence Phillips); Fred Hutchinson
Cancer Research Center, Seattle, Wash (Shirley Beresford); George Washington
University Medical Center, Washington, DC (Judith Hsia); Harbor-UCLA Research
and Education Institute, Torrance, Calif (Rowan Chlebowski); Kaiser Permanente
Center for Health Research, Portland, Ore (Evelyn Whitlock); Kaiser Permanente
Division of Research, Oakland, Calif (Bette Caan); Medical College of Wisconsin,
Milwaukee (Jane Morley Kotchen); MedStar Research Institute/Howard University,
Washington, DC (Barbara V. Howard); Northwestern University, Chicago/Evanston,
Ill (Linda Van Horn); Rush-Presbyterian St Luke's Medical Center, Chicago,
Ill (Henry Black); Stanford Prevention Research Center, Stanford, Calif (Marcia
L. Stefanick); State University of New York, Stony Brook (Dorothy Lane); Ohio
State University, Columbus (Rebecca Jackson); University of Alabama, Birmingham
(Cora Beth Lewis); University of Arizona, Tucson/Phoenix (Tamsen Bassford);
University of New York, Buffalo (Jean Wactawski-Wende); University of California
at Davis, Sacramento (John Robbins); University of California at Irvine, Orange
(Allan Hubbell); University of California, Los Angeles (Howard Judd); University
of California at San Diego, LaJolla/Chula Vista (Robert D. Langer); University
of Cincinnati, Cincinnati, Ohio (Margery Gass); University of Florida, Gainesville/Jacksonville
(Marian Limacher); University of Hawaii, Honolulu (David Curb); University
of Iowa, Iowa City/Davenport (Robert Wallace); University of Massachusetts/Fallon
Clinic, Worcester (Judith Ockene); University of Medicine and Dentistry of
New Jersey, Newark (Norman Lasser); University of Miami, Miami, Fla (Mary
Jo O’Sullivan); University of Minnesota, Minneapolis (Karen Margolis);
University of Nevada, Reno (Robert Brunner); University of North Carolina,
Chapel Hill (Gerardo Heiss); University of Pittsburgh, Pittsburgh, Pa (Lewis
Kuller); University of Tennessee, Memphis (Karen C. Johnson); University of
Texas Health Science Center, San Antonio (Robert Brzyski); University of Wisconsin,
Madison (Gloria Sarto); Wake Forest University School of Medicine, Winston-Salem,
NC (Denise Bonds); Wayne State University School of Medicine/Hutzel Hospital,
Detroit, Mich (Susan Hendrix).
Funding/Support: The National Heart, Lung,
and Blood Institute funds the Women’s Health Initiative program. Wyeth-Ayerst
provided the study pills (active and placebo).
Role of the Sponsor: The National Heart, Lung,
and Blood Institute participated in the design, conduct, and oversight of
the trial and reviewed and approved the analysis plan for this manuscript
and the completed manuscript. Wyeth-Ayerst provided study pills only and had
no involvement in the design or conduct of the trial.