Vol.3, No.7, 416-422 (2011) Health
Copyright © 2011 SciRes. Openly accessible at http://www.scirp.org/journal/HEALTH/
Patterns of medication use for the treatment of
menopausal symptoms before and after the women’s
health initiative; implications for decision-making
practices of women and women’s health professionals
Chioma Uzoigwe Smith1, Srini Rajagopalan2, Shiva Sajjan1, Shuvayu Sankar Sen1, Wenchen
Kenneth Wu3, Henry Hu1
1Global Health Outcomes, Merck & Co., Inc., Whitehouse Station, USA; chiomaada@gmail.com
2Med Data Analytics, Inc., Milltown, USA;
3Department of Pharmacy Administration and Allied Health Sciences, St. John’s University, Queens, USA.
Received 6 May 2011; revised 27 May 2011; accepted 10 June 2011.
Background: The Women’s Health Initiative (W-
HI) published findings in 2002 that changed the
perception of the use of hormone replacement
therapy (HRT) for the reduction of cardiovascu-
lar risks. Menopausal w omen using HRT for the
relief of vasomotor symptoms were advised to
use the lowest possible dose of HRT over the
shortest possible duration. Objective: This stu-
dy sought to examine patterns of HRT use for
the treatment of menopausal symptoms before
and after the WHI among women at least 40
years of age. Methods: A retrospective analysis
was performed on a total of 1367 women in the
pre-WHI group and 6467 women in the post-WHI
group using the U.S. General Electric (GE) Cen-
tricity electronic medical record database. Me-
nopause diagnosis was assessed using ICD-9
codes. Clinical characteristics and medication
use were assessed for women with at least 3
years of enrollment (1 year baseline, 2 years
follow-up). Results: The proportion of women in
the post-WHI group that initiated HRT was sig-
nificantly less than that of women in the
pre-WHI group (31.3% vs. 56.9%, respectively; p
< 0.001). Combination HRT use declined signif-
icantly (21.9% pre-WHI cohort vs. 7.2% post-
WHI cohort, p < 0.001) among increases in non-
HRT use, namely SSRIs (15.2% pre-WHI cohor t v.
22.3% post-WHI cohort, p < 0.001) and tranqui-
lizers (9.5% pre-WHI cohort v. 15.8% post-WHI
cohort, p < 0.001). Conclusion: The results of
the WHI 2002 publication made an impression
on the perception of HRT’s role in the relief of
menopausal symptoms. Decision-ma king on the
part of women seeking treatment for vasomotor
symptoms and women’s health professionals
demonstrates that despite HRT precautions, wo-
men continue to exhibit a need for HRT use.
This study’s findings suggest that women seek-
ing treatment for menopausal symptom relief
and women’s health professionals continue to
work together to find the appropriate balance
between therapy use and adherence to therapy
use guidelines.
Keywords: Women’s Health Initiative (WHI);
Hormone Replacement T herapy (HRT); Women ’s
Health; Menopause
Menopause is a normal part of aging signaling the end
of menstruation and occurs 12 months after a woman’s
last menstrual period. Women typically menstruate until
approximately 50 years of age. Signs and symptoms of
menopause include irregular periods, decreased fertility,
vaginal dryness, sleep disturbances, mood swings, in-
creased abdominal fat, thinning hair, fatigue, headaches,
depression, loss of breast fullness, urinary symptoms and
hot flashes [1,2]. About 70% of women experience me-
nopause symptoms of varying severity [2]. Those that
experience severe symptoms may seek relief in the form
of hormone replacement therapy (HRT), which has been
widely prescribed to menopausal women for the past
several decades. Several studies highlight the quality of
life improvements HRT brings to women seeking relief
from vasomotor symptoms [3-5].
While HRT relieves vasomotor symptoms such as hot
C. U. Smith et al. / Health 3 (2011) 416-422
Copyright © 2011 SciRes. Openly accessible at http://www.scirp.org/journal/HEALTH/
flashes, it was also believed to provide cardioprotective
effects for women at risk of coronary heart disease
(CHD), a conclusion that was drawn from observational
studies [6,7]. To better understand the effects of HRT,
the Women’s Health Initiative (WHI), was championed
in 1991 to investigate the most common causes of death,
disability and impaired quality of life in postmenopausal
women [7]. The largest clinical trial to date, it included
over 161,000 postmenopausal women 50 - 79 years of
age. Patients were randomly assigned to placebo or one
of 2 treatment arms: a combined oral HRT formula-
tion—conjugated equine estrogen (CEE) (0.625 mg) +
progestin (2.5 mg)—for women with an in-tact uterus, or
CEE only for women who had undergone a hysterectomy.
The CEE + progestin arm was abruptly halted in 2002
after only 5.2 years of follow-up (the trial was originally
to end after about 8.5 years of follow-up) because the
risk of invasive breast cancer exceeded the projected
boundary for the study [7]. Furthermore, results showed
that among the 16,608 patients enrolled (8,506 patients
in estrogen + progestin group, 8,102 patients in placebo
group), absolute excess risks per 10,000 person-years
attributable to estrogen + progestin therapy would result
in 7 more cases of heart disease, 8 more cases of breast
cancer, 8 more cases of stroke, 18 more cases of blood
clots, and an increase in false positive mammograms [7].
Other results showed 6 fewer colorectal cancers and 5
fewer hip fractures. The WHI published these ground-
breaking results in 2002 and the U.S. Food and Drug
Administration (FDA) followed with its own recom-
mendations for HRT use—HRT was not to be prescribed
for CHD prevention. It was to be prescribed only for
menopausal symptom relief at the lowest dose for the
shortest duration possible.
The WHI publication and ensuing media coverage
changed the perception of the HRT/CHD relationship in
postmenopausal women [8]. Where it was once thought
that HRT use served the dual purpose of relieving me-
nopausal symptoms while providing cardiovascular pro-
tection, the new conclusions initiated cautious use of
HRT. Consequently, prescribing practices changed,
where high-dose combined HRT use realized a substan-
tial decline, while low-dose HRT use increased [9,10].
Other studies reported a significant decline in HRT pre-
scriptions and a significant decline in the average num-
ber of new HRT users per month less than one year after
the WHI publication [6,11-14]. In addition, among HRT
users, there was significant increase in discontinuation of
HRT use post-WHI [15,16]. Women also turned to al-
ternative therapies such as non-hormonal medications
and other HRT formulations for which long-term health
consequences were not well-known [17].
Several publications, however, have challenged the
initial WHI findings, arguing that the WHI was prema-
ture to suggest the increased CHD risks of long-term
HRT use [18,19]. These publications report that com-
pared to women taking placebo, combined HRT shows
increased CHD risk only during the first year of use,
followed by much smaller risks thereafter (follow-up
periods were for at least 6 years) [20,21]. Furthermore,
HRT use did not significantly affect all-cause mortality
rates and, paradoxically, reduced CHD risk was ob-
served among younger women (60 years of age) and
women who initiated HRT no more than 10 years post
menopause [17,22,23]. The risks of HRT use remain a
contentious issue.
The emergence of research refuting the WHI results in
2002 begs the question of whether medical professionals
and women using HRT prematurely gave up on the ben-
efits HRT provides for the relief of vasomotor symptoms.
Though use of high-dose HRT declined after the WHI
publication in 2002, the data reflects that menopausal
women were still using HRT in high proportions. There-
fore, HRT remains a desired therapy of choice for me-
nopausal women. This study revisits HRT utilization
patterns before and after the WHI among patients newly
diagnosed with menopause. It aims to add to the historic
landscape of the changing trends in HRT use and support
cautious—but not extreme—discretionary use of HRT
for the relief of vasomotor symptoms.
2.1. Study Design
This retrospective study was performed using the
General Electric (GE) Centricity EMR system, a nation-
wide de-identified ambulatory electronic medical data-
base of nearly 15 million patient records. Medication use
patterns were assessed between 1999 and 2000 (pre-
WHI) and 2003 and 2004 (post-WHI). Data collected for
each cohort included one-year baseline and two years
follow-up; therefore, the 1999-2000 cohort was followed
through July 2002 (to account for a complete two years
of follow-up) and the 2003-2004 cohort (post July 2002)
was followed through 2007 (1998 data was collected but
excluded for very low sample size). For diagnosis of
menopause symptoms, ICD-9 codes of N95.1 and 627.2
were used. Generic product identifier (GPI) codes were
used to evaluate the use of HRT, non-HRTs and other
products1. ICD-9 codes were also used to identify the
1Other HRT included androgen + female hormones, topical sex hor-
mones, monophasic preparations (<50 mcg estrogen and 50 mcg
estrogen), biphasic and triphasic preparations. Non-hormonal therapies
included serotonin-norepinephrine reuptake inhibitors (SNRIs), selec-
tive serotonin reuptake inhibitors (SSRIs), non-barbiturate seda-
tives/hypnotics, tranquilizers, anti-epileptics, anti-hypertensives, anti-
depressants, and natural products.
C. U. Smith et al. / Health 3 (2011) 416-422
Copyright © 2011 SciRes. Openly accessible at http://www.scirp.org/journal/HEALTH/
presence of comorbidities.
2.2. Study Population, Eligibility and Dose
The study sample only included newly diagnosed
menopausal women, who were free of menopausal di-
agnosis at the one-year baseline period and at least 40
years of age during the two follow-up periods (pre-WHI
and post-WHI) between January 1, 1999 and December
31, 2007. A total of 1,397 women were in the pre-WHI
group; 6,467 in the post-WHI group. HRT included only
oral formulations and dose categories were defined as
ultra low dose (<0.3 mg conjugated estrogen), low dose
(0.3 mg conjugated estrogen), medium dose (0.45 mg
conjugated estrogen), high dose (0.625 mg conjugated
estrogen or 1 mg or 1.5 mg estrogen) and very high dose
(1.25 mg conjugated estrogen or 2 mg estrogen).
2.3. Statistical Analysis
We used Chi-square tests to discern the statistical dif-
ferences for categorical variables except for one instance
in which Fisher’s exact test was used because expected
frequency was less than 5 in one cell count. Medication
use was evaluated in the two-year follow up periods for
each cohort (2000-2002 pre-WHI cohort, 2005-2007
post-WHI cohort) and defined as the first prescription
filled on or after diagnosis date (1999-2007). Medica-
tions were categorized as HRT (estrogen and progesto-
gen), other HRT (e.g., combined oral contraceptives of
various regimens containing estrogen and progestogen,
androgen + female hormones) and non-HRT (statins,
anti-depressants, tranquilizers, etc). All analyses were
performed using SAS version 9.1 and a p value less than
0.05 was considered statistically significant.
Mean age at menopause diagnosis was 57.3 years ±
10.9 in the pre-WHI group, 58.2 years ± 11.0 in the
post-WHI group (Table 1). There were significant de-
creases in the proportions of diabetes, dyslipidemia and
hypertension after the end the WHI. The proportion of
obese women also decreased significantly after the WHI.
Approximately 80% of women in both cohorts were
under 70 years of age.
Significantly fewer women in the post-WHI group
initiated hormone therapy after menopause diagnosis
than did those in the pre-WHI cohort (31.3% vs. 56.9%,
respectively; p < 0.001) (Tab le 2 ). The use of combina-
tion therapy also precipitously declined among the
post-WHI cohort. After the WHI’s end, SNRIs, SSRIs
and tranquilizers realized the most significant increases
Table 1. Descriptive characteristics of menopause patients
in GE database 1998-2007 before (1999-2000) and after
(2003-2004) the WHI.
2003-2004 p-value
Sample size (N) 1397 (17.8) 6467 (82.2)
Age (yrs)
categories at index
date (mean, SD) 57.34 ± 10.85 58.2 ± 11.03<0.006
40 - 49 (N, %) 402 (28.8) 1612 (24.9)
50 - 59 473 (33.9) 2304 (35.6)
60 - 69 275 (19.7) 1278 (19.8)
70 - 79 190 (13.6) 924 (14.3)
80+ 57 (4.1) 349 (5.4)
Ankylosing spondylitis
(N, %) 1 (0.1) 26 (0.4) 0.06
Depression 105 (7.5) 489 (7.6) 0.95
Diabetes 151 (10.8) 357 (5.5) <0.001
Dyslipidemia 218 (15.6) 814 (12.6)0.00
Heart failure 4 (0.3) 16 (0.3) 0.79
Hypertension 243 (17.4) 648 (10.0)<0.001
Obesity 74 (5.3) 168 (2.6) <0.001
Osteoporosis 52 (3.7) 190 (2.9) 0.12
Rheumatoid arthritis 5 (0.4) 30 (0.5) 0.60
Spondylosis 15 (1.1) 49 (0.8) 0.23
Table 2. First medication after menopause diagnosis.
2003-2004 p-value
Sample size (N) 1154 6060
Replacement Therapy
(HRT) (N, %) 624 (56.9) 1591 (31.3) <0.001
Estrogen 362 (33.0) 1148 (22.6) <0.001
Estrogen + Progestogen240 (21.9) 363 (7.2) <0.001
Progestogen only 116 (10.6) 187 (3.7) <0.001
Other HRT 105 (9.6) 510 (10.0) 0.42
Antidepressants 79 (7.2) 374 (7.4) 0.37
Antiepileptics 39 (3.6) 291 (5.7) 0.03
Antihypertensives 32 (2.9) 245 (4.8) 0.03
Non-Barbiturates 55 (5.0) 435 (8.6) 0.002
SNRIs 18 (1.6) 363 (7.2) <0.001
SSRIs 167 (15.2) 1133 (22.3) 0.003
Tranquilizers 104 (9.5) 800 (15.8) <0.001
Other therapeutic
productsa 2 (0.2) 32 (0.5) 0.11
aincludes all other gynecologic medications and other therapeutic products
not containing estrogen or progesterone.
C. U. Smith et al. / Health 3 (2011) 416-422
Copyright © 2011 SciRes. Openly accessible at http://www.scirp.org/journal/HEALTH/
in use2. A significantly higher proportion of women in
the post-WHI cohort initiated non-HRT post diagnosis
than did women in the pre-WHI cohort (66.1% vs.
42.0% respectively, p < 0.001) (data not shown).
As Table 3 shows, the proportions of women in the
post-WHI cohort initiating lower doses of estrogen
therapy after menopause diagnosis increased signifi-
cantly compared to the proportions used by pre-WHI
cohort women. Patients who changed HRT dose or
switched to a different medication had shorter average
duration of therapy (in days) on the initial HRT in the
post-WHI cohort compared to the pre-WHI cohort and in
both cohorts 46% of patients discontinued therapy (Ta-
ble 4 and Table 5).
The incidence rates of menopause diagnosis between
1998 and 2007 are displayed in Figure 1. There ap-
peared to be an increase in menopause diagnosis leading
to the end of WHI trial. Most notable is the sizeable de-
crease in incidence from the trial’s end (1.6 in 2002) to 2
years post-WHI (1.35). After 2004, the incidence rates
remain relatively steady through 2007.
Table 3. Estrogen dosing levels of first prescription after
1999-2000 Post-Cohort
2003-2004 p-value
Sample size (N) 593 1497
Ultra Low
Dose 50 (8.4) 257 (17.2) <0.001
Low Dose 46 (7.8) 293 (19.6) <0.001
Medium Dose 0 (0.0) 109 (7.3) <0.001
High Dose 357 (60.2) 714 (47.7) <0.001
Very High
Dose 52 (8.8) 115 (7.7) 0.35
Table 4. Pre-WHI cohort HRT average duration of therapy
(in days) for all patients.
Switch N Mean SD MinMax
Persistent 86 730 0 730730
Dose Change 92 301.5 254.4 5 730
Switch to other HRT 12 286.8 287.2 29 730
Switch to non-HRT 145 300.6 278.6 5 730
Discontinued 289 178.2 173.1 1 685
Switch N Mean SD MinMax
Table 5. Post-WHI cohort HRT average duration of the-
rapy (in days) for all patients.
Switch N Mean SD MinMax
Persistent 126730 0 730 730
Dose Change 222235.7 230.3 2 730
Switch to other HRT 38 224.7 244.3 2 730
Switch to non-HRT 469213 224.5 2 730
Discontinued 736176.7 174.4 1 697
Figure 1. Menopause diagnosis rates (1998-2007).
In light of the publications that refute the initial find-
ings of the WHI in 2002 [17-23], this publication high-
lights patterns of HRT use before and after the WHI in
women newly diagnosed with menopause. By revisiting
the issue of patterns of HRT use, we attempted to under-
stand the impact the 2002 WHI publication had on the
choices women made to treat their vasomotor symptoms.
Our data indicated significant decreased use of HRT
overall between pre-and post-WHI cohorts, with the
greatest decline in use among women using estrogen and
progestin combined. High dosages of HRT fell out of
favor post-WHI, leading to increases in use of lower
dosages of HRT. Concordantly, use of non-HRTs, partic-
ularly SSRIs, SNRIs and tranquilizers, increased signif-
icantly after the WHI ended. These results are in align-
ment with previous studies that investigated HRT use
trends before and after the end of the WHI [6,8-
14,24,25]. A study documenting HRT use in postmeno-
pausal women in the UK between April 2001 and Sep-
tember 2005 reported that the average proportion of
women on HRT declined after the WHI interim results
were published in July 2002 (28% before July 2002 vs.
10.9% after July 2002) [13]. A 2008 Australian study
reported a dramatic drop (–55.4%) in the use of fixed
combination (estrogen + progestogen) therapy in the 12
months following the end of the WHI estrogen + proges-
tin arm [12]. A US-based study that sought to character-
ize the impact of the end of the WHI on HRT prescrip-
2Though SNRIs and SSRIs are antidepressants, they are teased out o
the antidepressants classification because they are commonly pre-
scribed off-label to treat meno
ause s
C. U. Smith et al. / Health 3 (2011) 416-422
Copyright © 2011 SciRes. Openly accessible at http://www.scirp.org/journal/HEALTH/
tion patterns reported that after the WHI trial, women
were less likely to initiate HRT [25]. Altogether, disse-
mination of the WHI findings may explain the precipit-
ous decline in HRT use, particularly estrogen + progestin
combinations (22% of pre-WHI cohort, 7% of post-WHI
cohort). A decline in fixed combination prescribing as
reported by previous studies may have also contributed
to this decline. In a Canadian study that used a health-
care database to assess the impact of the WHI publica-
tion on the rate of HRT prescriptions, results showed a
significant increase post-WHI in the percentage of
women using low-dose estrogen therapy (<0.625 mg)
where 8.3% of the pre-WHI cohort was using such ther-
apy, compared to 14.8% of the post-WHI cohort (p <
0.001) [6].
While the 2002 publication may have impacted diag-
nosis rates, resulting fear surrounding the safety of HRT
and therefore, decreased doctor visits that would result
in a diagnosis, may also have contributed to the inci-
dence rate decline. Though depression was prevalent in
about the same proportions in both cohorts, its presence
was disproportionately low compared to the proportions
of women using antidepressants (including SNRIs and
SSRIs) for menopausal symptom relief. After the WHI
trial’s conclusion, many menopausal women sought al-
ternative methods to relieve vasomotor symptoms [26].
After HRT, antidepressants are increasingly becoming
next in line to treat symptoms of menopause. Some clini-
cal trials have shown that antidepressants, most com-
monly those in the SSRI and SNRI classes, have reduced
occurrences of hot flashes [26]. The benefits of off-label
use of antidepressants to treat menopause symptoms are
thought to be two-fold: 1) they treat the mood fluxes that
accompany symptoms of menopause and 2) they relieve
vasomotor symptoms [27]. Use of antidepressants to
treat menopause symptoms appears to be controversial,
especially for menopausal women who claim to expe-
rience no symptoms of depression or anxiety; however,
this argument is beyond the scope of this analysis.
Our analysis shows significant declines in baseline
comorbid conditions, including diabetes, dyslipidemia,
hypertension and obesity, between the time periods in
question. As we are not certain when women in our
sample began using HRT, it can be speculated that the
declines in CV risk-factors may be attributable to patient
self-selection. In other words, the communication of
HRT risks from the 2002 WHI publication may have
discouraged women who had high CV risk factors from
seeking treatment for menopausal symptoms; therefore,
proportions of CV risk-factors in the post-WHI cohort
may reflect underestimates. In the post-WHI cohort,
average persistence mirrored that in the pre-WHI cohort
(mean duration 730 days, each); however, dose changes
and switches reflect shorter average duration of initial
therapies among the post-WHI cohort. This suggests
compliance recommended guidelines for HRT use,
which may have encouraged higher satisfaction with use
of lower-dose HRTs.
In each cohort, discontinuation of therapy was evident
in a plurality of women (46%), but this leaves a propor-
tion of 54% that did not discontinue HRT. Furthermore,
discontinuation rates were the same for both time pe-
riods. This shows that despite the risks the WHI found,
women still want to use HRT, but appear to be cautious
about their choices. The changes seen may also reflect
the publication’s influence on women’s health profes-
sionals who may have changed prescribing practices to
help their patients seek relief of vasomotor symptoms.
The findings of this analysis should be interpreted in
the context of study limitations. The GE Centricity da-
tabase is an electronic health database in which physi-
cians complete patient records; inherent limitations with
this type of data collection include completeness of pa-
tients’ records and human error. Missing information
such as dosing, when a prescription was written, whether
a prescription was filled or refilled, or the accuracy of
comorbidity recording may be called into question.
However, we believe missing information occurred in
random fashion and unlikely resulted in systematic bias
in findings. We assumed that the selected drugs taken
after menopause diagnosis were actually for the relief of
menopausal symptoms, though in cases where antide-
pressants are used, for example, we cannot discern if
they were prescribed for menopausal symptoms or to
treat symptoms of depression or other mental disorders.
This analysis only considered oral HRT formulations and
therefore, results cannot be generalized to populations of
women using HRTs in other forms. Lastly, the two-year
length of follow-up does not allow for generalization of
results to women who have remained on HRT for longer
Our results are consistent with studies that have dem-
onstrated that menopausal women reacted quickly to
ensure their health and well-being regarding HRT
[6,8-14]. Given the trend that HRT use did not come to a
complete halt, this study highlights that clearly there is
still a need to find the proper balance between meno-
pause symptom relief and exposure to health risks. To
credit the WHI 2002 publication, women at high cardi-
ovascular risk became cautious about their HRT use;
however, the publication may have given women ex-
treme pause towards the use of HRT, such that those who
still sought relief of vasomotor symptoms unnecessarily
deprived themselves of the level of relief HRT could
C. U. Smith et al. / Health 3 (2011) 416-422
Copyright © 2011 SciRes. Openly accessible at http://www.scirp.org/journal/HEALTH/
The results of the WHI stirred faith in the once-as-
sumed cardioprotective effects of HRT for menopausal
women. Since the WHI ended, use of high-dose HRT
declined, while use of non-HRT, such as antidepressants,
increased. The results of this study highlight the impact
the WHI had on the choices physicians and women
made to treat vasomotor symptoms, as well as the im-
portance women place on their health outcomes during
the stage of amenorrhea. This study’s findings suggest
that women seeking treatment for menopausal symptom
relief and women’s health professionals continue to
work together to find the appropriate balance between
therapy use and adherence to therapy use guidelines.
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