Hersh AL, Stefanick ML, Stafford RS. National Use of Postmenopausal Hormone TherapyAnnual Trends and Response to Recent Evidence. JAMA. 2004;291(1):47–53. doi:10.1001/jama.291.1.47
Author Affiliations: Stanford Prevention Research Center, Program on Prevention Outcomes and Practices, Stanford University School of Medicine, Stanford, Calif.
Context Postmenopausal hormone therapy use increased dramatically during the
past 2 decades because of a prevailing belief in its health benefits. Recent
evidence from randomized trials published in July 2002 demonstrated adverse
cardiovascular disease events and other risks with hormone therapy in the
form of oral estrogen combined with progestin.
Objective To describe patterns of hormone therapy use from 1995 until July 2003,
including the impact of recent evidence.
Design, Setting, and Population Two databases were used to describe national trends in hormone therapy
use from January 1995 to July 2003. The National Prescription Audit database
provided data on the number of hormone therapy prescriptions filled by retail
pharmacies and the National Disease and Therapeutic Index database provided
data on patient visits to office-based physicians during which hormone therapy
Main Outcome Measures Annual number of hormone therapy prescriptions and characteristics of
visits to physicians during which hormone therapy was prescribed.
Results Annual hormone therapy prescriptions increased from 58 million in 1995
to 90 million in 1999, representing approximately 15 million women per year,
then remained stable through June 2002. Adoption of new oral estrogen/progestin
combinations, primarily Prempro, accounted for most of this growth. Obstetrician/gynecologists
provided more than 70% of hormone therapy prescriptions, and more than one
third of patients were older than 60 years. Following the publication of trial
results in July 2002, hormone therapy prescriptions declined in successive
months. Relative to January-June 2002, prescriptions from January-June 2003
declined by 66% for Prempro and 33% for Premarin. Small increases were observed
in vaginal formulations and in new prescriptions for low-dose Premarin. If
prescription rates observed through July 2003 remain stable, a decline to
57 million prescriptions for 2003, similar to the rate in 1995, is projected.
Conclusions Clinical practice responded rapidly to recent evidence of harms associated
with hormone therapy. Since July 2002, many patients have discontinued hormone
therapy or are tapering to lower doses.
Patterns of hormone therapy use among postmenopausal women in the United
States ideally should reflect known risks and benefits. However, definitive
information on these risks and benefits was lacking until recently. The Heart
and Estrogen/Progestin Replacement Study (HERS)1 and
HERS follow-up (HERS II)2 concluded that postmenopausal
hormone therapy with combination oral estrogen/progestin offered no cardiovascular
disease benefit among women with established disease. The estrogen plus progestin
trial of the Women's Health Initiative (WHI)3 demonstrated
that hormone therapy with an estrogen/progestin combination caused increased
risk of breast cancer and cardiovascular disease in postmenopausal women.
These findings from randomized trials contrast with prior observational studies
that suggested cardiovascular benefits.4- 6 Based
on the quality of recent data, new guidelines recommend against routine hormone
therapy use for chronic conditions,7 and current
users have been advised to taper doses toward discontinuation.8,9
Prior studies from nationally representative databases showed that in
1975, hormone therapy prescriptions peaked at 30 million.10- 12 Prescriptions
subsequently declined to approximately 15 million in the early 1980s as evidence
emerged showing an increased risk of endometrial cancer with unopposed estrogen
use.10- 12 Prescription
growth resumed as progestins were prescribed in combination with estrogen,
and prescriptions for hormone therapy reached 36 million in 1992, representing
approximately 6 million women and 17% of women older than 50 years.10 More recent estimates of current hormone therapy
use among women aged 50 to 74 years in 1995 ranged from 38% from a national
telephone sample13 to 40% in a large health
maintenance organization.14 These estimates
suggest a large increase in hormone therapy use between 1992 and 1995, if
these patterns reflect national practices.
National trends in hormone therapy use since 1995 have not been reported,
and the impact of recent evidence on hormone therapy prescriptions in subsequent
months is unknown. Our objective was to describe these trends using national
data on hormone therapy prescriptions and patient visits to physicians during
which hormone therapy was prescribed.
We used 2 nationally representative databases published by IMS HEALTH
(Plymouth Meeting, Pa), an independent pharmaceutical research company, to
describe national trends in hormone therapy use from January 1995 through
July 2003. Information on hormone therapy prescriptions from pharmacies was
obtained from the National Prescription Audit Plus (NPA). Information on visits
to office-based physicians was obtained from the National Disease and Therapeutic
Index (NDTI). Both databases use samples to estimate national patterns.
The NPA consists of a national random computerized sample of approximately
20 000 retail pharmacies, independent pharmacies, mail order pharmacies,
and mass merchandise and discount houses. These stores are sampled from the
company's pharmacy database of more than 29 000 stores, accounting for
more than half of all retail pharmacies in the United States and constitute
a nationally representative sample. The sample is resized on a semiannual
basis. Pharmacy data are collected daily and reported in monthly aggregates
with the prescription as the major unit.
National Prescription Audit Plus provided monthly data on the total
number of dispensed prescriptions provided to consumers (new plus refill)
for all hormone therapy formulations and for individual brands. These include
oral, transdermal, vaginal, and injectable estrogens; oral and transdermal
combined estrogen/progestin; and oral estrogen/androgen. Injectable estrogens
are not represented adequately in NPA because these prescriptions rarely are
filled at retail pharmacies10 and therefore
Prescription data were organized into 6 categories: Premarin (conjugated
estrogen) (Wyeth Pharmaceuticals, Collegeville, Pa); other oral estrogens
and estrogen/androgen; Prempro (conjugated estrogen/medroxyprogesterone) (Wyeth
Pharmaceuticals); other oral estrogen/progestin combinations; transdermal;
and vaginal. The number of hormone therapy prescriptions was reported annually
by category and in aggregate from January 1995 through July 2003. For January
2002 through July 2003, monthly totals were determined to examine the short-term
impact of WHI and HERS II study findings on hormone therapy prescriptions.
We report 2 annual totals for 2002: an annualized estimate based on January
through June and an annualized estimate based on July through December. For
2003, the annualized total reflects the most recently available data through
July. Estimated sampling errors for monthly dispensed prescriptions were available
and 95% confidence intervals (CIs) were derived to indicate the reliability
of our estimates.
The approximate number of women exposed to any form of hormone therapy
annually from 1995 to 2003 was estimated based on the number of prescriptions
filled. Based on prior reports10 and NPA documentation,
hormone therapy prescriptions averaged 6 per year, lasting approximately 2
months. Therefore, the number of women exposed to hormone therapy was estimated
by dividing the total number of prescriptions for each year by 6.
The NDTI is a continuing survey providing nationally representative
information on patient visits to physicians and associated medication use.
The sample consists of approximately 3500 physicians each calendar quarter
stratified by specialty and geographic region, selected from the master lists
of the American Medical Association and the American Osteopathic Association.
National estimates for patient visits and associated medication use are derived
from this sample and documented both quarterly and annually. For each patient
encounter, physicians describe all diagnoses, indicate all newly prescribed
or continuing medications used specifically for each diagnosis, and report
a "desired action" for the medication. The desired action is the medication's
intended physiological, symptom-relieving, or preventive role as reported
by the physician. Each report of a medication constitutes a drug "mention."
The data reflect the status of the medication at the completion of the visit.
Therefore, visits to physicians during which a medication is discontinued
are not captured and the physicians do not report the medication. Additional
information provided by the reports includes patient age, physician specialty,
and concomitant medications prescribed.
Annual data were obtained for patient visits during which hormone therapy
was reported as either estrogen or estrogen/progestin combinations from 1995
through June 2003. For the sample sizes available, the 95% CIs around the
estimates of visit characteristics are approximately ±10%. To detect
possible short-term changes in practice, we collected semiannual data for
2002 and 2003, reported in 6-month intervals, and data for January through
June of 2002 and 2003. For each year, the desired action, the percentage of
each formulation (oral, injectable, transdermal, and vaginal), physician specialty,
and patient age were recorded.
Data from NPA and NDTI were combined to estimate the overall number
of women receiving hormone therapy as oral estrogen and progestin simultaneously.
This population consists of 2 subgroups: women receiving combination formulations,
such as Prempro, and women receiving estrogen and concomitant progestin as
separate prescriptions. Both groups were designated collectively as estrogen/progestin.
The estimate was obtained for oral estrogen/progestin combinations directly
from NPA based on the number of prescriptions. The NDTI data were used to
determine the frequency with which oral progestin was prescribed concomitantly
with oral estrogen in 2001 and in 2003, which was 18% and 14%, respectively.
The number of women receiving oral estrogen with concomitant progestin was
obtained by multiplying this percentage by the total number of prescriptions
for oral estrogen and oral estrogen/androgen from NPA. The sum of estrogen
plus progestin combinations and estrogen with concomitant progestin constituted
the total population of estrogen/progestin.
In examining national data on annual trends in hormone therapy use based
on prescriptions and physician visits, 3 phases of practice patterns are apparent.
Prescriptions increased significantly between 1995 and 1999 following the
introduction of oral estrogen/progestin combinations, then remained stable
through the first 6 months of 2002 (Figure
1). Following the release of WHI and HERS II in July 2002, hormone
therapy prescriptions declined in successive months through July 2003 (Figure 1 and Figure 2). Based on data from July 2003, hormone therapy prescriptions
declined by 38% (95% CI, 37%-39%) overall relative to months prior to July
2002, with a decline of 74% (95% CI, 73%-75%) for Prempro. The percentage
of women aged 50 to 74 years taking hormone therapy increased from 33% to
42% between 1995 and 2001. By July 2003, this exposure had declined to 28%
of women in this age group.
Between 1995 and June 2002, annual hormone therapy prescriptions increased
by 57% from 58 million in 1995 to 91 million in 2001 and annualized to 89
million for January through June 2002 (Figure
1, Table 1). Prescriptions
remained relatively stable from January 1999 through June 2002, peaking at
92 million in 2000. In 1995, oral estrogens dominated hormone therapy prescribing
(Table 1). Combined oral estrogen/progestin
emerged in 1995 and prescriptions increased rapidly from 1.3 million (2% of
hormone therapy) in 1995 to 24 million (26% of hormone therapy) by 2001, accounting
for more than 70% of the overall growth in hormone therapy prescriptions during
this period (Table 1, Figure 3). While vaginal and transdermal
prescriptions also increased during this period, the percentage of total prescriptions
remained constant, ranging from 3% for vaginal to 8% to 9% for transdermal
formulations (Table 1, Figure 3).
Since 1995, oral estrogen and oral estrogen/progestin collectively accounted
for approximately 85% of hormone therapy. A single formulation dominated each
category: Premarin among oral estrogen and Prempro among oral estrogen/progestin.
Small declines in Premarin and Prempro prescriptions from 1999 and 2001 were
associated with increases in use of other brands within oral estrogen and
oral estrogen/progestin such that total prescriptions within these categories
remained generally stable from 1999 to 2001 (Figure 3, Table 1).
Based on the number of annual prescriptions, in 1995, 9.7 million women were
estimated to have taken hormone therapy, increasing to 15 million annually
between 1999 and 2001 (Figure 1, Table 1).
Overall. When annualized, the number of prescriptions from January through June
2002 was similar to prior years, equaling 89 million (Figure 1). A decline in the number of monthly hormone therapy prescriptions
initiated immediately following the publication of WHI3 and
HERS II2 in July 2002 and continued in successive
months (Figure 2). Hormone therapy
prescriptions reached their lowest level in July 2003 (4.58 million; 95% CI,
4.57-4.59), 38% below mean monthly levels from January through June 2002.
If this monthly rate remains constant for the remainder of 2003, the projected
number of hormone therapy prescriptions will be 57 million (Figure 1, Table 1).
Specific Formulations. The decline in hormone therapy prescriptions varied by formulation but
was concentrated most heavily among oral estrogen and oral estrogen/progestin
(Figure 3). Premarin and Prempro
prescriptions alone accounted for 80% of the overall decline observed between
July 2002 and July 2003. To illustrate this trend, monthly prescriptions were
compared for hormone therapy during the 6-month periods between January to
June 2002 to January to June 2003 (Figure
4). Prescriptions for Prempro in 2003 declined by 66% (95% CI, 65%-67%)
relative to 2002, reaching a monthly low of 386 000, a level last seen
in 1996. Prescriptions for Premarin declined by 33% (95% CI, 32%-34%) during
this period, reaching a monthly low of 1.8 million, a level below monthly
rates from 1995. Although overall prescriptions for oral Premarin declined,
new prescriptions for Premarin, 0.3 mg, a lower-dose estrogen than that used
in WHI, increased by 6% during the second half of 2002. This increase, however,
was not sustained in 2003. Recent trials had a lesser impact on other hormone
therapy formulations, with smaller declines observed for all other oral estrogen
(23%), all other oral estrogen/progestin (18%), and transdermal formulations
(14%) (Figure 4). Vaginal formulations
did not decline during this period; however, use of this formulation remains
limited overall, and the small increase (7%) did not exceed the confidence
limits of the estimates.
The percentage of overall visits for hormone therapy involving oral
estrogen/progestin combinations increased from 5% in 1995 to more than 28%
in 2001 and the first half of 2002, similar to trends described above for
prescriptions. We observed variation in patient age between visits for estrogen/progestin
and estrogen (Table 2). Patients
60 years or older were more common among visits during which estrogen was
prescribed, while patients younger than 60 years were more common among visits
during which estrogen/progestin was prescribed. Oral hormone therapy formulations
predominated and most visits were to obstetrician/gynecologists (Table 2). Physicians reported prescribing
hormone therapy primarily for treatment of menopausal symptoms (>90%), with
osteoporosis (4%) and cardiovascular disease prevention (1%) reported at low
The percentage of visits for estrogen/progestin declined from 29% during
the first half of 2002 to 21% during the first half of 2003 (Table 2). We observed changes in the hormone therapy formulations
prescribed, with a decline in oral formulations and an increase in vaginal
preparations during this period. No changes were noted in the reported desired
action or in the physician specialty. Small changes in patient age relative
to prior years were noted, with a small decline in the percentage of women
older than 60 years using hormone therapy (Table 2).
Of the estimated 15 million women who were prescribed hormone therapy
in 2001, oral estrogen plus progestin was estimated to account for 5.6 million
women, representing 42% of oral hormone therapy and 38% of hormone therapy
overall. Furthermore, an estimated 67% of these women were older than 60 years
and 6% were 75 years or older. If patterns observed through July 2003 remain
constant throughout the year, estrogen plus progestin use would decline by
56% to 2.5 million women in 2003, representing 33% of oral hormone therapy
and 25% of hormone therapy overall. No major changes in the age distribution
of women prescribed oral estrogen plus progestin was observed.
Our results based on national hormone therapy use data showed 3 successive
patterns since 1995. From 1995 to 1999, annual hormone therapy prescriptions
increased, primarily because of the adoption of oral estrogen/progestin combinations.
Between 1999 and June 2002, hormone therapy prescriptions stabilized at approximately
90 million annually. Following publication of HERS II2 and
WHI3 in July 2002, hormone therapy prescriptions
declined substantially, with the largest decline among oral estrogen and estrogen/progestin.
The overall number of hormone therapy prescriptions in January 2003 was comparable
with monthly figures from 1995.
Our findings suggest a rapid response to clinical trial evidence and
revised guidelines. Many women have discontinued hormone therapy, especially
those using Premarin and Prempro. The small increase in low-dose Premarin
suggests that tapering of dosages is occurring as well. This example shows
effective information dissemination of scientific evidence and clinical guidelines
to patients and physicians, which has resulted in prompt changes in clinical
practice. In addition, the subsequent media cascade undoubtedly enhanced dissemination.
Our findings support prior literature suggesting that physicians may rapidly
abandon well-established therapies when studies demonstrate harm.15,16 Whether acting alone or with the
involvement of physicians, patients also played a major role in the decline
in hormone therapy use that we observed. The less dramatic changes in the
use of other hormone therapy formulations (transdermal, vaginal, oral brands
other than Premarin and Prempro) may reflect less certainty among physicians
and patients about the generalizability of recent findings.
Growth in hormone therapy use from 1995 to 1999 primarily was attributable
to oral estrogen/progestin combinations, a newly available formulation. Our
results show that this formulation attracted new patients who previously had
not received hormone therapy, suggesting an influence of pharmaceutical innovation
targeting convenience on medical practice patterns and market expansion. We
observed a similar trend following the introduction of alendronate, the first
oral daily bisphosphonate, in which identification and treatment of osteoporosis
increased significantly in subsequent years.17 The
availability of combination therapy for women with a uterus also might explain
the increase in the percentage of visits for hormone therapy to obstetrician/gynecologists
relative to that of internists.
Although HERS did not immediately impact hormone therapy prescriptions,
growth stabilized soon thereafter as additional studies,18,19 preliminary
results from WHI,20,21 and an
influential guideline22 were reported. This
period may have set the stage for the decline in hormone therapy use following
the publication of the WHI results. Features of the WHI trial design also
likely enhanced its impact relative to prior studies. The WHI studied primary
prevention of cardiovascular disease events, which applies to a wide range
of women. Given the importance attached to breast cancer,23,24 the
inclusion of breast cancer outcomes in WHI may have further influenced recent
trends. In this regard, it will be interesting to determine the longer-term
impact of the more recent (May 2003) findings of a 2-fold increase in dementia25 and a somewhat negative effect on global cognitive
function26 in the estrogen plus progestin arm
of the WHI Memory Study (WHIMS).
Although physicians reported prescribing hormone therapy primarily for
relief of menopausal symptoms, recent trials addressed chronic disease prevention.
More than one third of women taking estrogens and one quarter of women taking
estrogen/progestin were older than 60 years. Many of these older patients
may have initiated hormone therapy use previously for symptom relief and continued
subsequently for disease prevention. Despite the small decrease in the proportion
of older women among visits for hormone therapy, substantial numbers of younger
women also discontinued therapy. The abandonment of hormone therapy has important
clinical implications for treatment of vasomotor symptoms and fracture prevention.
Some women whose vasomotor symptoms return may reconsider treatment alternatives
that may include lower-dose hormone therapy along with herbal products. For
women at risk of osteoporosis, bisphosphonates may sustain benefits in bone
mineral density achieved by prior hormone therapy use.27 For
all women discontinuing hormone therapy, nutrition and physical activity for
osteoporosis prevention are essential.
Prescriptions for hormone therapy peaked in 2000-2001 at 91 million,
corresponding to an estimate of approximately 6 million women using oral estrogen
plus progestin. Using this estimate and applying the updated adverse event
rates reported by WHI for coronary heart disease,28 breast
cancer,29 and stroke30 and
the rate originally reported for pulmonary embolus,3 we
estimate that in 2001, 14 500 adverse events were attributable to oral
estrogen plus progestin, with 3500 cardiovascular disease events, 2000 breast
cancers, 4000 strokes, and 5000 cases of pulmonary embolism. Although the
attributable risks may be small, this contrasts with prior estimates that
survival benefits outweighed risks.31 If hormone
therapy prescription rates from through July 2003 remain constant, we estimate
a 56% decline to 6500 adverse events for 2003.
Our estimate for hormone therapy use in 1995 differs somewhat from prior
reports. One study estimated that 38% of postmenopausal women were current
hormone therapy users based on a telephone survey of postmenopausal women
between ages 50 and 74 years.13 Based on US
Census data,32,33 our estimate
for the number of hormone therapy exposures corresponds to 33% of women aged
50 to 74 years and 27% of women older than 50 years in 1995. An important
source of bias in the prior study was that participants were more highly educated
than nonparticipants,13 a characteristic that
is associated with increased use of hormone therapy. Nonetheless, a significant
increase in hormone therapy use occurred between 1992 (when an estimated 17%
of women older than 50 years were exposed10)
and 1995. Another study reporting that 40% of women older than 50 years were
prescribed conjugated equine estrogen14 may
not be generalizable to the US population because this study was conducted
in a large managed care organization. Using our estimates, the percentage
of women between ages 50 and 74 years exposed to hormone therapy increased
from 33% in 1995 to 42% in 2001.
We acknowledge several limitations of our analysis. The NPA lacks patient
demographic and clinical information, including concomitant prescriptions.
The NDTI provided this information and our results incorporate information
from both sources. Both databases are nationally representative and showed
similar trends, lending support to this approach. Our estimate of the number
of women receiving hormone therapy was based on an assumption of the average
prescription length that may not apply to all formulations and brands. We
were unable to stratify hormone therapy use on specific parameters, such as
patient age or physician specialty, to examine trends according to these variables,
which limits the depth of our analysis. The NDTI data capture patient-physician
encounters during which hormone therapy was reported as a treatment. Therefore,
we were unable to obtain specific data on characteristics of patients who
visited physicians and discontinued hormone therapy. The NPA underestimates
prescriptions for injectable estrogens, leading to a possible underestimate
of overall hormone therapy use. However, use of injectable estrogens since
1995 is low based on NDTI data and therefore is unlikely to represent a significant
In summary, we described 3 phases of hormone therapy use since 1995.
The recent sharp and continuing decline in hormone therapy prescriptions appears
to be an appropriate response to evidence substantiating cardiovascular disease
harms and breast cancer risk associated with estrogen/progestin. Future patterns
of hormone therapy use remain uncertain but will likely be shaped by multiple
influences including professional and public attitudes toward risks and benefits,
the outcome of the estrogen-only arm of WHI, and pharmaceutical marketing.