Bioidentical Hormones - U.S. Senate Special Committee on Aging

Evidence-based Cardiology
hormone use and health status were updated biennially by
questionnatre. The most recent analysis Included 70533
women wtth up to 20 years average bfolow up for a total
experience of 808825 person-years during which time the
study accrued 1258 major coronary events (nonfatal
myocardial Infarction or coronary death). 2 1 There were 662
major coronary events during the 358 125 person-years of
never users, 337 events during the 185497 person-years
of past users, and 259 events during the 265 203 personyears
of current users of postmenopausal hormone therapy.
Conjugated equine estrogen (CEE) accounted for about two
thirds of the estrogen used. Proportional hazards models
were used to calculate relative risks for Incidence of clinical
outcomes, using women who had never used hormones as
the reference group. Multivarlate adjustments were made
for age, body mass Index, history of diabetes, hypertension,
high cholesterol level, cigarette smoking, and parental
history of premature heart disease.
The adjusted relative risk of major coronary disease
in current users compared to never users was 0-61 (95%
Cl 0-52-471), and in past users It was 0-82 (95% Cl
0-72-0-94). Current users of CEE alone had a relative risk
of 0-55 (95% Cl 045-0-68), and current users of CEE with
medroxyprogesterone acetate (MPAj had a relative risk of
0-53 (95% Cl 0-49-0-85). Duration of hormone use
appeared to have little Influence; however the relative risk
appeared to be lowest In current users for less tian 1 year
(0-41, 95% Cl 0-21-0.77) (IRgure 20.3). The reduced risk
for CHD was observed at all estrogen doses, but appeared to
be more marked at the doses of 0-3 mg conjugated equine
estrogen lt5-Mls, 95% Cl 0-37-0-92) and 0-625 mg (0-54,
95% Cl 0-44-0-67) than at the dose of 1-25mg or higher
(0-70, 95% Cl 0-51-0-97) (Flgure 20.3).
An earlier publication from the Nurses' Health Study
noted that the rates of coronary revascularization did
not differ between current users and non-users.17 Since It
differs from the findings for fatal and non-fatal myocardial
Oaaile,, I -l.S >w
heee,, 2-4-9 ya
loye-
neolcftom aoeas-.g
.q~~~imsa ss as a-25,-n
, R.res. , {a, Co
Figure 20.3 Relative risks and 95% confidence intervals for
CHD by duration and dose of current hormone use in the
Nurses' Health Study 2
183
Infarction, this observation argues against an immediate
beneficial effect of estrogen on the vessel wall. Most patients
undergo revascularization for symptoms and, If estrogens
had a direct effect, symptoms would have been less likely in
users. The data as regards to revascularization have implicatons
for the Interpretation of the data for CHD events: if
estrogen confers no immediate benefit, the finding of lower
CHD rates in current users may be due to the compliance
bias known to operate In subjects who are regularly taking
medications, or to selection bias as to who goes onto estrogen
and who is removed from therapy.
Data on risk for CHD in healthy women soon after initiation
of estrogen therapy are spare and inconsistent,
although most studies suggest reduced Initial risk in estrogen
users. As noted above, the Nurses' Health Study observed
the lowest relative risk during the first year of use.21 Several
other studies found little or no association of hormone use
with risk In the first year or two after initiating therapy,2830
while two suggested some early Increase In risk.31. 2 By
contrast (see below) the data for secondary prevention are
much more consistent in suggesting cardiovascular harm
after initiation of therapy.
ClrcaI trials
A pooled analysis of 23 randomized controlled trials, which
were done for the study of non-cardiovascular short-tem
effects of hormone therapy but which recorded numbers of
clinical events, found twelve cardiovascular (arterlal) events In
the hormone groups and five In the' rnrtrol gm.,< s33 T1,ou-h
not statstcaly slgMflcant, the results were In the opposite
direction to that predicted by the observational studies.
Large clinical trials of estrogen In healthy women with
sufficient statistical power to provide a definitive answer
to the question of benefit for cardiovascular disease are
underway (Table 20.1). The first of these forms part of the
Women's Health Initiative (WHi) in the USA. The WHI
enrolled 27347 women aged 50-79 In the trials of
menopausal hormone therapy during 1993-1998 and will
be completed in 2005 after 8-4 years average follow up.3?'
The study comprises two randomized controlled clinical
trials: the 16 608 women with an intact uterus randomized
to CEE 0-625 mg/day plus MPA 2-5 mg/day or placebo,
and the 10 739 women with a hysterectomy randomized to
CEE 0.625 mg/day or placebo. No results have yet been
published, but in 2000 the trial participants were advised
that during the first 2 years after randomization small
excesses in numbers of heart attacks, strokes, and blood
clots in the lungs were observed In the active treatment
groups. 5 In 2001 a follow up communlcatlon to partict
pants stated that small absolute excesses of these conditions
persisted beyond the first 2 years, but that the trials will
continue because the overall risk and benefit remained
uncertain.35