See BOX WARNING.
The use of unopposed estrogens in women who have a uterus is associated with an increased risk
of endometrial cancer.
Estrogen and estrogen/progestin therapy has been associated with an increased risk of
cardiovascular events such as myocardial infarction and stroke, as well as venous thrombosis and
pulmonary embolism (venous thromboembolism or VTE). Should any of these occur or be
suspected, estrogens should be discontinued immediately.
Risk factors for arterial vascular disease (e.g., hypertension, diabetes mellitus, tobacco use,
hypercholesterolemia, and obesity) and/or venous thromboembolism (e.g., personal history or
family history of VTE, obesity, and systemic lupus erythematosus) should be managed
Coronary Heart Disease And Stroke
In the Women's Health Initiative study (WHI), an increase in the number of myocardial
infarctions and strokes has been observed in women receiving CE compared to placebo. These
observations are preliminary. (See CLINICAL PHARMACOLOGY, Clinical Studies.)
In the CE/MPA substudy of WHI, an increased risk of coronary heart disease (CHD)events
(defined as nonfatal myocardial infarction and CHD death) was observed in women receivingCE/MPA compared to women receiving placebo (37 vs 30 per 10,000 women-years). The
increase in risk was observed in year one and persisted.
In the same substudy of WHI, an increased risk of stroke was observed in women receiving
CE/MPA compared to women receiving placebo (29 vs 21 per 10,000 women-years). The
increase in risk was observed after the first year and persisted.
In postmenopausal women with documented heart disease (n = 2,763, average age 66.7 years) a
controlled clinical trial of secondary prevention of cardiovascular disease (Heart and
Estrogen/Progestin Replacement study; HERS) treatment with CE/MPA (0.625mg/2.5mg per
day) demonstrated no cardiovascular benefit. During an average follow-up of 4.1 years, treatment
with CE/MPA did not reduce the overall rate of CHD events in postmenopausal women with
established coronary heart disease. There were more CHD events in the CE/MPA-treated group
than in the placebo group in year 1, but not during the subsequent years. Two thousand three
hundred and twenty-one women from the original HERS trial agreed to participate in an open
label extension of HERS, HERS II. Average follow-up in HERS II was an additional 2.7 years,
for a total of 6.8 years overall. Rates of CHD events were comparable among women in the
CE/MPA group and the placebo group in HERS, HERS II and overall.
Large doses of estrogen (5 mg conjugated estrogens per day), comparable to those used to treat
cancer of the prostate and breast, have been shown in a large prospective clinical trial in men to
increase the risks of nonfatal myocardial infarction, pulmonary embolism, and thrombophlebitis.
Venous Thromboembolism (VTE)
In the Women's Health Initiative study (WHI), an increase in VTE has been observed in women
receiving CE compared to placebo. These observations are preliminary. (See CLINICAL PHARMACOLOGY, Clinical Studies.)
In the CE/MPA substudy of WHI, a 2-fold greater rate of VTE, including deep venous
thrombosis and pulmonary embolism, was observed in women receiving CE/MPA compared to
women receiving placebo. The rate of VTE was 34 per 10,000 women-years in the CE/MPA
group compared to 16 per 10,000 women-years in the placebo group. The increase in VTE risk
was observed during the first year and persisted.
If feasible, estrogens should be discontinued at least 4 to 6 weeks before surgery of the type
associated with an increased risk of thromboembolism, or during periods of prolonged
The use of unopposed estrogens in women with intact uteri has been associated with an increased
risk of endometrial cancer. The reported endometrial cancer risk among unopposed estrogen users
is about 2- to 12- fold greater than in non-users, and appears dependent on duration of treatment
and on estrogen dose. Most studies show no significant increased risk associated with use of
estrogens for less than one year. The greatest risk appears associated with prolonged use, with
increased risks of 15- to 24-fold for five to ten years or more and this risk has been shown to
persist for at least 8 to 15 years after estrogen therapy is discontinued.
Clinical surveillance of all women taking estrogen/progestin combinations is important. Adequate
diagnostic measures, including endometrial sampling when indicated, should be undertaken to
rule out malignancy in all cases of undiagnosed persistent or recurring abnormal vaginal bleeding.
There is no evidence that the use of natural estrogens results in a different endometrial risk profilethan synthetic estrogens, of equivalent estrogen dose. Adding a progestin to estrogen therapy has been shown to reduce the risk of endometrial hyperplasia, which may be a precursor to endometrial cancer.
The use of estrogens and progestins by postmenopausal women has been reported to increase the
risk of breast cancer. The most important randomized clinical trial providing information about
this issue is the Women's Health Initiative (WHI) substudy of CE/MPA (see CLINICAL PHARMACOLOGY, Clinical Studies). The results from observational studies are generally
consistent with those of the WHI clinical trial and report no significant variation in the risk of
breast cancer among different estrogens or progestins, doses, or routes of administration.
The CE/MPA substudy of WHI reported an increased risk of breast cancer in women who took
CE/MPA for a mean follow-up of 5.6 years. Observational studies have also reported an
increased risk for estrogen/progestin combination therapy, and a smaller increased risk for
estrogen alone therapy, after several years of use. In the WHI trial and from observational studies,
the excess risk increased with duration of use. From observational studies, the risk appeared to
return to baseline in about five years after stopping treatment. In addition, observational studies
suggest that the risk of breast cancer was greater, and became apparent earlier, with
estrogen/progestin combination therapy as compared to estrogen alone therapy.
In the CE/MPA substudy, 26% of the women reported prior use of estrogen alone and/or
estrogen/progestin combination hormone therapy. After a mean follow-up of 5.6 years during the
clinical trial, the overall relative risk of invasive breast cancer was 1.24 (95% confidence interval
1.01 – 1.54), and the overall absolute risk was 41 vs 33 cases per 10,000 women-years, for
CE/MPA compared with placebo. Among women who reported prior use of hormone therapy, the
relative risk of invasive breast cancer was 1.86, and the absolute risk was 46 vs 25 cases per
10,000 women-years, for CE/MPA compared with placebo. Among women who reported no
prior use of hormone therapy, the relative risk of invasive breast cancer was 1.09, and the
absolute risk was 40 vs 36 cases per 10,000 women-years for CE/MPA compared with placebo.
In the same substudy, invasive breast cancers were larger and diagnosed at a more advanced stage
in the CE/MPA group compared with the placebo group. Metastatic disease was rare with no
apparent difference between the two groups. Other prognostic factors such as histologic subtype,
grade and hormone receptor status did not differ between the groups.
The use of estrogen plus progestin has been reported to result in an increase in abnormal
mammograms requiring further evaluation. All women should receive yearly breast examinations
by a healthcare provider and perform monthly breast self-examinations. In addition,
mammography examinations should be scheduled based on patient age, risk factors, and prior
In the Women's Health Initiative Memory Study (WHIMS), 4,532 generally healthy
postmenopausal women 65 years of age and older were studied, of whom 35% were 70 to 74
years of age and 18% were 75 or older. After an average follow-up of 4 years, 40 women being
treated with CE/MPA (1.8%, n = 2,229) and 21 women in the placebo group (0.9%, n = 2,303)
received diagnoses of probable dementia. The relative risk for CE/MPA versus placebo was 2.05
(95% confidence interval 1.21 – 3.48), and was similar for women with and without histories of
menopausal hormone use before WHIMS. The absolute risk of probable dementia for CE/MPA
versus placebo was 45 versus 22 cases per 10,000 women-years, and the absolute excess risk for
CE/MPA was 23 cases per 10,000 women-years.
It is unknown whether these findings apply to younger postmenopausal women. (See CLINICAL PHARMACOLOGY, Clinical Studies and PRECAUTIONS, Geriatric Use.)
It is unknown whether these findings apply to estrogen alone therapy.
A 2- to 4-fold increase in the risk of gallbladder disease requiring surgery in postmenopausal
women receiving estrogens has been reported.
Estrogen administration may lead to severe hypercalcemia in patients with breast cancer and bone
metastases. If hypercalcemia occurs, use of the drug should be stopped and appropriate measures
taken to reduce the serum calcium level.
Retinal vascular thrombosis has been reported in patients receiving estrogens. Discontinue
medication pending examination if there is a sudden partial or complete loss of vision, or a
sudden onset of proptosis, diplopia, or migraine. If examination reveals papilledema or retinal
vascular lesions, estrogens should be permanently discontinued.
Benign hepatic adenomas appear to be associated with the use of oral contraceptives. Although
benign, and rare, these may rupture and may cause death through intra-abdominal hemorrhage.
Such lesions have not yet been reported in association with other estrogen or progestagen
preparations but should be considered in estrogen users having abdominal pain and tenderness,
abdominal mass, or hypovolemic shock. Hepatocellular carcinoma has also been reported in
women taking estrogen-containing oral contraceptives. The relationship of this malignancy to
these drugs is not known at this time.