CONTRAINDICATIONS
Estrogens Should not Be Used in Individuals with Any of the Following Conditions:
1. Known or suspected pregnancy (see BOXED WARNING). Estrogens may cause fetal
harm when administered to a pregnant woman.
2. Undiagnosed abnormal genital bleeding.
3. Known or suspected cancer of the breast except in appropriately selected patients being
treated for metastatic disease.
4. Known or suspected estrogen-dependent neoplasia.
5. Active thrombophlebitis or thromboembolic disorders.
WARNINGS
1. Induction of Malignant Neoplasms:
Endometrial Cancer: The reported endometrial cancer risk among unopposed estrogen users is
about 2- to 12-fold greater than in nonusers, 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. In three studies, persistence of risk was
demonstrated for 8 to over 15 years after cessation of estrogen treatment. In one study a significant
decrease in the incidence of endometrial cancer occurred six months after estrogen withdrawal.
Concurrent progestin therapy may offset this risk but the overall health impact in postmenopausal
women is not known (see PRECAUTIONS).
Breast Cancer: While the majority of studies have not shown an increased risk of breast cancer in
women who have ever used estrogen replacement therapy, some have reported a moderately
increased risk (relative risks of 1.3-2.0) in those taking higher doses or those taking lower doses for
prolonged periods of time, especially in excess of 10 years.
Congenital Lesions With Malignant Potential: Estrogen therapy during pregnancy is associated
with an increased risk of fetal congenital reproductive tract disorders, and possibly other birth
defects. Studies of women who received DES during pregnancy have shown that female offspring
have an increased risk of vaginal adenosis, squamous cell dysplasia of the uterine cervix, and clear
cell vaginal cancer later in life; male offspring have an increased risk of urogenital abnormalities and
possibly testicular cancer later in life. Although some of these changes are benign, others are
precursors of malignancy.
2. Gallbladder Disease: Two studies have reported a 2- to 4-fold increase in the risk of
gallbladder disease requiring surgery in women receiving postmenopausal estrogens.
3. Cardiovascular Disease: 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. These risks cannot necessarily be extrapolated
from men to women. However, to avoid the theoretical cardiovascular risk to women caused
by high estrogen doses, the dose for estrogen replacement therapy should not exceed the
lowest effective dose.
4. Elevated Blood Pressure: Occasional blood pressure increases during estrogen
replacement therapy have been attributed to idiosyncratic reactions to estrogens. More often,
blood pressure has remained the same or has dropped. One study showed that
postmenopausal estrogen users have higher blood pressure than nonusers. Two other studies
showed slightly lower blood pressure among estrogen users compared to nonusers.
Postmenopausal estrogen use does not increase the risk of stroke. Nonetheless, blood
pressure should be monitored at regular intervals with estrogen use. Ethinyl estradiol and
conjugated estrogens have been shown to increase renin substrate. In contrast to these oral
estrogens, transdermally administered estradiol has been reported not to affect renin
substrate.
5. Hypercalcemia: Administration of estrogens may lead to severe hypercalcemia in
patients with breast cancer and bone metastases. If this occurs, the drug should be stopped
and appropriate measures taken to reduce the serum calcium level.
Estraderm
Effects Similar to Those Caused by Estrogen-Progestogen Oral Contraceptives: There are
several serious adverse effects of oral contraceptives and other high-dose oral estrogen treatments,
most of which have not, up to now, been documented as consequences of postmenopausal estrogen
replacement therapy. This may reflect the comparatively low doses of estrogen used in
postmenopausal women.
Thromboembolic Disease: It is now well established that users of oral contraceptives have an
increased risk of various thromboembolic and thrombotic vascular disease, such as thrombophlebitis,
pulmonary embolism, stroke, and myocardial infarction. Cases of retinal thrombosis, mesenteric
thrombosis, and optic neuritis have been reported in oral contraceptive users. There is evidence that
the risk of several of these adverse reactions is related to the dose of the drug. An increased risk of
postsurgery thromboembolic complications has also been reported in users of oral contraceptives. If
feasible, estrogen should be discontinued at least 4 weeks before surgery of the type associated
with an increased risk of thromboembolism, or during periods of prolonged immobilization.
While an increased rate of thromboembolic and thrombotic disease in postmenopausal users of
estrogens has not been found, this does not rule out the possibility that such an increase may be
present or that subgroups of women who have underlying risk factors or who are receiving
relatively large doses of estrogens may have increased risk. Therefore, estrogens should not be
used in persons with active thrombophlebitis or thromboembolic disorders, and they should not be
used in persons with a history of such disorders in association with estrogen use. They should be
used with caution in patients with cerebral vascular or coronary artery disease and only for those in
whom estrogens are clearly needed.
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 risk of nonfatal myocardial infarction, pulmonary embolism, and thrombophlebitis.
When estrogen doses of this size are used, any of the thromboembolic and thrombotic adverse
effects associated with oral contraceptive use should be considered a clear risk.
Hepatic Adenoma: Benign hepatic adenomas have been associated with the use of oral
contraceptives. Although benign and rare, these tumors may rupture and cause death from
intra-abdominal hemorrhage. Such lesions have not yet been reported in association with other
estrogen or progestogen preparations, but they should be considered if abdominal pain and
tenderness, abdominal mass, or hypovolemic shock occurs in patients receiving estrogen.
Hepatocellular carcinoma has also been reported in women taking estrogen-containing oral
contraceptives. The causal relationship of this malignancy to these drugs is not known.
Glucose Tolerance: A worsening of glucose tolerance has been observed in a significant
percentage of patients on estrogen-containing oral contraceptives. For this reason, diabetic patients
should be carefully observed while receiving estrogen.
PRECAUTIONS
General
Addition of a Progestin: Studies of the addition of a progestin for 10 or more days of a cycle of
estrogen administration have reported a lowered incidence of endometrial hyperplasia than would be
induced by estrogen treatment alone. Morphological and biochemical studies of endometria suggest
that 10-14 days of progestin are needed to provide maximal maturation of the endometrium and to
reduce the likelihood of hyperplastic changes.
There are, however, possible risks which may be associated with the use of progestins in estrogen
replacement regimens. These include: (1) adverse effects on lipoprotein metabolism (lowering HDL
and raising LDL) which could diminish the purported cardioprotective effect of estrogen therapy
(see Drug/Laboratory Test Interactions); (2) impairment of glucose tolerance; and (3) possible
enhancement of mitotic activity in breast epithelial tissue, although few epidemiological data are
available to address this point (see Drug/Laboratory Test Interactions). The choice of progestin, its
dose, and its regimen may be important in minimizing these adverse effects, but these issues will
require further study before they are clarified.
Physical Examination: A complete medical and family history should be taken prior to the
initiation of any estrogen therapy. The pretreatment and periodic physical examinations should
include special reference to blood pressure, breasts, abdomen, and pelvic organs, and should include
a Papanicolaou smear. As a general rule, estrogen should not be prescribed for longer than one
year without reexamining the patient.
Fluid Retention: Because estrogens may cause some degree of fluid retention, conditions which
might be exacerbated by this factor, such as asthma, epilepsy, migraine, and cardiac or renal
dysfunction, require careful observation.
Uterine Bleeding and Mastodynia: Certain patients may develop undesirable manifestations of
estrogenic stimulation, such as abnormal uterine bleeding and mastodynia.
Impaired Liver Function: Estrogens may be poorly metabolized in patients with impaired liver
function and should be administered with caution.
Additional Information for Estraderm
Prolonged administration of unopposed estrogen therapy has been reported to increase the risk of
endometrial hyperplasia in some patients. Estrogens should be used with caution in patients who
have or have had endometriosis.
Oral contraceptives, appear to be associated with an increased incidence of mental depression.
Although it is not clear whether this is due to the ectogenic or progestogenic component of the
contraceptive, patients with a history of depression should be carefully observed.
Preexisting uterine leiomyomata may increase in size during prolonged estrogen use. If this occurs,
estrogen therapy should be discontinued while the cause is investigated.
In patients with a history of jaundice during pregnancy, there is an increased risk that jaundice will
recur with the use of estrogen-containing oral contraceptives. If jaundice develops in any patient
receiving estrogen, the medication should be discontinued while the cause is investigated.
Because the prolonged use of estrogens influences the metabolism of calcium and phosphorus,
estrogens should be used with caution in patients with metabolic bone diseases associated with
hypercalcemia and in patients with renal insufficiency.