Estrogens
Indications: Carcinoma, breast, adjunct; Carcinoma, prostate; Hypogonadism, female; Kraurosis vulvae; Menopause; Osteoporosis; Ovarian failure, primary; Vaginitis, atrophic
WARNING:
Tablets:
1. ESTROGENS HAVE BEEN REPORTED TO INCREASE THE RISK OF ENDOMETRIAL CARCINOMA IN POSTMENOPAUSAL WOMEN. Close clinical surveillance of all women taking estrogens 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 currently no evidence that "natural" estrogens are more or less hazardous than "synthetic" estrogens at equiestrogenic doses.
2. ESTROGENS SHOULD NOT BE USED DURING PREGNANCY. There is no indication for estrogen therapy during pregnancy or during the immediate postpartum period. Estrogens are ineffective for the prevention or treatment of threatened or habitual abortion. Estrogens are not indicated for the prevention of postpartum breast engorgement. Estrogen therapy during pregnancy is associated with an increased risk of congenital defects in the reproductive organs of the fetus, and possibly other birth defects. Studies of women who received diethylstilbestrol (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. The 1985 DES Task Force concluded that use of DES during pregnancy is associated with a subsequent increased risk of breast cancer in the mothers, although a causal relationship remains unproven and the observed level of excess risk is similar to that for a number of other breast cancer risk factors.
Injection and Vaginal Cream:
1. ESTROGENS HAVE BEEN REPORTED TO INCREASE THE RISK OF ENDOMETRIAL CARCINOMA. Three independent, case-controlled studies have reported an increased risk of endometrial cancer in postmenopausal women exposed to exogenous estrogens for more than 1 year.1-3 This risk was independent of the other known risk factors for endometrial cancer. These studies are further supported by the finding that incidence rates of endometrial cancer have increased sharply since 1969 in 8 different areas of the United States with population-based cancer-reporting systems, an increase which may be related to the rapidly expanding use of estrogens during the last decade.4 The 3 case-controlled studies reported that the risk of endometrial cancer in estrogen users was about 4.5-13.9 times greater than in nonusers. The risk appears to depend on both duration of treatment1 and on estrogen dose.3 In view of these findings, when estrogens are used for the treatment of menopausal symptoms, the lowest dose that will control symptoms should be utilized and medication should be discontinued as soon as possible. When prolonged treatment is medically indicated, the patient should be reassessed, on at least a semiannual basis, to determine the need for continued therapy. Although the evidence must be considered preliminary, one study suggests that cyclic administration of low doses of estrogen may carry less risk than continuous administration.3 It therefore appears prudent to utilize such a regimen. Close clinical surveillance of all women taking estrogens is important. In all cases of undiagnosed persistent or recurring abnormal vaginal bleeding, adequate diagnostic measures should be undertaken to rule out malignancy. There is no evidence at present that "natural" estrogens are more or less hazardous than "synthetic" estrogens at equiestrogenic doses.
2. ESTROGENS SHOULD NOT BE USED DURING PREGNANCY. The use of female sex hormones, both estrogens and progestogens, during early pregnancy may seriously damage the offspring. It has been shown that females exposed in utero to diethylstilbestrol, a nonsteroidal estrogen, have an increased risk of developing, in later life, a form of vaginal or cervical cancer that is ordinarily extremely rare.5,6 This risk has been estimated as not greater than 4 per 1000 exposures.7 Furthermore, a high percentage of such exposed women (from 30-90%) have been found to have vaginal adenosis,8-12 epithelial changes of the vagina and cervix. Although these changes are histologically benign, it is not known whether they are precursors of malignancy. Although similar data are not available with the use of other estrogens, it cannot be presumed they would not induce similar changes. Several reports suggest an association between intrauterine exposure to female sex hormones and congenital anomalies, including congenital heart defects and limb-reduction defects.13-16 One case-controlled study 16 estimated a 4.7-fold increased risk of limb-reduction defects in infants exposed in utero to sex hormones (oral contraceptives, hormone withdrawal tests for pregnancy, or attempted treatment for threatened abortion). Some of these exposures were very short and involved only a few days of treatment. The data suggest that the risk of limb-reduction defects in exposed fetuses is somewhat less than 1 per 1000. In the past, female sex hormones have been used during pregnancy in an attempt to treat threatened or habitual abortion. There is considerable evidence that estrogens are ineffective for these indications, and there is no evidence from well-controlled studies that progestogens are effective for these uses. If conjugated estrogens is used during pregnancy, or if the patient becomes pregnant while taking this drug, she should be apprised of the potential risks to the fetus, and the advisability of pregnancy continuation.
DESCRIPTION:
Conjugated estrogens is a mixture of estrogens, obtained exclusively from natural sources, occurring as the sodium salts of water-soluble estrogen sulfates blended to represent the average composition of material derived from pregnant mares' urine. It contains as concomitant components, as sodium sulfate conjugates, 17 alpha-dihydroequilin, 17 alpha-estradiol, and 17 beta-dihydroequilenin as salts of their sulfate esters.
Tablets
Tablets for oral administration are available in 0.3, 0.625, 0.9, 1.25, and 2.5 mg strengths of conjugated estrogens.
Premarin Tablets Contain the Following Inactive Ingredients: Calcium phosphate tribasic, calcium sulfate, calcium sulfate, carnauba wax, cellulose, glyceryl monooleate, lactose, magnesium stearate, methylcellulose, pharmaceutical glaze, polyethylene glycol, stearic acid, sucrose, titanium dioxide. 0.3 mg Tablets Also Contain: D&C yellow no. 10, FD&C blue no. 1, FD&C blue no. 2, FD&C yellow no. 6. 0.625 mg Tablets Also Contain: FD&C blue no. 2, D&C red no. 27, FD&C red no. 40. 0.9 mg Tablets Also Contain: D&C red no. 6, D&C red no. 7. 1.25 mg Tablets Also Contain: Black iron oxide, D&C yellow no. 10, FD&C yellow no. 6, talc. 2.5 mg Tablets Also Contain: FD&C blue no. 2, D&C red no. 7, talc.
Injection
Each Secule vial contains 25 mg of conjugated estrogens, in a sterile lyophilized cake which also contains lactose 200 mg, sodium citrate 12.2 mg, and simethicone 0.2 mg. The pH is adjusted with sodium hydroxide or hydrochloric acid. A sterile diluent (5 ml) containing 2% benzyl alcohol in sterile water is provided for reconstitution. The reconstituted solution is suitable for intravenous or intramuscular injection.
Vaginal Cream
Each gram of Premarin vaginal cream contains 0.625 mg conjugated estrogens, in a nonliquefying base containing cetyl esters wax, cetyl alcohol, white wax, glyceryl monostearate, propylene glycol monostearate, methyl stearate, benzyl alcohol, sodium lauryl sulfate, glycerin, and mineral oil. Premarin vaginal cream is applied intravaginally.
CLINICAL PHARMACOLOGY:
Estrogen drug products act by regulating the transcription of a limited number of genes. Estrogens diffuse through cell membranes, distribute themselves throughout the cell, and bind to and activate the nuclear estrogen receptor, a DNA-binding protein which is found in estrogen-responsive tissues. The activated estrogen receptor binds to specific DNA sequences, or hormone-response elements, which enhance the transcription of adjacent genes and in turn lead to the observed effects. Estrogen receptors have been identified in tissues of the reproductive tract, breast, pituitary, hypothalamus, liver, and bone of women.
Estrogens are important in the development and maintenance of the female reproductive system and secondary sex characteristics. By a direct action, they cause growth and development of the uterus, fallopian tubes, and vagina. With other hormones, such as pituitary hormones and progesterone, they cause enlargement of the breasts through promotion of ductal growth, stromal development, and the accretion of fat. Estrogens are intricately involved with other hormones, especially progesterone, in the processes of the ovulatory menstrual cycle and pregnancy, and affect the release of pituitary gonadotropins. They also contribute to the shaping of the skeleton, maintenance of tone and elasticity of urogenital structures, changes in the epiphyses of the long bones that allow for the pubertal growth spurt and its termination, and pigmentation of the nipples and genitals.
Estrogens occur naturally in several forms. The primary source of estrogen in normally cycling adult women is the ovarian follicle, which secretes 70-500 mug of estradiol daily, depending on the phase of the menstrual cycle. This is converted primarily to estrone, which circulates in roughly equal proportion to estradiol, and to small amounts of estriol. After menopause, most endogenous estrogen is produced by conversion of androstenedione, secreted by the adrenal cortex, to estrone by peripheral tissues. Thus, estrone especially in its sulfate ester form is the most abundant circulating estrogen in postmenopausal women. Although circulating estrogens exist in a dynamic equilibrium of metabolic interconversions, estradiol is the principal intracellular human estrogen and is substantially more potent than estrone or estriol at the receptor.
Information Regarding Lipid Effects
The results of a clinical trial conducted in a 97% Caucasian population at low risk for cardiovascular disease show that Premarin significantly increases HDL-C and the HDL2-C subfraction and significantly decreases LDL-C.
Pharmacokinetics
Absorption
Conjugated estrogens used in therapy are soluble in water and are well absorbed from the gastrointestinal tract after release from the drug formulation. Maximum plasma concentrations of the various conjugated and unconjugated estrogens are attained within 4-10 hours after oral administration.
Estrogens used in therapy are also well absorbed through the skin and mucous membranes. When applied for a local action, absorption is usually sufficient to cause systemic effects. When conjugated with aryl and alkyl groups for parenteral administration, the rate of absorption of oily preparations is slowed with a prolonged duration of action, such that a single intramuscular injection of estradiol valerate or estradiol cypionate is absorbed over several weeks.
Distribution
Although naturally-occurring estrogens circulate in the blood largely bound to sex hormone-binding globulin (SHBG) and albumin, only unbound estrogens enter target tissue cells. (Conjugated estrogens bind mainly to albumin; unconjugated estrogens bind to both albumin and SHBG.) The apparent terminal-phase disposition half-life (t1/2) of the various estrogens is prolonged by the slow absorption from Premarin and ranges from 10-24 hours.
Metabolism
Administered estrogens and their esters are handled within the body essentially the same as the endogenous hormones. Metabolic conversion of estrogens occurs primarily in the liver (first-pass effect), but also at local target tissue sites. Complex metabolic processes result in a dynamic equilibrium of circulating conjugated and unconjugated estrogenic forms which are continually interconverted, especially between estrone and estradiol and between esterified and non-esterified forms. A significant proportion of the circulating estrogen exists as sulfate conjugates, especially estrone sulfate, which serves as a circulating reservoir for the formation of more active estrogenic species. A certain proportion of the estrogen is excreted into the bile, then reabsorbed from the intestine and returned to the liver through the portal venous system. During this enterohepatic recirculation, estrogens are desulfated and resulfated and undergo degradation through conversion to less active estrogens (estriol and other estrogens), oxidation to nonestrogenic substances (catecholestrogens, which interact with catecholamine metabolism, especially in the central nervous system), and conjugation with glucuronic acids (which are then rapidly excreted in the urine).
When given orally, naturally-occurring estrogens and their esters are extensively metabolized (first-pass effect) and circulate primarily as estrone sulfate, with smaller amounts of other conjugated and unconjugated estrogenic species. This results in limited oral potency. By contrast, synthetic estrogens, such as ethinyl estradiol and the nonsteroidal estrogens, are degraded very slowly in the liver and other tissues, which results in their high intrinsic potency. Estrogen drug products administered by non-oral routes are not subject to first-pass metabolism, but also undergo significant hepatic uptake, metabolism, and enterohepatic recycling.
Excretion
Water-soluble estrogen conjugates are strongly acidic and are ionized in body fluids, which favor excretion through the kidneys since tubular reabsorption is minimal.
INDICATIONS AND USAGE:
Estrogens Products Are Indicated in the Treatment of:
1. Treatment of moderate to severe vasomotor symptoms associated with the menopause. There is no adequate evidence that estrogens are effective for nervous symptoms or depression which might occur during menopause and they should not be used to treat these conditions.
2. Treatment of vulvar and vaginal atrophy.
3. Treatment of hypoestrogenism due to hypogonadism, castration or primary ovarian failure.
4. Treatment of breast cancer (for palliation only) in appropriately selected women and men with metastatic disease.
5. Treatment of advanced androgen-dependent carcinoma of the prostate (for palliation only).
6. Prevention of osteoporosis. Since estrogen administration is associated with risk, selection of patients ideally should be based on prospective identification of risk factors for developing osteoporosis. Unfortunately, there is no certain way to identify those women who will develop osteoporotic fractures. Most prospective studies of efficacy for this indication have been carried out in white menopausal women, without stratification by other risk factors, and tend to show a universally salutary effect on bone. Thus, patient selection must be individualized based on the balance of risks and benefits. A more favorable risk/benefit ratio exists in a hysterectomized woman because she has no risk of endometrial cancer (see Boxed Warning).
Estrogen replacement therapy reduces bone resorption and retards or halts postmenopausal bone loss. Case-control studies have shown an approximately 60% reduction in hip and wrist fractures in women whose estrogen replacement was begun within a few years of menopause. Studies also suggest that estrogen reduces the rate of vertebral fractures. Even when started as late as 6 years after menopause, estrogen prevents further loss of bone mass for as long as the treatment is continued. When estrogen therapy is discontinued, bone mass declines at a rate comparable to the immediate postmenopausal period. There is no evidence that estrogen replacement therapy restores bone mass to premenopausal levels.
At skeletal maturity there are sex and race differences in both the total amount of bone present and its density, in favor of men and blacks. Thus, women are at higher risk than men because they start with less bone mass and, for several years following natural or induced menopause, the rate of bone mass decline is accelerated. White and Asian women are at higher risk than black women.
Early menopause is one of the strongest predictors for the development of osteoporosis. In addition, other factors affecting the skeleton which are associated with osteoporosis include genetic factors (small build, family history), endocrine factors (nulliparity, thyrotoxicosis, hyperparathyroidism, Cushing's syndrome, hyperprolactinemia, Type I diabetes), lifestyle (cigarette smoking, alcohol abuse, sedentary exercise habits), and nutrition (below average body weight, dietary calcium intake).
The mainstays of prevention and management of osteoporosis are estrogen, an adequate lifetime calcium intake, and exercise. Postmenopausal women absorb dietary calcium less efficiently than premenopausal women and require an average of 1500 mg/day of elemental calcium to remain in neutral calcium balance. By comparison, premenopausal women require about 1000 mg/day and the average calcium intake in the USA is 400-600 mg/day. Therefore, when not contraindicated, calcium supplementation may be helpful.
Weight-bearing exercise and nutrition may be important adjuncts to the prevention and management of osteoporosis. Immobilization and prolonged bed rest produce rapid bone loss, while weight-bearing exercise has been shown both to reduce bone loss and to increase bone mass. The optimal type and amount of physical activity that would prevent osteoporosis have not been established, however in two studies an hour of walking and running exercises two or three times weekly significantly increased lumbar spine bone mass.
Injection
Intravenous conjugated estrogens are indicated in the treatment of abnormal uterine bleeding due to hormonal imbalance in the absence of organic pathology.
Vaginal Cream
Conjugated estrogens vaginal cream is indicated in the treatment of atrophic vaginitis and kraurosis vulvae.
Conjugated estrogens vaginal cream HAS NOT BEEN SHOWN TO BE EFFECTIVE FOR ANY PURPOSE DURING PREGNANCY AND ITS USE MAY CAUSE SEVERE HARM TO THE FETUS. (See BOXED WARNING.)
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. There is insufficient information regarding women who have had previous thromboembolic disease.
6. Conjugated estrogens tablets should not be used in patients hypersensitive to their ingredients.
WARNINGS:
Tablets
Induction of Malignant Neoplasms
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 studies have reported a moderately increased risk (relative risks of 1.3-2.0) in those women taking higher doses or those taking lower doses for prolonged periods of time, especially in excess of 10 years. Other studies have not shown this relationship.
In the 3-year clinical Postmenopausal Estrogen Progestin Intervention (PEPI) trial of 875 women to assess differences among placebo, unopposed Premarin, and 3 different combination hormone therapy regimens, 1 new case of breast cancer was detected in the placebo group (n=174), 1 in the Premarin alone group (n=175), none in the continuous Premarin plus continuous medroxyprogesterone acetate group (n=174), and 2 in the continuous Premarin plus cyclic medroxyprogesterone acetate group (n=174).
Women on this therapy should have regular breast examinations and should be instructed in breast self-examination, and women over the age of 50 should have regular mammograms.
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 1 year. The greatest risk appears associated with prolonged use, with increased risks of 15- to 24-fold for 5-10 years or more. In 3 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 6 months after estrogen withdrawal. Concurrent progestin therapy may offset this risk but the overall health impact in postmenopausal women is not known (see PRECAUTIONS).
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.
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.
Thromboembolic Disorders and Other Vascular Problems
In some studies, women on estrogen replacement therapy, given alone or in combination with a progestin, have been reported to have an increased risk of thrombophlebitis and/or thromboembolic 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 risk of nonfatal myocardial infarction, pulmonary embolism, and thrombophlebitis. The physician should be aware of the possibility of thrombotic disorders (thrombophlebitis, retinal thrombosis, cerebral embolism, and pulmonary embolism) during estrogen replacement therapy and be alert to their earliest manifestations. Should any of these occur or be suspected, estrogen replacement therapy should be discontinued immediately. Patients who have risk factors for thrombotic disorders should be kept under careful observation.
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.
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.
Injection and Vaginal Cream
Induction of Malignant Neoplasms
Long-term, continuous administration of natural and synthetic estrogens in certain animal species increases the frequency of carcinomas of the breast, cervix, vagina, and liver. There are now reports that estrogens increase the risk of carcinoma of the endometrium in humans (see BOXED WARNING.) At the present time there is no satisfactory evidence that estrogens given to postmenopausal women increase the risk of cancer of the breast,17 although a recent long-term follow-up of a single physician's practice has raised this possibility.18 Because of the animal data, there is a need for caution in prescribing estrogens for women with a strong family history of breast cancer, or who have breast nodules, fibrocystic disease, or abnormal mammograms.
Gallbladder Disease
A recent study has reported a 2- to 3-fold increase in the risk of surgically confirmed gallbladder disease in women receiving postmenopausal estrogens,17 similar to the 2-fold increase previously noted in users of oral contraceptives.19,24a.
Effects Similar to Those Caused by Estrogen-Progestogen Oral Contraceptives
There are several serious adverse effects of oral contraceptives, most of which have not, up to now, been documented as consequences of postmenopausal estrogen therapy. This may reflect the comparatively low doses of estrogen used in postmenopausal women. It would be expected that the larger doses of estrogen used to treat prostatic or breast cancer are more likely to result in these adverse effects, and, in fact, it has been shown that there is an increased risk of thrombosis in men receiving estrogens for prostatic cancer.20-23.
Thromboembolic Disease: It is now well established that users of oral contraceptives have an increased risk of various thromboembolic and thrombotic vascular diseases, such as thrombophlebitis, pulmonary embolism, stroke, and myocardial infarction.24-31 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.32,33 An increased risk of postsurgery thromboembolic complications has also been reported in users of oral contraceptives.34,35 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,17-24,25-36 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 (expect in treatment of malignancy) 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 men37 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 appear to be associated with the use of oral contraceptives.38-40 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 progestogen 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.39 The relationship of this malignancy to these drugs is not known at this time.
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.
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.
PRECAUTIONS:
Tablets
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. The potential risks include adverse effects on lipoprotein metabolism, impairment of glucose tolerance, and possible enhancement of mitotic activity in breast epithelial tissue, although few epidemiological data are available to address this point (see PRECAUTIONS).
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.
Cardiovascular Risk
A causal relationship between estrogen replacement therapy and reduction of cardiovascular disease in postmenopausal women has not been proven. Furthermore, the effect of added progestins on this putative benefit is not yet known.
In recent years many published studies have suggested that there may be a cause-effect relationship between postmenopausal oral estrogen replacement therapy without added progestins and a decrease in cardiovascular disease in women.
Although Most of the Observational Studies Which Assessed This Statistical Association Have Reported a 20-50% Reduction in Coronary Heart Disease Risk and Associated Mortality in Estrogen Takers, the Following Should be Considered When Interpreting These Reports:
1. Because only one of these studies was randomized and it was too small to yield statistically significant results, all relevant studies were subject to selection bias. Thus, the apparently reduced risk of coronary artery disease cannot be attributed with certainty to estrogen replacement therapy. It may instead have been caused by life-style and medical characteristics of the women studied with the result that healthier women were selected for estrogen therapy. In general, treated women were of higher socioeconomic and educational status, more slender, more physically active, more likely to have undergone surgical menopause, and less likely to have diabetes than the untreated women. Although some studies attempted to control for these selection factors, it is common for properly designed randomized trials to fail to confirm benefits suggested by less rigorous study designs. Thus, ongoing and future large-scale randomized trials may fail to confirm this apparent benefit.
2. Current medical practice often includes the use of concomitant progestin therapy in women with intact uteri (see PRECAUTIONS and WARNINGS). While the effects of added progestins on the risk of ischemic heart disease are not known, all available progestins reverse at least some of the favorable effects of estrogens on HDL and LDL cholesterol levels.
3. While the effects of added progestins on the risk of breast cancer are also unknown, available epidemiological evidence suggests that progestins do not reduce, and may enhance, the moderately increased breast cancer incidence that has been reported with prolonged estrogen replacement therapy (see WARNINGS).
Because relatively long-term use of estrogens by a woman with a uterus has been shown to increase the risk of endometrial cancer, physicians often recommend that these women should take progestins as well as estrogens. When considering prescribing concomitant estrogens and progestins for hormone replacement therapy, physicians and patients are advised to carefully weigh the potential benefits and risks of the added progestin. Large-scale randomized, placebo-controlled, clinical trials and future epidemiological studies are required to clarify these issues.
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 1 year without reexamining the patient.
Familial Hyperlipoproteinemia
Estrogen therapy may be associated with massive elevations of plasma triglycerides leading to pancreatitis and other complications in patients with familial defects of lipoprotein metabolism.
Fluid Retention
Because estrogens may cause some degree of fluid retention, conditions which might be influenced 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 considered with caution.
Uterine Fibroids
Preexisting uterine leiomyomata may increase in size during prolonged high-dose estrogen use.
Hypocalcemia
Estrogens should be used with caution in individuals with metabolic bone disease associated with severe hypocalcemia.
Laboratory Tests
Estrogen administration should generally be guided by clinical response at the smallest dose, rather than laboratory monitoring, for relief of symptoms for those indications in which symptoms are observable. For prevention of osteoporosis, however, see DOSAGE AND ADMINISTRATION.
Drug/Laboratory Test Interactions
1. Accelerated prothrombin time, partial thromboplastin time, and platelet aggregation time; increased platelet count; increased factors II, VII antigen, VIII antigen, VIII coagulant activity, IX, X, XII, VII-X complex, II-VII-X complex, and beta-thromboglobulin; decreased levels of anti-factor Xa and antithrombin III, decreased antithrombin III activity; increased levels of fibrinogen and fibrinogen activity; increased plasminogen antigen and activity.
2. Increased thyroid-binding globulin (TBG) leading to increased circulating total thyroid hormone, as measured by protein-bound iodine (PBI), T4 levels (by column or by radioimmunoassay) or T3 levels by radioimmunoassay. T3 resin uptake is decreased, reflecting the elevated TBG. Free T4 and free T3 concentrations are unaltered.
3. Other binding proteins may be elevated in serum, i.e., corticosteroid binding globulin (CBG), sex hormone-binding globulin (SHBG), leading to increased circulating corticosteroids and sex steroids respectively. Free or biologically active hormone concentrations are unchanged. Other plasma proteins may be increased (angiotensinogen/renin substrate, alpha-1-antitrypsin, ceruloplasmin).
4. Increased plasma HDL and HDL-2 subfraction concentrations, reduced LDL cholesterol concentration, increased triglyceride levels.
5. Impaired glucose tolerance.
6. Reduced response to metyrapone test.
7. Reduced serum folate concentration.
Carcinogenesis, Mutagenesis, and Impairment of Fertility
Long-term continuous administration of natural and synthetic estrogens in certain animal species increases the frequency of carcinomas of the breast, cervix, vagina, and liver. (See CONTRAINDICATIONS and WARNINGS.)
Pregnancy Category X
Estrogens should not be used during pregnancy. (See CONTRAINDICATIONS and BOXED WARNING.)
Nursing Mothers
As a general principle, the administration of any drug to nursing mothers should be done only when clearly necessary since many drugs are excreted in human milk. In addition, estrogen administration to nursing mothers has been shown to decrease the quantity and quality of the milk.
Pediatric Use
See DOSAGE AND ADMINISTRATION.
Injection and Vaginal Cream
General
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, estrogens should not be prescribed for longer than 1 year without another physical examination being performed.
Fluid Retention: Because estrogens may cause some degree of fluid retention, conditions which might be influenced by this factor, such as asthma, epilepsy, migraine, and cardiac or renal dysfunction, require careful observation.
Familial Hyperlipoprotenemia: Estrogen therapy may be associated with massive elevations of plasma triglycerides leading to pancreatitis and other complications in patients with familial defects of lipoprotein metabolism.
Certain patients may develop undesirable manifestations of excessive estrogenic stimulation, such as abnormal or excessive uterine bleeding, mastodynia, etc.
Drug/Laboratory Tests Interactions
Certain endocrine and liver function tests may be affected by estrogen-containing oral contraceptives. The following similar changes may be expected with larger doses of estrogen:
* Increased sulfobromophthalein retention.
* Increased prothrombin and factors VII, VIII, IX, and X; decreased antithrombin 3; increased norepinephrine-induced platelet aggregability.
* Increased thyroid binding globulin (TBG) leading to increased circulating total thyroid hormone, as measured by PBI, T4 by column, or T4 by radioimmunoassay. Free T3 resin uptake is decreased, reflecting the elevated TBG; free T4 concentration is unaltered.
* Impaired glucose tolerance.
* Decreased pregnanediol excretion.
* Reduced response to metyrapone test.
* Reduced serum folate concentration.
* Increased serum triglyceride and phospholipid concentration.
Carcinogenesis, Mutagenesis, and Impairment of Fertility
See WARNINGS for information on carcinogenesis.
Pregnancy Category X
(See CONTRAINDICATIONS and BOXED WARNING.)
Nursing Mothers
It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from estrogens, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
Pediatric Use
Safety and effectiveness in children have not been established.
Additional Information for Vaginal Cream
Prolonged administration of unopposed estrogen therapy has been reported to increase the risk of endometrial hyperplasia in some patients.
Oral contraceptives appear to be associated with an increased incidence of mental depression.24a Although it is not clear whether this is due to the estrogenic or progestogenic component of the contraceptive, patients with a history of depression should be carefully observed.
Preexisting uterine leiomyomata may increase in size during estrogen use.
The pathologist should be advised of estrogen therapy when relevant specimens are submitted.
Patients with a past history of jaundice during pregnancy have an increased risk of recurrence of jaundice while receiving estrogen-containing oral-contraceptive therapy. If jaundice develops in any patient receiving estrogen, the medication should be discontinued while the cause is investigated.
Estrogens may be poorly metabolized in patients with impaired liver function and should be administered with caution in such patients.
Because estrogens influence the metabolism of calcium and phosphorus, they should be used with caution in patients with metabolic bone diseases that are associated with hypercalcemia or in patients with renal insufficiency.
Because of the effects of estrogens on epiphyseal closure, they should be used judiciously in young patients in whom bone growth is not yet complete.
Concomitant Progestin Use: The lowest effective dose appropriate for the specific indication should be utilized. Studies of the addition of a progestin for 7 or more days of a cycle of estrogen administration have reported a lowered incidence of endometrial hyperplasia. Morphological and biochemical studies of the endometrium suggest that 10-13 days of progestin are needed to provide maximal maturation of the endometrium and to eliminate any hyperplastic changes. Whether this will provide protection from endometrial carcinoma has not been clearly established. There are possible additional risks which may be associated with the inclusion of a progestin in estrogen replacement regimens. If concomitant progestin therapy is used, potential risks may include adverse effects on carbohydrate and lipid metabolism. The choice of progestin and dosage may be important in minimizing these adverse effects.
Additional Information for Injection
Certain endocrine and liver function tests may be affected by estrogen-containing oral contraceptives. The following similar changes may be expected with larger doses of estrogen:
* Increased sulfobromophthalein retention.
* Increased prothrombin and factors VII, VIII, IX, and X; decreased antithrombin 3; increased norepinephrine-induced platelet aggregability.
* Increased thyroid binding globulin (TBG) leading to increased circulating total thyroid hormone, as measured by PBI, T4 by column, or T4 by radioimmunoassay. Free T3 resin uptake is decreased, reflecting the elevated TBG; free T4 concentration is unaltered.
* Impaired glucose tolerance.
* Decreased pregnanediol excretion.
* Reduced response to metyrapone test.
* Reduced serum folate concentration.
* Increased serum triglyceride and phospholipid concentration.
ADVERSE REACTIONS:
See WARNINGS regarding induction of neoplasia, adverse effects on the fetus, increased incidence of gallbladder disease, and adverse effects similar to those of oral contraceptives, including thromboembolism.
The Following Additional Adverse Reactions Have Been Reported With Estrogen Therapy (see WARNINGS Regarding Induction of Neoplasia, Adverse Effects on the Fetus, Increased Incidence of Gallbladder Disease, Cardiovascular Disease, Elevated Blood Pressure, and Hypercalcemia; see PRECAUTIONS Regarding Cardiovascular Risk).
Genitourinary System: Changes in vaginal bleeding pattern and abnormal withdrawal bleeding or flow, breakthrough bleeding, spotting, increase in size of uterine leiomyomata, vaginal candidiasis, change in amount of cervical secretion.
Breasts: Tenderness, enlargement.
Gastrointestinal: Nausea, vomiting, abdominal cramps, bloating, cholestatic jaundice, increased incidence of gallbladder disease, pancreatitis.
Skin: Chloasma or melasma that may persist when drug is discontinued, erythema multiform, erythema nodosum, hemorrhagic eruption, loss of scalp hair, hirsutism.
Cardiovascular: Venous thromboembolism, pulmonary embolism.
Eyes: Steepening of corneal curvature, intolerance to contact lenses.
CNS: Headache, migraine, dizziness, mental depression, chorea.
Miscellaneous: Increase or decrease in weight, reduced carbohydrate tolerance, aggravation of porphyria, edema, changes in libido.
OVERDOSAGE:
Serious ill effects have not been reported following acute ingestion of large doses of estrogen-containing oral contraceptives by young children. Overdosage of estrogen may cause nausea and vomiting, and withdrawal bleeding may occur in females.
DOSAGE AND ADMINISTRATION:
Tablets
For treatment of moderate to severe vasomotor symptoms, and/or vulvar and vaginal atrophy associated with the menopause, the lowest dose that will control symptoms should be chosen and medication should be discontinued as promptly as possible. Vasomotor Symptoms: 0.625 mg daily. Vulvar and Vaginal Atrophy: 0.3-1.25 mg or more daily, depending upon the tissue response of the individual.
Conjugated estrogens therapy may be given continuously with no interruption in therapy, or in cyclical regimens (regimens such as 25 days on drug followed by 5 days off drug) as is medically appropriate on an individualized basis.
Attempts to discontinue or taper medication should be made at 3- to 6-month intervals.
For Treatment of Female Hypoestrogenism due to Hypogonadism, Castration, or Primary Ovarian Failure
Female Hypogonadism
0.3-0.625 mg daily, administered cyclically (e.g., 3 weeks on and 1 week off). Doses are adjusted depending on the severity of symptoms and responsiveness of the endometrium.
In clinical studies of delayed puberty due to female hypogonadism, breast development was induced by doses as low as 0.15 mg. The dosage may be gradually titrated upward at 6- to 12-month intervals as needed to achieve appropriate bone age advancement and eventual epiphyseal closure. Clinical studies suggest that doses of 0.15, 0.3, and 0.6 mg are associated with mean ratios of bone age advancement to chronological age progression DBA/DCA) of 1.1, 1.5, and 2.1, respectively. (Premarin in the dose strength of 0.15 mg is not available commercially). Available data suggest that chronic dosing with 0.625 mg is sufficient to induce artificial cyclic menses with sequential progestin treatment and to maintain bone mineral density after skeletal maturity is achieved.
Female Castration or Primary Ovarian Failure
1.25 mg daily, cyclically. Adjust dosage, upward or downward, according to severity of symptoms and response of the patient. For maintenance, adjust dosage to lowest level that will provide effective control.
For Treatment of Breast Cancer, For Palliation Only, In Appropriately Selected Women and Men With Metastatic Disease
Suggested dose is 10 mg 3 times daily for a period of at least 3 months.
For Treatment of Advanced Androgen-Dependent Carcinoma of the Prostate, for Palliation Only
1.25-2.5 mg 3 times daily. The effectiveness of therapy can be judged by phosphatase determinations as well as by symptomatic improvement of the patient.
For Prevention of Osteoporosis
0.625 mg daily. Premarin therapy may be given continuously with no interruption in therapy, or in cyclical regimens (regimens such as 25 days on drug followed by 5 days off drug) as is medically appropriate on an individualized basis.
Injection
Abnormal Uterine Bleeding due to Hormonal Imbalance
One 25 mg injection, intravenously or intramuscularly. Intravenous use is preferred since more rapid response can be expected from this mode of administration.
Repeat in 6-12 hours if necessary. The use of conjugated estrogens intravenous for injection does not preclude the advisability of other appropriate measures.
The usual precautionary measures governing intravenous administration should be adhered to. Injection should be made SLOWLY to obviate the occurrence of flushes.
Infusion of conjugated estrogens intravenous for injection with other agents is not generally recommended. In emergencies, however, when an infusion has already been started it may be expedient to make the injection into the tubing just distal to the infusion needle. If so used, compatibility of solutions must be considered.
Compatibility of Solutions
Conjugated estrogens intravenous is compatible with normal saline, dextrose, and invert sugar solutions. IT IS NOT COMPATIBLE WITH PROTEIN HYDROLYSATE, ASCORBIC ACID, OR ANY SOLUTION WITH AN ACID pH.
Treated patients with an intact uterus should be monitored closely for signs of endometrial cancer, and appropriate diagnostic measures should be taken to rule out malignancy in the event of persistent or recurring abnormal vaginal bleeding.
Directions for Storage and Reconstitution
Storage Before Reconstitution: Store package in refrigerator, 2-8°C (36-46°F).
To Reconstitute: First withdraw air from secule vial so as to facilitate introduction of sterile diluent. Then, flow the sterile diluent slowly against side of secule vial and agitate gently. DO NOT SHAKE VIOLENTLY.
Storage After Reconstitution: It is common practice to utilize the reconstituted solution within a few hours. If it is necessary to keep the reconstituted solution for more than a few hours, store the reconstituted solution under refrigeration (2-8°C). Under these conditions, the solution is stable for 60 days, and is suitable for use unless darkening or precipitation occurs.
Vaginal Cream
Given Cyclically for Short-Term Use Only
For treatment of atrophic vaginitis, or kraurosis vulvae.
The lowest dose that will control symptoms should be chosen and medication should be discontinued as promptly as possible.
Administration should be cyclic (e.g., 3 weeks on and 1 week off).
Attempts to discontinue or taper medication should be made at 3- to 6-month intervals.
Usual Dosage Range
One half to 2 g daily, intravaginally, depending on the severity of the condition. Treated patients with an intact uterus should be monitored closely for signs of endometrial cancer, and appropriate diagnostic measures should be taken to rule out malignancy in the event of persistent or recurring abnormal vaginal bleeding.
Instructions for Use of Gentle Measure Applicator:
1. Remove cap from tube.
2. Screw nozzle end of applicator onto tube.
3. Gently squeeze tube from the bottom to force sufficient cream into the barrel to provide the prescribed dose. Use the marked stopping points on the applicator as a guideline to measure the correct dose.
4. Unscrew applicator from tube.
5. Lie on back with knees drawn up. To deliver medication, gently insert applicator deeply into vagina and press plunger downward to its original position.
To Cleanse: Pull plunger to remove it from barrel. Wash with mild soap and warm water.
Do not boil or use hot water.
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PATIENT PACKAGE INSERT:
What You Should Know about Estrogens
Estrogens are female hormones produced by the ovaries. The ovaries make several different kinds of estrogens. In addition, scientists have been able to make a variety of synthetic estrogens. As far as we know, all these estrogens have similar properties and, therefore, much the same usefulness, side effects, and risks. This leaflet is intended to help you understand what estrogens are used for, the risks involved in their use, and how to use them as safely as possible.
This leaflet includes the most important information about estrogens, but not all the information. If you want to know more, you should ask your doctor for more information, or you can ask your doctor or pharmacist to let you read the package insert prepared for the doctor.
Uses of Estrogen
THERE IS NO PROPER USE OF ESTROGENS IN A PREGNANT WOMAN.
Estrogens are Prescribed by Doctors for a Number of Purposes, Including:
1. To provide estrogen during a period of adjustment when a woman's ovaries stop producing a majority of her estrogens, in order to prevent certain uncomfortable symptoms of estrogen deficiency. (With the menopause, which generally occurs between the ages of 45 and 55, women produce a much smaller amount of estrogens.)
2. To prevent symptoms of estrogen deficiency when a woman's ovaries have been removed surgically before the natural menopause.
3. To prevent pregnancy. (Estrogens are given along with a progestogen, another female hormone; these combinations are called oral contraceptives, or birth-control pills. Patient labeling is available to women taking oral contraceptives and they will not be discussed in this leaflet.)
4. To treat certain cancers in women and men.
Estrogens in the Menopause
In the natural course of their lives, all women eventually experience a decrease in estrogen production. This usually occurs between ages 45 and 55, but may occur earlier or later. Sometimes the ovaries may need to be removed before natural menopause by an operation, producing a "surgical menopause."
When the amount of estrogen in the blood begins to decrease, many women may develop typical symptoms: feelings of warmth in the face, neck, and chest, or sudden intense episodes of heat and sweating throughout the body (called "hot flashes" or "hot flushes"). These symptoms are sometimes very uncomfortable. Some women may also develop changes in the vagina (called "atrophic vaginitis") that cause discomfort, especially during and after intercourse.
Estrogens can be prescribed to treat these symptoms of the menopause. It is estimated that considerably more than half of all women undergoing the menopause have only mild symptoms or no symptoms at all and, therefore, do not need estrogens. Other women may need estrogens for a few months, while their bodies adjust to lower estrogen levels. Sometimes the need will be for periods longer than 6 months. In an attempt to avoid overstimulation of the uterus (womb), estrogens are usually given cyclically during each month of use, such as 3 weeks of pills followed by 1 week without pills.
Sometimes women experience nervous symptoms or depression during menopause. There is no evidence that estrogens are effective for such symptoms without associated vasomotor symptoms. In the absence of vasomotor symptoms, estrogens should not be used to treat nervous symptoms, although other treatment may be needed.
You may have heard that taking estrogens for long periods (years) after the menopause will keep your skin soft and supple and keep you feeling young. There is no evidence that this is so, however, and such long-term treatment carries important risks.
The Dangers of Estrogens
Endometrial Cancer: There are reports that if estrogens are used in the postmenopausal period for more than a year, there is an increased risk of endometrial cancer (cancer of the lining of the uterus). Women taking estrogens have roughly 5-10 times as great a chance of getting this cancer as women who take no estrogens. To put this another way, while a postmenopausal woman not taking estrogens has 1 chance in 1000 each year of getting endometrial cancer, a woman taking estrogens has 5-10 chances in 1,000 each year. For this reason it is important to take estrogens only when they are really needed. The risk of this cancer is greater the longer estrogens are used and when larger doses are taken. Therefore, you should not take more estrogen than your doctor prescribes. It is important to take the lowest dose of estrogen that will control symptoms and to take it only as long as it is needed. If estrogens are needed for longer periods of time, your doctor will want to reevaluate your need for estrogens at least every 6 months. Women using estrogens should report any vaginal bleeding to their doctors; such bleeding may be of no importance, but it can be an early warning of endometrial cancer. If you have undiagnosed vaginal bleeding, you should not use estrogens until a diagnosis is made and you are certain there is no endometrial cancer. Note: If you have had your uterus removed (total hysterectomy), there is no danger of developing endometrial cancer.
Other Possible Cancers: Estrogens can cause development of other tumors in animals, such as tumors of the breast, cervix, vagina, or liver, when given for a long time. At present there is no good evidence that women using estrogens in the menopause have an increased risk of such tumors, but there is no way yet to be sure they do not; and one study raises the possibility that use of estrogens in the menopause may increase the risk of breast cancer many years later This is a further reason to use estrogens only when clearly needed. While you are taking estrogens, it is important that you go to your doctor at least once a year for a physical examination. Also, if members of your family have had breast cancers, or if you have breast nodules, or abnormal mammograms (breast X rays), your doctor may wish to carry out more frequent examinations of your breasts.
Gallbladder Disease: Women who use estrogens after menopause are more likely to develop gallbladder disease needing surgery than women who do not use estrogens. Birth-control pills have a similar effect.
Abnormal Blood Clotting: Oral contraceptives increase the risk of blood clotting in various parts of the body. This can result in a stroke (if the clot is in the brain), a heart attack (a clot in a blood vessel of the heart), or a pulmonary embolus (a clot which forms in the legs or pelvis, then breaks off and travels to the lungs). Any of these can be fatal. At this time, use of estrogens in the menopause is not known to cause such blood clotting, but this has not been fully studied and there could still prove to be such a risk. It is recommended that if you have had clotting in the legs or lungs, or a heart attack or stroke, while you were using estrogens or birth-control pills, you should not use estrogens (unless they are being used to treat cancer of the breast or prostate). If you have had a stroke or heart attack, or if you have angina pectoris, estrogens should be used with great caution and only if clearly needed for example, if you have severe symptoms of the menopause).
Special Warning About Pregnancy
You should not receive estrogen if you are pregnant. If this should occur, there is a greater than usual chance that the developing child will be born with a birth defect, although the possibility remains fairly small. A female child may have an increased risk of developing cancer of the vagina or cervix later in life (in the teens or twenties). Every possible effort should be made to avoid exposure to estrogens during pregnancy. If exposure occurs, see your doctor.
Other Effects of Estrogens
In addition to the serious known risks of estrogens described above, estrogens have the following side effects and potential risks:
Nausea and Vomiting: The most common side effect of estrogen therapy is nausea. Vomiting is less common.
Effects on Breasts: Estrogens may cause breast tenderness or enlargement and may cause the breasts to secrete a liquid. These effects are not dangerous .
Effects on the Uterus: Estrogens may cause benign fibroid tumors of the uterus to get larger.
Effects on Liver: Women taking oral contraceptives develop, on rare occasions, a tumor of the liver which can rupture and bleed into the abdomen and may cause death. So far, these tumors have not been reported in women using estrogens in the menopause, but you should report any swelling or unusual pain or tenderness in the abdomen to your doctor immediately. Women with a past history of jaundice (yellowing of the skin and white parts of the eyes) may get jaundice again during estrogen use. If this occurs, stop taking estrogens and see your doctor.
Other Effects: Estrogens may cause excess fluid to be retained in the body. This may make some conditions worse, such as asthma, epilepsy, migraine, heart disease, or kidney disease.
Summary
Estrogens have important uses, but they have serious risks as well. You must decide, with your doctor, whether the risks are acceptable to you in view of the benefits of treatment. Except where your doctor has prescribed estrogens for use in special cases of cancer of the breast or prostate, you should not use estrogens if you have cancer of the breast or uterus, are pregnant, have undiagnosed abnormal vaginal bleeding, clotting in the legs or lungs, or have had a stroke, heart attack or angina, or clotting in the legs or lungs in the past while you were taking estrogens.
You can use estrogens as safely as possible by understanding that your doctor will require regular physical examinations while you are taking them, will try to discontinue the drug as soon as possible, and will use the smallest dose possible. Be alert for signs of trouble including:
* Abnormal bleeding from the vagina.
* Pains in the calves or chest, sudden shortness of breath, or coughing blood.
* Severe headache, dizziness, faintness, or changes in vision.
* Breast lumps (you should ask your doctor how to examine your own breasts).
* Jaundice (yellowing of the skin).
* Mental depression.
Your doctor has prescribed this drug for you and you alone. Do not give the drug to anyone.