Action And Clinical Pharmacology: Estrogens are secreted mainly by the gonads and, to a very small amount, by the adrenals. In addition, they are formed, to an important degree, from peripheral conversion of adrenal and gonadal androgens to estrogens. They circulate in both unconjugated and conjugated forms in the blood, with the unconjugated estrogens, either free or bound to proteins, mainly albumin, or to the specific sex-hormone binding globulin (SHBG) which shows a great affinity for estradiol.
Estrogens are metabolized mainly in the liver, with the metabolites being conjugated with glucuronic acid or sulfuric acid and even double conjugates such as estriol-3-sulfate-16a-glucuronide are formed. About 1/3 to 1/2 of the circulating estrogens are secreted in the bile and of this fraction 20% is reabsorbed after hydrolysis in the intestinal tract. The exact site of the hydrolysis is not known, but it probably takes place in the intestinal lumen and is catalyzed by enzymes secreted into the intestinal tract or present in the microflora. Estradiol is the most potent of the known naturally occurring estrogens in stimulating the growth of the reproductive tissues. Estradiol promotes uterine growth in the rat without undergoing chemical transformation and responsive tissues, such as the uterus and vagina, show a characteristic affinity for estradiol.
When administered to humans about 65% of the dose is excreted in the urine, almost entirely in the water soluble form as b-glucuronides or sulfate esters. Estrone, estradiol and estriol account for about 1/2 of the excreted products. A number of steroids with 3 oxygen functions have been identified such as 16-epiestriol, 16-ketoestradiol, 16-hydroxyestrone and 2-methoxyestrone with estradiol being a precursor to these compounds.
Estradiol is the most potent physiologic estrogen and, in fact, is the major estrogenic hormone secreted by the human. Estradiol controls the development and maintenance of the female sex organs, the secondary sex characteristics and the mammary glands as well as certain functions of the human uterus and accessory organs, particularly the proliferation of the endometrium, the development of the decidua, and the cyclic changes in the cervix and vagina. The production of estradiol by the ovaries is under the control of pituitary gonadotropins, follicle stimulating hormone (FSH) and luteinizing hormone (LH). In menopausal women, the depletion of ovarian follicles leads to lower plasma estradiol and elevated plasma FSH and LH.
Estrogen deficiency is manifested by hot flushes, sweating, insomnia, paresthesia, irritability, and urogenital atrophy. As replacement therapy in estrogen deficiency states (such as the menopause), low doses of estradiol in cyclic regimens have been found to relieve such deficiency.
Estrogen deficiency is the main cause of postmenopausal bone loss and contributes to age-associated losses leading to osteoporosis. Numerous clinical studies have demonstrated that estrogen therapy prevents bone loss and reduces the incidence of vertebral, hip, and Colles’ fractures.
Although the mechanism of action of estrogen on bone metabolism is still not completely elucidated, estrogens have been shown to have several effects: increase in renal tubular absorption of calcium, thus reducing urinary calcium; decrease in the sensitivity of bone to the parathyroid hormone (PTH); increase in the intestinal absorption of calcium and increase in circulating levels of active 1-25-dihydroxyvitamin D. Recent research has shown that osteoblasts also possess receptors for estrogens.
Indications And Clinical Uses: For the symptomatic relief of menopausal symptoms. Estradiol-17b may also contribute to the prevention of osteoporosis in naturally occurring or surgically induced estrogen-deficiency states when combined with other important therapeutics such as diet, calcium and exercises. In patients with intact uteruses, estradiol-17b should always be supplemented by sequential administration of progestogen.
Contra-Indications: Should not be administered to patients with any of the following conditions: active hepatic dysfunction or disease especially of the obstructive type, a history of breast or endometrial cancer except in special circumstances, endometrial hyperplasia, known or suspected estrogen-dependent neoplasia, known or suspected pregnancy, undiagnosed vaginal bleeding, a history of cerebrovascular accident, coronary thrombosis, or in the presence of classical migraine, active thrombophlebitis or thromboembolic disorders, partial or complete loss of vision or diplopia, from ophthalmic vascular disease, a history of thrombophlebitis, thrombosis or thromboembolic disorders associated with previous estrogen use, endometriosis and leiomyoma of the uterus, lactation.
Manufacturers’ Warnings In Clinical States: Malignant Neoplasm: 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 is now evidence that unopposed estrogens increase the risk of carcinoma of the endometrium in humans.
Three independent case control studies have shown an increased risk of endometrial cancer in postmenopausal women exposed to unopposed exogenous estrogens for prolonged periods. This risk was independent of the other known risk factors for endometrial cancer. The 3 case control studies reported that the risk of endometrial cancer in estrogen users was about 4.5 to 13.9 times greater than in nonusers. The risk appears to depend on both duration of treatment and on estrogen dose. 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, sequential administration of progestogen is indicated for women with intact uteruses.
Studies of the addition of a progestogen for 7 or more days of a cycle of estrogen administration have reported a lowered incidence of endometrial hyperplasia. Morphological and biochemical studies of endometrium suggest that 10 to 13 days of progestogen 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 progestogen in estrogen replacement regimens. The potential risks include adverse effects on carbohydrate and lipid metabolism. The choice of progestogen and dosage may be important in minimizing these adverse effects.
Close clinical surveillance of all women taking estrogens is important. In all cases of undiagnosed abdominal vaginal bleeding, adequate diagnostic measures should be undertaken to rule out malignancy.
At the present time there is no satisfactory evidence that estrogens given to postmenopausal women increase the risk of cancer of the breast. 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.
Thromboembolic Disease: Although the estrogen content of oral contraceptive therapy has been associated with an increased risk of various thromboembolic, thrombotic and vascular disease, to date no such increased risk in postmenopausal users of estrogens has been detected. Nevertheless, the physician should be alert to earliest manifestations of thrombotic disorders (thrombophlebitis, retinal thrombosis, cerebral embolism and pulmonary embolism). If these occur or are suspected, estrogen therapy should be discontinued immediately.
Precautions: Before estradiol-17b is administered, the patient should have a complete physical examination including a blood pressure determination. Breasts and pelvic organs should be examined and a Papanicolaou smear and endometrial biopsy should be taken. The first follow-up visit should be done 3 months after estradiol-17b tablets are prescribed. Thereafter, examinations should be performed at least once a year or more frequently if indicated. Baseline tests should include blood sugar, calcium, triglyceride, cholesterol and liver function tests.
If any surgical procedures are performed, the pathologist should be advised of the patient’s therapy when specimens are sent for examination. If feasible, estrogens should also be discontinued at least 4 weeks before surgery which may be associated with an increased risk of thromboembolism, or during periods of prolonged immobilization. Liver function tests should be made periodically in subjects who have, or are suspected of having, hepatic disease.
Patients who develop visual disturbances, classical migraine, transient aphasia, paralysis, or loss of consciousness should discontinue medication.
Patients taking estrogens may experience corneal edema, that may cause visual disturbances and/or changes in tolerance to contact lenses, especially the rigid type of contact lenses. Soft contact lenses usually do not cause disturbances. If visual changes or alterations in tolerance to contact lenses occur, temporary or permament cessation of wear is advised.
Patients with essential hypertension whose blood pressure is well controlled may be given estradiol-17b tablets but only under close supervision. If a significant elevation of blood pressure in previously normotensive or hypertensive subjects occurs at any time during the administration of the drug, cessation of medication is necessary.
Development of sudden enlargement, pain, or tenderness of uterine fibroids requires discontinuation of medication. Pre-existing uterine leiomyoma may increase in size during estrogen use.
Estrogens may cause fluid retention. Where this may be undesirable such as in cardiac or renal dysfunction, epilepsy, asthma or migraine, particular caution is indicated.
Elevation of blood pressure in previously normotensive or hypertensive patients necessitates cessation of medication.
Diabetic patients or those with a predisposition to diabetes should be observed closely to detect any alterations in carbohydrate metabolism.
In patients with metastatic carcinoma and hypercalcemia, estrogen medication should be used with caution. It should also be used with caution in patients with metabolic disease and in patients with renal insufficiency.
When liver or endocrine functions tests are indicated, the results should not be considered reliable unless therapy has been discontinued for 2 to 4 months.
Certain patients may develop undesirable manifestations of excessive estrogenic stimulation, such as abnormal or excessive uterine bleeding and mastodynia.
Prolonged administration of unopposed estrogen therapy has been reported to increase the risk of endometrial hyperplasia in some patients.
A recent study has reported a 2- to 3-fold increase in the risk of surgically confirmed gallbladder disease in women receiving postmenopausal estrogens similar to the 2-fold increase previously noted in users of oral contraceptives.
Estrace 2 mg tablets contain tartrazine which may cause allergic-type reactions in susceptible individuals.
Benign hepatic adenomas have been reported with the use of combined estrogen and progestogen oral contraceptives. Although 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, abnormal 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.
In patients with 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, with the use of estrogens, the drug should be discontinued while the cause is investigated.
Estrogens may diminish the effectiveness of anticoagulants and antidiabetic agents.
Preparations inducing liver enzymes, e.g., barbiturates, hydantoins, carbamazepine, meprobamate, phenylbutazone or rifampicin may interfere with the activity of orally administered estrogens.
The results of certain endocrine and liver function tests may be affected by estrogen-containing oral contraceptives. The following changes have been observed with large doses of oral estrogen: increased sulfobromophthalein retention; increased prothrombin time; increased factors VII, VIII, IX, X; decreased antithrombin III; following administration of estradiol-17b tablets for 28 days no effect on antithrombin III levels was seen; increased norepinephrine-induced platelet aggregability; increased thyroxine-binding globulin (TBG), leading to increased circulating total thyroid hormone (T4) as measured by column or radioimmunoassay; free T3 resin unptake is decreased, reflecting the elevated TBG, free T4 concentration is unaltered; TBG was not affected in clinical trials with estradiol-17b; reduced response to the metyrapone test; reduced serum folate concentration; increased serum triglyceride and phospholipid concentration.
The results of these tests should not be considered reliable unless therapy has been discontinued for 2 to 4 months. The pathologist should be informed that the patient is receiving estrogen therapy when relevant specimens are submitted.
Adverse Reactions: The following adverse reactions have been reported with the use of estrogens.
Genitourinary: breakthrough bleeding, spotting and withdrawal bleeding, dysmenorrhea, increased cervical mucus, endometrial hyperplasia, reactivation of endometriosis, sodium and water retention, premenstrual like syndrome, increase in size of uterine leiomyoma, vaginal candidiasis, and change in cervical eversion and in degree of cervical secretion.
Breast: breast swelling, tenderness and secretion.
Gastrointestinal: nausea, anorexia, vomiting, abdominal cramps, bloating and cholestatic jaundice.
Skin: loss of scalp hair, allergic reactions and rashes, hemorrhagic eruption, itching, erythema nodosum, erythema multiforme, pigmentation of skin, melasma.
CNS: headaches, mental depression, increase or decrease in libido, nervousness, dizziness, fatigue, and irritability.
Cardiovascular: change in blood pressure in susceptible individuals and aggravation of migraine headaches.
Thromboembolic Effects: A statistically significant association has been demonstrated between the use of estrogen-progestin preparations and the following serious reactions: thrombophlebitis, pulmonary embolism and cerebral thrombosis. Although available evidence is suggestive of an association, such a relationship has been neither confirmed nor refuted for the following serious reactions: coronary thrombosis and neuro-ocular lesions (e.g., retinal thrombosis and optic neuritis). Altered coagulation tests (increase in prothrombin time and Factors VII, VIII, IX, X).
Miscellaneous: increase or decrease in weight, reduced carbohydrate tolerance, precipitation or aggravation of porphyria cutanea tarda in predisposed individuals, edema and increased blood sugar levels.
Symptoms And Treatment Of Overdose: Symptoms and Treatment: Numerous reports of ingestion of large doses of estrogen-containing oral contraceptives by young children indicate that serious ill effects do not occur. Overdosage of estrogen may cause nausea, and withdrawal bleeding may occur in females. Remove ingested drug by gastric lavage and give symptomatic treatment. tag_DosageDosage
Dosage And Administration: The lowest dose of estrogen required to prevent menopausal symptoms and to prevent development of osteoporosis should be used.
In general, estrogen is usually administered cyclically for the first 21 to 25 days of each month. In patients with intact uteruses a progestin should be sequentially administered for the last 12 to 14 days of estrogen administration in order to prevent development of endometrial hyperplasia as a result of estrogen stimulation.
In hysterectomized patients estrogen alone should be given continuously.
Menopausal Symptoms: Treatment of menopausal symptoms is usually initiated with a 1 mg tablet/day. Thereafter, the dosage should be adjusted to the needs of the individual. Attempts to taper or discontinue the medication should be made at 3- to 6-month intervals.
For Prevention of Osteoporosis: Prophylactic therapy with estradiol-17b to prevent postmenopausal bone loss should be initiated with 0.5 mg/day as soon as possible after menopause. The dose may be titrated upward and downward based on the patient’s clinical status and plasma estradiol levels. Ideally, plasma estradiol levels should be maintained around 50 pg/mL.
Availability And Storage: 0.5 mg: Each white, scored, compressed tablet contains: estradiol-17b micronized 0.5 mg. Nonmedicinal ingredients: acacia, dibasic calcium phosphate, cornstarch, lactose, magnesium stearate, silicon dioxide and talc.
1 mg: Each lavender, scored, compressed tablet contains: estradiol-17b micronized 1 mg. Nonmedicinal ingredients: acacia, dibasic calcium phosphate, cornstarch, D&C red No. 27 aluminum lake, FD&C blue No. 1 aluminum lake, lactose, magnesium stearate, silicon dioxide and talc. Bottles of 100.
2 mg: Each turquoise, scored, compressed tablet contains: estradiol-17b micronized 2 mg. Nonmedicinal ingredients: acacia, dibasic calcium phosphate, cornstarch, FD&C blue No. 1 and yellow No. 5 aluminum lake, lactose, magnesium stearate, silicon dioxide and talc. Bottles of 100.
ESTRACE® Roberts Estradiol-17b (micronized) Estrogen