ESTERIFIED ESTROGENS AND METHYLTESTOSTERONE

- Warnings and Precautions Associated with Estrogens Induction of malignant neoplasms. Long term continuous administration of natural and synthetic estrogens in certain animal species increases this frequency of carcinomas of the breast, cervix, vagina, and liver. There is now evidence that estrogens increase the risk of carcinoma of the endometrium in humans. At the present time there is no satisfactory evidence that estrogens given to postmenopausal women increase the risk of cancer of the breast,18 although a recent long-term follow-up of a single physician's practice has raised this possibility.18a 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,18 similar to the 2-fold increase previously noted in users of oral contraceptives as in the case of oral contraceptives the increased risk appeared after two years of use. Effects similar to those caused by estrogen-progesterone 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 or postpartum breast engorgement 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 and women for postpartum breast engorgement. a. 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. 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 post- surgery 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 (except 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 esterified 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. b. Hepatic adenoma. 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 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. The relationship of this malignancy to these drugs is not known at this time. c. Elevated blood pressure. Increased blood pressure is not uncommon in women using oral contraceptives. There is now a report that this may occur with use of estrogens in the menopause and blood pressure should be monitored with estrogen use, especially if high doses are used. d. Glucose tolerance. A worsening of glucose tolerance has been observed in a significant percentage of patients of estrogen- containing oral contraceptives. For this reason, diabetic patients should be carefully observed while receiving estrogens. 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. Associated with Methyltestosterone In patients with breast cancer, androgen therapy may cause hypercalcemia by stimulating osteolysis. In this case the drug should be discontinued. Prolonged use of high doses of androgens has been associated with the development of peliosis hepatis and hepatic neoplasms including hepatocellular carcinoma. (See PRECAUTIONS – Carcinogenesis ). Peliosis hepatis can be a life-threatening or fatal complication. Cholestatic hepatitis and jaundice occur with 17-alpha-alkylandrogens at a relatively low dose. If cholestatic hepatitis with jaundice appears or if liver function tests become abnormal, the androgen should be discontinued and the etiology should be determined. Drug-induced jaundice is reversible when the medication is discontinued. Edema with or without heart failure may be a serious complication in patients with preexisting cardiac, renal, or hepatic disease. In addition to discontinuation of the drug, diuretic therapy may be required. Precautions Associated with Estrogens A. General Precautions 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 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. Certain patients may develop undesirable manifestations of excessive estrogenic stimulation, such as abnormal or excessive uterine bleeding, mastodynia, etc. Oral contraceptives appear to be associated with an increased incidence of mental depression. 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 they 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 complete. 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: a. Increased sulfobromophthalein retention. b. Increased prothrombin and factors VII, VIII, IX and X; decreased antithrombin 3: increased norepinephrine induced platelet aggregability. c. 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 uptakes is decreased, reflecting the elevated TBG; free T4 concentration is unaltered. d. Impaired glucose tolerance. e. Decreased pregnanediol excretion. f. Reduced response to metyrapone test. g. Reduced serum folate concentration. h. Increased serum triglyceride and phospholipid concentration. B. Pregnancy Category X See CONTRAINDICATIONS . C. 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. Associated with Methyltestosterone A. General Precautions Women should be observed for signs of virilization (deepening of the voice, hirsutism, acne, clitoromegaly, and menstrual irregularities). Discontinuation of drug therapy at the time of evidence of mild virilism is necessary to prevent irreversible virilization. Such virilization is usual following androgen use at high doses. Prolonged dosage of androgen may result in sodium and fluid retention. This may present a problem, especially in patients with compromised cardiac reserve or renal disease. Hypersensitivity may occur rarely. PBI may be decreased in patients taking androgens. Hypercalcemia may occur. If this does occur, the drug should be discontinued. B. Information for the Patient The physician should instruct patients to report any of the following side effects of androgens: Women: Hoarseness, acne, changes in menstrual periods, or more hair on the face. All Patients: Any nausea, vomiting, changes in skin color of ankle swelling. C. Laboratory Tests Women with disseminated breast carcinoma should have frequent determination of urine and serum calcium levels during the course of androgen therapy. Because of the hepatotoxicity associated with the use of 17-alpha-alkylated androgens, liver function tests should be obtained periodically. Hemoglobin and hematocrit should be checked periodically for polycythemia in patients who are receiving high doses of androgens. D. Drug Interactions Anticoagulants C-17 substituted derivatives of testosterone, such as methandrostenolone, have been reported to decrease the anticoagulant requirements of patients receiving oral anticoagulants. Patients receiving oral anticoagulant therapy require close monitoring, especially when androgens are started or stopped. Oxyphenbutazone. Concurrent administration of oxyphenbutazone and androgens may result in elevated serum levels of oxyphenbutazone. Insulin. In diabetic patients the metabolic effects of androgens may decrease blood glucose and insulin requirements. E. Drug/Laboratory Test Interferences Androgens may decrease levels of thyroxine-binding globulin, resulting in decreased T4 serum levels and increased resin uptake of T3 and T4. Free thyroid hormone levels remain unchanged, however, and there is no clinical evidence of thyroid dysfunction. F. Carcinogenesis Animal Data. Testosterone has been tested by subcutaneous injection and implantation in mice and rats. The implant induced cervical-uterine tumours in mice, which metastasized in some cases. There is suggestive evidence that injection of testosterone into some strains of female mice increases their susceptibility to hepatoma. Testosterone is also known to increase the number of tumours and decrease the degree of differentiation of chemically induced carcinomas of the liver in rats. Human Data. There are rare reports of hepatocellular carcinoma in patients receiving long-term therapy with androgens in high doses. Withdrawal of the drugs did not lead to regression of the tumours in all cases. Geriatric Patients treated with androgens may be at an increased risk for the development of prostatic hypertrophy and prostatic carcinoma. G. Pregnancy Teratogenic Effects. Pregnancy Category X (see CONTRAINDICATIONS ). H. Nursing Mothers It is not known whether androgens are 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 androgens, 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.