s, 18 similar to the 2-fold increase previously noted in users of oral contraceptives. 19-24a in the case of oral contraceptives the increased risk appeared after two years of use. 24 3. 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. 20-23 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. 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, 18-36 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 (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 37 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. 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. 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 41 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. 4. 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-alkyl androgens 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.

estrogens are similar to those of endogenous estrogens. they are soluble in water and are well absorbed from the gastrointestinal tract. in responsive tissues (female genital organs, breasts, hypothalamus, pituitary) estrogens enter the cell and are transported into the nucleus. as a result of estrogen action, specific rna and protein synthesis occurs. estrogen pharmacokinetics metabolism and inactivation occur primarily in the liver. some estrogens are excreted into the bile; however they are reabsorbed from the intestine and returned to the liver through the portal venous system. water soluble esterified estrogens are strongly acidic and are ionized in body fluids, which favor excretion through the kidneys since tubular reabsorption is minimal. androgens endogenous androgens are responsible for the normal growth and development of the male sex organs and for maintenance of secondary sex characteristics. these effects include the growth and maturation of prostate, seminal vesicles, penis, and scrotum; the development of male hair distribution, such as beard, pubic, chest and axillary hair, laryngeal enlargement, vocal cord thickening, alterations in body musculature, and fat distribution. drugs in this class also cause retention of nitrogen, sodium, potassium, phosphorus, and decreased urinary excretion of calcium. androgens have been reported to increase protein anabolism and decrease protein catabolism. nitrogen balance is improved only when there is sufficient intake of calories and protein. androgens are responsible for the growth spurt of adolescence and for the eventual termination of linear growth centers. in children, exogenous androgens accelerate linear growth rates, but may cause a disproportionate advancement in bone maturation. use over long periods may result in fusion of the epiphyseal growth centers and termination of growth process. androgens have been reported to stimulate the production of red blood cells by enhancing the production of erythropoietic stimulating factor. androgen pharmacokinetics testosterone given orally is metabolized by the gut and 44 percent is cleared by the liver in the first pass. oral doses as high as 400 mg per day are needed to achieve clinically effective blood levels for full replacement therapy. the synthetic androgens (methyltestosterone and fluoxymesterone) are less extensively metabolized by the liver and have longer half-lives. they are more suitable than testosterone for oral administration. testosterone in plasma is 98 percent bound to a specific testosterone estradiol binding globulin, and about 2 percent is free. generally, the amount of this sex-hormone binding globulin in the plasma will determine the distribution of testosterone between free and bound forms, and the free testosterone concentration will determine its half-life. about 90 percent of a dose of testosterone is excreted in the urine as glucuronic and sulfuric acid conjugates of testosterone and its metabolites; about 6 percent of a dose is excreted in the feces, mostly in the unconjugated form. inactivation of testosterone occurs primarily in the liver. testosterone is metabolized to various 17-keto steroids through two different pathways. there are considerable variations of the half-life of testosterone as reported in the literature, ranging from 10 to 100 minutes. in many tissues the activity of testosterone appears to depend on reduction to dihydrotestosterone, which binds to cytosol receptor proteins. the steroid-receptor complex is transported to the nucleus where it initiates transcription events and cellular changes related to androgen action.