Estra Pellets

1. Induction of malignant neoplasma.nLong term continuous administration of natural and synthetic estrogen in certain animal species increases the frequency of carcinomas of the breast, cervix, vagina, and liver. There is new evidence that estrogens increase the risk of carcinoma of the endometrium in humans. (See Boxed Warning.)

At the present ime there is no satisfactory evidencethat estrogens given to postmenopausal women increase the risk of cancer of the breast, 18 althogh a recent long-term followup of a single physician's practice has raised this possibility. 18a Because of the animal data there is a heed for caution, in prescribing estrogens for women with a strong history of breast cancer or who have breast nodules, fibrocystic disease, or abnormal mammograms.

2. Gallbladder disease. A recent study has reported a 2 to 3 -fold increase in the risk of surgically confirmed gall bladder disease in women receiving postmenopausal estrogens 18 similar to the 2 fold increase previously noted in users of oral contraceptives. 19,24 In the case of oral contraceptives the increased risk appeared after two years of use. 24

3. Effects similar to those caused by estrogen-progsten oral contraceptives. There are several serios adverse effects or oral contraceptives, most of which have not, up to now, benn 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 postpartm brast 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 we establish that users of oral contraceptives have an increased risk of various thromboembolicand thrombotic vascular disease, such as thrombophlebitis, pulminary embolism, stroke, and myocardial infarction. 24-31 Cases of retinal thrombosis, mesenteric thrombosis and optic neuritishave been reported in oral contraceptive users. There is evidence that the risk of several of thse adverse reactions is related to the dose of the drug. 32,33 An increase risk of postsurgerythromboembolic complications has also been reported in users of oral contrceptives. 34,35 if feasable, 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 estrogen has not been found, 18,36 this does not rule out that such an increase maymay be present or that sugroups of women having underlyingrisk factors or who are receiving relatively large doses of estrogen may have an increased risk. Therefore estrogens should not be used in persons with active thrombophlebitis or thromboembolic disorders and they should not be used (except in treatent 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 estrogens (5mg conjugated estrogens per day), comparable to those used to treat cancer of the prostat and breast, have been shown in a large prospectiveclinical 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 th thromboembolicand 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 intraabdominal hemorrhage. Such lesions have not yet been reported in association with other estrogenor progesten preparations but should be considered in estrogen users having abdominalpain and tenderness,abdominal mass, or hypovolemic shock. Hepatocellular carcinoma has also been reported in women taking estrogen-containing orarl contraceptives. 39 The relationship of this malignancy to these drugs is not know 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 the use of estrogens in menopause 41 and blood pressure should be monitoredwith 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 on estrogen-containing oral contraceptives. For this reason, diabetic patients should be carefully observed while receiving estrogen.

4. Hypercalcemia. Administration of estrogens may lead to severe hypercalceemia 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.