Menest Warnings, Precautions, Pregnancy, Nursing, Abuse - Estrogens

Menest Warnings, Precautions, Pregnancy, Nursing, Abuse - Estrogens

WARNINGS

1. 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 is now evidence 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 ¹⁸ although a recent long-term followup 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.
2. Gall bladder 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 2 years of use. ²⁴
3. Effects similar to those caused by estrogen-progestagen 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 post-menopausal 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
   
   1. 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 post-surgery 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.
   2. 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 progestagen 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.
   3. 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.
   4. 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 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.
   See footnotes at end of article.

1. General Precautions:
   
   1. A complete medical and family history should be taken prior to the initiation of any estrogen therapy. The pre-treatment and periodic physical examinations should include special reference to blood pressure, breast, abdomen, and pelvic organs, and should include a Papanicolau smear. As a general rule, estrogen should not be prescribed for longer than 1 year without another physical examination being performed.
   2. Fluid retention Because estrogens may cause some degree of fluid retention, conditions which might be influenced by this factor, such as epilepsy, migraine, and cardiac or renal dysfunction, require careful observation.
   3. Certain patients may develop undesirable manifestations of excessive estrogenic stimulation, such as abnormal or excessive uterine bleeding, mastodynia, etc.
   4. Oral contraceptives appear to be associated with an increased incidence of mental depression. ²⁴ Although it is not clear whether this is due to the estrogenic or progestagenic component of the contraceptive, patients with a history of depression should be carefully observed.
   5. Pre-existing uterine leiomyomata may increase in size during estrogen use.
   6. The pathologist should be advised of estrogen therapy when relevant specimens are submitted.
   7. 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.
   8. Estrogens may be poorly metabolized in patients with impaired liver function and they should be administered with caution in such patients.
   9. 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.
   10. Because of the effects of estrogens on epiphyseal closure, they should be used judiciously in young patients in whom bone growth is not complete.
   11. 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 endometrium suggest that 10 to 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 progestin in estrogen replacement regimens. The potential risks include adverse effects on carbohydrate and lipid metabolism. The choice of progestin and dosage may be important in minimizing these adverse effects.
   12. 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:
       
       1. Increased sulfobromophthalein retention.
       2. Increased prothrombin and factors VII, VIII, IX, and X; decreased antithrombin 3; increased norepinephrine-induced platelet aggregability.
       3. 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.
       4. Impaired glucose tolerance.
       5. Decreased pregnanediol excretion.
       6. Reduced response to metyrapone test.
       7. Reduced serum folate concentration.
       8. Increased serum triglyceride and phospholipid concentration.
2. Information for patients: See text which appears after PHYSICIAN REFERENCES.
3. Pregnancy Category X See Contraindications and Boxed Warning .
4. 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.