TABLETS

ESTROGENS HAVE BEEN REPORTED TO INCREASE THE RISK OF ENDOMETRIAL CARCINOMA IN POSTMENOPAUSAL WOMEN. Close clinical surveillance of all women taking estrogens is important. Adequate diagnostic measures, including endometrial sampling when indicated, should be undertaken to rule out malignancy in all cases of undiagnosed persistent or recurring abnormal vaginal bleeding. There is currently no evidence that "natural" estrogens are more or less hazardous than "synthetic" estrogens at equiestrogenic doses.

ESTROGENS SHOULD NOT BE USED DURING PREGNANCY. Estrogen therapy during pregnancy is associated with an increased risk of congenital defects in the reproductive organs of the male and female fetus, an increased risk of vaginal adenosis, squamous cell dysplasia of the uterine cervix, and vaginal cancer in the female later in life. The 1985 DES Task Force concluded that women who used DES during their pregnancies may subsequently experience an increased risk of breast cancer. However, a causal relationship is still unproven, and the observed level of risk is similar to that for a number of other breast-cancer risk factors. There is no indication for estrogen therapy during pregnancy. Estrogens are ineffective for the prevention or treatment of threatened or habitual abortion.

INJECTION AND VAGINAL CREAM

ESTROGENS HAVE BEEN REPORTED TO INCREASE THE RISK OF ENDOMETRIAL CARCINOMA. Three independent, case-controlled studies have reported an increased risk of endometrial cancer in postmenopausal women exposed to exogenous estrogens for more than one year.^1-3 This risk was independent of the other known risk factors for endometrial cancer. These studies are further supported by the finding that incidence rates of endometrial cancer have increased sharply since 1969 in eight different areas of the United States with population-based cancer-reporting systems, an increase which may be related to the rapidly expanding use of estrogens during the last decade.⁴ The three case-controlled 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 treatment1 and on estrogen dose.³ 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, the patient should be reassessed, on at least a semiannual basis, to determine the need for continued therapy. Although the evidence must be considered preliminary, one study suggests that cyclic administration of low doses of estrogen may carry less risk than continuous administration.³ It therefore appears prudent to utilize such a regimen. Close clinical surveillance of all women taking estrogens is important. In all cases of undiagnosed persistent or recurring abnormal vaginal bleeding, adequate diagnostic measures should be undertaken to rule out malignancy. There is no evidence at present that "natural" estrogens are more or less hazardous than "synthetic" estrogens at equiestrogenic doses.

ESTROGENS SHOULD NOT BE USED DURING PREGNANCY. The use of female sex hormones, both estrogens and progestogens, during early pregnancy may seriously damage the offspring. It has been shown that females exposed in utero to diethylstilbestrol, a nonsteroidal estrogen, have an increased risk of developing, in later life, a form of vaginal or cervical cancer that is ordinarily extremely rare.^5,6 This risk has been estimated as not greater than 4 per 1,000 exposures.⁷ Furthermore, a high percentage of such exposed women (from 30% to 90%) have been found to have vaginal adenosis,8-12 epithelial changes of the vagina and cervix. Although these changes are histologically benign, it is not known whether they are precursors of malignancy. Although similar data are not available with the use of other estrogens, it cannot be presumed they would not induce similar changes. Several reports suggest an association between intrauterine exposure to female sex hormones and congenital anomalies, including congenital heart defects and limb-reduction defects. 13-16 One case-controlled study 16 estimated a 4.7-fold increased risk of limb-reduction defects in infants exposed in utero to sex hormones (oral contraceptives, hormone withdrawal tests for pregnancy, or attempted treatment for threatened abortion). Some of these exposures were very short and involved only a few days of treatment. The data suggest that the risk of limb-reduction defects in exposed fetuses is somewhat less than 1 per 1,000. In the past, female sex hormones have been used during pregnancy in an attempt to treat threatened or habitual abortion. There is considerable evidence that estrogens are ineffective for these indications, and there is no evidence from well-controlled studies that progestogens are effective for these uses. If Premarin (conjugated estrogens) is used during pregnancy, or if the patient becomes pregnant while taking this drug, she should be apprised of the potential risks to the fetus, and the advisability of pregnancy continuation.