Other clinical uses of estrogens and progestins include the treatment of dysfunctional uterine bleeding, dys-menorrhea, endometriosis, and rarely, metastatic pros-tate cancer.
Administration of estrogen alone or estrogen–progestin combinations multiplies by 1.2 to 1.8 the relative risk of breast cancer in postmenopausal women. The risk is slightly greater in women taking estrogen–progestin (conjugated equine estrogens plus medroxyproges-terone acetate) compared with women taking estrogen alone (conjugated equine estrogens). In addition, the risk is greater for lean women (low body mass index) with either therapy. Thus, the ability of progestins to protect the endometrium from cancer risk is not ob-served in breast tissue. Oral contraceptive use in younger women does not seem to be associated with an increased breast cancer risk.
Oral contraceptive use lessens the incidence of ovarian cancer.
Hepatocellular carcinoma and benign hepatomas are rare complications of oral contraceptive and tamoxifen use.
Estrogen replacement therapy is associated with an in-creased risk of thromboembolic disease, and alternative therapies for osteoporosis and cardiovascular protec-tion are recommended for individuals with prior throm-boembolic episodes. The problems generally are more severe and/or more frequent when either of the syn-thetic estrogens, ethinyl estradiol or mestranol, is used. These preparations alter liver function more signifi-cantly than do the natural estrogens, such as the sulfate conjugates or esterified estrogens. Alterations in the synthesis of specific liver proteins, such as coagulation factors and fibrinogen, are implicated in the formation of thromboembolisms. Conjugated estrogens, tamox-ifen, clomiphene and raloxifene also increase the fre-quency of thromboembolic disease.
Current estimates are that oral contraceptive use doubles to triples the overall risk of thromboembolic disease. The increased use in recent years of oral con-traceptives with lower estrogen content probably con-tributes to the decreased risk. However, the risk is greater in women who smoke, who are over age 35, or who are diabetic.
Mild hypertension and fluid retention frequently oc-cur in oral contraceptive users. Systolic blood pressure is elevated 5 to 6 mm Hg; diastolic blood pressure in-creases are on the order of 1 to 2 mm Hg. Hypertension is not commonly a problem in postmenopausal women receiving conjugated estrogens.
A 0.5% incidence of migraines has been reported among users of oral contraceptives. Migraine headaches may be a warning signal for an oncoming stroke, and immediate discontinuation of oral contraceptive use is recommended.
Diethylstilbestrol (DES) was once given to prevent spontaneous abortion, but it no longer has such a med-ical indication. There is a 0.01 to 0.1% incidence of a rare vaginal and cervical clear cell adenocarcinoma among the daughters of mothers who received DES during their first trimester of pregnancy. An increased cancer incidence in male offspring of mothers who had received DES has also been noted.
Progestins may be teratogenic during the first trimester of pregnancy. Therefore, if pregnancy is sus-pected, oral contraceptive use should not be initiated or use should be stopped promptly.
There is some delay in the return of fertility after dis-continuation of oral contraceptive use. Gonadotropin profiles should be normal 3 months after combination oral contraceptive use is stopped. The incidence of pro-longed amenorrhea extending beyond 6 months is 2 to 3%. This reaction is especially a problem with the use of progestin-only minipills.
The use of oral contraceptives may interfere with lacta-tion. In addition, the hormones may be present in the mother’s milk, hence be taken in by the nursing child. If breast feeding is planned, the use of oral contraceptives should be discontinued until after weaning.
There is a 2.5-fold increased incidence of gallbladder disease in postmenopausal women receiving estrogens. This occurrence may be related to changes in plasma lipid metabolism.
Estrogen usage is associated with a mild decrease in glucose tolerance. Estrogens do not cause diabetes, but their concurrent use in the diabetic patient may neces-sitate adjustment in insulin dosage.