Common side effects associated with estrogen use in-clude nausea, weight gain, and edema. Progestin use is associated with weight gain and mild depression. Tolerance to these effects usually develops over several months.
Low-dose estrogen combination oral contraceptives result in irregular midcycle bleeding episodes in some patients. High-progestin preparations, especially the progestin-only minipill, can cause irregular bleeding and prolonged amenorrhea.
Endometrial hyperplasia frequently develops in premenopausal and postmenopausal women receiving estrogens alone. This reaction is generally regarded to be a premalignant state, because individuals reported to have endometrial hyperplasia later have a higher than normal incidence of endometrial carcinoma. Administration of estrogens only is associated with a 1.7-to 15-fold increased risk of endometrial carcinoma. The relative risk rises with increased dosage and duration of estrogen use. Women receiving progestins 10 days per month during estrogen therapy generally do not de-velop endometrial carcinoma. Women taking combina-tion oral contraceptives have slightly less risk of devel-oping endometrial carcinoma than nonusers. This may be related to the constant exposure of the endometrium to both progestin and estrogen.
Ovarian enlargement is the most common side effect of clomiphene use. The occurrence of multiple births fol-lowing ovulation induction with clomiphene is 4 to 9%; 90% of these multiple births are twins. Since clo-miphene is teratogenic, therapy should be discontinued if there is a chance that conception has occurred. Rarely, irreversible ocular toxicities have been reported with clomiphene use.
Nausea, vomiting, and hot flashes may accompany tamoxifen administration. Tamoxifen may cause a tran-sient flare of tumor growth and increased pain due to bone metastases. These reactions are thought to be due to an initial estrogenic action of this drug. Mild or transient depression of platelet counts often occurs in pa-tients receiving tamoxifen. At very high doses, generally no longer used in cancer treatment, ocular toxicity has been reported. There is a slight risk of hepatocellular carcinoma in humans receiving long-term (5 years) ta-moxifen therapy as well as a slightly (0.4%) elevated in-cidence of endometrial cancer.
Raloxifene and clomiphene use is associated with an increased frequency of vasomotor disturbances (hot flashes) and thromboembolism formation.
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