estrogens conjugated synthetic (Rx)

>10%

Abdominal pain

Back pain

Bloating

Breast enlargement

Breast tenderness

Headache

Nausea

Peripheral edema

Vomiting

Frequency Not Defined

Amenorrhea

Breakthrough bleeding

Corneal curvation change

Depression

Diarrhea

Melasma

Spotting

Weight changes

Postmarketing reports

Abdominal discomfort, abdominal distension

Muscle spasms

Dizziness

Insomnia

Breast pain

Alopecia

Rash

Urticaria

Deep vein thrombosis, thrombosis

Contraindications

Documented hypersensitivity; active or history of breast cancer, arterial thromboembolic disease (stroke, MI), thrombophlebitis, DVT/PE, thrombogenic valvular disease, protein C, protein S, or antithrombin deficiency, or other known thrombophilic disorders

Known anaphylactic reaction or angioedema to drug or components

Uncontrolled hypertension, diabetes mellitus with vascular involvement

Jaundice with prior oral contraceptive use

History of migraine with aura

Estrogen-dependent neoplasia

Undiagnosed abnormal vaginal bleeding

Liver disease, liver tumors

Known or suspected pregnancy

Cautions

Caution in history of hyperlipidemias, HTN, hepatic/renal impairment, uterine leiomyomata, porphyria, patients with defects of lipoprotein metabolism, hypertriglyceridemia, ovarian cancer, SLE, and the elderly

Discontinue if the following develop jaundice, any signs of VTE, migraine with unusual severity, significant blood pressure increase, severe depression, increased risk of thromboembolic complications after surgery

Discontinue 4 weeks before major surgery or prolonged immobilization

Do not use with conditions that predispose to hyperkalemia

There are, possible risks that may be associated with use of progestins with estrogens compared to estrogen-alone regimens, including a possible increased risk of breast cancer, adverse effects on lipoprotein metabolism (e.g., lowering HDL, raising LDL), and impairment of glucose tolerance

Use caution in patients with asthma, diabetes mellitus, epilepsy, migraine, porphyria, systemic lupus erythematosus, and hepatic hemangiomas; exacerbations may occur

Increased risk of ovarian and endometrial cancer

Long-term postmenopausal estrogen treatment has been associated with increased risk of MI, stroke, DVT/PE, and dementia

Patients on warfarin/oral anticoagulants: Estrogens increase thromboembolic risk; increase in anticoagulant dose may be warranted

Not approved for osteoporosis prevention

Exogenous estrogens may exacerbate symptoms of angioedema in women with hereditary angioedema

Estrogens increase the risk of gallbladder disease

Estrogen administration reported to lead to severe hypercalcemia in women with breast cancer and bone metastases; if hypercalcemia occurs, discontinue use and take appropriate measures to reduce serum calcium level

Estrogens may cause some degree of fluid retention; monitor any woman with a condition(s) that might predispose her to fluid retention, such as cardiac or renal impairment; discontinue estrogen-alone therapy, with evidence of medically concerning fluid retention

Retinal vascular thrombosis may occur; discontinue therapy, if there is sudden partial or complete loss of vision, or a sudden onset of proptosis, diplopia, or migraine, pending visual examination; permanently discontinue if examination reveals papilledema or renal vascular lesions

Consider discontinuation of therapy if pancreatitis occurs; in women with pre-existing hypertriglyceridemia, estrogen therapy may be associated with elevations of plasma triglycerides leading to pancreatitis

Monitor thyroid function in order to maintain free thyroid hormone levels in an acceptable range; women dependent on thyroid hormone replacement therapy who are also receiving estrogens may require increased doses of their thyroid replacement therapy; monitor thyroid function in women during treatment to maintain their free thyroid hormone levels in an acceptable range

Use with caution in women with hypoparathyroidism as estrogen-induced hypocalcemia may occur; consider whether benefits of estrogen therapy, outweigh risks

A few cases of malignant transformation of residual endometrial implants reported in women treated post-hysterectomy with estrogen-alone therapy; consider addition of progestin in women known to have residual endometriosis post-hysterectomy

Pregnancy

Drug is not indicated for use in pregnancy; there are no data with use in pregnant women; however, epidemiologic studies and meta-analyses have not found an increased risk of genital and nongenital birth defects (including cardiac anomalies or limb- reduction defects) following exposure to combined hormonal contraceptives (estrogen and progestins) before conception or during early pregnancy

Lactation

Estrogens are present in human milk and can reduce milk production in breastfeeding women; reduction is less likely to occur once breastfeeding is well- established; developmental and health benefits of breastfeeding should be considered along with mother’s clinical need for therapy and any potential adverse effects on breastfed child or underlying maternal condition

Pregnancy Categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

Mechanism of Action

Replaces natural estrogen. Important for development and maintenance of the female reproductive system and secondary sexual characteristics.

Derived from plant sources; B but not A contains delta 8,9-dehydroestrone sulfate

Pharmacokinetics

Onset: 2-4 wk (menopause; PO)

Peak plasma time: 8 hr (PO)

Bioavailability: Readily absorbed from GI tract

Protein Bound: 80%

Metabolism: In liver to inactive sulfates and glucuronides which are then excreted in urine and bile

Metabolites: Estradiol, estrone, estriol

Excretion: Mainly in urine as conjugates with small amount of unchanged drug, most estrogens are also excreted in bile and undergo enterohepatic recycling