estradiol (Rx)

Frequency Not Defined

Anxiety

Abdominal cramping

Amenorrhea

Bloating

Breakthrough bleeding

Breast enlargement

Breast tenderness

Delayed ejaculation

Depression

Dry mouth

Headache

Hypertension

Impotency

Influenza

Leukorrhea

Melasma

Muscle cramps

Nausea

Nervousness

Peripheral edema

Polydipsia

Pruritus

Rash

Swelling

Skin irritation and redness at application site (transdermal)

Spotting

Syncope

Toothache

Vaginal discomfort, vaginal erosion, vaginal ulceration, adherence of the vaginal ring to the vaginal wall (Estring)

Vomiting

Weight changes

Postmarketing Reports

Nasopharyngitis

Upper respiratory tract infection

Vaginal mycosis

Metrorrhagia

Dysmenorrhea

Ovarian cyst

Vaginal discharge

Gynecomastia

Palpitations

Ventricular extrasystoles

Flatulence

Rash pruritic, urticaria

Retinal vein occlusion

Tremor

Arthralgia

Application site rash

Asthenia

Chest discomfort

Fatigue

Feeling abnormal

Heart rate increased

Insomnia

Malaise

Muscle spasms

Pain in extremity

Contraindications

Documented hypersensitivity

Known anaphylactic reaction or angioedema with topical emulsion

Known protein C, protein S, or antithrombin deficiency or other known thrombophilic disorder

Active or previous breast cancer

Arterial thromboembolic disease (stroke, myocardial infarction [MI]), thrombophlebitis, DVT/PE, thrombogenic valvular disease

Estrogen-dependent neoplasia

Uncontrolled hypertension, diabetes mellitus with vascular involvement, jaundice with previous oral contraceptive (OC) use

Undiagnosed abnormal vaginal bleeding

Liver disease, liver tumors

Cautions

Severe anaphylactic reactions including hives , pruritus, swollen lips-tong-face, respiratory compromise, abdominal pain, vomiting during transdermal treatment reported

Increased risks of stroke and DVT reported with estrogen-alone and estrogen plus progestin therapy; immediately discontinue estrogen with or without progestogen if any of these occur or are suspected

Use caution in patients with family history of breast cancer or DVT/PE; current or previous depression, endometriosis, diabetes mellitus, hypertension, bone mineral density changes, renal or hepatic impairment, bone metabolic disease, systemic lupus erythematosus; conditions exacerbated by fluid retention (eg, migraine, asthma, epilepsy)

Discontinue if the following develop: Jaundice, visual problems (may cause contact lens intolerance), any signs of venous thromboembolism, migraine with unusual severity, significang blood pressure increase, severe depression, increased risk of thromboembolic complications after surgery

Discontinue 4 weeks before major surgery or prolonged immobilization

Patients on warfarin or other oral anticoagulants (increase in anticoagulant dose may be warranted)

Some studies link OC use with increased risk of breast cancer, whereas other studies have not shown any change in risk; risk depends on conditions where naturally high hormone levels persist for long periods, including early-onset menstruation (<12 years), late-onset menopause (>55 years), first child after age 30 years, nulliparity

Increased risk of ovarian cancer reported in women who used hormonal therapy for menopausal symptoms

Increased risk of cervical cancer with OC use; however human papillomavirus (HPV) remains main risk factor for this cancer; evidence suggests long-term (≥5 years) use of OCs may be associated with increased risk

Increased risk of liver cancer with OC use; risk increases with longer duration of use

Hypercalcemia may occur in patients with breast cancer or bone metastases; discontinue therapy if hypercalcemia occurs, and take appropriate measures to reduce serum calcium level

Exogenous estrogens may exacerbate symptoms of angioedema in women with hereditary angioedema; consider whether benefits of estrogen therapy outweigh the risks in such women

Angioedema involving eye/eyelid, face, larynx, pharynx, tongue and extremity (hands, legs, ankles, and fingers) with or without urticaria reported; discontinue therapy permanently if angioedema occurs

Femring is more potent than Estring and should be used with progesterone therapy to prevent endometrial hyperplasia

Caution regarding unintentional exposure in children (see Black Box Warnings)

Clinical surveillance of all women using estrogen-alone or estrogen plus progestogen therapy important; perform adequate diagnostic measures, including directed or random endometrial sampling when indicated to rule out malignancy in postmenopausal women with undiagnosed persistent or recurring abnormal genital bleeding with unknown etiology

Risk of endometrial cancer increases with use of unopposed estrogens (see Black Box Warnings)

An increased risk of invasive breast cancer reported with estrogen plus progestin in WHI substury; estrogens with or without progestins should be prescribed at lowest doses and for shortest duration

There is no evidence that the use of "natural" estrogens results in different endometrial risk profile from use of synthetic estrogens at equivalent estrogen doses

Cases of ring adherence to vaginal or bladder wall, making ring removal difficult, reported in women using vaginal rings and may require surgical removal of device; women should be carefully evaluated for vaginal or bladder wall ulceration or erosion; cases of vaginal erosion and vaginal ulceration reported with other estradiol vaginal rings

Manage appropriately risk factors for arterial vascular disease (e.g., hypertension, diabetes mellitus, tobacco use, hypercholesterolemia, and obesity) and/or venous thromboembolism (e.g., personal history or family history of VTE, obesity, and systemic lupus erythematosus)

A 2 to 4-fold increase in risk of gallbladder disease requiring surgery in postmenopausal women receiving estrogens reported

Retinal vascular thrombosis reported in patients receiving estrogens; discontinue medication pending examination if there is sudden partial or complete loss of vision, or a sudden onset of proptosis, diplopia, or migraine; discontinue therapy if examination reveals papilledema or retinal vascular lesions

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

In patients with pre-existing hypertriglyceridemia, estrogen therapy may be associated with elevations of plasma triglycerides leading to pancreatitis and other complications

Estrogens may be poorly metabolized in patients with impaired liver function; exercise caution in patients with a history of cholestatic jaundice associated with past estrogen use or with pregnancy; in the case of recurrence, discontinue medication

Patients dependent on thyroid hormone replacement therapy who are also receiving estrogens may require increased doses of thyroid replacement therapy; these patients should have their thyroid function monitored in order to maintain their free thyroid hormone levels in an acceptable range

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

Estradiol absorption increased when sunscreen applied 10 minutes before Elestrin application; do not apply sunscreen to application site until at least 25 minutes after application

Pregnancy

Therapy 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 or nongenital birth defects (including cardiac anomalies and limb-reduction defects) following exposure to combined hormonal contraceptives (estrogen and progestins) before conception or during early pregnancy

Lactation

Therapy not indicated for use in females of reproductive potential; estrogens present in human milk and can reduce milk production in breast-feeding females; reduction can occur at any time but is less likely to occur once breast-feeding is well- established

Consider developmental and health benefits of breast-feeding along with mother’s clinical need for therapy and any potential adverse effects on breast-fed child from therapy or from 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

Endogenous estrogen; reduces release of gonadotropin-releasing hormone and luteinizing hormone-releasing hormone from hypothalamus; reduces gonadotropin release from pituitary; increases synthesis of DNA, RNA, and various proteins in target tissues

Absorption

Readily absorbed through GI tract, skin, mucous membrane

Onset: PO, 2-4 weeks; transdermal, 4 hr

Duration: Estradiol valerate, 7-8 days; estradiol cypionate, 11 days

Distribution

Widely distributed

Protein bound: To globulin and albumin

Elimination

Half-life: 1.5-5 hr (IM); 4 hr (transdermal)

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