Estradiol

Pronunciation

U.S. Brand Names

Alora®; Climara®; Delestrogen®; Depo®-Estradiol; Esclim®; Estrace®; Estraderm®; Estrasorb™; Estring®; EstroGel®; Femring™; Femtrace®; Gynodiol®; Menostar™; Vagifem®; Vivelle®; Vivelle-Dot®

Synonyms

Estradiol Acetate; Estradiol Cypionate; Estradiol Hemihydrate; Estradiol Transdermal; Estradiol Valerate

Generic Available

Yes: Oral tablet, patch

Canadian Brand Names

Climara®; Delestrogen®; Depo®-Estradiol; Estrace®; Estraderm®; Estradot®; Estring®; EstroGel®; Oesclim®; Vagifem®; Vivelle®

Use

Treatment of moderate-to-severe vasomotor symptoms associated with menopause; treatment of vulvar and vaginal atrophy; hypoestrogenism (due to hypogonadism, castration, or primary ovarian failure); prostatic cancer (palliation), breast cancer (palliation), osteoporosis (prophylaxis); abnormal uterine bleeding due to hormonal imbalance; postmenopausal urogenital symptoms of the lower urinary tract (urinary urgency, dysuria)

Pregnancy Risk Factor

Pregnancy Implications

Estrogens are not indicated for use during pregnancy or immediately postpartum. Increased risk of fetal reproductive tract disorders and other birth defects have been observed with diethylstilbestrol (DES); do not use during pregnancy.

Lactation

Enters breast milk/use caution

Contraindications

Hypersensitivity to estradiol or any component of the formulation; undiagnosed abnormal vaginal bleeding; history of or current thrombophlebitis or venous thromboembolic disorders (including DVT, PE); active or recent (within 1 year) arterial thromboembolic disease (eg, stroke, MI); carcinoma of the breast, except in appropriately selected patients being treated for metastatic disease; estrogen-dependent tumor; hepatic dysfunction or disease; porphyria; pregnancy

Warnings/Precautions

Cardiovascular-related considerations: Estrogens with or without progestin should not be used to prevent coronary heart disease. Use caution with cardiovascular disease or dysfunction. May increase the risks of hypertension, myocardial infarction (MI), stroke, pulmonary emboli (PE), and deep vein thrombosis; incidence of these effects was shown to be significantly increased in postmenopausal women using conjugated equine estrogens (CEE) in combination with medroxyprogesterone acetate (MPA). Nonfatal MI, PE, and thrombophlebitis have also been reported in males taking high doses of CEE (eg, for prostate cancer). Estrogen compounds are generally associated with lipid effects such as increased HDL-cholesterol and decreased LDL-cholesterol. Triglycerides may also be increased; use with caution in patients with familial defects of lipoprotein metabolism. Whenever possible, estrogens should be discontinued at least 4-6 weeks prior to surgeries associated with an increased risk of thromboembolism or during periods of prolonged immobilization.

Neurological considerations: The risk of dementia may be increased in postmenopausal women; increased incidence was observed in women 65 years of age taking CEE in combination with MPA.

Cancer-related considerations: Unopposed estrogens may increase the risk of endometrial carcinoma in postmenopausal women. Estrogens may increase the risk of breast cancer. An increased risk of invasive breast cancer was observed in postmenopausal women using CEE in combination with MPA; a smaller increase in risk was seen with estrogen therapy alone in observational studies. An increase in abnormal mammograms has also been reported with estrogen and progestin therapy. Estrogen use may lead to severe hypercalcemia in patients with breast cancer and bone metastases; discontinue estrogen if hypercalcemia occurs.

Estrogens may cause retinal vascular thrombosis; discontinue permanently if papilledema or retinal vascular lesions are observed on examination. Use with caution in patients with diseases which may be exacerbated by fluid retention, including asthma, epilepsy, migraine, diabetes or renal dysfunction. Use with caution in patients with a history of severe hypocalcemia, SLE, hepatic hemangiomas, endometriosis, and gallbladder disease. Use caution with history of cholestatic jaundice associated with past estrogen use or pregnancy. Safety and efficacy in pediatric patients have not been established. Prior to puberty, estrogens may cause premature closure of the epiphyses, premature breast development in girls or gynecomastia in boys. Vaginal bleeding and vaginal cornification may also be induced in girls.

Before prescribing estrogen therapy to postmenopausal women, the risks and benefits must be weighed for each patient. Women should be informed of these risks and benefits, as well as possible effects of progestin when added to estrogen therapy. Estrogens with or without progestin should be used for shortest duration possible consistent with treatment goals. Conduct periodic risk:benefit assessments.

When used solely for prevention of osteoporosis in women at significant risk, nonestrogen treatment options should be considered. When used solely for the treatment of vulvar and vaginal atrophy, topical vaginal products should be considered. Use caution applying topical products to severely atrophic vaginal mucosa. Absorption of topical emulsion is increased by application of sunscreen; do not apply both products within close proximity of each other. Application of gel formulation with sunscreen has not been evaluated. Transdermal patch may contain conducting metal (eg, aluminum); remove patch prior to MRI.

Adverse Reactions

Frequency not defined.

Cardiovascular: Edema, hypertension, MI, venous thromboembolism

Central nervous system: Anxiety, dizziness, epilepsy exacerbation, headache, irritability, mental depression, migraine, mood disturbances, nervousness

Dermatologic: Chloasma, erythema multiforme, erythema nodosum, hemorrhagic eruption, hirsutism, loss of scalp hair, melasma, rash, pruritus

Endocrine & metabolic: Breast enlargement, breast tenderness, libido (changes in), increased thyroid-binding globulin, increased total thyroid hormone (T4), increased serum triglycerides/phospholipids, increased HDL-cholesterol, decreased LDL-cholesterol, impaired glucose tolerance, hypercalcemia

Gastrointestinal: Abdominal cramps, abdominal pain, bloating, cholecystitis, cholelithiasis, diarrhea, flatulence, gallbladder disease, nausea, pancreatitis, vomiting, weight gain/loss

Genitourinary: Alterations in frequency and flow of menses, changes in cervical secretions, endometrial cancer, increased size of uterine leiomyomata, Pap smear suspicious, vaginal candidiasis

Vaginal: Trauma from applicator insertion may occur in women with severely atrophic vaginal mucosa

Hematologic: Aggravation of porphyria, antithrombin III and antifactor Xa decreased, levels of fibrinogen increased, platelet aggregability increased and platelet count; increased prothrombin and factors VII, VIII, IX, X

Hepatic: Cholestatic jaundice

Local: Transdermal patches: Burning, erythema, irritation, thrombophlebitis

Neuromuscular & skeletal: Chorea, back pain

Ocular: Intolerance to contact lenses, steeping of corneal curvature

Respiratory: Pulmonary thromboembolism

Miscellaneous: Anaphylactoid/anaphylactic reactions, carbohydrate intolerance

Postmarketing and/or case reports: Vivelle®; Liver function tests increased (rare), leg pain

Overdosage/Toxicology

Symptoms of overdose include fluid retention, jaundice, thrombophlebitis, nausea, and vomiting. Toxicity is unlikely following single exposure of excessive doses. Treatment following emesis and charcoal administration should be supportive and symptomatic.

Drug Interactions

Substrate of CYP1A2 (major), 2A6 (minor), 2B6 (minor), 2C8/9 (minor), 2C19 (minor), 2D6 (minor), 2E1 (minor), 3A4 (major); Inhibits CYP1A2 (weak); Induces CYP3A4 (weak)

Anticoagulants: Increase potential for thromboembolic events

Corticosteroids: Estrogens may enhance the effects of hydrocortisone and prednisone.

CYP1A2 inducers: May decrease the levels/effects of estradiol. Example inducers include aminoglutethimide, carbamazepine, phenobarbital, and rifampin.

CYP3A4 inducers: CYP3A4 inducers may decrease the levels/effects of estradiol. Example inducers include aminoglutethimide, carbamazepine, nafcillin, nevirapine, phenobarbital, phenytoin, and rifamycins.

Ethanol/Nutrition/Herb Interactions

Ethanol: Avoid ethanol (routine use increases estrogen level and risk of breast cancer). Ethanol may also increase the risk of osteoporosis.

Food: Folic acid absorption may be decreased

Herb/Nutraceutical: St John's wort may decrease estradiol levels. Avoid black cohosh, dong quai (has estrogenic activity). Avoid red clover, saw palmetto, ginseng.

Mechanism of Action

Estrogens are responsible for the development and maintenance of the female reproductive system and secondary sexual characteristics. Estradiol is the principle intracellular human estrogen and is more potent than estrone and estriol at the receptor level; it is the primary estrogen secreted prior to menopause. Following menopause, estrone and estrone sulfate are more highly produced. Estrogens modulate the pituitary secretion of gonadotropins, luteinizing hormone, and follicle-stimulating hormone through a negative feedback system; estrogen replacement reduces elevated levels of these hormones in postmenopausal women.

Pharmacodynamics/Kinetics

Absorption: Oral, topical: Well absorbed

Distribution: Crosses placenta; enters breast milk

Protein binding: 37% to sex hormone-binding globulin; 61% to albumin

Metabolism: Hepatic via oxidation and conjugation in GI tract; hydroxylated via CYP3A4 to metabolites; first-pass effect; enterohepatic recirculation; reversibly converted to estrone and estriol

Excretion: Primarily urine (as metabolites estrone and estriol); feces (small amounts)

Dosage

All dosage needs to be adjusted based upon the patient's response

Oral:

Prostate cancer (androgen-dependent, inoperable, progressing): 10 mg 3 times/day for at least 3 months

Breast cancer (inoperable, progressing in appropriately selected patients): 10 mg 3 times/day for at least 3 months

Osteoporosis prophylaxis in postmenopausal females: 0.5 mg/day in a cyclic regimen (3 weeks on and 1 week off)

Female hypoestrogenism (due to hypogonadism, castration, or primary ovarian failure): 1-2 mg/day; titrate as necessary to control symptoms using minimal effective dose for maintenance therapy

Moderate to severe vasomotor symptoms associated with menopause: 1-2 mg/day, adjusted as necessary to limit symptoms; administration should be cyclic (3 weeks on, 1 week off). Patients should be re-evaluated at 3- to 6-month intervals to determine if treatment is still necessary.

I.M.

Prostate cancer: Valerate: 30 mg or more every 1-2 weeks

Moderate to severe vasomotor symptoms associated with menopause:

Cypionate: 1-5 mg every 3-4 weeks

Valerate: 10-20 mg every 4 weeks

Female hypoestrogenism (due to hypogonadism):

Cypionate: 1.5-2 mg monthly

Valerate: 10-20 mg every 4 weeks

Topical:

Emulsion: Moderate-to-severe vasomotor symptoms associated with menopause: 3.84 g applied once daily in the morning

Gel: Moderate-to-severe vasomotor symptoms associated with menopause, vulvar and vaginal atrophy: 1.25 g/day applied at the same time each day

Transdermal: Indicated dose may be used continuously in patients without an intact uterus. May be given continuously or cyclically (3 weeks on, 1 week off) in patients with an intact uterus (exception - Menostar™, see specific dosing instructions). When changing patients from oral to transdermal therapy, start transdermal patch 1 week after discontinuing oral hormone (may begin sooner if symptoms reappear within 1 week):

Once-weekly patch:

Moderate to severe vasomotor symptoms associated with menopause (Climara®): Apply 0.025 mg/day patch once weekly. Adjust dose as necessary to control symptoms. Patients should be re-evaluated at 3- to 6-month intervals to determine if treatment is still necessary.

Osteoporosis prophylaxis in postmenopausal women:

Climara®: Apply patch once weekly; minimum effective dose 0.025 mg/day; adjust response to therapy by biochemical markers and bone mineral density

Menostar™: Apply patch once weekly. In women with a uterus, also administer a progestin for 14 days every 6-12 months

Twice-weekly patch:

Moderate to severe vasomotor symptoms associated with menopause, vulvar/vaginal atrophy, female hypogonadism: Titrate to lowest dose possible to control symptoms, adjusting initial dose after the first month of therapy; re-evaluate therapy at 3- to 6-month intervals to taper or discontinue medication:

Alora®, Esclim®, Estraderm®, Vivelle-Dot®: Apply 0.05 mg patch twice weekly

Vivelle®: Apply 0.0375 mg patch twice weekly

Prevention of osteoporosis in postmenopausal women:

Alora®, Vivelle®, Vivelle-Dot®: Apply 0.025 mg patch twice weekly, increase dose as necessary

Estraderm®: Apply 0.05 mg patch twice weekly

Vaginal cream: Vulvar and vaginal atrophy: Insert 2-4 g/day intravaginally for 2 weeks, then gradually reduce to ¹ /2 the initial dose for 2 weeks, followed by a maintenance dose of 1 g 1-3 times/week

Vaginal ring:

Postmenopausal vaginal atrophy, urogenital symptoms: Estring®: 2 mg intravaginally; following insertion, ring should remain in place for 90 days

Moderate to severe vasomotor symptoms associated with menopause; vulvar/vaginal atrophy: Femring™: 0.05 mg intravaginally; following insertion, ring should remain in place for 3 months; dose may be increased to 0.1 mg if needed

Vaginal tablets: Atrophic vaginitis: Vagifem®: Initial: Insert 1 tablet once daily for 2 weeks; maintenance: Insert 1 tablet twice weekly; attempts to discontinue or taper medication should be made at 3- to 6-month intervals

Dosing adjustment in hepatic impairment:

Mild to moderate liver impairment: Dosage reduction of estrogens is recommended

Severe liver impairment: Not recommended

Administration

Injection formulation: Intramuscular use only

Emulsion: Apply to clean, dry skin while in a sitting position. Contents of two pouches (total 3.48 g) are to be applied individually, once daily in the morning. Apply contents of first pouch to left thigh; massage into skin of left thigh and calf until thoroughly absorbed (~3 minutes). Apply excess from both hands to the buttocks. Apply contents of second pouch to the right thigh; massage into skin of right thigh and calf until thoroughly absorbed (~3 minutes). Apply excess from both hands to buttocks. Wash hands with soap and water. Allow skin to dry before covering legs with clothing. Do not apply to other areas of body. Do not apply to red or irritated skin.

Gel: Apply to clean, dry, unbroken skin at the same time each day. Apply gel to the arm, from the wrist to the shoulder. Spread gel as thinly as possible over one arm. Allow to dry for 5 minutes prior to dressing. Gel is flammable; avoid fire or flame until dry. After application, wash hands with soap and water. Prior to the first use, pump must be primed. Do not apply gel to breast.

Transdermal patch: Aerosol topical corticosteroids applied under the patch may reduce allergic reactions. Do not apply transdermal system to breasts, but place on trunk of body (preferably abdomen). Rotate application sites allowing a 1-week interval between applications at a particular site. Do not apply to oily, damaged or irritated skin; avoid waistline or other areas where tight clothing may rub the patch off. Apply patch immediately after removing from protective pouch. In general, if patch falls off, the same patch may be reapplied or a new system may be used for the remainder of the dosing interval. Swimming, bathing or showering are not expected to affect use of the patch. Note the following exceptions:

Estraderm®: Do not apply to an area exposed to direct sunlight.

Menostar™: Swimming, bathing, or wearing patch while in a sauna have not been studied; adhesion of patch may be decreased or delivery of estradiol may be affected. Remove patch slowly after use to avoid skin irritation. If any adhesive remains on the skin after removal, first allow skin to dry for 15 minutes, then gently rub area with an oil-based cream or lotion. If patch falls off, a new patch should be applied for the remainder of the dosing interval.

Vaginal ring: Exact positioning is not critical for efficacy, however, patient should not feel anything once inserted. In case of discomfort, ring should be pushed further into vagina. If ring is expelled prior to 90 days, it may be rinsed off and reinserted.

Monitoring Parameters

Yearly physical examination that includes blood pressure and Papanicolaou smear, breast exam, mammogram. Monitor for signs of endometrial cancer in female patients with uterus. Adequate diagnostic measures, including endometrial sampling, if indicated, should be performed to rule out malignancy in all cases of undiagnosed abnormal vaginal bleeding. When using Menostar™ in a woman with a uterus, endometrial sampling is recommended at yearly intervals or when clinically indicated.

Menopausal symptoms: Assess need for therapy at 3- to 6-month intervals

Prevention of osteoporosis: Bone density measurement

Reference Range

Children: <10 pg/mL (SI: <37 pmol/L)

Male: 10-50 pg/mL (SI: 37-184 pmol/L)

Female:

Premenopausal: 30-400 pg/mL (SI: 110-1468 pmol/L)

Postmenopausal: 0-30 pg/mL (SI: 0-110 pmol/L)

Test Interactions

Pathologist should be advised of estrogen/progesterone therapy when specimens are submitted. Reduced response to metyrapone test.

Dietary Considerations

Ensure adequate calcium and vitamin D intake when used for the prevention of osteoporosis.

Patient Education

Inform prescriber of all prescriptions, OTC medications, or herbal products you are taking, and any allergies you have. Do not take any new medication during therapy without consulting prescriber. Use/apply exactly as directed and maintain prescribed cycles or term as prescribed. Avoid routine use of alcohol (ethanol may increase the risk of breast cancer or osteoporosis). Annual gynecologic and regular self-breast exams are important. If you have diabetes, monitor glucose levels closely (may impair glucose tolerance). You may experience nausea, vomiting or abdominal pain (small, frequent meals may help); dizziness or mental depression (use caution when driving); rash; hair loss; headache; or breast pain, increased/decreased libido, or enlargement/tenderness of breasts. difficult/painful menstrual cycles. Report significant swelling of extremities; sudden acute pain in legs or calves, chest, or abdomen; shortness of breath; severe headache or vomiting; sudden blindness; weakness or numbness of arm or leg; unusual vaginal bleeding; yellowing of skin or eyes; unusual bruising or bleeding, or other persistent adverse reactions. You may become intolerant to wearing contact lenses, notify prescriber if this occurs. Pregnancy/breast-feeding precautions: Inform prescriber if you are pregnant. Do not get pregnant while taking this medication. Consult prescriber for appropriate barrier contraceptive measures. This medication may cause fetal defects and should not be used during pregnancy. Consult prescriber if breast-feeding.

Transdermal patch: Apply to clean dry skin. Do not apply transdermal patch to breasts. Apply to trunk of body (preferably abdomen). Rotate application sites. Aerosol topical corticosteroids may reduce allergic skin reaction; report persistent skin reaction.

Intravaginal cream: Insert high in vagina. Wash hands and applicator before and after use.

Topical emulsion: Contents of two pouches are applied one at time to each thigh and rubbed into thigh and calf. Excess on hands should be applied to buttocks. Wash hands with soap and water after application. Allow skin to dry before covering legs with clothes. Do not apply sunscreen soon after or before applying emulsion. Do not apply to red or irritated skin.

Topical gel: Apply dose to one arm at the same time each day. Allow to dry for 5 minutes prior to dressing. Wash hands with soap and water after application. Do not apply to red or irritated skin. Do not apply to breast.

Cardiovascular Considerations

It is important to recognize that estrogens may induce or worsen hypertension. These problems are less severe with lower doses. Furthermore, estrogens may precipitate thromboembolic events, particularly in women who smoke. It is important that patients on long-term estrogens undergo monitoring of blood pressure and avoid cigarette use.

Several observational trials evaluating the use of estrogen in primary prevention of coronary artery disease in women found a decrease in cardiovascular events. However, a recent trial (HERS) found that women with coronary disease derived no cardiovascular protection compared to those treated with placebo. Substantial evidence suggests that estrogen therapy increases bone mineralization and therefore may be of added benefit in patients with osteoporosis. Estrogen also has a favorable effect on lipids (decreases total cholesterol and LDL, increases HDL) but increases triglycerides. Therapy should be initiated after careful evaluation of risk:benefit for therapy.

Dental Health: Effects on Dental Treatment

No significant effects or complications reported

Dental Health: Vasoconstrictor/Local Anesthetic Precautions

No information available to require special precautions

Mental Health: Effects on Mental Status

May cause dizziness, fatigue, headache, irritability, nervousness, and mood disturbances

Mental Health: Effects on Psychiatric Treatment

Associated with an increased risk of developing dementia in postmenopausal women

65 years of age when treated with conjugated estrogen and medroxyprogesterone acetate.

Dosage Forms

Cream, vaginal (Estrace®): 0.1 mg/g (12 g) [refill tube]: 0.1 mg/g (42.5 g) [tube with applicator]

Emulsion, topical, as hemihydrate (Estrasorb™): 2.5 mg/g (56s) [each pouch contains 4.35 mg estradiol hemihydrate; contents of two pouches delivers estradiol 0.05 mg/day]

Gel, topical (EstroGel®): 0.06% (93 g) [pump; delivers estradiol 0.75 mg/1.25 g; 64 doses]

Injection, oil, as cypionate (Depo®-Estradiol): 5 mg/mL (5 mL) [contains chlorobutanol; in cottonseed oil]

Injection, oil, as valerate (Delestrogen®):

10 mg/mL (5 mL) [contains chlorobutanol; in sesame oil]

20 mg/mL (5 mL) [contains benzyl alcohol; in castor oil]

40 mg/mL (5 mL) [contains benzyl alcohol; in castor oil]

Ring, vaginal, as base (Estring®): 2 mg [total estradiol 2 mg; releases 7.5 mcg/day over 90 days] (1s)

Ring, vaginal, as acetate (Femring™): 0.05 mg [total estradiol 12.4 mg; releases 0.05 mg/day over 3 months] (1s); 0.1 mg [total estradiol 24.8 mg; releases 0.1 mg/day over 3 months] (1s)

Tablet, oral, as acetate (Femtrace®): 0.45 mg, 0.9 mg, 1.8 mg

Tablet, oral, micronized: 0.5 mg, 1 mg, 2 mg

Estrace®: 0.5 mg, 1 mg, 2 mg [2 mg tablets contain tartrazine]

Gynodiol®: 0.5 mg, 1 mg, 1.5 mg, 2 mg

Tablet, vaginal, as base (Vagifem®): 25 mcg [contains lactose]

Transdermal system: 0.05 mg/24 hours (4s) [once-weekly patch]; 0.1 mg/24 hours (4s) [once-weekly patch]

Alora® [twice-weekly patch]:

0.025 mg/24 hours [9 cm² , total estradiol 0.77 mg] (8s)

0.05 mg/24 hours [18 cm² , total estradiol 1.5 mg] (8s, 24s)

0.075 mg/24 hours [27 cm² , total estradiol 2.3 mg] (8s)

0.1 mg/24 hours [36 cm² , total estradiol 3.1 mg] (8s)

Climara® [once-weekly patch]:

0.025 mg/24 hours [6.5 cm² , total estradiol 2.04 mg] (4s)

0.0375 mg/24 hours [9.375 cm² , total estradiol 2.85 mg] (4s)

0.05 mg/24 hours [12.5 cm² , total estradiol 3.8 mg] (4s)

0.06 mg/24 hours [15 cm² , total estradiol 4.55 mg] (4s)

0.075 mg/24 hours [18.75 cm² , total estradiol 5.7 mg] (4s)

0.1 mg/24 hours [25 cm² , total estradiol 7.6 mg] (4s)

Esclim® [twice-weekly patch]:

0.025 mg/day [11 cm² , total estradiol 5 mg] (8s)

0.0375 mg/day [16.5 cm² , total estradiol 7.5 mg] (8s)

0.05 mg/day [22 cm² , total estradiol 10 mg] (8s)

0.075 mg/day [33 cm² , total estradiol 15 mg] (8s)

0.1 mg/day [44 cm² , total estradiol 20 mg] (8s)

Estraderm® [twice-weekly patch]:

0.05 mg/24 hours [10 cm² , total estradiol 4 mg] (8s)

0.1 mg/24 hours [20 cm² , total estradiol 8 mg] (8s)

Menostar™ [once-weekly patch]: 0.014 mg/24 hours [3.25 cm² , total estradiol 1 mg] (4s)

Vivelle® [twice-weekly patch]:

0.05 mg/24 hours [14.5 cm² , total estradiol 4.33 mg] (8s)

0.1 mg/24 hours [29 cm² , total estradiol 8.66 mg] (8s)

Vivelle-Dot® [twice-weekly patch]:

0.025 mg/day [2.5 cm² , total estradiol 0.39 mg] (8s)

0.0375 mg/day [3.75 cm² , total estradiol 0.585 mg] (8s)

0.05 mg/day [5 cm² , total estradiol 0.78 mg] (8s)

0.075 mg/day [7.5 cm² , total estradiol 1.17 mg] (8s)

0.1 mg/day [10 cm² , total estradiol 1.56 mg] (8s)

References

American College of Physicians, "Guidelines for Counseling Postmenopausal Women About Preventive Hormone Therapy," Ann Intern Med , 1992, 117(12):1038-41.

Belchetz PE, "Hormone Treatment for Postmenopausal Women," N Engl J Med , 1994, 330(15):1062-71.

Ettinger B, Friedman GD, Bush T, et al, "Reduced Mortality Associated with Long-Term Postmenopausal Estrogen Therapy," Obstet Gynecol , 1996, 87(1):6-12.

Grodstein F, Stampfer MJ, Colditz GA, et al, "Postmenopausal Hormone Therapy and Mortality," N Engl J Med , 1997, 336(25):1769-75.

Hulley S, Grady D, Bush T, et al, "Randomized Trial of Estrogen Plus Progestin for Secondary Prevention of Coronary Heart Disease in Postmenopausal Women. Heart and Estrogen/Progestin Replacement Study (HERS) Research Group," JAMA , 1998, 280(7):605-13.

Shumaker SA, Legault C, Rapp SR, et al, "WHIMS Investigators. Estrogen Plus Progestin and the Incidence of Dementia and Mild Cognitive Impairment in Postmenopausal Women: The Women's Health Initiative Memory Study: A Randomized Controlled Trial," JAMA , 2003, 289(20):2651-62.

Stallard S, Litherland JC, Cordiner CM, et al, "Effect of Hormone Replacement Therapy on the Pathological Stage of Breast Cancer: Population Based, Cross Sectional Study," BMJ , 2000, 320(7231):348-9.

U.S. Food and Drug Administration, Department of Health and Human Services, "FDA Approves New Labels for Estrogen and Estrogen with Progestin Therapies for Postmenopausal Women Following Review of Women's Health Initiative Data," January 8, 2003. Available at: http://www.fda.gov/medwatch/SAFETY/2003/safety03.htm#prempr. Accessed April 17, 2003.

"Writing Group for the Women's Health Initiative Investigators. Risks and Benefits of Estrogen Plus Progestin in Healthy Postmenopausal Women: Principle Results From the Women's Health Initiative Randomized Controlled Trial," JAMA , 2002, 288:321-33.

International Brand Names

Absorlent Matrix® (ES); Adgyn Estro® (GB); Aerodiol® (AT, BE, BR, CH, CR, DE, DK, DO, FR, GB, GT, HN, IE, IT, PA, SV, TR); Akrofolline® [inj.] (TR); Alcis® (ES); Armonil® (IT); Avixis® (AR); Benzo-Ginestryl® (MX); Calidiol® (PL, SI); Cerella® (DE); Cerina® (CH); Climaderm 7 Dias® (CL, CR, DO, GT, HN, PA, SV); Climaderm 100® (CL); Climaderm® (AR, CO, MX); Climagest® (GB); Climara® (AT, AU, BE, CA, CH, CZ, DK, FI, FR, IE, IT, LU, NL, NO, NZ, PL, PT, RO, RU, SE, SI, TH, TR, YU, ZA); Climaval® (GB); Climen® (AT, TH); Cliogan® (ES); Cutanum® (DE); Cyclabil® (FI, NO); Cycloderm® (AT); Cyclo-Progynova® (TH); Delestrogen® (CA); Délidose® (FR); Depo®-Estradiol (CA); Dermatrans® (CL); Dermestril® (AU, BE, CH, CZ, DE, ES, FI, FR, GB, GT, HU, IL, IT, LU, PL, RO, RU); Dermestril-Septem® (BE, DE, FI); Dermestril Septem® (FR, HU); Dermestril-Septem® (IT, PT); Dilena® (BR, ID); Divigel® (CH, CO, CZ, DK, FI, HU, IE, LU, NO, PL, RU, SE, SG, TH); Divina® (FI); Divitren® (FI); Elamax® (BR); Ell-Cranell® (DE); Elleste Solo® (GB); Enadiol® (CL); Endomina® (ES); ephelia® (DE); Ephelia® (IT); Epiestrol 7D® (CL); Epiestrol® (CH, CL, IE, IT); Esclima® (IT); Estalis® (AT, BR, NO); Estrabeta® (DE); Estrace® (CA); Estradelle® (BR); Estraderm® (AR, AU, CA, DK, ES, FI, GB, HR, IE, NO, SE); Estraderm® Matrix (DK, ES, FI, NO, SE); Estraderm MTX® (MX); Estraderm MX® (AR, AT, CH, CZ, DE, GB, HU, IN, IT, NO, PL, PT, SG); Estraderm TTS® (AR, BE, BG, BR, CH, CO, CZ, DE, FR, GB, HK, HU, IE, IL, IT, LU, MT, MX, NL, NZ, PL, RO, SI, TR, YU); Estradiol Asofarma® (AR); Estradiol Benzoato® (CL); Estradiol Benzoato L.CH.® (CL); Estradiol Bexal® (ES); Estradiol Depot® (PL); Estradiol G Gam® (FR); Estradiol Implants® (GB); Estradiol Jenapharm® (DE); Estradiol Lindo® (DE); Estradiolo Amsa® (IT); Estradiolo Angelini® (IT); Estradiol-Pflaster Exterius® (DE); Estradiol® (RO); Estradiol Valerianato® (CL); Estradiol Valerianato L.CH.® (CL); Estradot® (AT, CA, CH, DE, FI, IE, NO, PL, PT, SE); Estrahexal® (CZ); Estramon® (AT, CH, DE, HU, IE); Estranova E® (CL); Estrapatch® (FR); Estrena® (FI); Estreva® (BE, BR, CH, CO, CZ, DE, EC); Estréva® (FR); Estreva® (PL, RO, TR); Estrifam® (DE); Estrimax® (CZ, HU); Estring® (AT, AU, CA, CH, CZ, DE, DK, FI, GB, NL, NO, NZ); Estrium® (PL); Estroclim® (IT); Estrodose® (IT); Estrofem® (AR, AT, AU, BE, CH, CY, CZ, DK, EG, FI, FR, HK, HR, HU, ID, IE, IL, IT, JO, KW, LB, LU, NL, NZ, PL, PT, RO, RU, SG, SI, SY, TH, TR, YU); Estrofen® (BR, EC); Estrogel® (AT); EstroGel® (CA); Estrogel® (DK, EC, FI); Estrolent® (RO); Estromikron® (PL); Estronar-Gel® (PT); Estronorm® (DE); Estropatch® (LU); Estroplast® (PL); Etrosteron® (AR); Eutocol® (AR); Evopad® (ES); Evorel® (AR, CO, DE, DK, FI, GB, IE, IL, NO, SE, ZA); Evorel Sequi® (GB); Fem7® (AR, BR, CH, CL, CO, CR, CZ, DE, DO, EC, GT, HN, HR, MX, NL, PA, PL, RO, SG, SI, SV); Femalon® (CL); Femanest® (DK, SE); Fematab® (IE); Fematrix® (GB, IE); Femiderm TTS® (CL); Feminova® (BE); Femoston® (AT, DE, GB); Femsept® (FR); FemSeven® (AT, GB, ID, IT, RO, SE); Femtab® (GB); Femtran® (AU, NZ); Filena® (AT); Gelestra® (IT); Ginaikos® (IT); Ginatex® (AR); Ginedisc® (AR, BR, CO, MX); Gynamon® (DE); Gynokadin® (DE); Gynokadin Gel® (DE); GynPolar® (DE); Hormodiol® (AR); Klimapur® (AT); Klimareduct® (AT); Klimonorm® (TH); Lindisc 50® (AR, BR, EC); Lindisc® (CL, CO); Linoladiol® (AT, DE); Linoladiol N® (CZ, HU); Menodin® (CO); Meno-Implant® (BE, NL); Meno-Patch® (IL); Menorest® (AU, CH, CL, CO, DE, ES, FI, FR, GB, IE, IT, LU, NL, PL, PT, RU); Menorest TTS® (AT); Menoring® (GB); Meriestra® (ES); Merimono® (AT, BR, DE, FI); Mirion® (CL); Mopraxon® (DE); Neofollin® (CZ, SK); Nuvelle® (GB, IE, PT); Octodiol® (CZ); Oesclim® (CA, CL, CZ, FR, HR, HU, PL, RO, SE); Oestraclin® (ES); Oestradiol-Benzoate Intervet® (AT); Oestradiol Benzoate March® (TH); Oestradiol "Dak"® (DK); Oestradiol Implant® (GB, SG, ZA); Oestradiol Implants® (AU); Oestradiol-K Streuli® (CH); Oestradiol-Retard Théramex® (MC); Oestradiol Streuli® (CH); Oestradiolum benzoicum® (PL); Oestradiol® (YU); Oestring® (SE); Oestriol IMI Pharma® (SE); Oestrodose® (ES, FR, IL); Oestrogel® (BE, CH, CZ, FR, GB, HU, IE, IL, LU, RO, RU, SG, TH); Oestrogel Orifarm® (DK); Oromone® (FR); Pantostin® (DE); Pausigin® (PT); Pelanin® (JP); Perikliman® (AT); Postoval® (BR, CL); Prefest® (BR); Primaquin® (CL); Primofol Depot® (CL); Primogyna® (CL); Primogyn® (AU, MX, ZA); Primogyn Depot® (EC); Progyluton® (IL); Progynon Depot 100 mg® (DE); Progynon Depot® (AR, AT, AU, CO, ES, LU, TH); Progynon® (DK, SE); Progynova® (AT, AU, BE, CH, CO, DE, ES, FI, FR, GB, HR, ID, IL, IT, LU, NL, NO, NZ, PL, RO, RU, SG, TH, ZA); Progynova Parches® (ES); Provames® (FR); Reglovar® (BR); Replasyn® (AR); Riselle® (BR, CZ, RO, YU); Ronfase® (AR); Rontagel® (AR); Sandrena® (AU, BR, CH, DE, DK, GB, IT, NL, NZ); Sisare® (DE); Sprediol® (IT); Substitol® (AT); Systen® (AT, BE, BG, BR, CH, CZ, FR, HR, HU, IT, LU, MX, NL, PL); Thaïs® (FR); Thaïs Sept® (FR); Tradelia® (DE); Tradelia seven® (DE); Transdiol® (AR); Trial® (AR); Trial SAT® (AR); Trisequens® (AT, BR, GB); Vagifem® (AT, AU, BE, CA, CH, CZ, DE, DK, EG, ES, FI, GB, HK, HR, HU, IE, IL, IT, LU, NL, NO, NZ, PL, PT, RO, SE, SG, SI, TH, TR, YU); Vivelle® (CA); Vivelle Dot® (BE, DK); Zerella® (AT, IT); Zumenon® (AT, BE, CH, FI, GB, LU, NL, PT)

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