What is this medication?
Female Reproductive Hormone; Estrogen
Estrogen replacement therapy in estrogen deficiency states
“ALERT: US Boxed Warning
There is an increased risk of endometrial cancer in a woman with a uterus who uses unopposed estrogens. Adding a progestin to estrogen therapy has been shown to reduce the risk of endometrial hyperplasia, which may be a precursor to endometrial cancer. Use adequate diagnostic measures, including directed or random endometrial sampling when indicated, to rule out malignancy in all cases of undiagnosed persistent or recurring abnormal genital bleeding.
Do not use estrogen-alone therapy for the prevention of cardiovascular disease. The Women’s Health Initiative (WHI) estrogen-alone substudy reported increased risks of stroke and deep vein thrombosis (DVT) in postmenopausal women (50 to 79 years of age) during 7.1 years of treatment with daily oral conjugated estrogens (CE) (0.625 mg) alone, relative to placebo.
Do not use estrogen plus progestin therapy for the prevention of cardiovascular disease. The WHI estrogen plus progestin substudy reported increased risks of DVT, pulmonary embolism, stroke, and myocardial infarction in postmenopausal women (50 to 79 years of age) during 5.6 years of treatment with daily oral CE (0.625 mg) combined with medroxyprogesterone acetate (MPA) (2.5 mg), relative to placebo.
The WHI estrogen plus progestin substudy demonstrated an increased risk of invasive breast cancer.
Do not use estrogen-alone therapy for the prevention of dementia. The WHI Memory Study (WHIMS) estrogen-alone ancillary study of the WHI reported an increased risk of developing probable dementia in postmenopausal women ≥65 years of age during 5.2 years of treatment with daily CE (0.625 mg) alone, relative to placebo. It is unknown whether this finding applies to younger postmenopausal women.
Do not use estrogen plus progestin therapy for the prevention of dementia. The WHIMS estrogen plus progestin ancillary study of the WHI reported an increased risk of developing probable dementia in postmenopausal women ≥65 years of age during 4 years of treatment with daily CE (0.625 mg) combined with MPA (2.5 mg), relative to placebo. It is unknown whether this finding applies to younger postmenopausal women.
Risk vs benefits:
Only daily oral CEs (0.625 mg) and daily oral CE (0.625 mg) and MPA (2.5 mg) were studied in the estrogen-alone and estrogen plus progestin substudies of the WHI, respectively. Therefore, the relevance of the WHI findings regarding the adverse cardiovascular events and dementia to lower CE doses, other routes of administration, or other estrogen alone products is not known. Likewise, the relevance of the WHI findings regarding the adverse cardiovascular events, dementia, and breast cancer to lower CE plus other MPA doses, other routes of administration, or other estrogen plus progestin products is not known. Without such data, it is not possible to definitively exclude these risks or determine the extent of the risks for other products. Discuss with your patient the benefits and risks of estrogen-alone or estrogen plus progestin therapy, taking into account her individual risk profile. Prescribe estrogens with or without progestins at the lowest effective doses and for the shortest duration consistent with treatment goals and risks for the individual woman.”
How does this medication work?
Estradiol acts like natural estradiol to support development and function of the female reproductive system, secondary sex characteristics and urogenital structures. Estradiol inhibits the pituitary release of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) thereby inhibiting ovulation.
How should I take this medication?
Breast Cancer, Metastatic
Estrace: Take 10mg three times daily; post-menopausal women take 2mg three times daily.
Hormone Therapy for Transgender Females (Male-to-Female)
Estrace: Take 2mg to 6mg daily.
Hypoestrogenism due to Hypogonadism
Estrace: Take 1mg to 2mg daily.
Osteoporosis Prevention (Females)
Estrace: Take the lowest effective dose.
Vasomotor Symptoms (Moderate to Severe) Associated with Menopause
Estrace: Take 0.5mg to 2mg once daily.
Vulvar and Vaginal Atrophy
Estrace: Take 0.5mg to 1mg daily.
*When treating symptoms of menopause, evaluate hormone therapy routinely for appropriate dose, duration, and route of administration for each individual patient based on treatment goals, risk factors, and overall health.
How Do You Take Estrace/Estradiol: You can take Estrace/Estradiol tablets with food or after a meal to reduce nausea. Take the medication exactly as prescribed by your doctor.
Contact Your Doctor if You Ever Experience: If you experience a sudden, intense, severe headache or chest pain; sudden loss of coordination; sudden loss of vision or speech disturbances; chest or calf pain; weakness in the extremities; sudden shortness of breath of pain with breathing (may indicate thromboembolic disorder); persistent or recurrent vaginal bleeding (may indicate endometrial cancer); edema; abdominal pain or jaundice (may indicate hepatitis or gallbladder disease).
Hormone Replacement Therapy
Hormone Replacement Therapy (HRT) refers to the use of an estrogen and a progestin in post-menopausal women. In estrogen replacement therapy (ERT) only estrogen is administered. It is critically important to include a progestin to reduce an estrogen induced risk of endometrial hyperplasia in women. Estrogen replacement therapy is only used in women who have had a hysterectomy and thus are not at risk for these problems.
Treatment of Menopausal Symptoms
HRT effectively relieves or eliminates vasomotor symptoms (hot flushes, sweating), sleep disturbance and poor concentration in a dose-dependent manner.
Treatment of Urogenital Problems
HRT effectively treats post-menopausal vaginal dryness and dyspareunia with vaginal therapy being most effective. Furthermore, there is evidence supporting the usage of vaginal estrogens in reducing the frequency of post-menopausal urinary tract infections.
Prevention and Treatment of Osteoporosis
HRT (with or without a progestin) taken for a period of at least 5 to 10 years is estimated to reduce the risk of osteoporosis-related hip fractures by at least 25%, wrist fractures by 25% to 75% and vertebral fractures by at least 50%; the reduction in risk is directly related to the duration of use. For optimal protection against fracture, HRT should be started within 3 to 5 years after the last menstrual period.
Other Uses: There is limited evidence that HRT may help minimize weight gain, prevent skin wrinkling and dryness which typically occur following menopause.
Place in Therapy
Current clinical research suggests that HRT should not be used routinely and/or long-term in post-menopausal women. Those women who are likely to experience benefits from HRT should fully understand the fully the benefits along with the risks associated with HRT and agree to regular medical examinations. Only short-term therapy is recommended due to the risks of breast cancer, thromboembolism, and coronary heart disease.
Benefits Versus Risks Associated with HRT
|Effects of HRT||Oral Estrogen||Transdermal Patch||Transdermal Gel||Vaginal Ring||Vaginal Cream|
|Reduced hot flushes||Yes||Yes||Yes||No||No|
|Increased Triglycerides||Yes||No, decreased||No||No||No|
|Liver protein induction||Yes||No||?||No||Yes, if conjugated|
|Gallbladder disease risk||Yes||Yes||?||No||No|
|Skin irritation||—||Common||Less common||—||—|
Common Problems and Suggestions
|Bleeding after 12 months of continuous estrogen plus continuous progestin||Most common in early menopause. Evaluate endometrium or switch to cyclic progestin or increase dose of progestin for a few months|
|Bloating||Usually disappears after the first few months. If persistent, reduce the dose of estrogen or switch to a different estrogen or progestin|
|Breast tenderness||Usually disappears after the first few months. If persistent, reduce the dose of estrogen or progestin|
|Discontinuing HRT||Withdrawal bleeding may occur. Decrease dose slowly or dose on alternate days for several weeks|
|Gastrointestinal side effects||Nausea usually disappears after the first few months; if persistent then reduce the dose of estrogen or use a transdermal form|
|Headache with oral therapy||Try transdermal therapy|
|Migraine headache exacerbated||Try continuous estrogen, specifically if headache occurs during the week off estrogen|
|Skin irritation with patch||Try estradiol gel|
|Triglyceride levels high||Use a transdermal patch|
General Dosage Considerations
Progestin must be included in HRT for women with an intact uterus to reduce the estrogenic-induced risk of endometrial hyperplasia and carcinoma. A progestin is not needed if a woman has had a hysterectomy. The progestin dosage depends on the estrogen dose.
Estrogen doses required to treat menopausal vasomotor symptoms should be titrated to individual response. Younger women have been shown to need higher doses. It is encouraged that women discontinue every three to six months to determine if estrogen is still needed.
Estrogen Dosing Considerations:
To Preserve Bone Mineralization and Prevent Bone Thinning
Oral Conjugated Estrogen: 0.625mg daily.
Oral Estradiol-17β: 1-2mg daily.
Estradiol-16β Transdermal Patch: 50mcg daily.
Continuous Estrogen Plus Progestin (Continuous Combined Regimen)
This regimen provide relief from menopausal symptoms while avoiding withdrawal bleeding. It is designed to induce amenorrhea, however spotting can in the first 6 to 12 months on regimens of conjugated estrogens plus progestins. Most women develop amenorrhea within 12 months.
- Oral conjugated estrogen 0.3mg to 1.25mg daily plus oral medroxyprogesterone 2.5mg to 5mg or micronized progesterone 100mg daily.
- Ethinyl estradiol 5mcg plus norethindrone 1mg daily.
Continuous Estrogen Plus Cyclic Progestin
This regimen provides relief from menopausal symptoms with regular withdrawal bleeding. It may be tolerated than continuous progestin during the first year of menopause.
- Oral conjugated estrogen 0.3mg to 1.25mg daily (or equivalent oral or transdermal) plus oral medroxyprogesterone 5mg to 10mg daily or micronized progesterone 200mg daily for 12-14 days per months.
- Transdermal estradiol 50mcg daily for 2 weeks then combined with norethindrone 250mcg for 2 weeks.
- Oral conjugated estrogen 0.3mg to 1.25mg daily (or equivalent oral or transdermal) continuously with medroxyprogesterone 10mg daily for 14 days every 3 months. With this regimen, withdrawal bleeding occurs only once every 3 months, however a minor percentage of women may have spotting and withdrawal bleeding.
Menopausal vasomotor symptoms may return during estrogen-free days.
- Oral conjugated estrogen 0.3mg to 1.25mg daily (or equivalent oral or transdermal) for 21 to 25 days each month with medroxyprogesterone 10mg daily for the last 12-14 days of every month.
Used if estrogen is contraindicated.
- Oral medroxyprogesterone 10mg to 20mg daily on response.
Vaginal preparations in the form of creams, gels, ovules only treat urogenital symptoms. Vaginal preparations can be applied daily until symptoms resolve and can be used as a maintenance therapy with creams/gels/ovules being used twice weekly or a vaginal ring.
Available Dosage Forms
|Dosage Forms||Trade Name||Source||Equivalent Dose|
|Estrogen, conjugated||Premarin||Pregnant mare serum||0.625mg|
|Estrone sulfate||Ogen||Either soybean or Mexican yam||0.625mg|
|Estrone sulfate, conjugated||C.E.S.||Plant sterols||0.625mg|
|Ethinyl estradiol (plus norethindrone)||FemHRT||5mcg|
|Estradiol-17β patch||Estraderm, Vivelle (2/week)||Soy plant||50mcg|
|Estradiol-17β (plus norethindrone) patch||Estracomb||Soy plant||50mcg|
|Estradiol-17||Estring Ring||Mainly soybean|
What should I watch for while using this medication?
Do not use in women with an increased risk of invasive breast cancer
Do not use in women to prevent or treat dementia
Do not use unopposed estrogen in women with a uterus
Do not use in women with endometriosis
Use with caution in women with pre-existing hypertriglyceridemia
Use with caution in women with ovarian cancer
Use with caution in women with retinal vascular thrombosis
Use with caution in asthma, carbohydrate intolerance, cardiovascular disease, fluid retention, hepatic dysfunction, hypoparathyroidism, migraines, porphyria, and system lupus erythematosus
What if I miss a dose?
If you miss a dose, make sure to take it as soon as possible. However, if it is almost time for your next dose, skip the missed dose and continue with your regular schedule.
How should I store this medication?
Keep out of the reach of children at all times. Store at room temperature, 59 to 86° F (15 to 30° C). Protect from light. Keep the container tightly closed. Properly dispose of any unused medication after the expiration date.
What are the possible side effects of using this medication?
The frequency of side effects is not well defined and some of the adverse reactions are dependent on the dosage form and combination therapy used:
Cardiovascular: Edema (10% to 13%)
Central Nervous System: Headache (9% to 50%), pain (6% to 13%), depression (1% to 11%), anxiety (4% to 10%)
Dermatologic: Skin rash (7% to 10%)
Endocrine and Metabolic: Weight gain (4% to 10%)
Gastrointestinal: Abdominal pain (6% to 16%)
Genitourinary: Mastalgia (5% to 35%), vaginal hemorrhage (33%), breast tenderness (3% to 17%), endometrium disease (15%), breakthrough bleeding (6% to 11%), abnormal bleeding (4% to 10%)
Infection: Infection (3% to 12%), fungal infection (3% to 10%)
Neuromuscular and Skeletal: Arthralgia (4% to 12%), back pain (3% to 11%)
Respiratory: Nasopharyngitis (4% to 20%), upper respiratory tract infection (6% to 17%), flu-like symptoms (8% to 13%), sinusitis (4% to 13%), sinus headache (9% to 11%)
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