Estrace (Estradiol) 2mg

 Female Reproductive Hormone; Estrogen

“ALERT: US Boxed Warning

Endometrial cancer:

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.

Cardiovascular disease:

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.

Breast cancer:

The WHI estrogen plus progestin substudy demonstrated an increased risk of invasive breast cancer.

Dementia:

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.”

CSA NA – FDA Approved – REMS (N) – Can Ship

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.  

Estrogen replacement therapy in estrogen deficiency states

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

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. 

Perform regular breast examinations and see your physician regularly 

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.  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.

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).  

Patient Education

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
Urogenital benefit	Yes	Yes	Yes	Yes	Yes
Osteoporosis benefit	Yes	Yes	Yes	No	No
Reduced LDL	Yes	Yes	?	No	No
Increased HDL	Yes	No	No	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
Need progestin	Yes	Yes	Yes	No	Depends
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.

1. Oral conjugated estrogen 0.3mg to 1.25mg daily plus oral medroxyprogesterone 2.5mg to 5mg or micronized progesterone 100mg daily.
2. 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.

1. 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.
2. Transdermal estradiol 50mcg daily for 2 weeks then combined with norethindrone 250mcg for 2 weeks.
3. 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.  

Cyclic Estrogen

Menopausal vasomotor symptoms may return during estrogen-free days.

1. 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.

Progestin Only

Used if estrogen is contraindicated.

1. Oral medroxyprogesterone 10mg to 20mg daily on response.

Vaginal Preparations

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
Oral Estrogens
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
Estradiol-17	Estrace	Soy	1mg
Ethinyl estradiol (plus norethindrone)	FemHRT		5mcg
Transdermal Estrogens
Estradiol-17β patch	Estraderm, Vivelle (2/week)	Soy plant	50mcg
	Climara (1/week)	Soy	50mcg
Estradiol-17β (plus norethindrone) patch	Estracomb	Soy plant	50mcg
Estradiol-17β gel	Estrogel	Plant	2.5g
Vaginal Estrogens
Conjugated estrogens	Premarin	Equine
Dienestrol	Ortho Dienestrol	Synthetic
Estradiol-17	Estring Ring	Mainly soybean
Oral Progestins
Medroxyprogesterone	Provera	Soybean	5mg
Micronized progesterone	Prometrium	Plant	200mg

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:

>10%

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%)