Estradiol (Oestradiol) is a potent female sex hormone that is primarily produced by the ovaries. It is important for the development of female sexual organs and secondary sexual characteristics. It is also available as injections, tablets, and patches in the following disorders:

Estradiol (Oestradiol) Uses:

• Metastatic Breast Cancer:

  • Useful for postmenopausal men and women who have been properly chosen and are being treated for metastatic breast cancer (palliation).

• Hypoestrogen (female).

  • This is used to treat hypoestrogenism caused by castration, hypogonadism or primary ovarian failure.

• Prevention of osteoporosis (female)

  • It is used to prevent osteoporosis postmenopausal
  • Use limitations: Only those women who have a high risk of developing osteoporosis after menopause should think about taking nonestrogen medicine.

• Advanced Prostate Cancer:

  • This is used to treat advanced androgen-dependent prostate cancer (palliation).

• Menopause is associated with vasomotor symptoms

  • This is used to treat menopausal vasomotor symptoms that range from mild to severe.

• Menopause associated with vaginal and vulvar atrophy

  • This medication is used to treat moderate to severe vaginal and vulvar atrophy that can be caused by menopause.
  • Use restrictions: If topical vaginal treatments are being used to treat vulvar or vaginal atrophy, this is not advised.

Estradiol (Oestradiol) Dose in Adults

Estradiol (Oestradiol) General dosing guidelines:

• Hormone therapy should be frequently assessed for each patient to determine the best dose, duration, and method of administration depending on treatment objectives, risk factors, and general health.
• For postmenopausal women with uteruses, combined estrogen/progestin therapy is recommended to lower the risk of endometrial cancer.
• In general, people who have had hysterectomies do not require a progestin; however, if endometriosis has a history, one can be required. Based on the patient's response, adjust the dose.

Estradiol (Oestradiol) Dose in the treatment of metastatic Breast cancer:

• Males and postmenopausal women should take oral (Estrace) 10 mg three times daily; postmenopausal women should take oral (Estrace) 2 mg three times daily (off-label dose).

Dosage of estradiol (oestradiol) for hormone therapy for transgender females (male to female), either alone or in combination (off-label):

• IM:
  • Cypionate: Every week, 2 to 10 mg
  • Valerate: Every two weeks, 5 to 30 mg.
• Oral: 2 to 6 mg daily
• Transdermal:
  • Every 3 to 5 days, apply a 0.025 to 0.2 mg/day patch.
  • Note: To make a 0.2 mg dose per day, apply two 0.1 mg patches.

Note: Increase blood estradiol levels while lowering serum testosterone levels to the typical range for females by adjusting the dose.

Estradiol (Oestradiol) Dose in the treatment of Hypoestrogenism (female) due to hypogonadism, castration, or primary ovarian failure:

• Oral (Estrace):
  • 1 to 2 mg daily; titrate as required to control symptoms using the lowest effective dose for maintenance therapy.
• IM: Valerate (Delestrogen):
  • Every four weeks, 10 to 20 mg
• Transdermal (Alora, Climara, Vivelle-Dot):
  • Observe the precise dose for transdermal products (below).

Dose for treating Hypoestrogenism (female) due to hypogonadism:

• IM: Cypionate (Depo-Estradiol): 1 to 2 mg per month

Estradiol (Oestradiol) Dose in the prevention of Osteoporosis (females):

• Oral (Estrace): The lowest effective dose has not been established; clinical investigations assessing bone mineral density used doses of at least 0.5 mg daily.
• Transdermal (Climara, Menostar, Minivelle, Alora, Vivelle-Dot) (Climara, Menostar, Minivelle, Alora, Vivelle-Dot):
  • Observe the precise dose for transdermal products (below).

Estradiol (Oestradiol) Dose in the treatment of advanced Prostate cancer:

• IM: Valerate (Delestrogen): 30 mg or more every 1 to 2 weeks
• Oral (Estrace): 1 to 2 mg thrice in a day.

Estradiol (Oestradiol) Dose in the treatment of moderate to severe vasomotor symptoms associated with menopause:

• Oral (Estrace):
  • 0.5 to 1 mg once daily.
  • Dosage range: 0.5 to 2 mg/day.
• IM: Cypionate (Depo-Estradiol):
  • 1 to 5 mg every 3 to 4 weeks
• IM: Valerate (Delestrogen):
  • 10 to 20 mg every 4 weeks
• Topical gel:
  • Divigel:
    • Initial: 0.25 g/day;
    • adjust dose based on patient response
  • Elestrin:
    • Initial: 0.87 g/day applied at the same time each day;
    • adjust dose based on patient response.
  • EstroGel:
    • 1.25 g/day applied at the same time each day
  • Topical spray (Evamist):
    • Initial: One spray (1.53 mg) per day.
    • Adjust dose based on patient response.
    • Dosing range: 1 to 3 sprays per day.
  • Transdermal (Alora, Climara, Minivelle, Vivelle-Dot):
    • Refer to transdermal product-specific dosing (below).
  • Vaginal ring (Femring):
    • Initial: 0.05 mg intravaginally;
    • following insertion, the dose is released daily for 3 months.
    • Usual dose: 0.05 mg to 0.1 mg intravaginally every 3 months.

Estradiol (Oestradiol) Dose in the treatment of moderate to severe vulvar and vaginal atrophy associated with menopause:

• IM: Valerate (Delestrogen):
  • 10 to 20 mg every 4 weeks
• Intravaginal: Vaginal ring (Femring):
  • Initial: 0.05 mg intravaginally;
  • following insertion, the dose is released daily for 3 months.
  • Usual dose: 0.05 mg to 0.1 mg intravaginally eevery 3 months.
• Oral (Estrace):
  • 0.5 to 1 mg/day.
• Topical gel (EstroGel):
  • 1.25 g/day applied at the same time every day
• Transdermal (Alora, Climara, Vivelle-Dot):
  • Refer to transdermal product-specific dosing (below).

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Transdermal product-specific dosing:

Note:

• Patients without uteruses may continually administer the recommended dose.
• Women who have a uterus can employ continuous or cyclic schedules (3 weeks on, 1 week off) (indication and product-specific; refer to manufacturers labeling).
• Start transdermal patch one week after stopping oral hormone therapy (may start earlier if symptoms return before one week has passed) while switching patients from oral to transdermal medication:

Estradiol (Oestradiol) Dose for treating Hypoestrogenism (female) due to hypogonadism, castration, or primary ovarian failure: Adjust dose as necessary to control symptoms.

• Initials: Alora Initial: Two times a week, apply a 0.05 mg/day patch.
• Initial: Once a week, apply a 0.025 mg/day patch.
• Initial instructions for Vivelle-Dot: Use a 0.025 mg/day patch twice a week.

Estradiol (Oestradiol) Dose in the treatment of Functional hypothalamic amenorrhea with low bone density (adolescent and young adult female; off-label):

• Due to a lack of data, the Endocrine Society guidelines are unable to provide an ideal dose.
• using a patch of 0.1 mg twice a week (with cyclic progesterone for endometrial protection) Adolescent girls (bone age 15 years) with low BMD linked with anorexia nervosa had improved spine and hip BMD.

Estradiol (Oestradiol) Dose in the prevention of Osteoporosis (female):

• Alora, Minivelle, Vivelle-Dot:
  • Initial: Two times a week, apply a 0.025 mg patch. dosage as necessary.
• Climara:
  • Initial: One time per week, apply a 0.025 mg/day patch; alter the dosage according on how the patient responds to the treatment.
• Estradot [Canadian product]:
  • The manufacturer's labelling does not include any precise initial dosage recommendations; instead, you should customise your dose based on your clinical situation, BMD status, and 17-beta estradiol levels (keeping them at 50 picograms/mL).
• Menostar:
  • Once a week, apply a 0.014 mg patch.
  • Every six to twelve months, provide a progestin for 14 days to women who have uteruses.

Estradiol (Oestradiol) Dose in the treatment of Vasomotor symptoms associated with menopause:

Note: Dosage as necessary.

• Alora, Estradot [Canadian product]:
  • Initial: Put on a 0.05 mg patch twice daily.
• Climara:
  • Initial: One time each week, apply a 0.025 mg/day patch.
• Minivelle, Vivelle-Dot:
  • Initial: Apply a patch containing 0.0375 mg twice a week.
• Oesclim [Canadian product]:
  • Initial: Apply a patch of 0.025 to 0.05 mg twice a week.

Estradiol (Oestradiol) Dose in the treatment of moderate to severe vulvar and vaginal atrophy associated with menopause:

Note: Dosage as necessary.

• Alora:
  • Initial: Apply a patch containing 0.05 mg twice a week.
• Climara:
  • Initial: Put on a 0.025 mg patch once each week.
• Vivelle-Dot:
  • Initial: Apply a patch containing 0.0375 mg twice a week.

Estradiol (Oestradiol) Dose in Children

Note: 

• In the US, estrasorb hasn't been sold for more than a year.
• Use the smallest effective dose for the shortest amount of time that is consistent with the patient's treatment objectives and risks; dosage adjustments must be made based on the patient's reaction to each dose.

Estradiol (Oestradiol) Dose in the treatment of Constitutional delay of growth and puberty (CDGP) (females): Limited data available:

• Children ≥12 years and Adolescents:

Note:

• Start with the lowest dose possible and then gradually increase.
• Find out your bone age every six months to prevent early epiphyseal closure.
• Add cyclic progesterone if the course of treatment lasts longer than a year, breast growth is significant and has plateaued, or breakthrough bleeding occurs.
• Continue for as long as clinically necessary or until menstruation has been established.
  • Oral (micronized, Estrace):
    • After 6 to 12 months of therapy, the dose may be increased to 10 mcg per kg once day from the initial dosage of 5 mcg per kg once daily.
    • Some have suggested starting with a fixed dose of 0.25 mg once day (half of the 0.5 mg pill) and rising to 0.5 mg once daily after six to twelve months using the dosage forms already available.
  • Transdermal:
    • Apply at night and remove in the morning for the first dosage of 3.1 to 6.2 mcg per day patches (e.g., 1/8 to 1/4 of a 25 mcg per day patch).
    • Every six months, increase the daily patch dose by 3.1 to 6.2 mcg (Palmert 2012).
  • Note:
    • In the literature, cutting patches to achieve low doses is frequently mentioned.
    • However, due to product availability or manufacturing changes, statistics for every transdermal product might not be available.

Estradiol (Oestradiol) Dose in the treatment of Hypogonadism (females): Limited data available:

• Children ≥12 years and Adolescents:

Note:

• Start with the lowest dose possible and then gradually increase.
• Find out your bone age every six months to prevent early epiphyseal closure.
• Add cyclic progesterone once breast development has reached a plateau or bleeding breakthrough has occurred.
• Continue for as long as clinically necessary or until menstruation has been established.
  • Oral (micronized):
    • Initial dose: 5 mcg per kg once daily for 6–12 months; may then increase to 10 mcg per kg once daily for 6–12 months; may be raised by 5 mcg per kg once daily up to 20 mcg per kg once daily at every 6–12 month interval.
    • Never go beyond the daily adult dose of 2 mg.
  • Transdermal:
    • Apply the patch at night and take it off in the morning for the initial dose of 3.1 to 6.2 mcg/day (e.g., 1/8 to 1/4 of a 25 mcg/day patch).
    • Do not exceed the adult dose of 50 to 100 mcg per 24 hours; increase by 3.1 to 6.2 mcg per day patch every six months.
  • Note:
    • The technique of cutting patches to get minimal doses is commonly mentioned in the literature; however, due to product availability/manufacturing changes, data relevant to a particular transdermal product may not be available.

Estradiol (Oestradiol) Dose in the treatment of Turner syndrome (females): Limited data available:

• Children ≥12 years and Adolescents:

  • Start with a low dose when you are 12 years old and progressively increase it over 2 to 4 years to the full adult dose.
  • Add cyclic progesterone after 2 years of oestrogen use or when breakthrough bleeding begins.
  • Note:
    • Till at least age 30, full dose oestrogen will be required.
  • IM: Cypionate (Depot-Estradiol):
    • The goal adult dose is 3 mg per month. One trial started at 0.2 mg per dose, increased dose at 6-month intervals in 0.2 mg per dose increments until a dose of 1 mg was reached, and then increased in 0.5 mg per dose increments thereafter to a final dose of 3 mg. Initial: 0.2 to 0.4 mg every 4 weeks, gradually increase dose over approximately 2 years.
  • Oral (micronized, Estrace):
    • Once full height is reached, raise to the adult dose of 1 to 2 mg per day. The initial dose is 5 mcg per kg once daily for the first 2 years, followed by 7.5 mcg per kg for the third year, and then 10 mcg per kg thereafter.
    • A fixed dose of 0.25 mg once daily has also been recommended, with the adult dose of 2 to 4 mg/day to be increased over a two-year period.
    • Note:
      • Considering the significant first-pass metabolism, alternative administration methods might be more advantageous.
  • Topical gel (Divigel):
    • Initial dosages are as follows: 0.1 mg of estradiol once daily for the first year, 0.2 mg once daily for the second year,
    • 0.5 mg once daily for the third year, 1 mg once daily for the fourth year, and 1.5 mg once daily for the fifth year.
    • Long-term dose is unclear; dosage is based on a trial with 23 girls that tracked development for 5 years.
    • Individual sachets containing 0.1 mg of estradiol were created because there were no commercially available items for lower levels.
  • Transdermal patch:
    • The goal adult dose is 100 to 200 mcg per day patch, which is gradually increased over the course of around 2 years from the initial dose of 6.25 mcg per day patch.

Note:

• The lowest-dose patches currently on the market deliver 14 and 25 g daily; the preferred dose fractionation mechanism is still unknown (eg, administering a partial patch, limiting to overnight use, or administering whole patches for 7 to 10 days per month).
• Some transdermal patches may not have data relevant to the product accessible for splitting or cutting; one centre utilised the Vivelle-Dot product and the following titration method:

• Treatment month:

  • 0 to <6 months of treatment:
    • Apply at night and take off in the morning, 125 mcg to 4.17 mcg per dose (equivalent to 1/8 to 1/ 6 of a 25 mcg per day patch) (not continuous)
  • 6 to <12 months of treatment:
    • Apply twice in a dilute solution 125 mcg to 4.17 mcg each dosage (equals 1/8 to 1/6 of a 25 mcg per day patch) (continuous)
  • 12 to <18 months of treatment:
    • Apply twice in a dilute solution of 25 mcg to 8.33 mcg each dosage (equivalent to 1/4 to 1/3 of a 25 mcg per day patch) (continuous)
  • 18 to <24 months of treatment:
    • Apply twice in a mild solution 5 mcg/dose (equals half of a 25 mcg/day patch) (continuous)
  • ≥24 months of treatment:
    • Apply a patch twice a week for 25 mcg per day; after six months, raise the patch strength by one for a final target of 100 mcg per day continuously.

Estradiol (Oestradiol, Alora) Pregnancy Risk Category: X

• Products approved only for women who are postmenopausal may not be used during pregnancy. 
• Some products are clearly indicated on the label as being contraindicated.
• Combining hormonal contraceptives with estrogen and progestin has not been proven to cause teratogenic side effect.

Estradiol use during breastfeeding:

• Breast milk contains estrogens.
• It has been shown that estrogens can reduce the quality and quantity human milk.
• Manufacturers advise breastfeeding mothers to be careful when administering the medication. Monitor your infant's growth closely.

Estradiol (Oestradiol, Alora) Dose in Kidney Disease:

For most products, the Manufacturer's labeling doesn't provide any dosage adjustments (has not been studied).

Estradiol (Oestradiol, Alora) Dose in Liver disease:

Its use is contraindicated with hepatic dysfunction or disease.

Side effects of Estradiol (Oestradiol, Alora):

Some adverse reactions observed with estrogen and/or progestin combination therapy.

• Cardiovascular:

  • Edema
  • Hypertension
  • Cerebrovascular Accident
  • Thrombophlebitis
  • Venous Thromboembolism
  • Deep Vein Thrombosis
  • Local Thrombophlebitis
  • Myocardial Infarction
  • Pulmonary Thromboembolism
  • Retinal Thrombosis

• Central Nervous System:

  • Headache
  • Hypoesthesia
  • Chorea
  • Dementia
  • Exacerbation Of Epilepsy
  • Irritability
  • Mood Disorder
  • Pain
  • Depression
  • Anxiety
  • Dizziness
  • Migraine
  • Nipple Pain
  • Nervousness

• Dermatologic:

  • Skin Rash
  • Pruritus
  • Chloasma
  • Urticaria
  • Erythema Multiforme
  • Erythema Nodosum
  • Localized Erythema
  • Loss Of Scalp Hair
  • Skin Discoloration

• Endocrine & Metabolic:

  • Fibrocystic Breast Changes
  • Fluid Retention
  • Galactorrhea
  • Hypocalcemia
  • Increased Serum Triglycerides
  • Weight Gain
  • Hot Flash
  • Hirsutism
  • Change In Libido
  • Change In Menstrual Flow
  • Exacerbation Of Diabetes Mellitus
  • Exacerbation Of Porphyria
  • Weight Loss

• Gastrointestinal:

  • Abdominal Pain
  • Nausea
  • Gastroenteritis
  • Diarrhea
  • Abdominal Cramps
  • Bloating
  • Carbohydrate Intolerance
  • Gallbladder Disease
  • Pancreatitis
  • Dyspepsia
  • Constipation
  • Flatulence
  • Vomiting

• Genitourinary:

  • Mastalgia
  • Vaginal Hemorrhage
  • Breast Tenderness
  • Change In Cervical Ectropion
  • Change In Cervical Secretions
  • Endometrial Hyperplasia
  • Nipple Discharge
  • Spotting
  • Uterine Fibroids
  • Uterine Pain
  • Vaginal Discomfort
  • Endometrium Disease
  • Breakthrough Bleeding
  • Leukorrhea
  • Abnormal Uterine Bleeding
  • Breast Hypertrophy
  • Dysmenorrhea
  • Cervical Polyp
  • Vulvovaginal Candidiasis
  • Urinary Tract Infection
  • Vaginitis

• Hematologic & Oncologic:

  • Hypercoagulability State
  • Malignant Neoplasm Of Breast
  • Ovarian Cancer
  • Hemorrhagic Eruption

• Hepatic:

  • Cholestatic Jaundice
  • Exacerbation Of Hepatic Hemangioma

• Hypersensitivity:

  • Anaphylactoid Reaction
  • Anaphylaxis
  • Angioedema
  • Hypersensitivity Reaction

• Infection:

  • Infection
  • Fungal Infection

• Local:

  • Application Site Reaction

• Neuromuscular & Skeletal:

  • Myalgia
  • Neck Pain
  • Arthropathy
  • Exacerbation Of Systemic Lupus Erythematosus
  • Leg Cramps
  • Arthralgia
  • Back Pain
  • Weakness
  • Limb Pain

• Ophthalmic:

  • Change In Corneal Curvature
  • Contact Lens Intolerance
  • Conjunctivitis

• Otic:

  • Otitis Media

• Respiratory:

  • Flu-Like Symptoms
  • Sinusitis
  • Sinus Headache
  • Bronchitis
  • Sinus Congestion
  • Pharyngitis
  • Rhinitis
  • Cough
  • Nasopharyngitis
  • Upper Respiratory Tract Infection
  • Asthma
  • Exacerbation Of Asthma

• Miscellaneous:

  • Accidental Injury
  • Cyst

Contraindication to Estradiol:

• Angioedema, anaphylaxis, or allergy to estradiol or any other formulation ingredient.
• An unidentified illness that results in irregular vaginal bleeding;
• Those who have DVT/PE or have had DVT/PE in the past;
• An ongoing or previous history of arterial embolic illness, such as MI or stroke
• Patients who are receiving treatment for metastatic disease or who have a history of breast cancer, whether confirmed or unconfirmed, are not allowed.
• An estrogen-dependent tumor (known, suspected)
• Hepatic impairment and disease
• Antithrombin deficiencies known, protein C and protein A known;
• Pregnancy (Note - Products approved for women after menopause cannot be used during pregnancy. Some products are clearly indicated on the label as being contraindicated.

Canadian labeling: Additional contraindications not listed on the labelling in the US

• Notice: The dosage form may vary per product. Please refer to the product label.
  • Breastfeeding
  • Endometrial hyperplasia
  • Active thrombophlebitis
  • Ophthalmic vascular disease can lead to partial or complete vision loss, or diplopia.
  • History of or presence of hepatic carcinomas (benign and/or malignant); porphyria
  • Classic migraine.

Precautions and warnings

• Anaphylaxis

  • Anaphylaxis is a condition that requires immediate medical attention. It can occur at any time during treatment.
  • There have been reports of angioedema reported in the lips, tongue, feet, hands and larynx.

• Breast cancer: [US Boxed Warning]

  • According to statistics from the Women's Health Initiative (WHI), postmenopausal women who take medroxyprogesterone and conjugated estrogens (CE) are more likely to develop invasive breast cancer.
  • Because of their oestrogen or progestin dosages, timing of therapy commencement, length of treatment, and patient characteristics, women who get hormone therapy after menopause may have an increased chance of developing breast cancer.
  • Hormone therapy may cause an increase in breast density. There have been reports of abnormal mammogram results that need further examination. This can be caused by estrogen alone, or combined therapy with progestin.
  • Patients with breast cancer and bone metastases may experience severe hypercalcemia as a result of high oestrogen levels.
  • According to observational studies, this risk drops when therapy is stopped.
  • WHI found no evidence that women who had a hysterectomy and CE were at increased risk of breast cancer.

• Dementia: [US Boxed Warning]

  • Using estrogens with or without progestin to prevent dementia is not recommended.
  • According to the Women's Health Initiative Memory Study, women over 65 were more likely than males to acquire dementia if they had used CE alone or in combination (WHIMS).
  • WHI memory studies were conducted on women over 65 years old. The findings of the WHI memory studies are not applicable to younger women after menopause.

• Endometrial cancer: [US BoxedWarn]

  • Women who use estrogen unopposed are more likely to develop endometrial carcinoma.
  • A progestin can be added to oestrogen therapy to lower the risk of endometrial Hyperplasia, which is a precursor to endometrial cancer.
  • It is crucial to do appropriate diagnostic tests and endometrial sampling if there are any abnormalities in the vaginal blood flow.
  • The duration and dosage of treatment are key factors in endometrial cancer risk. Patients who have been receiving therapy for longer than five years are at risk. It may persist even after treatment is stopped.
  • If low doses of progestin are being administered to vaginal atrophy patients, it should be avoided. This recommendation is supported by insufficient long-term data (>1 year)
  • There is no proof that using natural estrogens with equal oestrogen dosages carries a higher risk than using synthetic estrogens.

• Endometriosis

  • Estrogens can exacerbate endometriosis.
  • Progestin should be considered for women with endometriosis following hysterectomy.
  • The malignant transformation of the remaining implants after a post-hysterectomy has been unaffected by estrogen therapy.

• The Lipid Effects

  • Glycerides may be increased in hypertriglyceridemia patients. Stop taking medication if you suspect that you have pancreatitis.
  • Estrogen chemicals may increase HDL cholesterol and lower LDL cholesterol, among other lipid effects.

• Ovarian cancer:

  • Although an association might exist, the likelihood of developing a serious condition is low. It is also possible to influence the likelihood of an interaction by the length of treatment.
  • There is inconsistent information regarding the risks of ovarian cancer and the use estrogen/progestin therapy, or menstrual estrogen.

• Retinal vascular embolism

  • Retinal vein thrombosis can be caused by estrogens
  • Stop using if you have migraines, vision loss, proptosis, diplopia or other symptoms.
  • Stop using permanent contraceptives if retinal vascular disease or papilledema is found during examination

• Asthma

  • Asthma: Be careful
  • This could make the situation worse.

• Carbohydrate intolerance

  • You should assess the risk factors for diabetes, including their age, cardiovascular health, and metabolic.
  • Diabetes patients may have impaired glucose tolerance.

• Cardiovascular disease: [US Boxed Warning]

  • It is important to avoid heart disease by not combining estrogens with progestin.
  • The Women's Health Initiative data has shown that CE is at higher risk of stroke and deep vein embolism. Postmenopausal women between 50-79 years old have been reported to experience an increase in stroke, DVT, and pulmonary emboli (PE).
  • SLE, diabetes mellitus, and obesity are all risk factors.
  • Women with DVT, PE, or other arterial thromboembolic disorders are not advised to take the medication (stroke and MI).
  • Negative cardiovascular events have been reported by males who have used estrogens to treat prostate carcinoma.
  • It is important to manage your risk factors. Stop using the medication immediately if you are concerned about adverse cardiovascular events.
  • Patients at high risk of developing thrombotic conditions are more likely to receive transdermal treatment.

• Fluid retention can cause more serious diseases

  • Fluid retention can lead to complications in certain conditions, including renal dysfunction and cardiac problems.

• Epilepsy:

  • Take care with epilepsy.
  • This could make the situation worse.

• Gallbladder disease

  • Gallbladder disease that requires surgery may be more common in women who use estrogen after menopause.

• Hepatic dysfunction

  • Stop using if you have jaundice or are suffering from acute or chronic liver disorders.
  • Hepatic impairment or disease can be reasons to stop taking this medication.
  • Patients with hepatic dysfunction may have a lower ability to metabolize estrogens.
  • If you have had cholestatic jaundice from estrogen use in the past or are pregnant, be cautious.

• Hepatic hemomangiomas

  • Take care with hepatic hemomangiomas.
  • This could make the situation worse.

• Angioedema is hereditary

  • Exogenous estrogens can cause angioedema in women with angioedema.

• Hypoparathyroidism

  • Hypoparathyroidism patients should be cautious when using it
  • Estrogen can cause hypocalcemia.

• Migraine

  • Patients with Migraine may experience worsening symptoms if they are given medication.

• Porphyria

  • Patients suffering from Porphyria need to be treated with caution
  • This could make the situation worse.

• SLE:

  • Patients suffering from SLE should be cautious when using it
  • This could make the situation worse.

Estradiol (systemic): Drug Interaction

Note: Drug Interaction Categories:

• Risk Factor C: Monitor When Using Combination
• Risk Factor D: Consider Treatment Modification
• Risk Factor X: Avoid Concomitant Use

Risk Factor C (Monitor therapy)
Ajmaline	Estrogen Derivatives may enhance the adverse/toxic effect of Ajmaline. Specifically, the risk for cholestasis may be increased.
Anthrax Immune Globulin (Human)	Anthrax Immune Globulin's thrombogenic action may be enhanced by oestrogen derivatives (Human).
Antidiabetic Agents	The therapeutic benefit of anti-diabetic agents may be reduced by hyperglycemia-associated agents.
Ascorbic Acid	May raise the level of oestrogen derivatives in the serum.
Bosentan	May lower the serum level of CYP3A4 substrates (High risk with Inducers).
Broccoli	May lower the serum level of CYP1A2 substrates (High risk with Inducers).
C1 inhibitors	The thrombogenic impact of C1 inhibitors may be enhanced by oestrogen derivatives.
Cannabis	May lower the serum level of CYP1A2 substrates (High risk with Inducers).
Chenodiol	Estrogen derivatives may lessen Chenodiol's therapeutic efficacy. When administered with any oestrogen derivative, chenodiol's clinical reaction should be continuously monitored.
CloZAPine	CYP1A2 Inhibitors (Weak) may raise the level of CloZAPine in the serum. Management: Separate drug interaction monographs go into further detail about the medications indicated as exceptions to this book.
Corticosteroids (Systemic)	Estrogen derivatives may raise the level of corticosteroids in the blood (Systemic).
CYP1A2 Inducers (Moderate)	May lower the serum level of CYP1A2 substrates (High risk with Inducers).
CYP3A4 Inducers (Moderate)	May lower the serum level of CYP3A4 substrates (High risk with Inducers).
CYP3A4 Inhibitors (Moderate)	May raise the level of oestrogen derivatives in the serum.
CYP3A4 Inhibitors (Strong)	May raise the level of oestrogen derivatives in the serum.
Cyproterone	May lower the serum level of CYP1A2 substrates (High risk with Inducers).
Dantrolene	Dantrolene's hepatotoxic action may be enhanced by oestrogen derivatives.
Deferasirox	May lower the serum level of CYP3A4 substrates (High risk with Inducers).
Erdafitinib	May lower the serum level of CYP3A4 substrates (High risk with Inducers).
Erdafitinib	P-glycoprotein/ABCB1 Substrates serum levels can rise.
Herbs (Estrogenic Properties)	Estrogen derivatives' harmful or toxic effects might be amplified.
Immune Globulin	Estrogen derivatives may intensify Immune Globulin's thrombogenic action.
Ivosidenib	May lower the serum level of CYP3A4 substrates (High risk with Inducers).
LamoTRIgine	Estrogen derivatives may lower the level of lamotrigine in the blood.
Lenalidomide	Lenalidomide's ability to induce thrombosis may be enhanced by oestrogen derivatives.
Mivacurium	The serum concentration of mivacurium may rise in response to oestrogen derivatives.
Nonsteroidal Anti-Inflammatory Agents (COX-2 Selective)	Could make oestrogen derivatives' thrombogenic impact stronger. The serum concentration of oestrogen derivatives may rise in response to non-steroidal anti-inflammatory drugs (COX-2 selective).
P-glycoprotein/ABCB1 Inhibitors	Pglycoprotein/ABCB1 Substrates serum levels can rise. Additionally, p-glycoprotein inhibitors may improve the distribution of pglycoprotein substrates to particular cells, tissues, and organs where high levels of p-glycoprotein are present (e.g., brain, T-lymphocytes, testes, etc.).
Ranolazine	P-glycoprotein/ABCB1 Substrates serum levels can rise.
ROPINIRole	The serum concentration of ROPINIRole may rise in response to oestrogen derivatives.
Sarilumab	May lower the serum level of CYP3A4 substrates (High risk with Inducers).
Siltuximab	May lower the serum level of CYP3A4 substrates (High risk with Inducers).
Succinylcholine	The serum content of succinylcholine may rise as a result of oestrogen derivatives.
Teriflunomide	May lower the serum level of CYP1A2 substrates (High risk with Inducers).
Thalidomide	The thrombogenic effect of thalidomide may be enhanced by oestrogen derivatives.
Theophylline Derivatives	Theophylline derivatives' serum levels may be raised by oestrogen derivatives. Dyphylline is an exception.
Thyroid Products	Estrogen derivatives may reduce a thyroid product's ability to treat you.
Tocilizumab	May lower the serum level of CYP3A4 substrates (High risk with Inducers).
Ursodiol	Ursodiol's therapeutic effects could be lessened by oestrogen derivatives.
Risk Factor D (Consider therapy modification)
Anticoagulants	Estrogen derivatives might lessen an anticoagulant's ability to stop bleeding. More particular, some estrogens and progestin-estrogen combos may have prothrombotic actions that work against any anticoagulant effects. Management: Carefully balance the potential advantages of estrogens against the probable elevated risk of thromboembolism and procoagulant effects. Under some conditions, use is deemed contraindicated. For particular advice, consult the relevant policies.
Cosyntropin	Cosyntropin's diagnostic potential may be diminished by oestrogen derivatives. Treatment: Stop taking any medications that include oestrogen 4 to 6 weeks before cosyntropin (ACTH) testing.
CYP3A4 Inducers (Strong)	May speed up CYP3A4 substrate metabolism (High risk with Inducers). Management: Take into account a substitute for one of the interfering medications. Specific contraindications may apply to some combinations. the relevant manufacturer's label.
Dabrafenib	May lower the serum level of CYP3A4 substrates (High risk with Inducers). Management: When possible, look for substitutes for the CYP3A4 substrate. If concurrent therapy cannot be avoided, pay special attention to the substrate's clinical consequences (particularly therapeutic effects).
Enzalutamide	May lower the serum level of CYP3A4 substrates (High risk with Inducers). Treatment: Enzalutamide should not be used concurrently with CYP3A4 substrates that have a limited therapeutic index. Enzalutamide use, like with the use of any other CYP3A4 substrate, should be done cautiously and under close observation.
Hyaluronidase	Estrogen derivatives may lessen Hyaluronidase's therapeutic impact. Treatment: Standard doses of hyaluronidase may not produce the desired clinical response in patients receiving estrogens (especially at higher doses). Hyaluronidase may be needed at higher doses.
Lorlatinib	May lower the serum level of CYP3A4 substrates (High risk with Inducers). Management: Avoid taking lorlatinib at the same time as any CYP3A4 substrates for which even a small drop in serum levels of the substrate could result in therapeutic failure and negative clinical outcomes.
Mitotane	May lower the serum level of CYP3A4 substrates (High risk with Inducers). Treatment: When administered in individuals receiving mitotane, doses of CYP3A4 substrates may need to be significantly modified.
Pitolisant	May lower the serum level of CYP3A4 substrates (High risk with Inducers). Management: Pitolisant should not be used in conjunction with a CYP3A4 substrate that has a limited therapeutic index. When administered with pitolisant, other CYP3A4 substrates need to be checked more carefully.
Pomalidomide	Could make oestrogen derivatives' thrombogenic impact stronger. Care should be taken while using hormone replacement treatment, and hormonal contraceptives are not advised, according to Canadian pomalidomide labelling. These precise guidelines are not included on the pomalidomide labelling in the US.
Somatropin	Estrogen derivatives may lessen Somatropin's therapeutic impact. shown to be of concern in postmenopausal women receiving oral hormone replacement treatment. Monitor for decreased growth hormone effectiveness. To get the desired therapy outcome, a higher somatropin dose could be necessary. Non-oral estrogens do not seem to be affected by this interaction (e.g., transdermal, vaginal ring).
St John's Wort	May lower the serum level of CYP3A4 substrates (High risk with Inducers). Management: Take into account a substitute for one of the interfering medications. Specific contraindications may apply to some combinations. the relevant manufacturer's label.
Tipranavir	Estrogen derivatives may intensify Tipranavir's unfavourable effect on the skin. A high incidence of skin rash was linked to the use of tipranavir/ritonavir and ethinyl estradiol/norethindrone together. The serum levels of oestrogen derivatives may drop when taking tipranavir. Management: Women who use hormonal contraceptives should think about non-hormonal alternatives.
TiZANidine	The concentration of TiZANidine in the serum may rise in response to CYP1A2 Inhibitors (Weak). Management: Whenever you can, stay away from these pairings. Tizanidine should be started at an adult dose of 2 mg and increased in 2 to 4 mg increments depending on the patient's reaction if combination use is required. Watch out for tizanidine side effects, such as increased effects.
Risk Factor X (Avoid combination)
Anastrozole	Estrogen derivatives may lessen anastrozole's therapeutic efficacy.
Dehydroepiandrosterone	Estrogen derivatives' harmful or toxic effects might be amplified.
Exemestane	Estrogen derivatives may reduce Exemestane's therapeutic efficacy.
Hemin	Estrogen derivatives may lessen Hemin's therapeutic impact.
Indium 111 Capromab Pendetide	Indium 111 Capromab Pendetide's diagnostic effectiveness may be reduced by oestrogen derivatives.
Ospemifene	Estrogen derivatives may intensify Ospemifene's harmful or hazardous effects. Ospemifene's therapeutic efficacy may be lessened by oestrogen derivatives.

Monitoring parameters:

Females:

• Baseline risk for breast cancer and CVD before treatment.
• Age-appropriate breast and pelvic exams, blood pressure, unexplained bleeding lasting more than six months for endometrial pathology (earlier in patients who are obese, diabetic, or have a history of endometrial cancer), serum triglycerides (2 weeks after starting therapy in patients with baseline level >200 mg/dL), and TSH are all important to monitor during treatment (6 to 12 weeks after starting oral therapy in patients taking thyroid replacement).

Menopausal symptoms:

• Efficacy starts 1 to 3 months after initiating therapy, and thereafter as needed, every 6 to 12 months.
• At the very least once a year, the length of the treatment should be assessed.

Note:

• Bone density measurement

Menostar:

• Management of vasomotor symptoms or GSM does not benefit from monitoring of FSH and serum estradiol. 
• Endometrial sample is advised every year or as clinically necessary in women who have uteruses.

Transgender hormone therapy:

• Serum testosterone levels (goal: 50 ng/dL), serum estradiol levels (target: 100 to 200 pg/mL), prolactin levels (as necessary), standard cancer and laboratory screening as in non-transgender people for all tissues, every three months during the first year, then annually or biannually after that.

How to administer Estradiol (Oestradiol, Alora)?

It's crucial to take progestin into account while giving estrogens postmenopausally to women who have uteruses.

• Injection formulation: Intramuscular only
  • Estradiol Cypionate:
    • To dissolve any crystals that might have formed during storage, shake the vial gently or warm it.
  • Estradiol valerate
    • Use a dry needle to inject into the upper outer quadrant of the gluteal muscles.
    • When used with a wet needle, the solution could become hazy.
• Gel
  • Apply to dry, clean skin every day.
  • After applying, wash your hands.
  • The gel can be flammable so avoid flame or fire until your skin is completely dry.
• Divigel
  • Apply solely to the vaginal, breast, and face areas. Never apply to skin that is inflamed.
  • Each day, you should apply the full contents of the packet to the upper thigh on either your right or left leg (or alternate sites).
  • Spread the adhesive over a surface measuring 5x7 inches
  • Wash the application area for at least 1 hour.
  • Before dressing, let the gel dry.
• Elestrin
  • Apply to the breasts and vaginal areas only.
  • Use only two fingers to spread the entire amount on your upper arm and shoulder region.
  • Make sure the skin has had at least five minutes to dry before putting on your clothes.
  • Before the first use of the pump, it must be primed.
  • The pump has 30 metered doses after priming; the pump should be discarded after 30 doses, even though it may not have been empty.
  • Wait 5 seconds before you pump the next dose if more than one dose is required.
  • You should not permit others to touch the gel application site for at least 2 hours after it has been applied.
  • Allow at least two hours between applying the gel and swimming.
  • Allow at least 25 minutes to pass before covering the area with sunscreen.
  • The absorption of estradiol increases when sunscreen and gel are used on the same area for more than 7 consecutive days.
  • Applying sunscreen to locations where the gel has been used for more than seven days in a row is not advised.
• EstroGel
  • Apply to the breasts and vaginal areas only.
  • Apply the dosage to the palm of your other hand and then the wrist and shoulder of the other arm.
  • Spread the gel as thinly as you can over one arm without massaging or rubbing it in.
  • Give the skin five minutes to dry before clothing.
  • The pump has to be primed before being used for the first time.
  • The pump has 32 daily doses (50g canister) and 14 daily doses after priming (12.5g canister).
  • Discard the pump after each dose has been consumed.
  • You should not permit others to touch the application site more than one hour after gel has been applied.
  • Between applying gel and swimming, wait as long as you can.
  • When sunscreen was applied an hour after gel had been applied to the same area for more than 7 days straight, the rate of estradiol absorption decreased. However, absorption increased when moisturising lotion was applied an hour after gel was applied to the same area for more than 7 days in a row.
  • It has not been proven that sunscreen or lotion applied before gel application can have any effect.
• Spray:
  • Spray the pump three times with the cap on before using it for the first time.
  • Keep the container vertical and straight up while spraying.
  • Spray the inner surface of your forearm starting at the elbow.
  • Apply to adjoining but not overlapping areas if more than one spray is required.
  • Each day, apply at the same moment.
  • Spray for 2 minutes.
  • Do not rub the skin.
  • The application area should be cleaned for at least 60 minutes.
  • Use just on the skin of your forearm on clean, dry, and undamaged skin.
  • Children should not be exposed to any skin that has been treated with the drug.
  • Wear long sleeves if you have to contact children.
  • Direct exposure is a possibility. Wash the child as soon as possible with soap and water.
  • The spray solution burns readily. Till the spray has dried, stay away from flame, fire, and smoking.
  • If you feel the need, apply sunscreen at least an hour before using Evamist.
• Transdermal patch
  • General instructions for use:
    • Apply the patch right away to your buttocks or lower abdomen after removing the protective pouch.
    • Apply to clean, dry skin that hasn't been lotion- or oil-sprayed, powdered, or oiled.
    • Avoid the area around your waistline and other areas that could rub the patch; don't apply to your breasts.
    • The patch should be applied and held in place for 10 seconds.
    • Allow a one-week gap between applications at each application site by rotating the application locations.
    • For the remainder of the dosage time, the patch can be reapplied if it gets loose, or a new system can be utilised.
    • Replace the patch by applying it again to a different site. To avoid irritation to the skin, remove the patch slowly.
    • After removing any adhesive, allow the skin to dry for at least 15 minutes. Then, use an oil-based lotion or cream to gently rub the affected area.
    • Fold the adhesive ends of any used or unused patches together before putting them in a bag or other airtight container for disposal.
• Climara, Menostar
  • It has not been proven safe to swim, bathe, or wear a patch in a sauna.
• Vaginal ring
  • It is not necessary to position the implant precisely for maximum efficacy. However, patients should not feel any discomfort once they are in place.
  • If you feel discomfort, push the ring further into your vagina.
  • You can rinse the ring with warm water and have it reinserted if it is not removed within 90 days.
  • To avoid accidental bladder insertion, ensure that the ring is properly placed in your vaginal area.
  • Femring can be left in place during treatment for a vaginal infections.

Mechanism of action of Estradiol (Oestradiol, Alora):

• Estrogens are essential for the growth and upkeep of the female reproductive system as well as the development of secondary sexual traits.
• The primary intracellular human oestrogen is estradiol, which is more powerful at the receptor level than estrone and estriol.
• The primary intracellular human oestrogen is also estradiol. At the receptor level, it is more effective than estrone or estriol.
• Estrogens control the pituitary secretion gonadotropins, luteinizing hormones and other negative feedback mechanisms. 
• Estrogen replacement can reduce estrogen levels in postmenopausal women.

Absorption

• The gut, mucous membranes and skin absorb the nutrients well.
• The average serum estradiol levels (C) differ by product.

Injection:

• Following IM injection, estradiol valerate and estradiol cypionate are absorbed over a period of many weeks.

Distribution:

• Widely distributed;
• high concentrations in the sex hormone target organs

Protein binding:

• Bound to sex hormone-binding globulin and albumin

Metabolism:

• Oral estradiol also undergoes enterohepatic recirculation by conjugation in the liver, followed by excretion of sulphate and glucuronide conjugates into the bile, then hydrolysis in the intestine and oestrogen reabsorption. Hepatic; partial metabolism via CYP3A4 enzymes; estradiol is reversibly converted to estrone and estriol.
• The main type identified in postmenopausal women is sulphate conjugates.
• Less estradiol is metabolised when applied transdermally, which results in higher circulating levels of estradiol and lower levels of estrone and conjugates.

Excretion:

• Primarily urine (as estradiol, estrone, estriol, and their glucuronide and sulfate conjugates)

International Brand Names of Estradiol:

• Alora
• Climara
• Delestrogen
• Depo-Estradiol
• Divigel
• Climara 50
• Climara 75
• Divigel
• Estrace
• Estradot 100
• Estradot 25
• Estradot 37.5
• Estradot 50
• Estradot 75
• Estrogel
• Lupin-Estradiol
• Oesclim
• PMS-Estradiol Valerate
• SANDOZ Estradiol Derm 100
• SANDOZ Estradiol Derm 50
• Elestrin
• Estrace
• Estrogel
• Evamist
• Femring
• Menostar
• Minivelle
• Vivelle-Dot
• Climara 100
• Climara 25
• SANDOZ Estradiol Derm 75
• Aerodiol
• Bedol
• Climaderm
• Climara
• Dermestril
• Dermestril Septem
• Estramon
• Estrapatch
• Estreva
• Estreva Gel
• Estrifam
• Estro-Pause
• Estrofem
• Estrofem Forte
• Estrogel
• Estrozhel
• Evopad
• Evorel
• Evorel Conti
• Fem
• Femanest
• Fematab
• Fematrix
• Feminova
• Femsept
• Femseven
• Femtran
• Ginoderm Gel
• Gynokadin
• Prosu 2
• Provames
• Pyvihel
• Sandrena
• Sandrena Gel
• Sisare Gel
• Thais
• Tradelia
• Valiera
• Vivelle-Dot
• Vivelledot
• Divigel
• Enadiol
• Estra Gel
• Estrade
• Estraderm
• Estraderm MX
• Estraderm TTS
• Estradiol Depot
• Estradot
• Gynova
• GynPolar
• Kliovance
• Lindisc
• Linoladiol N
• Lumelin 2
• MenodinRetard
• Menorest
• Merimono
• Oesclim
• Oestrodose
• Postmenop
• Preda
• Primogyn Depot
• Progyluton 21
• Progynon
• Progynon Depot
• Progynova
• Zumenon

Estradiol Brand Names in Pakistan:

Estradiol Injection 5 mg/ml
Ovlogyn	Zafa Pharmaceutical Laboratories (Pvt) Ltd.
Progynon Depot	Bayer Health Care

 

Estradiol Gel 60 mg
Oestrodose	Galaxy Pharma (Pvt) Ltd.

 

Estradiol Gel 1.25 gms
Oestrogel	Galaxy Pharma (Pvt) Ltd.