Estradiol

Estradiol is a synthetic sex hormone belonging to pharmacology class of Estrogen Derivative.

Estradiol can be used in the treatment of Breast cancer, metastatic; Osteoporosis, postmenopausal, prevention; Prostate cancer, advanced; Secondary amenorrhea, hypoestrogenism; Vasomotor symptoms associated with menopause; Vulvar and vaginal atrophy associated with menopause.

Estradiol is Well absorbed from the gastrointestinal tract, skin, and mucous membranes. Time to peak plasma concentration: 1.5-2 hours (oral) and Widely distributed in the body, with high concentrations in the sex hormone target organs. Enters breast milk. Plasma protein binding: Approx 30-52% to albumin and approx 46-69% to sex hormone binding globulin which get Metabolised in the liver partially by CYP3A4 enzymes to estrone and estriol. Undergoes enterohepatic recirculation (oral) and get excreted Mainly via urine as estradiol, estrone, estriol and its glucuronide and sulfate conjugates.

The common side effects of Estradiol includes: Increased risk of breast, endometrial, or ovarian cancers; endometrial hyperplasia, exacerbation of endometriosis, asthma, diabetes mellitus, epilepsy, migraine, porphyria, SLE, and hepatic hemangiomas; breakthrough bleeding and spotting, CV disorders.

Estradiol is available in the form of transdermal gel, injectable solution, tablet, transdermal patch, topical emulsion.

The molecule is available in India, Japan, Germany, China.

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 patients who are postmenopausal.

Estradiol is available in transdermal gel, injectable solution, tablet, transdermal patch, topical emulsion.

Estradiol can be used in the treatment of Breast cancer, metastatic; Osteoporosis, postmenopausal, prevention; Prostate cancer, advanced; Secondary amenorrhea, hypoestrogenism; Vasomotor symptoms associated with menopause; Vulvar and vaginal atrophy associated with menopause. It is also used to treat Hormone therapy for transgender females (assigned male at birth).

Estradiol is a synthetic sex hormone similar to endogenous estrogen. In post-menopausal women, estradiol substitutes for the loss of estrogen production and alleviates menopausal symptoms. It also reduces bone resorption and prevents postmenopausal bone loss.

Estradiol is approved for use in the following clinical indications:

• Breast cancer, metastatic: Treatment of metastatic breast cancer (palliation) in appropriately selected males and postmenopausal females.
• Osteoporosis, postmenopausal, prevention: Prevention of postmenopausal osteoporosis.
• Prostate cancer, advanced: Treatment of androgen-dependent advanced prostatic cancer (palliation).
• Secondary amenorrhea, hypoestrogenism: Treatment of hypoestrogenism due to hypogonadism, castration, or primary ovarian failure.
• Vasomotor symptoms associated with menopause: Treatment of moderate to severe vasomotor symptoms associated with menopause.
• Vulvar and vaginal atrophy associated with menopause: Treatment of moderate to severe vulvar and vaginal atrophy associated with menopause.

Although not approved there have been certain off labelled uses documented for Estradiol which includes:

Hormone therapy for transgender females (assigned male at birth)

Breast cancer, metastatic: Oral (Estrace): Males and postmenopausal females: 10 mg 3 times/day or (off-label dosing) postmenopausal females: 2 mg 3 times/day

Hormone therapy for transgender females (assigned male at birth), monotherapy or combination therapy (off-label use) :

IM:

Estradiol cypionate: 2 to 10 mg every week.

Estradiol valerate: 5 to 30 mg every 2 weeks.

Oral: 2 to 6 mg/day.

Transdermal: Apply 0.025 to 0.2 mg/day patch every 3 to 5 days. Note: Apply two 0.1 mg patches to create a 0.2 mg/day dose.

Note: Adjust dose with a goal of elevating serum estradiol levels and suppressing serum testosterone levels into the normal female range. Alternative routes of administration (eg, sublingual administration of the oral tablet or subcutaneous administration of the IM injection) may be used by some centers (limited data; additional study needed)

Osteoporosis, postmenopausal, prevention (alternative agent):

Note: For use as an alternative to first-line therapies to prevent bone loss in patients with moderate to severe vasomotor symptoms of menopause. In patients without menopausal vasomotor symptoms who require fracture risk reduction, other first-line therapies are preferred. Avoid initiating in patients >60 years of age or who are >10 years beyond menopause. Ensure adequate calcium and vitamin D intake during therapy.

Transdermal:

Note: Initial dose and dosage adjustments are individualized based on menopausal symptoms. Transdermal doses ≥0.025 mg/day have been associated with BMD benefits; separate therapy to reduce the risk of osteoporotic fractures is not required for patients who attain bone mineral density (BMD) targets .

Oral (Estrace): Initial dose and dosage adjustments are individualized based on menopausal symptoms. Oral doses ≥0.5 mg/day have been associated with BMD benefits; separate therapy to reduce the risk of osteoporotic fractures is not required for patients who attain BMD targets. The lowest effective dose has not been determined; estradiol increases BMD in a dose-dependent fashion, with higher doses (eg, 0.5 to 1 mg/day) being associated with greater BMD increases.

Duration of therapy: The optimal duration of therapy has not been established. Estrogens should be used for the shortest duration possible consistent with treatment goals. Extended use may be considered in patients in whom alternative therapies are not appropriate and when benefits of therapy are expected to outweigh risks.

Discontinuation of therapy: If continued osteoporosis therapy is necessary, switch to antiresorptive therapy (eg, with a bisphosphonate) following discontinuation.

Prostate cancer, advanced:

IM: 30 mg or more every 1 to 2 weeks.

Oral: 1 to 2 mg 3 times/day.

Secondary amenorrhea, hypoestrogenism:

Note: For functional hypothalamic amenorrhea (FHA), initiate only if menses have not returned after 6 to 12 months of nonpharmacologic (eg, behavioral, lifestyle) therapy. For hypoestrogenism due to other causes (eg, primary ovarian insufficiency), may initiate after diagnosis confirmed if no contraindications (eg, breast cancer). For patients with a uterus, give estrogen with either cyclical (preferred in FHA) or continuous progestogen (ie, a natural progesterone or synthetic progestin).

Oral: 1 to 2 mg per day.

Transdermal (Alora, Climara, Vivelle-Dot): 0.1 mg per day patch applied once weekly (Climara) or twice weekly (Alora, Vivelle-Dot) Note: For twice-weekly dosing, replace patch every 3 to 4 days. When switching from oral to transdermal therapy, start transdermal patch 1 week after discontinuing oral hormone (may begin sooner if symptoms reappear within 1 week).

IM: Note: IM route of administration is considered nonpreferred to oral or transdermal .

Duration of therapy: If amenorrhea is expected to be transient (eg, FHA), discontinue after ~18 months to assess for recovery . If amenorrhea is expected to be permanent (eg, primary ovarian insufficiency), continue at least until the average age of natural menopause (age ~50 years)

Vasomotor symptoms associated with menopause: Note: For use in symptomatic patients who are <60 years of age or within 10 years of menopause who do not have contraindications to hormone therapy (eg, breast cancer) . Nonoral estrogen preparations are preferred in patients with hypertriglyceridemia, risk factors for venous thromboembolic disease, active gallbladder disease, and/or migraine headache with aura. Initiate at the lowest dose and increase approximately every 4 weeks as needed to relieve symptoms . Evaluate routinely to minimize drug exposure and optimize administration route. Younger patients (eg, bilateral oophorectomy) may require higher doses. In patients with a uterus, give estrogen with a progestogen (i.e, a natural progesterone or synthetic progestin), dosed either cyclically (preferred in late menopausal transition or early postmenopause) or continuously (preferred if >2 to 3 years postmenopause).

Oral : Initial: 0.5 to 1 mg once daily. Dosage range: 0.5 to 2 mg per day

Topical gel:

Initial: 0.25 g per day. Dosage range: 0.25 to 1.25 g per day (equivalent to estradiol 0.25 to 1.25 mg per day); maximum: 1.25 g per day.

Initial: Apply 1 pump (0.87 g) at the same time each day (equivalent to estradiol 0.52 mg per day)

Topical spray: Initial: 1 spray (estradiol 1.53 mg) per day. Dosing range: 1 to 3 sprays per day.

Transdermal: Note: For twice-weekly dosing, replace patch every 3 to 4 days. When switching from oral to transdermal therapy, start transdermal patch 1 week after discontinuing oral hormone (may begin sooner if symptoms reappear within 1 week). When switching from other topical therapy, no waiting period is necessary.

Vaginal ring (Femring): Initial: 0.05 mg per day intravaginally every 3 months. Dosage range: 0.05 to 0.1 mg per day intravaginally every 3 months.

IM: Note: IM route of administration is considered nonpreferred to other routes

Duration of therapy: Not clearly established; continued use may be appropriate in patients ≥60 years of age or >10 years after menopause with a low risk of cardiovascular disease and breast cancer and with persistent vasomotor symptoms after attempted taper/discontinuation of estrogen and trial of alternative therapies. Evaluate routinely for comorbidities and appropriateness of lower doses, nonoral routes of administration (preferred in patients ≥60 years of age), choice of progestogen, and discontinuation of therapy

Vulvar and vaginal atrophy (moderate to severe) associated with menopause:

IM: 10 to 20 mg every 4 weeks.

Intravaginal: Vaginal ring (Femring): Initial: 0.05 mg intravaginally; following insertion, dose is released daily for 3 months. Usual dose: 0.05 mg to 0.1 mg intravaginally every 3 months.

Oral: 0.5 to 1 mg/day .

Topical gel: 1.25 g/day applied at the same time each day.

Transdermal: Note: Indicated dose may be used continuously in patients without a uterus. Continuous or cyclic schedules (3 weeks on, 1 week off) may be used in patients with a uterus (indication and product specific; refer to manufacturer's labeling). 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). Adjust dose as necessary.

Transdermal gel

• 0.06%
• 0.1%

Injectable solution

• 5mg/mL
• 10mg/mL
• 20mg/mL
• 40mg/mL

Tablet

• 0.45mg (as acetate)
• 0.5mg
• 0.9mg (as acetate)
• 1mg
• 1.5mg
• 2mg

Transdermal patch

• 0.025mg
• 0.0375mg
• 0.05mg
• 0.06mg
• 0.075mg
• 0.1mg

Topical emulsion

• 4.35mg/1.74g (0.25%)

Transdermal Gel, Injectable Solution, Tablet, Transdermal Patch, Topical Emulsion

Dose Adjustment in Pediatric Patient:

• Constitutional delay of growth and puberty (CDGP) (females): Limited data available: Children ≥12 years and Adolescents: Note: Begin with the lowest available dose and gradually increase. Obtain bone age every 6 months to avoid premature epiphyseal closure. If treatment continues beyond 1 year or breast growth is significant and has plateaued or breakthrough bleeding occurs, add cyclic progesterone. Continue until menstruation has been established, or longer if clinically indicated.
• Oral (micronized, Estrace): Initial dose: 5 mcg/kg once daily; after 6 to 12 months of therapy, may increase to 10 mcg/kg once daily. Using currently available dosage forms, some have recommended starting at a fixed dose of 0.25 mg once daily (1/2 of the 0.5 mg tablet) and increasing to 0.5 mg once daily after 6 to 12 months.
• Transdermal: Initial dose: 3.1 to 6.2 mcg/day patch (eg, ¹/₈ to ¹/₄ of a 25 mcg/day patch), apply at night, remove in the morning. Increase by 3.1 to 6.2 mcg/day patch every 6 months Note: The practice of cutting patches to achieve low doses is cited frequently in the literature ; however, product specific data may not be available for all transdermal products due to product availability/manufacturing changes.
• Hypogonadism (females): Limited data available: Children ≥12 years and Adolescents: Note: Begin with the lowest available dose and gradually increase. Obtain bone age every 6 months to avoid premature epiphyseal closure. Once breast growth is significant and has plateaued or breakthrough bleeding occurs, add cyclic progesterone. Continue until menstruation has been established, or longer if clinically indicated.
• Oral (micronized): Initial dose: 5 mcg/kg once daily for 6 to 12 months; may then increase to 10 mcg/kg/day for 6 to 12 months; dose may be increased at every 6 to 12 month intervals by 5 mcg/kg/day, up to 20 mcg/kg/day. Do not exceed adult dose of 2 mg daily .
• Transdermal: Initial dose: 3.1 to 6.2 mcg/day patch (eg, ¹/₈ to ¹/₄ of a 25 mcg/day patch), apply at night, remove in the morning. Increase by 3.1 to 6.2 mcg/day patch every 6 months; Do not exceed adult dose of 50 to 100 mcg/24 hours. Note: The practice of cutting patches to achieve low doses is cited frequently in the literature; however, product specific data may not be available for all transdermal products due to product availability/manufacturing changes.
• Turner syndrome (females): Limited data available: Children ≥12 years and Adolescents: Begin at ~12 years of age using a low dose and gradually increase dose over 2 to 4 years to full adult dose. After 2 years of estrogen or when breakthrough bleeding occurs, add cyclic progesterone. Note: Full dose estrogen will be needed until at least age 30 years .
• IM: Cypionate (Depot-Estradiol): Initial: 0.2 to 0.4 mg every 4 weeks, slowly increase dose over about 2 years to the goal adult dose: 3 mg/month; one trial started at 0.2 mg/dose, then increased dose at 6 month intervals in 0.2 mg/dose increments until dose of 1 mg reached and then increased in 0.5 mg/dose increments thereafter to a final dose of 3 mg .
• Oral (micronized, Estrace): Initial dose: 5 mcg/kg once daily for the first 2 years, followed by 7.5 mcg/kg for the 3rd year, then 10 mcg/kg thereafter; once final height is attained, increase to adult dose of 1 to 2 mg/day. A fixed dose of 0.25 mg once daily; increasing to the adult dose of 2 to 4 mg/day over the course of 2 years has also been suggested. Note: Due to extensive first-pass metabolism, other routes of administration may be preferable.
• Topical gel (Divigel): Initial: 0.1 mg of estradiol once daily for the first year, 0.2 mg of estradiol once daily for the second year, 0.5 mg of estradiol once daily for the third year, 1 mg of estradiol once daily for the fourth year, and 1.5 mg of estradiol once daily for the fifth year. Dosing based on a trial of 23 girls that followed development for 5 years; long-term dose is unknown. Due to lack of commercially available product for lower doses, individual sachets of 0.1 mg estradiol were prepared .
• Transdermal patch: Initial: 6.25 mcg/day patch; slowly increase over about 2 years to the goal adult dose: 100 to 200 mcg/day patch.
• Note: The lowest-dose commercially available patches deliver 14 and 25 μg daily; preferred dose fractionation method has not been established (eg, administering a partial patch, limiting to overnight use, or administering whole patches for 7 to 10 days per month). Product specific data may not be available for splitting/cutting some transdermal patches; one center has used the following titration method using Vivelle-Dot product:

Treatment month:

• 0 to <6 months of treatment: 3.125 mcg to 4.17 mcg/dose (equals ¹/₈ to ¹/₆ of a 25 mcg/day patch), apply at night, remove in the morning (not continuous)
• 0 to <12 months of treatment: 3.125 mcg to 4.17 mcg/dose (equals ¹/₈ to ¹/₆ of a 25 mcg/day patch) apply twice weekly (continuous)
• 12 to <18 months of treatment: 6.25 mcg to 8.33 mcg/dose (equals ¹/₄ to ¹/₃ of a 25 mcg/day patch), apply twice weekly (continuous)
• 18 to <24 months of treatment: 12.5 mcg/dose (equals ¹/₂ of a 25 mcg/day patch), apply twice weekly (continuous)
• ≥24 months of treatment: 25 mcg/day patch, apply twice weekly (continuous); then increase by one patch strength every 6 months to a final goal of 100 mcg/day continuously.

Estradiol may be contraindicated in the following conditions:-

Concerns related to adverse effects:

• Anaphylaxis: Anaphylaxis requiring emergency medical management has been reported and may develop at any time during therapy. Angioedema involving the face, feet, hands, larynx, and tongue has also been reported.

• Breast cancer: Based on data from the Women’s Health Initiative (WHI) studies, an increased risk of invasive breast cancer was observed in patients who are postmenopausal using conjugated estrogens (CE) in combination with medroxyprogesterone acetate (MPA). Observational studies noted this risk declines once therapy is discontinued. The WHI study did not observe an increased risk of invasive breast cancer in patients with a hysterectomy using CE alone. The risk of breast cancer in patients who are postmenopausal receiving hormone therapy may depend upon type of estrogen and/or progestogen, dose, timing of therapy initiation, duration of therapy, route of administration, and individual patient characteristics. Hormone therapy may be associated with increased breast density ; an increase in abnormal mammogram findings requiring further evaluation has been reported with estrogen alone or in combination with progestogen therapy. Estrogen use may lead to severe hypercalcemia in patients with breast cancer and bone metastases; discontinue estrogen if hypercalcemia occurs.

• Dementia: Do not use estrogens with or without progestogen to prevent dementia. In the Women’s Health Initiative Memory Study , an increased incidence of probable dementia was observed in patients ≥65 years of age taking CE alone or in combination with MPA. Because the WHIMS was conducted in patients ≥65 years of age, it is unknown if these findings apply to younger patients who are postmenopausal. However, hormone therapy is not recommended at any age to prevent or treat cognitive decline or dementia.

• Endometrial cancer: The use of unopposed estrogen in patients with a uterus is associated with an increased risk of endometrial cancer. The addition of a progestogen to estrogen therapy may decrease the risk of endometrial hyperplasia, a precursor to endometrial cancer. Perform adequate diagnostic measures, including endometrial sampling if indicated, to rule out malignancy in patients who are postmenopausal with undiagnosed abnormal vaginal bleeding. There is no evidence that the use of natural estrogens results in a different endometrial risk profile than synthetic estrogens at equivalent estrogen doses. The risk of endometrial cancer appears to be dose and duration dependent, greatest with use ≥5 years, and may persist following discontinuation of therapy. The use of a progestogen is not generally required when low doses of estrogen are used locally for vaginal atrophy, although long-term data (>1 year) supporting this recommendation are lacking.

• Endometriosis: Estrogens may exacerbate endometriosis. Malignant transformation of residual endometrial implants has been reported posthysterectomy with unopposed estrogen therapy. Consider adding a progestogen in patients with residual endometriosis posthysterectomy.

• Lipid effects: Estrogen compounds are generally associated with lipid effects such as increased HDL-cholesterol and decreased LDL-cholesterol. Triglycerides may also be increased in patients with preexisting hypertriglyceridemia; discontinue if pancreatitis occurs.

• Ovarian cancer: Available information related to the use of menopausal estrogen or estrogen/progestogen therapy and risk of ovarian cancer is inconsistent. If an association is present, the absolute risk is likely rare and may be influenced by duration of therapy .

• Retinal vascular thrombosis: Estrogens may cause retinal vascular thrombosis; discontinue if migraine, loss of vision, proptosis, diplopia, or other visual disturbances occur; discontinue permanently if papilledema or retinal vascular lesions are observed on examination.

There is no sufficient scientific evidence traceable regarding use and safety of Estradiol in concurrent use with alcohol.

Estrogens are present in breast milk.

Estrogens have been shown to decrease the quantity and quality of human milk. According to the manufacturer, the decision to breastfeed during therapy should consider the risk of infant exposure, the benefits of breastfeeding to the infant, and the benefits of treatment to the mother. Monitor the growth of the infant closely.

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

The adverse reactions related to Estradiol can be categorized as

Common Adverse effects:

Increased risk of breast, endometrial, or ovarian cancers; endometrial hyperplasia, exacerbation of endometriosis, asthma, diabetes mellitus, epilepsy, migraine, porphyria, SLE, and hepatic hemangiomas; breakthrough bleeding and spotting, CV disorders

Less Common Adverse effects:

impotence and feminizing effects in males (when used as palliative treatment for advanced prostate cancer), severe hypercalcemia in patients with breast cancer and bone metastases; UTI, vaginal irritation or infection (vaginal); breast budding or masses in prepubertal females, gynecomastia and breast masses in prepubertal males (due to secondary exposure to transdermal spray).

Rare Adverse effects:

Cough, sinus congestion, sinusitis, nasopharyngitis, pharyngitis, upper respiratory tract infection, bronchitis, rhinitis.

The clinically relevant drug interactions of Estradiol is briefly summarized here:

May increase plasma concentrations with CYP3A4 inhibitors (e.g. fluconazole, clarithromycin, verapamil, diltiazem).

May decrease plasma concentrations with CYP3A4 inducers (e.g. phenobarbital, carbamazepine, phenytoin, griseofulvin, rifampicin, efavirenz).

May increase or decrease plasma concentrations with protease inhibitors (e.g. ritonavir, nelfinavir). Decreases absorption of folic acid.

May increase serum concentration of tacrolimus, ciclosporin, fentanyl, and theophylline.

The most common side effects of Estradiol includes: Increased risk of breast, endometrial, or ovarian cancers; endometrial hyperplasia, exacerbation of endometriosis, asthma, diabetes mellitus, epilepsy, migraine, porphyria, SLE, and hepatic hemangiomas; breakthrough bleeding and spotting, CV disorders.

Pregnancy Category X

Labor and Delivery

There is no FDA guidance on use of Estradiol during labor and delivery.

Nursing Mothers

There is no FDA guidance on the use of Estradiol (oral) with respect to nursing mothers.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established. Large and repeated doses of estrogen over an extended period of time have been shown to accelerate epiphyseal closure, resulting in short adult stature if treatment is initiated before the completion of physiologic puberty in normally developing children. In patients in whom bone growth is not complete, periodic monitoring of bone maturation and effects on epiphyseal centers is recommended.

Estrogen treatment of prepubertal children also induces premature breast development and vaginal cornification, and may potentially induce vaginal bleeding in girls. In boys, estrogen treatment may modify the normal pubertal process. All other physiological and adverse reactions shown to be associated with estrogen treatment of adults could potentially occur in the pediatric population, including thromboembolic disorders and growth stimulation of certain tumors. Therefore, estrogens should only be administered to pediatric patients when clearly indicated and the lowest effective dose should always be utilized.

Geriatric Use

The safety and efficacy of estradiol tablets in geriatric patients has not been established. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greatest frequency of decreased hepatic, renal or cardiac function, and of concomitant disease or other drug therapy.

In the Women’s Health Initiative Memory Study, including 4,532 women 65 years of age and older, followed for an average of 4 years, 82% (n = 3,729) were 65 to 74 while 18% (n = 803) were 75 and over. Most women (80%) had no prior hormone therapy use. Women treated with conjugated estrogens plus medroxyprogesterone acetate were reported to have a two-fold increase in the risk of developing probable dementia. Alzheimer’s disease was the most common classification of probable dementia in both the conjugated estrogens plus medroxyprogesterone acetate group and the placebo group. Ninety percent of the cases of probable dementia occurred in the 54% of women that were older than 70.

Gender

There is no FDA guidance on the use of Estradiol (oral) with respect to specific gender populations.

Race

There is no FDA guidance on the use of Estradiol (oral) with respect to specific racial populations.

Renal Impairment

There is no FDA guidance on the use of Estradiol (oral) in patients with renal impairment.

Hepatic Impairment

There is no FDA guidance on the use of Estradiol (oral) in patients with hepatic impairment.

Females of Reproductive Potential and Males

There is no FDA guidance on the use of Estradiol (oral) in women of reproductive potentials and males.

Immunocompromised Patients

There is no FDA guidance one the use of Estradiol (oral) in patients who are immunocompromised.

Symptoms: Nausea, vomiting, dizziness, sleepiness, fatigue, bloating, abdominal pain, breast pain or tenderness, withdrawal bleeding.

Management: Symptomatic treatment was well tolerated; in multiple-dose trials, the largest dose of 10 mg was well tolerated.

Pharmacodynamics:

• Endogenous estrogens are largely responsible for the development and maintenance of the female reproductive system and secondary sexual characteristics. Although circulating estrogens exist in a dynamic equilibrium of metabolic interconversions, estradiol is the principal intracellular human estrogen and is substantially more potent than its metabolites, estrone and estriol, at the receptor level.
• The primary source of estrogen in normally cycling adult women is the ovarian follicle, which secretes 70 to 500 mcg of estradiol daily, depending on the phase of the menstrual cycle. After menopause, most endogenous estrogen is produced by conversion of androstenedione, secreted by the adrenal cortex, to estrone by peripheral tissues. Thus, estrone and the sulfate conjugated form, estrone sulfate, are the most abundant circulating estrogens in postmenopausal women.
• Estrogens act through binding to nuclear receptors in estrogen-responsive tissues. To date, two estrogen receptors have been identified. These vary in proportion from tissue to tissue.
• Circulating estrogens modulate the pituitary secretion of the gonadotropins, luteinizing hormone (LH) and follicle stimulating hormone (FSH), through a negative feedback mechanism. Estrogens act to reduce the elevated levels of these hormones seen in postmenopausal women.

Pharmacokinetics:

Absorption: Well absorbed from the gastrointestinal tract, skin, and mucous membranes. Time to peak plasma concentration: 1.5-2 hours (oral).

Distribution: Widely distributed in the body, with high concentrations in the sex hormone target organs. Enters breast milk. Plasma protein binding: Approx 30-52% to albumin and approx 46-69% to sex hormone binding globulin (SHBG).

Metabolism: Metabolized in the liver partially by CYP3A4 enzymes to estrone and estriol. Undergoes enterohepatic recirculation (oral).

Excretion: Mainly via urine as estradiol, estrone, estriol and its glucuronide and sulfate conjugates Patient Counseling Information

1. https://www.uptodate.com/contents/ Estradiol -drug-information?search= Estradiol &source=panel_search_result&selectedTitle=1~148&usage_type=panel&kp_tab=drug_general&display_rank=1#F154338
2. https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/022352s017lbl.pdf
3. https://www.medicaid.nv.gov/Downloads/provider/ Estradiol _2015-1215.pdf
4. https://www.mims.com/india/drug/info/ Estradiol ?type=full&mtype=generic#mechanism-of-action