Indications

Estrogen is a steroid hormone associated with the female reproductive organs and is responsible for developing female sexual characteristics. Estrone (E1), estradiol (E2), and estriol (E3) are the three primary endogenous estrogens.[1] Of the previously mentioned forms of estrogen, estradiol is the most common form of estrogen for hormone replacement therapy (HRT) in the treatment of symptoms of menopause. Estrogen for hormone replacement therapy has been heavily researched in medicine and remains a controversial topic. According to early studies, estrogen as hormone replacement therapy for postmenopausal women showed promising benefits of decreased risk of osteoporosis, coronary arterial disease, and mortality.[2] Later studies conducted by the Women's Health Initiative concluded that the risk was greater than the benefit of hormone replacement therapy in postmenopausal women.

The Women's Health Initiative ended clinical studies prematurely because participants in the study developed an increased risk of breast cancer and coronary artery disease.[3] Newer studies contradict the findings of the Women's Health Initiative, with evidence of improved quality of life and reduced risk of coronary artery disease and osteoporosis in women when they start estrogen hormone replacement therapy at the onset of menopause.[4] The FDA has approved estrogen for hormone replacement therapy in the treatment of symptoms of menopause.[5] Synthetic estrogens are also available for clinical use, designed to increase absorption and effectiveness by altering the chemical structure of estrogen for topical or oral administration. Synthetic steroid estrogens include ethinyl estradiol, estradiol valerate, estropipate, conjugate esterified estrogen, and quinestrol. Ethinyl estradiol is a commonly used synthetic estrogen to prevent pregnancy as a component of the oral contraceptive pill approved by the FDA.[6] Some nonsteroidal synthetic estrogens include dienestrol, diethylstilbestrol, benzestrol, methestrol, and hexestrol. According to the North American Menopause Society, vaginal estradiol and vaginal DHEA can be used for moderate to severe dyspareunia, which is a symptom of vulvovaginal atrophy resulting from menopause. Hormone therapy remains the gold standard for relieving vasomotor symptoms. Estrogen-only therapy can be used for symptomatic women who do not have a uterus.[7]

FDA-Approved Indications

• Primary ovarian insufficiency
• Female hypogonadism
• Symptoms associated with menopause, including vulvovaginal atrophy, dyspareunia, hot flashes, and night sweats, and the prevention of osteoporosis [8][9] 
• Oral contraceptive pill (OCP) to prevent pregnancy
• Moderate acne vulgaris 
• Prostate cancer with advanced forms of metastasis

Off-Label Uses

Estrogen/synthetic estrogen has the following non–FDA-approved indication for polycystic ovarian syndrome to relieve symptoms of hyperandrogenism and amenorrhea.[10][11] Vaginal estrogen therapy (eg, estradiol vaginal tablets or cream) may be considered for the treatment of genitourinary syndrome of menopause in breast cancer survivors, including those with a history of hormone receptor–positive breast cancer, when non-hormonal therapies have failed or are inadequate.[12]

Mechanism of Action

Estrogen enters the systemic circulation as either a free hormone or a protein-bound hormone, typically bound to sex hormone-binding globulin (SHBG) or albumin. Unbound (free) estrogen readily diffuses into cells without regulatory control. The cellular physiological response to estrogen begins in the cell cytoplasm, where estrogen binds to either the alpha-estrogen receptor or the beta-estrogen receptor. The activated estrogen-estrogen receptor complex then enters the nucleus of cells to induce DNA transcription by binding to nucleotide sequences known as estrogen response elements (EREs), thereby enacting a physiological response. Estrogen hormone levels in the body are regulated by the negative feedback effect of estrogen on the hypothalamus and pituitary gland. An example of negative feedback can be observed during the menstrual cycle.[13][14][15]

The effects of estrogen on various systems of the body are described below:

• Breast: Estrogen is responsible for developing mammary gland tissue and parenchymal and stromal changes in breast tissue at puberty in females. Estrogen is also responsible for the development of mammary ducts during puberty and pregnancy, and functions to secrete breast milk in postpartum lactation.
• Uterus: In the uterus, estrogen helps proliferate endometrial cells in the follicular phase of the menstrual cycle, thickening the endometrial lining in preparation for pregnancy.
• Contraception: Ethinyl estradiol, an ingredient of OCPs, functions to suppress the hypothalamic release of gonadotropin-releasing hormone (GnRH) and pituitary release of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) in preventing ovulation during the menstrual cycle.
• Vagina: Estrogen supports the proliferation of epithelial mucosa cells of the vagina and the vulva. In the absence of estrogen, the vaginal and vulvar mucosal epithelium becomes thin, presenting with symptoms of dryness known as vulvovaginal atrophy.[16]
• Bone: During puberty, estrogen aids in the development of long bones and the fusion of the epiphyseal growth plates.[17] Estrogen protects bones by inactivating osteoclast activity, preventing osteoporosis in both estrogen-deficient and postmenopausal women.[18]
• Cardiovascular: Estrogen affects plasma lipids by increasing high-density lipoproteins (HDL) and triglyceride levels, while decreasing low-density lipoproteins (LDL) and total plasma cholesterol, and thereby reducing the risk of coronary artery disease in postmenopausal women.[19]

Pharmacokinetics

Absorption: Estradiol is well absorbed from the gastrointestinal tract and the vaginal mucosa. The extent of absorption and resulting serum concentrations vary depending on the route and formulation. Oral estradiol is subject to significant first-pass metabolism in the liver, resulting in variations in its bioavailability. Vaginal absorption is efficient and bypasses much of the hepatic first-pass effect. Intramuscular formulations, such as estradiol valerate and estradiol cypionate, are absorbed slowly, resulting in prolonged release and sustained serum concentrations. Average serum estradiol concentrations differ across products and formulations.

Distribution: The distribution of exogenous estrogens resembles that of endogenous estrogens. Estradiol is widely distributed in the body, with higher concentrations in estrogen-responsive tissues. In systemic circulation, estradiol binds strongly to sex hormone-binding globulin (SHBG) and, to a lesser extent, to albumin, leaving only a small free fraction that is pharmacologically active.

Metabolism: Estradiol is primarily metabolized in the liver through oxidative and conjugative pathways. It undergoes reversible conversion to estrone, and both estradiol and estrone are further metabolized to estriol, the primary urinary estrogen metabolite. Hepatic metabolism involves CYP3A4. Estradiol and its metabolites undergo enterohepatic recirculation following conjugation with glucuronic acid or sulfate; they are excreted into the bile, hydrolyzed in the intestine, and reabsorbed. In postmenopausal women, a significant portion of circulating estrogens is present as estrone sulfate, which functions as a reservoir for conversion to active estrogens. Transdermal administration bypasses the liver, resulting in higher circulating estradiol levels and lower concentrations of estrone and conjugated estrone.[13][14][15]

Excretion: Estradiol, along with its primary metabolites estrone and estriol, is excreted primarily via the urine. These are eliminated mostly as glucuronide and sulfate conjugates. A minor fraction is excreted in the feces.

Administration

Estrogen hormone therapy may be prescribed in the following combinations as either estrogen-only medication or estrogen and hormone combination medication to treat symptoms of menopause, prevent osteoporosis, prevent pregnancy, treat hypoestrogenism, and treat metastatic breast and advanced prostate cancers.

Available Estrogen Preparations

Oral

• Estrogen: Conjugated may be prescribed in the dosage of 0.3 mg, 0.625 mg, 0.9 mg, and 1.25 mg tablets
• Estradiol may be prescribed in the dosage of 0.5 mg, 1 mg, and 2 mg tablets.
• Norethindrone/ethinyl estradiol 1.5 mg/30 mcg tablets for oral contraception

Vaginal Ring

• Combination estrogen-etonogestrel/ethinyl estradiol hormone vaginal ring for contraception: 0.12 mg/0.015 mg per day.  
• Estradiol only vaginal ring for vulvovaginal atrophy: 7.5 mcg per day[20]

Intramuscular Injection

• Estradiol valerate is administered as an intramuscular injection in the dosage of 10 mg per mL, 20 mg per mL, and 40 mg per mL for vasomotor symptoms of menopause, vulvovaginal atrophy, and hypoestrogenism.
• Estradiol cypionate is administered as an intramuscular injection in a dosage of 5 mg per mL to treat moderate-to-severe symptoms of menopause.
• Recommendations for IM or SC palliative treatment for advanced prostate cancer depend on the precise formulation used and whether it is accompanied by concomitant oral therapy.

Transdermal

Available as a topical cream, topical spray, vaginal cream, vaginal tablet insert, and transdermal patch

• Estradiol topical gel (0.006%): 0.52 mg per pump
• Estradiol topical spray applied to the inner surface of the forearm: 1.53 mg per actuation.
• Estradiol hemihydrate tablet for vaginal insert may be prescribed at the following dosage: 10 mcg or 25 mcg tablet.
• Estrogen, conjugated vaginal cream: 0.625 mg per gram applied intravaginally.
• Estradiol transdermal patches may be prescribed at the following dosages: 0.025 mg, 0.05 mg, 0.075 mg, or 0.1 mg per day.

Specific Patient Populations 

Hepatic Impairment: Systemic estrogens experience significant hepatic metabolism. Impaired liver function reduces metabolic clearance, increasing systemic exposure and the risk of adverse outcomes like cholestasis or hepatic neoplasms. Estrogen therapy is contraindicated in patients with active liver disease.

Renal Impairment: Estrogens are not primarily excreted through the kidneys; however, renal dysfunction can affect estrogen pharmacokinetics by changing plasma protein levels and hormone-binding globulins. No dosage adjustments are needed, but careful clinical monitoring is essential.

Pregnancy Considerations: Estrogens are avoided in pregnancy due to potential harm to the developing fetus, especially in sexual differentiation. If pregnancy occurs during treatment, discontinue the medication promptly.

Breastfeeding Considerations: Estrogens can be transferred into human breast milk and have been shown to reduce both milk production and quality. The presence of exogenous estrogen in breast milk may have unknown effects on the nursing infant’s development. As such, estrogen use during lactation is generally discouraged unless no suitable alternatives exist and the benefit outweighs the potential risk.

Pediatric Patients: Systemic estrogen use in children and adolescents is not routinely recommended due to unclear safety and efficacy. High or prolonged exposure may prematurely close epiphyseal growth plates, limiting adult height. Other effects include early breast development, vaginal changes or bleeding in females, and delayed puberty in males. Pediatric patients face risks seen in adults, like thromboembolic events and stimulation of estrogen-sensitive tissues. If estrogen therapy is necessary in pediatrics, monitor growth, puberty, and skeletal development closely, using the lowest effective dose.

Older Patients: According to the 2023 American Geriatrics Society (AGS) Beers Criteria, systemic estrogen therapy, including both natural and synthetic formulations, with or without progestins, should not be newly initiated in older women. Among women aged 60 years and older, the use of systemic hormone replacement therapy is associated with an increased risk of coronary artery disease, venous thromboembolism, and cerebrovascular accidents. However, low-dose intravaginal estrogen formulations such as creams or vaginal tablets containing estradiol ≤25 micrograms, administered up to twice weekly, are considered appropriate for the treatment of dyspareunia, recurrent lower UTI, and vaginal atrophy. These localized therapies are generally regarded as safe and effective.[21]

Adverse Effects

Natural and synthetic estrogen may cause the following common adverse effects: breast tenderness, nausea, vomiting, bloating, stomach cramps, headaches, weight gain, hyperpigmentation of the skin, hair loss, vaginal itching, abnormal uterine bleeding, also known as breakthrough bleeding, and anaphylaxis.

Weight gain may be recognized as an adverse effect associated with the oral contraceptive pill (OCP) containing ethinyl estradiol; however, studies investigating both short-term and long-term usage of OCPs have demonstrated no correlation with weight gain.[22][23]

Severe adverse drug reactions of estrogen include hypertension, cerebrovascular accident, myocardial infarction, venous thromboembolism, pulmonary embolism, exacerbation of epilepsy, irritability, exacerbation of asthma, galactorrhea and nipple discharge, hypocalcemia, gallbladder disease, hepatic hemangioma and adenoma, pancreatitis, breast hypertrophy, endometrial hyperplasia, vaginitis, vulvovaginal candidiasis (intravaginal preparations), enlargement of uterine fibroids, and risk of cervical cancer and breast cancer.

Drug-Drug Interactions

• CYP3A4 inhibitors: The inhibitors of CYP3A4 can increase plasma concentrations of estrogens, resulting in a higher incidence of estrogen-related adverse effects. Notable CYP3A4 inhibitors include erythromycin, clarithromycin, ketoconazole, itraconazole, ritonavir, and grapefruit juice.

• CYP3A4 inducers: In vitro and in vivo studies have demonstrated that CYP3A4 partially metabolizes estrogens. Inducers of CYP3A4 may decrease plasma concentrations of estrogens, leading to reduced therapeutic efficacy and alterations in the uterine bleeding profile. Common inducers of CYP3A4 include St. John’s Wort, phenobarbital, carbamazepine, and rifampin.

• Tizanidine: Ethinyl estradiol in combined oral contraceptives inhibits CYP1A2, leading to reduced presystemic metabolism of tizanidine and significantly increased plasma levels and pharmacodynamic effects. Coadministration may enhance tizanidine-induced hypotension; caution is warranted.

Drug-Laboratory Interactions

• Effects on hemostasis and coagulation parameters: Estrogen administration has a complex effect on the coagulation cascade. It decreases prothrombin time (PT) and activated partial thromboplastin time (aPTT). Additionally, estrogen enhances hepatic synthesis of several clotting factors, resulting in elevated plasma levels of Factors II, VII, VIII, IX, X, and XII. The coagulation complexes, such as II–VII–X and VII–X, are also increased. Conversely, estrogen reduces the levels and functional activity of natural anticoagulants, including antithrombin III and anti–factor Xa.

• Effects on thyroid function tests: Estrogens increase hepatic production of thyroid-binding globulin (TBG), resulting in elevated total serum concentrations of thyroid hormones. This results in increased T4 and T3 levels, along with elevated protein-bound iodine (PBI). However, levels of free T4 and free T3 remain unchanged, while T3 resin uptake is reduced due to higher TBG. These alterations may necessitate dose adjustments in patients undergoing thyroid hormone replacement therapy.

• Effects on other plasma-binding proteins: Estrogens upregulate the synthesis of various binding globulins. Levels of corticosteroid-binding globulin (CBG) and sex hormone–binding globulin (SHBG) are notably increased, leading to higher total levels of circulating corticosteroids and sex steroids. However, free hormone fractions may be reduced. Estrogens also increase the production of other liver-derived proteins, such as ceruloplasmin and alpha-1 antitrypsin.

• Effects on lipid profile: Estrogen therapy favorably alters lipid metabolism by increasing high-density lipoprotein (HDL) cholesterol levels and reducing low-density lipoprotein (LDL) cholesterol levels, while also increasing plasma triglycerides. Monitoring is required. 

• Effects on glucose tolerance and endocrine testing: Estrogens impair glucose tolerance, likely through reduced insulin sensitivity and altered hepatic glucose output. Additionally, estrogen blunts the response to the metyrapone test, likely due to increased levels of corticosteroid-binding globulin and alterations in the hypothalamic-pituitary-adrenal (HPA) axis.

Contraindications

The following are contraindications for the use of natural estrogen and synthetic estrogen derivatives:  

• Estrogen hormone receptor-sensitive malignancies, including breast cancer, ovarian cancer, and endometrial cancer
• Coronary artery disease
• History of thromboembolism or thrombophlebitis
• History of hypercoagulable disease (Factor V Leiden syndrome, Protein C or Protein S deficiencies, and metastatic disease)
• History of ischemic stroke
• Migraine headaches
• Seizure disorder
• History of dementia or neurocognitive disorders
• Hypertension
• Uterine leiomyomas
• Endometriosis
• Urinary incontinence
• Hyperlipidemia
• Gallbladder disease [24]
• Liver disease
• History of tobacco use
• Estradiol use in pregnancy is classified as pregnancy risk factor category X, and the use of esterified estrogens is contraindicated during pregnancy.

Box Warnings

The use of estrogen without progestins increases the risk of endometrial cancer. The use of estrogen with and without progestins resulted in an increased risk of myocardial infarction, stroke, pulmonary emboli, and deep vein thrombosis in postmenopausal women (aged 50 to 79 years) and an increased risk of invasive breast cancer in postmenopausal women (aged 50 to 79 years) with oral conjugated estrogens with medroxyprogesterone by studies established by the Women’s Health Initiative. The use of oral conjugated estrogens plus medroxyprogesterone acetate increased the risk of developing dementia in postmenopausal women older than 65 years of age, as established by the Women’s Health Initiative Memory Study.[3][25] 

Warnings and Precautions

US Preventive Services Task Force (USPSTF) Score-D: Using estrogen-alone or combined estrogen and progestin to prevent a chronic condition in postmenopausal women with or without a uterus is not recommended by the US Preventive Services Task Force (USPSTF).[26]

Gallbladder disease: The risk of gallbladder disease in postmenopausal women receiving estrogens has been reported.

Hypercalcemia: Estrogen can cause significant hypercalcemia in breast cancer patients with bone metastases. If hypercalcemia develops, discontinue the drug and take appropriate steps to lower the serum calcium level.

Retinal vascular thrombosis: According to the product label, retinal vascular thrombosis may occur in patients on estrogens. Discontinue the medication in the event of a sudden loss of vision, diplopia, proptosis, or. If papilledema or retinal lesions are identified, permanently discontinue the use of estrogens. However, the study found no increased risk of retinal artery occlusion or retinal vein occlusion in patients prescribed female hormone therapy regardless of age, diabetes, or hypertension.[27] Combined oral contraceptives with 30–40µg estrogen were linked to a modestly increased risk of retinal vein occlusion, while low-dose (20µg) and intrauterine hormonal methods showed no such association. Clinically, this suggests preferring lower-dose or non-systemic contraceptives in women at risk for thrombotic events.[28]

Monitoring

Before initiating estrogen therapy, clinicians should perform screening to assess the patient's risk of breast cancer, endometrial cancer, cardiovascular disease, including stroke, venous thrombosis, and myocardial infarction. Patients should also be screened for hypertension before starting estrogen therapy, and patients should continue to be monitored for the development of hypertension while taking estrogen. Routine women's wellness exams, including mammography and pap smear, should be continued during hormone replacement therapy with estrogen. Smoking cessation should be encouraged before the start and duration of OCPs since tobacco use increases the risk of venous thrombosis.[29]

The Endocrine Society recommends monitoring patients' improvement of postmenopausal symptoms while taking estrogen as hormone replacement therapy at the following intervals: first 1 to 3 months of treatment, then re-evaluated at 6 to 12 months of treatment annually after the first year.[30]

Toxicity

Signs and Symptoms of Overdose

Although estrogen toxicity is not commonly described in the literature, numerous studies have shown that chronic exposure to estrogen poses a risk for the development of hormone-sensitive malignancy, increases the estrogen-containing risk of dementia and cardiovascular diseases in postmenopausal women treated with hormone replacement therapy. Symptoms of excess estrogen exposure include heavy menstruation, irritability and mood swings, headaches, sleep disturbances, breast cysts, endometriosis, fibroids, gallbladder disease, and thyroid disorders. Excess estrogen should also be considered in males who present with symptoms of infertility and gynecomastia. High estrogen levels should raise suspicion for exposure to environmental estrogen, overexpression of the aromatase enzyme, and ectopic production of estrogens from hormone-producing malignant tissues. In addition to concerns about estrogen excess, it is crucial to consider potential drug-to-drug interactions that may induce or inhibit estrogen metabolism through the CYP3A4 enzyme in the liver.[14] A case report describes a 29-year-old woman who developed acute pulmonary embolism following the ingestion of 17 tablets containing cyproterone acetate 2 mg and ethinyl estradiol 0.035 mg in a suicide attempt.[Case Report: Pulmonary embolism due to exogenous estrogen intoxication. 2017]

Management of Overdose

A pulmonary embolism may require thrombolytic therapy depending on the patient's hemodynamic status, followed by systemic anticoagulation.[31]

Enhancing Healthcare Team Outcomes

Using estrogen to treat postmenopausal symptoms and as a component of the oral contraceptive pill to prevent pregnancy remains widely available as an FDA-approved therapy, regardless of the known risks and benefits to women's health. For any patient of postmenopausal age, clinicians must ask patients about any history of estrogen hormone replacement therapy or use of estrogen oral contraceptive pills, which should be included in the patient's medical history and physical exam. When clinicians first initiate estrogen therapies for patients, providers should evaluate patients for family history of breast cancer, endometrial cancer, ovarian cancer, history of cancer, and risk of newly developed malignancies sensitive to estrogen. 

Physicians and pharmacists need to educate patients about the potential adverse effects and box warnings of estrogen use. Routine women's wellness exams should also focus on the possible development of any malignancies or adverse effects of hormone replacement therapy, given a positive history. The role of the pharmacist when counseling patients new to prescribed estrogen therapies should include educating and assessing the patient for proper use of estrogen medication therapies, as they may be specified in various preparations, including oral, transdermal, vaginal inserts, and topical vaginal creams, to promote positive patient compliance and adherence to treatment. Nursing staff can also serve as a point of contact for medication-related questions, counseling regarding adverse effects, and coordinating activities among other interprofessional healthcare team members. This interprofessional approach among physicians, advanced practice providers, pharmacists, and nurses will maximize therapeutic effectiveness and minimize potential adverse effects when using estrogen therapy.

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Disclosure: Benjamin Delgado declares no relevant financial relationships with ineligible companies.

Disclosure: Preeti Patel declares no relevant financial relationships with ineligible companies.

Disclosure: Wilfredo Lopez-Ojeda declares no relevant financial relationships with ineligible companies.