Estrone (United States: Not available): Drug information

Concerns related to adverse effects:

• Bone disease: Prolonged estrogen use, with or without progestin, may influence calcium and phosphorus metabolism. Use caution in patients with metabolic and malignant bone disease associated with hyperglycemia.

• Breast cancer: [Canadian Boxed Warning]: The Women’s Health Initiative (WHI) trial examined the health benefits and risks of oral combined estrogen plus progestin therapy (n=16,608) and oral estrogen–alone therapy (n=10,739) in postmenopausal women 50 to 79 years of age. The estrogen plus progestin arm of the WHI trial (mean age 63.3 years) indicated an increased risk of invasive breast cancer in postmenopausal women receiving treatment with combined conjugated equine estrogens (0.625 mg/day) and medroxyprogesterone acetate (2.5 mg/day) for 5.2 years compared to those receiving placebo. The risk of breast cancer in postmenopausal patients on hormone therapy may depend upon type of estrogen and/or progestin, dose, timing of therapy initiation, duration of therapy, route of administration, and individual patient characteristics (AACE/ACE [Cobin 2017]; NAMS 2017). Hormone therapy may be associated with increased breast density (NAMS 2017); an increase in abnormal mammogram findings requiring further evaluation has been reported with estrogen alone or in combination with progestin therapy. Estrogen use may lead to severe hypercalcemia in patients with breast cancer and bone metastases. Due to increased risks, estrogens are contraindicated in patients with known or suspected breast cancer; however, patients with genitourinary syndrome of menopause (GSM) in whom nonhormone therapy has failed may be treated with local estrogen based on specific breast cancer diagnosis, evaluation of symptoms, and risk for recurrence. Products with the lowest systemic absorption are recommended (NAMS [Faubion 2018]).

• Dementia: In the Women’s Health Initiative Memory Study, an increased incidence of probable dementia was observed in women ≥65 years of age taking oral conjugated estrogen alone or in combination with medroxyprogesterone acetate.

• Endometrial cancer: The use of unopposed estrogen in patients with a uterus is associated with an increased risk of endometrial cancer. The risk of endometrial cancer appears to be dose and duration dependent, greatest with use ≥5 years, and may persist following discontinuation of therapy. Based on available data, the risk of endometrial cancer following low-dose vaginal estrogen is similar to rates observed in the general population. The use of a progestin 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 (NAMS 2017; NAMS 2020). When nonhormonal treatments are not effective for GSM, low-dose vaginal therapy that has limited systemic absorption may be considered in appropriately selected patients with endometrial cancer (ES [Stuenkel 2015]; NAMS 2017). Patients with endometrial cancer should be closely monitored (NAMS 2020).

• Endometriosis: Estrogens may exacerbate endometriosis.

• Hypertension: Use may be associated with an increase in BP; monitor.

• Inherited thrombophilia: Women with inherited thrombophilias (eg, protein C or S deficiency) may have increased risk of venous thromboembolism (DeSancho 2010; van Vlijmen 2011).

• Ovarian cancer: Available information related to the use of menopausal estrogen or estrogen/progestin 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 (AACE [Goodman 2011]; ES [Stuenkel 2015]; NAMS 2017).

• Retinal thrombosis: Estrogens may cause retinal thrombosis; discontinue if visual disturbances occur.

Disease-related concerns:

• Asthma: Use caution with asthma; may exacerbate disease.

• Cardiovascular disease: [Canadian Boxed Warning]: The WHI trial examined the health benefits and risks of oral combined estrogen plus progestin therapy (n=16,608) and oral estrogen–alone therapy (n=10,739) in postmenopausal women 50 to 79 years of age. The estrogen plus progestin arm of the WHI trial (mean age 63.3 years) indicated an increased risk of myocardial infarction (MI), stroke, pulmonary emboli, and deep vein thrombosis (DVT) in postmenopausal women receiving treatment with combined conjugated equine estrogen (0.625 mg/day) and medroxyprogesterone acetate (2.5 mg/day) for 5.2 years compared to those receiving placebo. The estrogen-alone arm of the WHI trial (mean age 63.6 years) indicated an increased risk of stroke and DVT in hysterectomized women treated with conjugated equine estrogen alone (0.625 mg/day) for 6.8 years compared to those receiving placebo. Estrogens with or without progestins should not be prescribed for primary or secondary prevention of cardiovascular diseases. Additional risk factors include diabetes mellitus, hypercholesterolemia, hypertension, systemic lupus erythematosus (SLE), obesity, tobacco use, and/or history of venous thromboembolism. Manage risk factors appropriately. The increased risks of cardiovascular outcomes associated with systemic estrogen or estrogen/progestin therapy may not be the same and are unlikely with low dose vaginal estrogen (Crandall 2018; NAMS 2020).

• Cerebrovascular insufficiency: Discontinue if classical migraine, loss of consciousness, paralysis, transient aphasia, or visual disturbances occur.

• Diabetes: May impair glucose tolerance; use caution in patients with diabetes.

• Diseases exacerbated by fluid retention: Use caution in patients with diseases that may be exacerbated by fluid retention, including cardiac or renal dysfunction.

• Epilepsy: Use caution with epilepsy; may exacerbate disease.

• Fibroids: Use with caution in patients with fibroids (leiomyomata); discontinue use with sudden enlargement, pain, or tenderness of fibroids.

• Gallbladder disease: Use of postmenopausal estrogen may be associated with an increased risk of gallbladder disease requiring surgery.

• Hepatic hemangiomas: Use caution in patients with hepatic hemangiomas; may exacerbate disease.

• Hepatic dysfunction: Use caution with a history of hepatic or biliary disorders. Discontinue if jaundice develops.

• Hereditary angioedema: Exogenous estrogens may exacerbate angioedema symptoms in patients with hereditary angioedema.

• Otosclerosis: Use caution in patients with otosclerosis.

• Porphyria: Use caution in patients with porphyria.

• Systemic lupus erythematosus: Use caution in patients with SLE; may exacerbate disease.

Special populations:

• Surgical patients: Whenever possible, estrogens should be discontinued at least 4 to 6 weeks prior to elective surgery associated with an increased risk of thromboembolism or during periods of prolonged immobilization.

Dosage form specific issues:

• Vaginal cream: Contains mineral oil that may not be compatible with latex rubber in condoms

Other warnings/precautions:

• Risks versus benefits: Systemic absorption occurs following vaginal use; however, the risk of adverse events associated with low-dose vaginal estrogens (defined as ≤0.5 g/day) may be lower than with systemic estrogens. Consider warnings, precautions, and adverse events observed with oral therapy and weigh risk versus benefit before and during therapy (NAMS [Pinkerton 2020]). Low-dose vaginal estrogen is preferred over systemic therapy for GSM in the absence of vasomotor symptoms due to increased efficacy and decreased systemic effects (eg, cardiovascular effects, cancer risk) (Crandall 2018; NAMS 2017; NAMS 2020). When used for the relief of menopausal symptoms, the benefit-risk of hormone therapy is most favorable if started in patients who have no contraindications to therapy, are <60 years of age, within 10 years of menopause onset, have a favorable lipid profile, and do not have the factor V Leiden genotype or metabolic syndrome. In addition, consider risk factors for cardiovascular disease when evaluating therapy and route of administration (AACE/ACE [Cobin 2017]; NAMS 2017). [Canadian Boxed Warning]: Estrogens with or without progestins should be prescribed at the lowest effective dose for the approved indication. Estrogens with or without progestins should be prescribed for the shortest period possible for the approved indication. Patients should be reevaluated as clinically appropriate to determine if treatment is still necessary. Available data related to treatment risks are from WHI studies, which evaluated oral conjugated estrogen 0.625 mg with or without medroxyprogesterone acetate 2.5 mg relative to placebo in postmenopausal women. Other combinations and dosage forms of estrogens and progestins were not studied but should be considered similar until comparable data are available.