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Estrogens (Conjugated/Equine, Systemic)

Medically reviewed on September 10, 2018

Pronunciation

See also: Prolia

(ES troe jenz KON joo gate ed, EE kwine)

Index Terms

  • C.E.S.
  • CE
  • CEE
  • Conjugated Estrogen
  • Estrogenic Substances, Conjugated
  • Oestrogens, Conjugated/Equine

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Solution Reconstituted, Injection:

Premarin: 25 mg (1 ea) [contains benzyl alcohol]

Tablet, Oral:

Premarin: 0.3 mg [contains fd&c blue #2 (indigotine), fd&c yellow #10 (quinoline yellow)]

Premarin: 0.45 mg [contains fd&c blue #2 (indigotine)]

Premarin: 0.625 mg [contains fd&c blue #2 (indigotine), fd&c red #40]

Premarin: 0.9 mg

Premarin: 1.25 mg [contains fd&c yellow #10 (quinoline yellow), fd&c yellow #6 (sunset yellow)]

Brand Names: U.S.

  • Premarin

Pharmacologic Category

  • Estrogen Derivative

Pharmacology

Conjugated estrogens contain a mixture of estrone sulfate, equilin sulfate, 17 alpha-dihydroequilin, 17 alpha-estradiol and 17 beta-dihydroequilin. Estrogens are responsible for the development and maintenance of the female reproductive system and secondary sexual characteristics. 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 postmenopausal women.

Absorption

Well absorbed

Distribution

Widely distributes throughout the body; sex hormone target organs contain higher concentrations

Metabolism

Hepatic via CYP3A4; estradiol is converted to estrone and estriol; estrone is also converted to estriol and is converted to estradiol (Note: A dynamic equilibrium of metabolic interconversions between estrogens exists in the circulation); also undergoes enterohepatic recirculation (avoided with vaginal administration); estrone sulfate is the main metabolite in postmenopausal women

Excretion

Urine (primarily estriol, also as estradiol, estrone, and conjugates)

Time to Peak

Total estrone: 7 hours

Half-Life Elimination

Total estrone: 27 hours

Protein Binding

Binds to sex-hormone-binding globulin and albumin

Use: Labeled Indications

Abnormal uterine bleeding (injection only): Treatment of abnormal uterine bleeding due to hormonal imbalance in the absence of organic pathology.

Limitations of use: For short term use only to provide a rapid and temporary increase in estrogen levels.

Breast cancer, metastatic: Treatment of breast cancer (palliation) in appropriately selected men and postmenopausal women.

Hypoestrogenism (female): Treatment of hypoestrogenism due to hypogonadism, castration, or primary ovarian failure.

Osteoporosis prevention (female): Prevention of postmenopausal osteoporosis.

Limitations of use: For use only in women at significant risk of osteoporosis; consider use of nonestrogen medications.

Prostate cancer, advanced: Treatment of androgen-dependent prostatic cancer (palliation).

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 due to menopause.

Limitations of use: When used solely for the treatment of vulvar and vaginal atrophy, topical vaginal products should be considered.

Note: The International Society for the Study of Women’s Sexual Health and The North American Menopause Society have endorsed the term genitourinary syndrome of menopause (GSM) as new terminology for vulvovaginal atrophy. The term GSM encompasses all genital and urinary signs and symptoms associated with a loss of estrogen due to menopause (Portman 2014).

Off Label Uses

Uremic bleeding

Data from one small randomized, double blind, placebo-controlled, crossover study in patients with chronic renal failure receiving hemodialysis and a history of bleeding, one small randomized, double blind, placebo-controlled, single center, crossover study in end-stage renal disease receiving hemodialysis without a history of bleeding, and one prospective, controlled single center study support the use of conjugated estrogens as an alternative treatment in the management of uremic bleeding due to the ability to shorten bleeding time [Heistinger 1990], [Livio 1986], [ Viganò 1988]. Clinical experience also suggests the utility of conjugated estrogens in the management of uremic bleeding [Hedges 2007]. Additional trials may be necessary to further define the role of conjugated estrogens in this setting.

Contraindications

Angioedema or anaphylactic reaction to estrogens or any component of the formulation; undiagnosed abnormal genital bleeding; DVT or PE (current or history of); active or history of arterial thromboembolic disease (eg, stroke, MI); breast cancer (except in appropriately selected patients being treated for metastatic disease); estrogen-dependent tumor (known or suspected); hepatic impairment or disease; known protein C, protein S, antithrombin deficiency or other known thrombophilic disorders; pregnancy

Canadian labeling: Additional contraindications (not in US labeling): Endometrial hyperplasia; partial or complete vision loss due to ophthalmic vascular disease; migraine with or without aura

Dosing: Adult

General dosing guidelines: When treating symptoms of menopause, hormone therapy should be evaluated routinely for appropriate dose, duration, and route of administration for each individual patient based on treatment goals, risk factors, and overall health (NAMS 2017). Combined estrogen/progestin therapy is indicated for postmenopausal persons with a uterus to decrease the risk of endometrial cancer. Individuals who have had a hysterectomy generally do not need a progestin; however, one may be needed if there is a history of endometriosis. Adjust dose based on patient response.

Abnormal uterine bleeding: Acute/heavy bleeding: IM, IV: 25 mg, may repeat in 6-12 hours if needed (manufacturer's labeling) or 25 mg IV repeated every 4 to 6 hours for 24 hours (ACOG 557 2013).

Breast cancer, metastatic: Oral: Males and postmenopausal females: 10 mg 3 times/day for at least 3 months

Hypoestrogenism (female) due to castration or primary ovarian failure: Oral: 1.25 mg/day given cyclically*; adjust according to severity of symptoms and patient response. For maintenance, adjust to the lowest effective dose.

Hypoestrogenism (female) due to hypogonadism: Oral: 0.3 or 0.625 mg/day given cyclically*; dose may be titrated in 6- to 12-month intervals; progestin treatment should be added to maintain bone mineral density once skeletal maturity is achieved.

Osteoporosis prevention (females): Oral: Initial: 0.3 mg/day cyclically* or daily, depending on medical assessment of patient. Dose may be adjusted based on bone mineral density and clinical response. The lowest effective dose should be used.

Prostate cancer, advanced: Oral: 1.25 to 2.5 mg 3 times/day

Uremic bleeding (off-label use): IV: 0.6 mg/kg/day for 5 days (Heistinger 1990; Livio 1986; Viganò 1988)

Vasomotor symptoms associated with menopause: Oral: Initial: 0.3 mg/day. May be given cyclically* or daily, depending on medical assessment of patient. Adjust dose based on patient’s response. The lowest dose that will control symptoms should be used.

Vulvar and vaginal atrophy associated with menopause: Oral: Initial: 0.3 mg/day. The lowest dose that will control symptoms should be used. May be given cyclically* or daily, depending on medical assessment of patient. Adjust dose based on patient’s response.

*Cyclic administration: Either 3 weeks on, 1 week off or 25 days on, 5 days off

Dosing: Geriatric

Refer to adult dosing.

Dosing: Renal Impairment

There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied).

Dosing: Hepatic Impairment

There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied). Use is contraindicated with hepatic dysfunction or disease.

Reconstitution

Injection: Reconstitute with sterile water for injection; slowly inject diluent against side wall of the vial. Agitate gently; do not shake violently.

Administration

Injection: May be administered IV or IM; when administered IV, drug should be administered slowly to avoid the occurrence of a flushing reaction

Oral tablet: Administer at the same time each day. May be administered without regard to meals.

Vasomotor symptoms associated with menopause: Recently menopausal women (<2 years) with a uterus may benefit from a cyclic regimen (continuous regimens may be associated with unscheduled bleeding) (ES [Stuenkel 2015]).

Dietary Considerations

Ensure adequate calcium and vitamin D intake when used for the prevention of osteoporosis. Powder for reconstitution for injection (25 mg) contains lactose 200 mg.

Storage

Injection: Refrigerate at 2°C to 8°C (36°F to 46°F) prior to reconstitution. Use immediately following reconstitution.

Tablets: Store at room temperature 20°C to 25°C (68°F to 77°F).

Drug Interactions

Ajmaline: Estrogen Derivatives may enhance the adverse/toxic effect of Ajmaline. Specifically, the risk for cholestasis may be increased. Monitor therapy

Anastrozole: Estrogen Derivatives may diminish the therapeutic effect of Anastrozole. Avoid combination

Anthrax Immune Globulin (Human): Estrogen Derivatives may enhance the thrombogenic effect of Anthrax Immune Globulin (Human). Monitor therapy

Anticoagulants: Estrogen Derivatives may diminish the anticoagulant effect of Anticoagulants. More specifically, the potential prothrombotic effects of some estrogens and progestin-estrogen combinations may counteract anticoagulant effects. Management: Carefully weigh the prospective benefits of estrogens against the potential increased risk of procoagulant effects and thromboembolism. Use is considered contraindicated under some circumstances. Refer to related guidelines for specific recommendations. Consider therapy modification

Antidiabetic Agents: Hyperglycemia-Associated Agents may diminish the therapeutic effect of Antidiabetic Agents. Monitor therapy

Ascorbic Acid: May increase the serum concentration of Estrogen Derivatives. Monitor therapy

Bosentan: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

C1 inhibitors: Estrogen Derivatives may enhance the thrombogenic effect of C1 inhibitors. Monitor therapy

Cannabis: May decrease the serum concentration of CYP1A2 Substrates (High risk with Inducers). Monitor therapy

Chenodiol: Estrogen Derivatives may diminish the therapeutic effect of Chenodiol. Management: Monitor clinical response to chenodiol closely when used together with any estrogen derivative. Monitor therapy

CloZAPine: CYP1A2 Inhibitors (Weak) may increase the serum concentration of CloZAPine. Monitor therapy

Corticosteroids (Systemic): Estrogen Derivatives may increase the serum concentration of Corticosteroids (Systemic). Monitor therapy

CYP1A2 Inducers (Moderate): May decrease the serum concentration of CYP1A2 Substrates (High risk with Inducers). Monitor therapy

CYP3A4 Inducers (Moderate): May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

CYP3A4 Inducers (Strong): May increase the metabolism of CYP3A4 Substrates (High risk with Inducers). Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Consider therapy modification

CYP3A4 Inhibitors (Moderate): May increase the serum concentration of Estrogen Derivatives. Monitor therapy

CYP3A4 Inhibitors (Strong): May increase the serum concentration of Estrogen Derivatives. Monitor therapy

Cyproterone: May decrease the serum concentration of CYP1A2 Substrates (High risk with Inducers). Monitor therapy

Dabrafenib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Seek alternatives to the CYP3A4 substrate when possible. If concomitant therapy cannot be avoided, monitor clinical effects of the substrate closely (particularly therapeutic effects). Consider therapy modification

Dantrolene: Estrogen Derivatives may enhance the hepatotoxic effect of Dantrolene. Monitor therapy

Deferasirox: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Dehydroepiandrosterone: May enhance the adverse/toxic effect of Estrogen Derivatives. Avoid combination

Enzalutamide: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Concurrent use of enzalutamide with CYP3A4 substrates that have a narrow therapeutic index should be avoided. Use of enzalutamide and any other CYP3A4 substrate should be performed with caution and close monitoring. Consider therapy modification

Exemestane: Estrogen Derivatives may diminish the therapeutic effect of Exemestane. Avoid combination

Hemin: Estrogen Derivatives may diminish the therapeutic effect of Hemin. Avoid combination

Herbs (Estrogenic Properties): May enhance the adverse/toxic effect of Estrogen Derivatives. Monitor therapy

Hyaluronidase: Estrogen Derivatives may diminish the therapeutic effect of Hyaluronidase. Management: Patients receiving estrogens (particularly at larger doses) may not experience the desired clinical response to standard doses of hyaluronidase. Larger doses of hyaluronidase may be required. Consider therapy modification

Immune Globulin: Estrogen Derivatives may enhance the thrombogenic effect of Immune Globulin. Monitor therapy

Indium 111 Capromab Pendetide: Estrogen Derivatives may diminish the diagnostic effect of Indium 111 Capromab Pendetide. Avoid combination

Ivosidenib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

LamoTRIgine: Estrogen Derivatives may decrease the serum concentration of LamoTRIgine. Monitor therapy

Lenalidomide: Estrogen Derivatives may enhance the thrombogenic effect of Lenalidomide. Monitor therapy

Mitotane: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Doses of CYP3A4 substrates may need to be adjusted substantially when used in patients being treated with mitotane. Consider therapy modification

Mivacurium: Estrogen Derivatives may increase the serum concentration of Mivacurium. Monitor therapy

Nonsteroidal Anti-Inflammatory Agents (COX-2 Selective): May enhance the thrombogenic effect of Estrogen Derivatives. Nonsteroidal Anti-Inflammatory Agents (COX-2 Selective) may increase the serum concentration of Estrogen Derivatives. Monitor therapy

Ospemifene: Estrogen Derivatives may enhance the adverse/toxic effect of Ospemifene. Estrogen Derivatives may diminish the therapeutic effect of Ospemifene. Avoid combination

Pitolisant: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Combined use of pitolisant with a CYP3A4 substrate that has a narrow therapeutic index should be avoided. Other CYP3A4 substrates should be monitored more closely when used with pitolisant. Consider therapy modification

Pomalidomide: May enhance the thrombogenic effect of Estrogen Derivatives. Management: Canadian pomalidomide labeling recommends caution with use of hormone replacement therapy and states that hormonal contraceptives are not recommended. US pomalidomide labeling does not contain these specific recommendations. Consider therapy modification

ROPINIRole: Estrogen Derivatives may increase the serum concentration of ROPINIRole. Monitor therapy

Sarilumab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Siltuximab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Somatropin: Estrogen Derivatives may diminish the therapeutic effect of Somatropin. Shown to be a concern with oral hormone replacement therapy in postmenopausal women. Management: Monitor for reduced growth hormone efficacy. A larger somatropin dose may be required to reach treatment goal. This interaction does not appear to apply to non-orally administered estrogens (e.g., transdermal, vaginal ring). Consider therapy modification

St John's Wort: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Consider therapy modification

Succinylcholine: Estrogen Derivatives may increase the serum concentration of Succinylcholine. Monitor therapy

Teriflunomide: May decrease the serum concentration of CYP1A2 Substrates (High risk with Inducers). Monitor therapy

Thalidomide: Estrogen Derivatives may enhance the thrombogenic effect of Thalidomide. Monitor therapy

Theophylline Derivatives: Estrogen Derivatives may increase the serum concentration of Theophylline Derivatives. Exceptions: Dyphylline. Monitor therapy

Thyroid Products: Estrogen Derivatives may diminish the therapeutic effect of Thyroid Products. Monitor therapy

Tipranavir: Estrogen Derivatives may enhance the dermatologic adverse effect of Tipranavir. The combination of tipranavir/ritonavir and ethinyl estradiol/norethindrone was associated with a high incidence of skin rash. Tipranavir may decrease the serum concentration of Estrogen Derivatives. Management: Women using hormonal contraceptives should consider alternative, non-hormonal forms of contraception. Consider therapy modification

TiZANidine: CYP1A2 Inhibitors (Weak) may increase the serum concentration of TiZANidine. Management: Avoid these combinations when possible. If combined use is necessary, initiate tizanidine at an adult dose of 2 mg and increase in 2 to 4 mg increments based on patient response. Monitor for increased effects of tizanidine, including adverse reactions. Consider therapy modification

Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Ursodiol: Estrogen Derivatives may diminish the therapeutic effect of Ursodiol. Monitor therapy

Test Interactions

Reduced response to metyrapone test.

Adverse Reactions

Percentages reported in postmenopausal women following oral use.

>10%:

Central nervous system: Headache (26% to 32%), pain (17% to 20%)

Gastrointestinal: Abdominal pain (15% to 17%)

Genitourinary: Vaginal hemorrhage (2% to 14%), mastalgia (7% to 12%)

Neuromuscular & skeletal: Back pain (13% to 14%), arthralgia (7% to 14%)

Respiratory: Pharyngitis (10% to 12%), sinusitis (6% to 11%)

1% to 10%:

Central nervous system: Depression (5% to 8%), dizziness (4% to 6%), nervousness (2% to 5%)

Dermatologic: Pruritus (4% to 5%)

Gastrointestinal: Diarrhea (6% to 7%), flatulence (6% to 7%)

Genitourinary: Vaginitis (5% to 7%), leukorrhea (4% to 7%), vulvovaginal candidiasis (5% to 6%)

Neuromuscular & skeletal: Weakness (7% to 8%), leg cramps (3% to 7%)

Respiratory: Increased cough (4% to 7%)

Frequency not defined (injection): Local: Injection site phlebitis, pain at injection site, swelling at injection site

<1%, postmarketing, and/or case reports: Abnormal uterine bleeding, alopecia, anaphylaxis, angioedema, bloating, breast hypertrophy, breast tenderness, cerebrovascular accident, change in cervical secretions, change in libido, chloasma, cholestatic jaundice, contact lens intolerance, decreased glucose tolerance, deep vein thrombosis, dementia, dysmenorrhea, edema, endometrial carcinoma, endometrial hyperplasia, erythema multiforme, erythema nodosum, exacerbation of asthma, exacerbation of epilepsy, exacerbation of hepatic hemangioma, exacerbation of porphyria, fibrocystic breast changes, galactorrhea, gallbladder disease, growth potentiation of benign meningioma, gynecomastia, hirsutism, hypersensitivity reaction, hypertension, increased serum triglycerides, irritability, ischemic colitis, malignant neoplasm of breast, migraine, mood changes, myocardial infarction, nausea, nipple discharge, ovarian carcinoma, pancreatitis, pelvic pain, pulmonary embolism, retinal thrombosis, skin rash, superficial venous thrombosis, thrombophlebitis, urticaria, uterine fibroids (increased size), vomiting, vulvovaginal candidiasis, weight changes

ALERT: U.S. Boxed Warning

Endometrial cancer:

There is an increased risk of endometrial cancer in a woman with a uterus who uses unopposed estrogens. Adding a progestin to estrogen therapy has been shown to reduce the risk of endometrial hyperplasia, which may be a precursor to endometrial cancer. Adequate diagnostic measures, including directed or random endometrial sampling when indicated, should be taken to rule out malignancy in all cases of undiagnosed persistent or recurring abnormal genital bleeding.

Cardiovascular disease:

Estrogen-alone therapy should not be used for the prevention of cardiovascular disease. The Women's Health Initiative (WHI) estrogen-alone substudy reported increased risks of stroke and deep vein thrombosis (DVT) in postmenopausal women (50 to 79 years of age) during 7.1 years of treatment with daily oral conjugated estrogens 0.625 mg alone, relative to placebo.

Estrogen plus progestin therapy should not be used for the prevention of cardiovascular disease. The WHI estrogen plus progestin substudy reported increased risks of DVT, pulmonary embolism (PE), stroke, and myocardial infarction (MI) in postmenopausal women (50 to 79 years of age) during 5.6 years of treatment with daily oral conjugated estrogens (0.625 mg) combined with medroxyprogesterone acetate (2.5 mg), relative to placebo.

Breast cancer:

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

Dementia:

Estrogen-alone therapy should not be used for the prevention of dementia. The WHI Memory Study (WHIMS) estrogen-alone ancillary study of the WHI reported an increased risk of developing probable dementia in postmenopausal women 65 years of age or older during 5.2 years of treatment with daily conjugated estrogens (0.625 mg) alone, relative to placebo. It is unknown whether this finding applies to younger postmenopausal women.

Estrogen plus progestin therapy should not be used for the prevention of dementia. The WHIMS estrogen plus progestin ancillary study of the WHI reported an increased risk of developing probable dementia in postmenopausal women 65 years of age or older during 4 years of treatment with daily conjugated estrogens (0.625 mg) combined with medroxyprogesterone acetate (2.5 mg), relative to placebo. It is unknown whether this finding applies to younger postmenopausal women.

Risk vs benefit:

In the absence of comparable data, these risks should be assumed to be similar for other doses of conjugated estrogens (with or without medroxyprogesterone acetate) and other dosage forms of estrogens (with or without progestins). Estrogens with or without progestins should be prescribed at the lowest effective doses and for the shortest duration consistent with treatment goals and risks for the individual woman.

Warnings/Precautions

Concerns related to adverse effects:

• Anaphylaxis: Anaphylaxis requiring emergency medical management has been reported within minutes to hours of taking conjugated estrogen (CE) tablets. Angioedema involving the face, feet, hands, larynx, and tongue has also been reported.

• Breast cancer: [US Boxed Warning]: Based on data from the Women’s Health Initiative (WHI) studies, an increased risk of invasive breast cancer was observed in postmenopausal women 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 women with a hysterectomy using CE alone. 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; discontinue estrogen if hypercalcemia occurs.

• Dementia: [US Boxed Warning]: Estrogens with or without progestin should not be used to prevent dementia. In the Women’s Health Initiative Memory Study (WHIMS), an increased incidence of probable dementia was observed in women ≥65 years of age taking CE alone or in combination with MPA. Because the WHI memory studies were conducted in women ≥65 years of age, it is unknown if these findings apply to younger postmenopausal women. However, hormone therapy is not recommended at any age to prevent or treat cognitive decline or dementia (AACE [Goodman 2011]; NAMS 2017).

• Endometrial cancer: [US Boxed Warning]: The use of unopposed estrogen in women with a uterus is associated with an increased risk of endometrial cancer. The addition of a progestin to estrogen therapy may decrease the risk of endometrial hyperplasia, a precursor to endometrial cancer. Adequate diagnostic measures, including endometrial sampling if indicated, should be performed to rule out malignancy in postmenopausal women 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 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 2013; NAMS 2017).

• Endometriosis: Estrogens may exacerbate endometriosis. Malignant transformation of residual endometrial implants has been reported posthysterectomy with unopposed estrogen therapy. Consider adding a progestin in women 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 women with preexisting hypertriglyceridemia; discontinue if pancreatitis occurs. Use with caution in patients with familial defects of lipoprotein metabolism.

• 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 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.

Disease-related concerns:

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

• Carbohydrate intolerance: May impair glucose tolerance; use caution in patients with diabetes. Prior to therapy, consider age, cardiovascular and metabolic risk factors in patients previously diagnosed with diabetes (AACE/ACE [Cobin 2017]).

• Cardiovascular disease: [US Boxed Warning]: Estrogens with or without progestin should not be used to prevent cardiovascular disease. Using data from the Women’s Health Initiative (WHI) studies, an increased risk of deep vein thrombosis (DVT) and stroke has been reported with CE and an increased risk of DVT, stroke, pulmonary emboli (PE) and myocardial infarction (MI) has been reported with CE with MPA in postmenopausal women 50 to 79 years of age. Additional risk factors include diabetes mellitus, hypercholesterolemia, hypertension, SLE, obesity, tobacco use, and/or history of venous thromboembolism (VTE). Risk factors should be managed appropriately; discontinue use immediately if adverse cardiovascular events occur or are suspected. Due to possible lower risk of thrombotic events, transdermal administration may be preferred for treating vasomotor symptoms of menopause in patients with risk factors for cardiovascular disease (AACE/ACE [Cobin 2017]; ACOG 556 2013; ES [Stuenkel 2015]). Use is contraindicated in women with active DVT, PE, arterial thromboembolic disease (stroke and MI), or a history of these conditions.

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

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

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

• Hepatic dysfunction: Estrogens are poorly metabolized in patients with hepatic dysfunction. Use caution with a history of cholestatic jaundice associated with prior estrogen use or pregnancy. Discontinue if jaundice develops or if acute or chronic hepatic disturbances occur. Use is contraindicated with hepatic impairment or disease.

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

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

• Hypoparathyroidism: Use caution in patients with hypoparathyroidism; estrogen-induced hypocalcemia may occur.

• Migraine: Use caution with migraine; may exacerbate disease.

• Porphyria: Use with caution in patients with porphyria; may exacerbate disease.

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

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information

• Thyroid replacement therapy: Estrogens may increase thyroid-binding globulin (TBG) levels leading to increased circulating total thyroid hormone levels. Women on thyroid replacement therapy may require higher doses of thyroid hormone while receiving estrogens.

Special populations:

• Pediatric: Prior to puberty, estrogens may cause premature closure of the epiphyses. Premature breast development, vaginal bleeding and vaginal cornification may be induced in girls. Modification of the normal puberty process may occur in boys.

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

Dosage form specific issues:

• Benzyl alcohol and derivatives: Some dosage forms may contain benzyl alcohol; large amounts of benzyl alcohol (≥99 mg/kg/day) have been associated with a potentially fatal toxicity (“gasping syndrome”) in neonates; the “gasping syndrome” consists of metabolic acidosis, respiratory distress, gasping respirations, CNS dysfunction (including convulsions, intracranial hemorrhage), hypotension and cardiovascular collapse (AAP ["Inactive" 1997]; CDC 1982); some data suggests that benzoate displaces bilirubin from protein binding sites (Ahlfors 2001); avoid or use dosage forms containing benzyl alcohol with caution in neonates. See manufacturer’s labeling.

• Injection: Although the injection is indicated for short term use only, all warnings and precautions associated with oral administration should be considered.

Other warnings/precautions:

• Duration of use: Extended use of menopausal hormone therapy may be considered for persistent vasomotor symptoms, issues related to quality of life, or for osteoporosis prevention in women at increased risk of fracture. Menopausal hormonal therapy does not need to be routinely discontinued in women >60 years of age and may continue in women >65 years of age after clinical evaluation and discussion of benefits and risks of treatment. Annual exams should be performed with a review of comorbidities; possible adjustments to safer lower-dose and/or route of administration should be discussed (ACOG 565 2013; NAMS 2017).

• Genitourinary syndrome of menopause: 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 2013; NAMS 2017).

• Laboratory changes: The use of estrogens and/or progestins may change the results of some laboratory tests (eg, coagulation factors, lipids, glucose tolerance, binding proteins). The dose, route, and the specific estrogen/progestin influence these changes.

• Osteoporosis use: In women with premature menopause, hormone therapy to prevent bone loss may be used unless otherwise contraindicated; therapy should be reassessed when the average age of menopause is reached. It is also an appropriate bone-active therapy for women with vasomotor symptoms who are <60 years of age or within 10 years of menopause onset. Use may be considered for women at high risk of fractures who are not candidates for other osteoporosis therapies (NAMS 2017).

• Risks vs benefits: When used for the relief of menopausal symptoms or increased risk of bone fracture/loss, 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. Risk factors for cardiovascular disease should also be considered when evaluating therapy and route of administration (AACE/ACE [Cobin 2017]; NAMS 2017). [US Boxed Warning]: Estrogens with or without progestin should be used for the shortest duration possible at the lowest effective dose consistent with treatment goals and risks for the individual woman. Patients should be reevaluated as clinically appropriate to determine if treatment is still necessary. Available data related to treatment risks are from Women’s Health Initiative (WHI) studies, which evaluated oral CE 0.625 mg with or without MPA 2.5 mg relative to placebo in postmenopausal women. Other combinations and dosage forms of estrogens and progestins were not studied. Outcomes reported from clinical trials using CE with or without MPA should be assumed to be similar for other doses and other dosage forms of estrogens and progestins until comparable data becomes available.

Monitoring Parameters

Prior to therapy, baseline risk for breast cancer and CVD. During therapy, age appropriate breast and pelvic exams; blood pressure; unscheduled bleeding lasting >6 months for endometrial pathology (sooner 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); TSH (6 to 12 weeks after starting oral therapy in patients taking thyroid replacement) (ES [Stuenkel 2015]).

Menopausal symptoms: Efficacy beginning 1 to 3 months after starting therapy, then every 6 to 12 months as appropriate. Duration of treatment should be evaluated at least annually (ES [Stuenkel 2015]).

Note: Monitoring of FSH and serum estradiol is not useful when managing vasomotor symptoms or GSM.

Abnormal uterine bleeding: Response to treatment that may be dependent upon etiology of bleed (ACOG 557 2013; Haamid 2017).

Prevention of osteoporosis: Bone density measurement

Uremic bleeding: Bleeding time

Pregnancy Considerations

Use is contraindicated during pregnancy.

Estrogens are not indicated for use during pregnancy or immediately postpartum. In general, the use of estrogen and progestin as in combination hormonal contraceptives have not been associated with teratogenic effects when inadvertently taken early in pregnancy.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience hair loss, enlarged breasts, leg cramps, abdominal cramps, bloating, nausea, vomiting, or injection site irritation. Have patient report immediately to prescriber signs of gallstones (pain in the upper right abdominal area, right shoulder area, or between the shoulder blades; jaundice; or fever with chills), signs of severe cerebrovascular disease (change in strength on one side is greater than the other, difficulty speaking or thinking, change in balance, or vision changes), signs of blood clots (numbness or weakness on one side of the body; pain, redness, tenderness, warmth, or swelling in the arms or legs; change in color of an arm or leg; angina; shortness of breath; tachycardia; or coughing up blood) signs of liver problems (dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or jaundice), signs of pancreatitis (severe abdominal pain, severe back pain, severe nausea, or vomiting), change in libido, severe headache, severe dizziness, passing out, pelvic pain, vision changes, blindness, bulging eyes, contact lens discomfort, lump in breast, breast soreness or pain, nipple discharge, abnormal vaginal bleeding, vaginitis, depression, mood changes, edema, or memory impairment (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.

Further information

Always consult your healthcare provider to ensure the information displayed on this page applies to your personal circumstances.

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