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Estradiol and Progesterone

Medically reviewed on Jan 9, 2019

Pronunciation

(es tra DYE ole & proe JES ter one)

Index Terms

  • 17-beta Estradiol [E2] and Progesterone [P4]
  • Bijuva
  • Progesterone and Estradiol
  • TX-001HR

Dosage Forms

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

Capsule, Oral:

Bijuva: Estradiol 1 mg and progesterone 100 mg [contains fd&c red #40]

Brand Names: U.S.

  • Bijuva

Pharmacologic Category

  • Estrogen and Progestin Combination

Pharmacology

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.

Progesterone opposes the action of estrogen by decreasing estrogen receptor levels, increasing the metabolism of estrogen to less active metabolites, or blunting the response to estrogen at the cellular level.

Distribution

Estradiol: Widely distributed; high concentrations in the sex hormone target organs.

Metabolism

Estradiol: Hepatic; estradiol is reversibly converted to estrone and estriol; oral estradiol also undergoes enterohepatic recirculation by conjugation in the liver, followed by excretion of sulfate and glucuronide conjugates into the bile, then hydrolysis in the intestine and estrogen reabsorption. Sulfate conjugates are the primary form found in postmenopausal women.

Progesterone: Hepatic to pregnanediols and pregnanolones, which are then conjugated to glucuronide and sulfate metabolites; metabolites excreted in the bile may be deconjugated and further metabolized in the intestine via reduction, dehydroxylation, and epimerization.

Excretion

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

Progesterone: Pregnanediol and pregnanolone conjugates are excreted in the bile and urine; progesterone metabolites are eliminated primarily via kidney, however, metabolites excreted via bile may undergo enterohepatic recycling or be excreted in the feces.

Onset of Action

Frequency and severity of moderate to severe vasomotor symptoms in postmenopausal women were reduced 3 weeks after treatment initiation (Lobo 2018); significant improvements in menopausal quality of life were observed at 12 weeks (Simon 2018).

Time to Peak

Estradiol: ~5 hours; progesterone: ~3 hours

Half-Life Elimination

Estradiol: ~26 hours; Estrone: ~23 hours; Progesterone: ~10 hours

Protein Binding

Estradiol: Bound to sex hormone-binding globulin and albumin.

Progesterone: ~96% to 99%, primarily to albumin (50% to 54%) and cortisol-binding protein (transcortin) (43% to 48%)

Use: Labeled Indications

Vasomotor symptoms associated with menopause: Treatment of moderate to severe vasomotor symptoms due to menopause.

Contraindications

Angioedema, anaphylactic, or hypersensitivity reaction to estradiol, progesterone, 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 or estrogen-dependent tumor (known or suspected); hepatic impairment or disease; known protein C, protein S, antithrombin deficiency or other known thrombophilic disorders

Dosing: Adult

Female: 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). Individuals who have had a hysterectomy generally do not need a progestin; however, one may be needed if there is a history of endometriosis.

Vasomotor symptoms associated with menopause: Oral: One estradiol 1 mg/progesterone 100 mg capsule once daily in the evening

Dosing: Geriatric

Refer to adult dosing.

Administration

Oral: Administer in the evening with food. In case of missed dose, administer with food as soon as possible, unless it is ≤2 hours until the next dose.

Storage

Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°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

Anticoagulants: Progestins may diminish the therapeutic effect of Anticoagulants. More specifically, the potential prothrombotic effects of some progestins and progestin-estrogen combinations may counteract anticoagulant effects. Management: Carefully weigh the prospective benefits of progestins 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

Antifungal Agents (Vaginal): May diminish the therapeutic effect of Progesterone. Avoid combination

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

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

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

C1 inhibitors: Progestins 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. Management: Drugs listed as exceptions to this monograph are discussed in further detail in separate drug interaction monographs. Monitor therapy

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

Cosyntropin: Estrogen Derivatives may diminish the diagnostic effect of Cosyntropin. Management: Discontinue estrogen containing drugs 4 to 6 weeks prior to cosyntropin (ACTH) testing. Consider therapy modification

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

CYP2C19 Inducers (Strong): May increase the metabolism of CYP2C19 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 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

Dabrafenib: May decrease the serum concentration of CYP2C19 Substrates (High risk with Inducers). Management: Seek alternatives to the CYP2C19 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

Enzalutamide: May decrease the serum concentration of CYP2C19 Substrates (High risk with Inducers). Conversely, concentrations of active metabolites may be increased for those drugs activated by CYP2C19. Management: Concurrent use of enzalutamide with CYP2C19 substrates that have a narrow therapeutic index should be avoided. Use of enzalutamide and any other CYP2C19 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

Herbs (Progestogenic Properties) (eg, Bloodroot, Yucca): May enhance the adverse/toxic effect of Progestins. 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

Lorlatinib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Avoid concurrent use of lorlatinib with any CYP3A4 substrates for which a minimal decrease in serum concentrations of the CYP3A4 substrate could lead to therapeutic failure and serious clinical consequences. Consider therapy modification

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

P-glycoprotein/ABCB1 Inhibitors: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates. P-glycoprotein inhibitors may also enhance the distribution of p-glycoprotein substrates to specific cells/tissues/organs where p-glycoprotein is present in large amounts (e.g., brain, T-lymphocytes, testes, etc.). Monitor therapy

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

Pomalidomide: Progestins may enhance the thrombogenic effect of Pomalidomide. 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

Ranolazine: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates. Monitor therapy

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

Ulipristal: Progestins may diminish the therapeutic effect of Ulipristal. Ulipristal may diminish the therapeutic effect of Progestins. Management: Ulipristal for uterine fibroids (Canadian indication): avoid progestins within 12 days of stopping ulipristal; as emergency contraceptive (U.S. indication): avoid progestins within 5 days of stopping ulipristal. Avoid combination

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

Adverse Reactions

Also see individual agents.

1% to 10%:

Central nervous system: Headache (3%)

Genitourinary: Breast tenderness (10%), vaginal hemorrhage (3%), pelvic pain (3%), vaginal discharge (3%)

Frequency not defined:

Cardiovascular: Cerebrovascular accident, deep vein thrombosis, myocardial infarction, pulmonary embolism

Central nervous system: Dementia

Hematologic & oncologic: Malignant neoplasm of breast

ALERT: U.S. Boxed Warning

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.

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.

Breast cancer:

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

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 undertaken to rule out malignancy in postmenopausal women with undiagnosed persistent or recurring abnormal genital bleeding.

Risk versus 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:

• Breast cancer: [US Boxed Warning]: The Women's Health Initiative (WHI) estrogen plus progestin substudy demonstrated an increased risk of invasive breast cancer. 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 conjugated estrogen (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 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 risk of developing probable dementia was observed in women ≥65 years of age taking CE alone or in combination with medroxyprogesterone acetate (MPA). 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]: 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 undertaken to rule out malignancy in postmenopausal women with undiagnosed persistent or recurring abnormal genital 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.

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

• 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 pending examination 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 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 patients with active DVT, PE, arterial thromboembolic disease (stroke and MI), or a history of these conditions.

• Diseases exacerbated by fluid retention: Use caution 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 in case of recurrence. Use is contraindicated with hepatic impairment or disease.

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

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

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

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

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

• Systemic lupus erythematosus: Use caution with systemic lupus erythematosus (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. Patients on thyroid replacement therapy may require higher doses of thyroid hormone while receiving estrogens.

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.

Other warnings/precautions:

• Duration of use: Extended use of menopausal hormone therapy may be considered for persistent vasomotor symptoms. Menopausal hormonal therapy does not need to be routinely discontinued in patients >60 years of age and may continue in patients >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).

• 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.

• Risks vs benefits: 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. 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 due to menopause.

Pregnancy Considerations

This combination is not indicated for use in females of reproductive potential.

In general, the use of estrogen and progestin as in combination hormonal contraceptives have not been associated with teratogenic effects when inadvertently taken prior to conception or 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 tender breasts. Have patient report immediately to prescriber signs of liver problems (dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or jaundice), 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 low calcium (muscle cramps or spasms, numbness and tingling, or seizures), 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), severe headache, severe dizziness, passing out, vision changes, blindness, bulging eyes, contact lens intolerance, lump in breast, breast soreness, nipple discharge, breast pain, edema, vaginal bleeding, vaginitis, pelvic pain, memory impairment, severe loss of strength and energy, 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), or signs of high calcium (weakness, confusion, fatigue, headache, nausea and vomiting, constipation, or bone pain) (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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