Version May 2024
Do not use estrogen-alone therapy 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.
The WHI estrogen plus progestin substudy reported increased risks of DVT, pulmonary embolism, stroke, and myocardial infarction 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.
The WHI estrogen plus progestin substudy demonstrated an increased risk of invasive breast cancer.
There is an increased risk of endometrial cancer in a woman with a uterus who uses unopposed estrogens. Adding a progestogen to estrogen therapy has been shown to reduce the risk of endometrial hyperplasia, which may be a precursor to endometrial cancer. Perform adequate diagnostic measures, including directed or random endometrial sampling when indicated, to rule out malignancy in postmenopausal women with undiagnosed persistent or recurring abnormal genital bleeding.
Do not use estrogen-alone therapy 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 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.
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 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.
Only daily oral conjugated estrogen (0.625 mg) and daily oral conjugated estrogen (0.625 mg) and medroxyprogesterone acetate (2.5 mg) were studied in the estrogen-alone and estrogen plus progestin substudies of the WHI, respectively. Therefore, the relevance of the WHI findings regarding adverse cardiovascular events and dementia to lower conjugated estrogen doses, other routes of administration, or other estrogen plus progestogen products is not known. Without such data, it is not possible to definitively exclude these risks or determine the extent of these risks for other products. Discuss with your patient the benefits and risks of estrogen-alone therapy, taking into account her individual risk profile. Prescribe estrogens with or without progestogens at the lowest effective doses and for the shortest duration consistent with treatment goals and risks for the individual woman.
Vasomotor symptoms associated with menopause: Note:For use in symptomatic patients who are <60 years of age or within 10 years of menopause who do not have contraindications to hormone therapy (eg, breast cancer) (NAMS 2022). Nonoral estrogen preparations are preferred in patients with hypertriglyceridemia, risk factors for venous thromboembolic disease, active gallbladder disease, and/or migraine headache with aura (Martin 2022; Renoux 2010). Combination products are only indicated for patients with a uterus; the progestogen (ie, a natural progesterone or synthetic progestin) component prevents estrogen therapy-associated endometrial hyperplasia. Use of a combination product offers less dosing flexibility for initiating and tapering estrogen compared to separate estrogen and progestogen products.
Oral: One estradiol 0.5 mg/progesterone 100 mg capsule once daily in the evening. Adjust dose based on clinical response.
Duration of therapy: Not clearly established; continued use may be appropriate in patients ≥60 years of age or >10 years after menopause with a low risk of cardiovascular disease and breast cancer and with persistent vasomotor symptoms after attempted taper/discontinuation of estrogen and trial of alternative therapies. Evaluate routinely for comorbidities and appropriateness of lower doses, nonoral routes of administration (preferred in patients ≥60 years of age), choice of progestogen, and discontinuation of therapy (NAMS 2022).
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
There are no dosage adjustments provided in the manufacturers labeling (has not been studied).
Use is contraindicated with hepatic dysfunction or disease.
Note: The Beers Criteria recommends avoiding systemic estrogen therapy in postmenopausal patients ≥65 years of age (independent of diagnosis or condition). In older postmenopausal patients already taking systemic estrogens, consider deprescribing (Ref). Duration of use is not clearly established; continued use may be appropriate in patients ≥60 years of age or >10 years after menopause with a low risk of cardiovascular disease and breast cancer with persistent vasomotor symptoms after attempted taper/discontinuation of estrogen and trial of alternative therapies. Evaluate routinely for comorbidities and appropriateness of lower doses, non-oral routes of administration (preferred in patients ≥60 years of age), choice of progestogen, and discontinuation of therapy (Ref).
Refer to adult dosing.
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Also see individual agents.
1% to 10%:
Genitourinary: Breast tenderness (10%), endometrial hyperplasia (≤1%), pelvic pain (3%), vaginal discharge (3%), vaginal hemorrhage (3%)
Nervous system: Headache (3%)
Frequency not defined:
Cardiovascular: Acute myocardial infarction, cerebrovascular accident, deep vein thrombosis, pulmonary embolism
Hematologic & oncologic: Malignant neoplasm of breast
Nervous system: Dementia
Postmarketing:
Dermatologic: Night sweats, pruritus
Endocrine & metabolic: Fluid retention, hot flash, weight gain
Gastrointestinal: Abdominal distension, adnominal distress, abdominal pain, diarrhea, nausea, vomiting
Genitourinary: Mastalgia, uterine hemorrhage
Nervous system: Dizziness, drowsiness, fatigue, feeling abnormal, insomnia, malaise, sleep disorder
Neuromuscular & skeletal: Limb pain, muscle spasm
Angioedema, anaphylactic, or hypersensitivity reaction to estradiol, progesterone, or any component of the formulation; undiagnosed abnormal genital bleeding; active or history of deep vein thrombosis or pulmonary embolism; active or history of arterial thromboembolic disease (eg, stroke, myocardial infarction); active or history of breast cancer; estrogen-dependent tumor; hepatic impairment or disease; protein C, protein S, antithrombin deficiency or other known thrombophilic disorders.
Concerns related to adverse effects:
• Breast cancer: Based on data from the Women’s Health Initiative (WHI) studies, an increased risk of invasive breast cancer was observed in patients who are postmenopausal using conjugated estrogens in combination with medroxyprogesterone acetate. Observational studies noted this risk declines once therapy is discontinued. The WHI study did not observe an increased risk of invasive breast cancer in patients with a hysterectomy using conjugated estrogens alone. The risk of breast cancer in patients who are postmenopausal on hormone therapy may depend upon type of estrogen and/or progestogen, dose, timing of therapy initiation, duration of therapy, route of administration, and individual patient characteristics (AACE/ACE [Cobin 2017]; NAMS 2022). Hormone therapy may be associated with increased breast density (NAMS 2022); an increase in abnormal mammogram findings requiring further evaluation has been reported with estrogen alone or in combination with progestogen therapy. Estrogen use may lead to severe hypercalcemia in patients with breast cancer and bone metastases; discontinue estrogen if hypercalcemia occurs.
• Dementia: Do not use estrogens with or without progestogen to prevent dementia. The WHI Memory Study (WHIMS) observed an increased incidence of probable dementia in patients ≥65 years of age taking conjugated estrogens alone or in combination with medroxyprogesterone acetate. It is unknown if findings from this study apply to patients who do not meet the same criteria. Hormone therapy is not recommended to prevent or treat cognitive decline or dementia (NAMS 2022).
• Endometrial cancer: The use of unopposed estrogen in patients with an intact uterus is associated with an increased risk of endometrial cancer. The addition of a progestogen to estrogen therapy may decrease the risk of endometrial hyperplasia, a precursor to endometrial cancer. 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 progestogen in patients with residual endometriosis posthysterectomy.
• Lipid effects: Estrogen compounds are generally associated with lipid effects such as increased high-density lipoprotein cholesterol and decreased low-density lipoprotein cholesterol. Triglycerides may also be increased in patients with preexisting hypertriglyceridemia; discontinue if pancreatitis occurs.
• Ovarian cancer: Available information related to the use of menopausal estrogen or estrogen/progestogen therapy and risk of ovarian cancer is inconsistent. If an association is present, the absolute risk is likely rare and may be influenced by duration of therapy (ES [Stuenkel 2015]; NAMS 2022).
• 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.
• Cardiovascular disease: Do not use estrogens with or without progestogen to prevent cardiovascular disease. Using data from the WHI studies, an increased risk of deep vein thrombosis (DVT) and stroke has been reported with conjugated estrogens and an increased risk of DVT, stroke, pulmonary emboli (PE), and myocardial infarction (MI) has been reported with conjugated estrogens with medroxyprogesterone acetate in patients 50 to 79 years of age who are postmenopausal. 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; 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]). Prior to therapy for menopausal symptoms, consider age, cardiovascular and metabolic risk factors in patients previously diagnosed with diabetes (AACE/ACE [Cobin 2017]).
• Diabetes: 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]).
• 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.
• Hepatic hemangiomas: Use caution with hepatic hemangiomas; may exacerbate disease.
• Hereditary angioedema: Exogenous estrogens may exacerbate angioedema symptoms in patients 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 SLE; may exacerbate disease.
Special populations:
• Surgery: Whenever possible, discontinue estrogens 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: Not clearly established; continued use may be appropriate in patients ≥60 years of age or >10 years after menopause with a low risk of cardiovascular disease and breast cancer with persistent vasomotor symptoms after attempted taper/discontinuation of estrogen and trial of alternative therapies. Evaluate routinely for comorbidities and appropriateness of lower doses, nonoral routes of administration (preferred in patients ≥60 years of age), choice of progestogen, and discontinuation of therapy (NAMS 2022).
• Risks versus 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. Consider cardiovascular disease risk factors when evaluating therapy and route of administration (AACE/ACE [Cobin 2017]; NAMS 2022). Use estrogens with or without progestogen for the shortest duration possible at the lowest effective dose consistent with treatment goals and risks for the individual patients. Reevaluate patients as clinically appropriate to determine if treatment is still necessary. Available data related to treatment risks are from WHI studies, which evaluated oral conjugated estrogens 0.625 mg with or without medroxyprogesterone acetate 2.5 mg relative to placebo in patients who are postmenopausal. Other combinations and dosage forms of estrogens and progestogens were not studied. Assume outcomes reported from clinical trials using conjugated estrogens with or without medroxyprogesterone acetate to be similar for other doses and other dosage forms of estrogens and progestogens until comparable data become available.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Capsule, Oral:
Bijuva: Estradiol 1 mg and progesterone 100 mg, Estradiol 0.5 mg and progesterone 100 mg [contains fd&c red #40 (allura red ac dye)]
No
Capsules (Bijuva Oral)
0.5-100 mg (per each): $10.57
1-100 mg (per each): $9.70
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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.
Hazardous agent (NIOSH 2016 [group 2]).
Use appropriate precautions for receiving, handling, administration, and disposal. Gloves (single) should be worn during receiving, unpacking, and placing in storage. NIOSH recommends single gloving for administration of intact capsules (NIOSH 2016). Facilities may perform assessment of some (non-antineoplastic) hazardous drugs to determine if appropriate for alternative containment strategies and handling requirements; assess risk to determine appropriate containment strategy (USP-NF 2017).
Vasomotor symptoms associated with menopause: Treatment of moderate to severe vasomotor symptoms due to menopause.
Beers Criteria: Estrogens (oral or topical patch products only), with or without progestins, are identified in the Beers Criteria as potentially inappropriate medications to be avoided in postmenopausal patients ≥65 years of age (independent of diagnosis or condition) due to their carcinogenic potential (breast and endometrium) and lack of cardioprotection or cognitive protection. Starting therapy in postmenopausal patients ≥60 years of age has greater risks (eg, heart disease, stroke, blood clots, dementia) than benefits. In postmenopausal patients already taking systemic estrogens, consider deprescribing (Beers Criteria [AGS 2023]).
Refer to individual components.
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.
Ajmaline: Estrogen Derivatives may enhance the adverse/toxic effect of Ajmaline. Specifically, the risk for cholestasis may be increased. Risk C: Monitor therapy
Anastrozole: Estrogen Derivatives may diminish the therapeutic effect of Anastrozole. Risk X: Avoid combination
Anthrax Immune Globulin (Human): Estrogen Derivatives may enhance the thrombogenic effect of Anthrax Immune Globulin (Human). Risk C: Monitor therapy
Antidiabetic Agents: Hyperglycemia-Associated Agents may diminish the therapeutic effect of Antidiabetic Agents. Risk C: Monitor therapy
Antifungal Agents (Vaginal): May diminish the therapeutic effect of Progesterone. Risk X: Avoid combination
C1 inhibitors: Estrogen Derivatives may enhance the thrombogenic effect of C1 inhibitors. Risk C: Monitor therapy
Chenodiol: Estrogen Derivatives may diminish the therapeutic effect of Chenodiol. Risk C: Monitor therapy
Chlorprothixene: Estrogen Derivatives may enhance the adverse/toxic effect of Chlorprothixene. Estrogen Derivatives may enhance the therapeutic effect of Chlorprothixene. Risk C: Monitor therapy
Chlorprothixene: Progestins may enhance the adverse/toxic effect of Chlorprothixene. Progestins may enhance the therapeutic effect of Chlorprothixene. Risk C: Monitor therapy
Clofazimine: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk C: Monitor therapy
CloZAPine: CYP1A2 Inhibitors (Weak) may increase the serum concentration of CloZAPine. Risk C: Monitor therapy
Corticosteroids (Systemic): Estrogen Derivatives may increase the serum concentration of Corticosteroids (Systemic). Risk C: 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. Risk D: Consider therapy modification
CYP3A4 Inducers (Moderate): May decrease the serum concentration of Estrogen Derivatives. Risk C: Monitor therapy
CYP3A4 Inducers (Strong): May decrease the serum concentration of Estrogen Derivatives. Risk C: Monitor therapy
CYP3A4 Inhibitors (Strong): May increase the serum concentration of Estrogen Derivatives. Risk C: Monitor therapy
Dantrolene: Estrogen Derivatives may enhance the hepatotoxic effect of Dantrolene. Risk C: Monitor therapy
Dehydroepiandrosterone: May enhance the adverse/toxic effect of Estrogen Derivatives. Risk X: Avoid combination
Exemestane: Estrogen Derivatives may diminish the therapeutic effect of Exemestane. Risk X: Avoid combination
Fexinidazole: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk X: Avoid combination
Fezolinetant: CYP1A2 Inhibitors (Weak) may increase the serum concentration of Fezolinetant. Risk X: Avoid combination
Fusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk X: Avoid combination
Growth Hormone Analogs: Estrogen Derivatives may diminish the therapeutic effect of Growth Hormone Analogs. Management: Initiate somapacitan at 2 mg once weekly in patients receiving oral estrogens. Monitor for reduced efficacy of growth hormone analogs; increased doses may be required. Risk D: Consider therapy modification
Hemin: Estrogen Derivatives may diminish the therapeutic effect of Hemin. Risk X: Avoid combination
Hyaluronidase: Estrogen Derivatives may diminish the therapeutic effect of Hyaluronidase. Risk C: Monitor therapy
Hydrocortisone (Systemic): Estrogen Derivatives may increase the serum concentration of Hydrocortisone (Systemic). Estrogen Derivatives may decrease the serum concentration of Hydrocortisone (Systemic). Risk C: Monitor therapy
Immune Globulin: Estrogen Derivatives may enhance the thrombogenic effect of Immune Globulin. Risk C: Monitor therapy
Indium 111 Capromab Pendetide: Estrogen Derivatives may diminish the diagnostic effect of Indium 111 Capromab Pendetide. Risk X: Avoid combination
LamoTRIgine: Estrogen Derivatives may decrease the serum concentration of LamoTRIgine. Risk C: Monitor therapy
Lenalidomide: Estrogen Derivatives may enhance the thrombogenic effect of Lenalidomide. Risk C: Monitor therapy
Melatonin: Estrogen Derivatives may increase the serum concentration of Melatonin. Risk C: Monitor therapy
MetyraPONE: Estrogen Derivatives may diminish the diagnostic effect of MetyraPONE. Management: Consider alternatives to the use of the metyrapone test in patients taking estrogen derivatives. Risk D: Consider therapy modification
MetyraPONE: Progestins may diminish the diagnostic effect of MetyraPONE. Management: Consider alternatives to the use of the metyrapone test in patients taking progestins. Risk D: Consider therapy modification
Mivacurium: Estrogen Derivatives may increase the serum concentration of Mivacurium. Risk C: 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. Risk C: Monitor therapy
Ospemifene: Estrogen Derivatives may enhance the adverse/toxic effect of Ospemifene. Risk X: Avoid combination
Pomalidomide: Estrogen Derivatives may enhance the thrombogenic effect of Pomalidomide. Risk C: Monitor therapy
Protease Inhibitors: May decrease the serum concentration of Estrogen Derivatives. Protease Inhibitors may increase the serum concentration of Estrogen Derivatives. Risk C: Monitor therapy
Raloxifene: Estrogen Derivatives may enhance the adverse/toxic effect of Raloxifene. Risk X: Avoid combination
ROPINIRole: Estrogen Derivatives may increase the serum concentration of ROPINIRole. Risk C: Monitor therapy
Sincalide: Drugs that Affect Gallbladder Function may diminish the therapeutic effect of Sincalide. Management: Consider discontinuing drugs that may affect gallbladder motility prior to the use of sincalide to stimulate gallbladder contraction. Risk D: Consider therapy modification
Succinylcholine: Estrogen Derivatives may increase the serum concentration of Succinylcholine. Risk C: Monitor therapy
Tacrolimus (Systemic): Estrogen Derivatives may increase the serum concentration of Tacrolimus (Systemic). Risk C: Monitor therapy
Thalidomide: Estrogen Derivatives may enhance the thrombogenic effect of Thalidomide. Risk C: Monitor therapy
Theophylline Derivatives: CYP1A2 Inhibitors (Weak) may increase the serum concentration of Theophylline Derivatives. Risk C: Monitor therapy
Thyroid Products: Estrogen Derivatives may diminish the therapeutic effect of Thyroid Products. Risk C: Monitor therapy
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. Risk D: Consider therapy modification
Tranexamic Acid: Estrogen Derivatives may enhance the thrombogenic effect of Tranexamic Acid. Risk X: Avoid combination
Ulipristal: May diminish the therapeutic effect of Progestins. Progestins may diminish the therapeutic effect of Ulipristal. Risk X: Avoid combination
Ursodiol: Estrogen Derivatives may diminish the therapeutic effect of Ursodiol. Risk C: Monitor therapy
Food increases the bioavailability (AUC) and maximum serum concentration of progesterone; the AUC of estradiol is not affected by food; however, the maximum serum concentration and time to maximum serum concentration is delayed.
This combination is not indicated for use in patients who may become pregnant.
In general, the use of estrogen and progestogen as in combination hormonal contraceptives have not been associated with teratogenic effects when inadvertently taken prior to conception or early in pregnancy.
Estrogens and progestogens are present in breast milk.
Use may decrease the quantity and quality of human milk. According to the manufacturer, the decision to breastfeed during therapy should consider the risk of infant exposure, the benefits of breastfeeding to the infant, and the benefits of treatment to the mother.
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. Evaluate duration of treatment at least annually (ES [Stuenkel 2015]).
Note: Monitoring of FSH and serum estradiol is not useful when managing vasomotor symptoms due to menopause.
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.
Onset: 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)
Distribution: Estradiol: Widely distributed; high concentrations in the sex hormone target organs
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%)
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.
Half-life elimination: Estradiol: ~26 hours; Estrone: ~23 hours; Progesterone: ~10 hours
Time to peak: Estradiol: ~5 hours; Progesterone: ~3 hours.
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
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