Estrogens, Conjugated (Monograph)

Brand names: Cenestin, Enjuvia, Premarin
Drug class: Estrogens
ATC class: G03CA57
VA class: HS300

Introduction

Mixture of estrogens available either as preparations that meet current official USP standards (i.e., conjugated estrogens USP)^{101 105 107 108 109} or as nonofficial preparations (i.e., synthetic conjugated estrogens A and synthetic conjugated estrogens B, which are prepared synthetically from plant sources).^{106 108 109 121 122}

Uses for Estrogens, Conjugated

Use of estrogens alone in postmenopausal women generally is referred to as estrogen replacement therapy (ERT); use of estrogens in combination with progestins usually is referred to as hormone replacement therapy (HRT) or postmenopausal hormone therapy. ^b Another therapeutic option involves use of estrogens in combination with an estrogen agonist-antagonist; this combination referred to as a tissue-selective estrogen complex (TSEC).²⁶³

ERT

Management of moderate to severe vasomotor symptoms associated with menopause.^{101 106 107 121 262 266}

Management of severe vaginal dryness, pain with sexual intercourse, and vulvar and vaginal atrophy associated with menopause.^{101 105 106 107 266} If used solely for this indication, consider use of topical vaginal preparations.^{101 105 106 107 266}

Osteoporosis

Prevention of osteoporosis.^{100 101 107 262 k l t u v ii} Used adjunctively with other measures (e.g., diet, calcium, vitamin D, weight-bearing exercise, physical therapy) to retard further bone loss and progression of osteoporosis in postmenopausal women.^{100 101 107 i j k l m t u v z ii}

Estrogens are effective for prevention of osteoporosis but are associated with a number of adverse effects.^{100 101 107} If prevention of postmenopausal osteoporosis is the sole indication for therapy, consider alternative therapy (e.g., alendronate, raloxifene, risedronate).^{101 107 112}

Has been effective in the treatment of osteoporosis in postmenopausal women.^{t u aa bb cc} Formerly recommended as first-line therapy; however, recommendations on appropriate use of HRT have been revised based on WHI study findings.^{r ss uu} (See Boxed Warning.) Evaluate risks and benefits of long-term HRT use in the management of osteoporosis, taking into account the increased risk of breast cancer and cardiovascular disease, availability of other pharmacologic modalities (e.g., alendronate, calcitonin, calcium, raloxifene, risedronate, vitamin D), and life-style factors that can be modified.^{101 107 t u v w x y gg ss vv xx yy}

Has been used in a limited number of anorexic women with chronic amenorrhea to reduce calcium loss^{† [off-label]} and, thereby, reduce risk of osteoporosis.^jj

Corticosteroid-induced Osteoporosis

Has been used to prevent bone loss in postmenopausal women receiving low- to moderate-dose corticosteroid therapy^{† [off-label]}.^{nn oo pp}

Hypoestrogenism

Treatment of hypoestrogenism secondary to hypogonadism, castration, or primary ovarian failure.¹⁰¹ Used for induction of puberty in adolescents with pubertal delay due to hypogonadism.¹⁰¹

Metastatic Breast Carcinoma

Palliative treatment of metastatic breast cancer in selected women and men.¹⁰¹ One of several second-line agents.^a

Prostate Carcinoma

Palliative treatment of advanced androgen-dependent prostate carcinoma.¹⁰¹

Abnormal Uterine Bleeding

Treatment of abnormal uterine bleeding due to hormonal imbalance in the absence of organic pathology.¹⁰⁴

Cardiovascular Risk Reduction† [off-label]

ERT or HRT does not decrease the incidence of cardiovascular disease.^{101 105 106 107 c f dd ss tt xx yy bbb} AHA, American College of Obstetricians and Gynecologists, FDA, and manufacturers recommend that hormone therapy not be used to prevent heart disease in healthy women (primary prevention) or to protect women with preexisting heart disease (secondary prevention).^{c f r ss tt xx yy fff}

Alzheimer’s Disease

Prior use of HRT, but not current HRT unless such use exceeds 10 years, associated with reduced risk of Alzheimer’s disease^{† [off-label]}.^ww Estrogens have not been shown to prevent progression of Alzheimer’s disease; American Academy of Neurology recommends that estrogens not be used for treatment of Alzheimer’s disease.^mm

Initiation of ERT or HRT in women ≥65 years of age not associated with an improvement in cognitive function.^{zz ddd eee} Some women receiving ERT or HRT experience detrimental effects.^{zz aaa ddd eee} Incidence of probable dementia in women receiving ERT or HRT was higher than that in women receiving placebo.^{aaa ddd} (See Boxed Warning.) Use of ERT or HRT to prevent dementia or cognitive decline in women ≥65 years of age is not recommended.^{ddd eee}

Postpartum Breast Engorgement

Used in the past for prevention of postpartum breast engorgement^{† [off-label]}; FDA has withdrawn approval of estrogen-containing drugs for this indication, since estrogens have not been shown to be safe for this use.¹¹⁰ (See Lactation under Cautions.)

Pregnancy

Not effective for any purpose during pregnancy; use contraindicated in pregnant women.^{101 104 105 106 107 121} (See Pregnancy under Cautions.)

Estrogens, Conjugated Dosage and Administration

General

• A progestin generally is added to estrogen therapy (HRT) in women with an intact uterus.^{101 104 105 107 121} Addition of a progestin for ≥10 days per cycle of estrogen or daily with estrogen reduces incidence of endometrial hyperplasia and attendant risk of endometrial carcinoma in women with an intact uterus.^{101 104 105 107 121}

• As an alternative to progestin, use of bazedoxifene (an estrogen agonist-antagonist) in fixed combination with conjugated estrogens reduces risk of endometrial hyperplasia.^{261 262 263}

• ERT is appropriate in women who have undergone a hysterectomy (to avoid unnecessary exposure to progestins).^{101 104 105 107 121}

Administration

Conjugated estrogens USP usually administered orally; may also administer intravaginally or by deep IM or slow IV injection.^{101 104 105 107}

Administer synthetic conjugated estrogens A and synthetic conjugated estrogens B orally.^{106 121}

Estrogen therapy generally is administered in a continuous daily dosage regimen or, alternatively, in a cyclic regimen.^{101 105 107} When administered cyclically, estrogen usually is given once daily for 3 weeks followed by 1 week without the drug or once daily for 25 days followed by 5 days off; regimen is repeated as necessary.^{101 105}

When parenteral administration of conjugated estrogens USP is required, IV injection is preferred because of the more rapid response compared with IM injection.¹⁰⁴

Oral Administration

Oral preparations containing medroxyprogesterone acetate in combination with conjugated estrogens USP as monophasic or biphasic regimens are commercially available in a mnemonic dispensing package to aid user in complying with the prescribed dosage schedule.¹⁰⁷

Oral preparation containing bazedoxifene acetate in fixed combination with conjugated estrogens is commercially available in a 30-day package including 2 blister packs of 15 tablets each.²⁶²

IV Administration

For solution and drug compatibility information, see Compatibility under Stability.

Administer by direct IV injection.¹⁰⁴

Reconstitution

Reconstitute vial containing 25 mg of conjugated estrogens USP with 5 mL of sterile water for injection.¹⁰⁴ Do not shake vigorously.¹⁰⁴ Administer immediately after reconstitution.¹⁰⁴

Rate of Administration

Administer slowly (to avoid flushing reaction).¹⁰⁴

IM Administration

Administer by deep IM injection.¹⁰⁴

Reconstitution

Reconstitute vial containing 25 mg of conjugated estrogens USP with 5 mL of sterile water for injection.¹⁰⁴ Do not shake vigorously.¹⁰⁴ Administer immediately after reconstitution.¹⁰⁴

Vaginal Administration

Administer intravaginally as a vaginal cream.¹⁰⁵

Dosage

Individualize dosage according to the condition being treated and the tolerance and therapeutic response of the patient.^{101 104 105 106 107 121}

To minimize risk of adverse effects, use the lowest possible effective dosage.^{101 104 105 106 107 121} Because of the potential increased risk of cardiovascular events, breast cancer, and venous thromboembolic events, limit estrogen, estrogen/progestin, or conjugated estrogens in fixed combination with bazedoxifene to the lowest effective doses and shortest duration of therapy consistent with treatment goals and risks for the individual woman.^{101 104 105 107 121 262}

Periodically reevaluate use of estrogen, estrogen/progestin, or conjugated estrogens in fixed combination with bazedoxifene (i.e., at 3- to 6-month intervals).^{101 104 105 107 121 262}

Pediatric Patients

Hypoestrogenism

Oral

Conjugated estrogens USP: 0.15 mg daily may induce breast development.¹⁰¹ Increase dosage at 6- to 12-month intervals to achieve appropriate bone age advancement and epiphyseal closure.¹⁰¹

Conjugated estrogens USP: 0.625 mg daily (with progestins) sufficient to induce artificial cyclic menses and to maintain bone mineral density (BMD) after skeletal maturity.¹⁰¹

Adults

Estrogen Replacement Therapy

Vasomotor Symptoms

Oral

Conjugated estrogens USP: Initially, 0.3 mg daily continuously or in cyclic regimen (25 days on, 5 days off).¹⁰¹ Adjust dosage based on patient response.¹⁰¹

Synthetic conjugated estrogens A: Initially, 0.45 mg daily.¹⁰⁶ May increase dosage up to 1.25 mg daily.¹⁰⁶

Synthetic conjugated estrogens B: Initially, 0.3 mg daily.^{121 266} May increase dosage up to 1.25 mg daily.²⁶⁶ Adjust dosage based on patient response.^{121 266}

Conjugated estrogens USP in fixed combination with medroxyprogesterone acetate (Prempro), monophasic regimen: Initially, conjugated estrogens USP 0.3 mg with medroxyprogesterone acetate 1.5 mg daily.¹⁰⁷ Alternatively, conjugated estrogens USP 0.45 mg with medroxyprogesterone acetate 1.5 mg daily, conjugated estrogens USP 0.625 mg with medroxyprogesterone acetate 2.5 mg daily, or conjugated estrogens USP 0.625 mg with medroxyprogesterone acetate 5 mg daily.¹⁰⁷

Conjugated estrogens USP with medroxyprogesterone acetate (Premphase), biphasic regimen: Conjugated estrogens USP 0.625 mg daily; medroxyprogesterone acetate 5 mg daily on days 15–28 of the cycle.¹⁰⁷

Conjugated estrogens in fixed combination with bazedoxifene acetate: Conjugated estrogens 0.45 mg with bazedoxifene 20 mg once daily.²⁶²

Vulvar and Vaginal Atrophy

Oral

Conjugated estrogens USP: Initially, 0.3 mg daily continuously or in cyclic regimen (25 days on, 5 days off).¹⁰¹ Adjust dosage based on patient response.¹⁰¹

Synthetic conjugated estrogens A: 0.3 mg daily.¹⁰⁶

Synthetic conjugated estrogens B: 0.3 mg daily.²⁶⁶

Conjugated estrogens USP in fixed combination with medroxyprogesterone acetate (Prempro), monophasic regimen: Initially, conjugated estrogens USP 0.3 mg with medroxyprogesterone acetate 1.5 mg daily.¹⁰⁷ Alternatively, conjugated estrogens USP 0.45 mg with medroxyprogesterone acetate 1.5 mg daily, conjugated estrogens USP 0.625 mg with medroxyprogesterone acetate 2.5 mg daily, or conjugated estrogens USP 0.625 mg with medroxyprogesterone acetate 5 mg daily.¹⁰⁷

Conjugated estrogens USP with medroxyprogesterone acetate (Premphase), biphasic regimen: Conjugated estrogens USP 0.625 mg daily; medroxyprogesterone acetate 5 mg daily on days 15–28 of the cycle.¹⁰⁷

Vaginal

Conjugated estrogens USP: 0.5–2 g daily in cyclic regimen (3 weeks on, 1 week off).¹⁰⁵

Osteoporosis

Prevention in Postmenopausal Women

Oral

Conjugated estrogens USP: Initially, 0.3 mg daily continuously or in cyclic regimen (25 days on, 5 days off).¹⁰¹ Adjust dosage based on clinical and BMD response.¹⁰¹

Conjugated estrogens USP in fixed combination with medroxyprogesterone acetate (Prempro), monophasic regimen: Initially, conjugated estrogens USP 0.3 mg with medroxyprogesterone acetate 1.5 mg daily.¹⁰⁷ Alternatively, conjugated estrogens USP 0.45 mg with medroxyprogesterone acetate 1.5 mg daily, conjugated estrogens USP 0.625 mg with medroxyprogesterone acetate 2.5 mg daily, or conjugated estrogens USP 0.625 mg with medroxyprogesterone acetate 5 mg daily.¹⁰⁷ Adjust dosage based on clinical and BMD response.¹⁰⁷

Conjugated estrogens USP with medroxyprogesterone acetate (Premphase), biphasic regimen: Conjugated estrogens USP 0.625 mg daily; medroxyprogesterone acetate 5 mg daily on days 15–28 of the cycle.¹⁰⁷

Conjugated estrogens in fixed combination with bazedoxifene acetate: Conjugated estrogens 0.45 mg with bazedoxifene 20 mg once daily.²⁶²

Hypoestrogenism

Female Hypogonadism

Oral

Conjugated estrogens USP: 0.3–0.625 mg daily in a cyclic regimen (3 weeks on, 1 week off).¹⁰¹ Adjust dosage based on symptom severity and endometrial responsiveness.¹⁰¹

Female Castration or Primary Ovarian Failure

Oral

Conjugated estrogens USP: 1.25 mg daily in a cyclic regimen.¹⁰¹ Adjust dosage based on symptom severity and clinical response.¹⁰¹

Metastatic Breast Carcinoma

Oral

Conjugated estrogens USP: 10 mg 3 times daily for ≥3 months.¹⁰¹

Prostate Carcinoma

Oral

Conjugated estrogens USP: 1.25–2.5 mg 3 times daily.¹⁰¹

Abnormal Uterine Bleeding

IV or IM

Conjugated estrogens USP: 25 mg; can repeat dose in 6–12 hours.¹⁰⁴

Cautions for Estrogens, Conjugated

Contraindications

• Undiagnosed abnormal genital bleeding.^{101 104 105 106 107 121 262}

• Known or suspected breast cancer or history of breast cancer (except when used for palliative treatment of metastatic disease in appropriately selected individuals).^{101 104 105 106 107 121 262}

• Known or suspected estrogen-dependent neoplasia.^{101 104 105 106 107 121 262}

• Active DVT or pulmonary embolism; history of DVT or pulmonary embolism.^{101 104 105 106 107 121 262}

• Active or recent (within past year) arterial thromboembolic disease (e.g., stroke, MI).^{101 104 105 106 107 121 262}

• Liver disease or impairment.^{101 104 105 107 121 262}

• Known protein C, protein S, or antithrombin deficiency, or other known thrombophilic disorders.^{262 264 265 266 267}

• Known or suspected pregnancy.^{101 104 105 106 107 121 262}

• Known hypersensitivity to estrogen or any ingredient in the formulation.^{101 104 105 106 107 121 262}

Warnings/Precautions

Warnings

Cardiovascular Disorders

Estrogen/progestin therapy associated with increased risk of MI, stroke, DVT, and pulmonary embolism.^{101 104 105 106 107 112 113 114 121} Estrogen therapy associated with increased risk of stroke and DVT.^{101 104 105 107 262} (See Boxed Warning.) Discontinue estrogens immediately if any of these events occur or are suspected.^{101 104 105 106 107 121} Use of ERT or HRT is not advised in women with a history of stroke or transient ischemic attacks.^ccc (See Contraindications under Cautions.)

Appropriately manage risk factors for cardiovascular disease (e.g., hypertension, diabetes mellitus, tobacco use, hypercholesterolemia, obesity) and/or venous thromboembolism (personal or family history of venous thromboembolism, obesity, systemic lupus erythematosus).^{101 104 105 106 107 121} (See Contraindications under Cautions.)

Discontinue estrogens, whenever feasible, at least 4–6 weeks prior to surgery that is associated with an increased risk of thromboembolism or during prolonged immobilization.^{101 104 105 106 107 121 262 ee}

Endometrial Cancer

Use of unopposed estrogen therapy in women who have a uterus is associated with increased risk of endometrial cancer.^{101 104 105 106 107 121 262} Clinical surveillance and evaluation are essential.^{101 104 105 106 107 121} Perform diagnostic tests to rule out malignancy in women with undiagnosed, persistent or recurring abnormal vaginal bleeding.^{101 104 105 106 107 121}

Incidence of endometrial hyperplasia is reduced substantially when progestins are used concomitantly.^{101 104 105 106 107 121 q r s ggg hhh} Concomitant use of estrogen agonist/antagonist bazedoxifene also reduces risk of endometrial hyperplasia associated with conjugated estrogens.²⁶²

Breast Cancer

HRT associated with increased risk of breast cancer^{101 104 105 106 107 112 113 114 121 n o p ff gg hh} or increase in abnormal mammograms requiring further evaluation.²⁶²

All postmenopausal women should receive yearly breast examinations by a clinician and perform monthly self-examinations.^{101 104 105 106 107 121 262} Schedule periodic mammography based on patient age and risk factors.^{101 104 105 106 107 121 262}

Dementia

ERT or HRT in women ≥65 years of age has been associated with increased risk of developing probable dementia.^{101 104 105 107 121 262} Whether these findings apply to younger women is unknown.^{101 104 105 107 121 zz aaa} (See Alzheimer’s Disease under Uses.)

Gallbladder Disease

ERT associated with increased risk of gallbladder disease requiring surgery.^{101 104 105 106 107 121 262}

Hypercalcemia

Estrogens may cause severe hypercalcemia in patients with breast cancer and bone metastases.^{101 104 105 106 107 121} Discontinue the drug and initiate appropriate therapy to reduce serum calcium concentrations if hypercalcemia occurs.^{101 104 105 106 107 121}

Ocular Effects

Retinal thrombosis reported.^{101 104 105 106 107 121 262} Discontinue pending examination if sudden partial or complete loss of vision or sudden onset of proptosis, diplopia, or migraine occurs.^{101 104 105 107 121 262} Discontinue estrogens if papilledema or retinal vascular lesions noted on examination.^{101 104 105 106 107 104 105 121 262}

General Precautions

Elevated BP

Rarely, substantial increases in BP attributed to idiosyncratic reactions to estrogen.^{101 104 105 106 107 121 262} ERT generally is not associated with elevated BP.^{101 104 105 107 121 d e g h} Monitor BP at regular intervals.^{101 104 105 106 107 121 d e g h}

Hypertriglyceridemia

Estrogen therapy may be associated with increases in plasma triglyceride concentrations resulting in pancreatitis in women with increased serum lipids.^{101 104 105 106 107 121 262} Consider discontinuance of therapy if pancreatitis occurs.^{262 264 265 266}

Fluid Retention

Estrogens may cause some degree of fluid retention; use with caution and careful monitoring in patients with conditions that might be aggravated by fluid retention (e.g., cardiac or renal impairment).^{101 104 105 106 107 121 262}

Hypocalcemia

Use with caution in patients with hypoparathyroidism since estrogen-induced hypocalcemia may occur.^{101 104 105 106 107 121 262 264 265 266}

Hereditary Angioedema

Estrogens may exacerbate symptoms of angioedema in women with hereditary angioedema.^{262 264 265 266 267}

Ovarian Cancer

Long-term estrogen therapy associated with increased incidence of ovarian cancer in some epidemiologic studies.^{101 104 105 106 107 121 262 kk ll} Other studies did not show a clinically important association.^{101 104 105 106 107 121 262}

Endometriosis

Estrogens may exacerbate endometriosis.^{101 104 105 106 107 121}

Malignant transformation of residual endometrial implants reported rarely in women receiving unopposed estrogen following hysterectomy.^{101 104 105 107} Consider the addition of progestin in women with residual endometriosis following hysterectomy.^{101 104 105 107 121}

Other Conditions

Estrogens may exacerbate asthma, diabetes mellitus, epilepsy, migraine, porphyria, systemic lupus erythematosus, and hepatic hemangiomas; use with caution in patients with these conditions.^{101 104 105 107 121 262}

Precautions Specific to Vaginal Administration

Exposure to conjugated estrogens USP vaginal cream may weaken latex condoms.¹⁰⁵ Consider the potential for the cream to weaken and contribute to protective failure of latex or rubber condoms, diaphragms, or cervical caps.¹⁰⁵

Use of Fixed Combinations

When a progestin is used in conjunction with estrogen therapy, consider the cautions, precautions, and contraindications associated with progestin therapy.^{107 a}

When bazedoxifene is used in combination with conjugated estrogens, consider the usual cautions, precautions, contraindications, and interactions associated with bazedoxifene.²⁶² Cautionary information applicable to specific populations (e.g., pregnant or nursing women, individuals with hepatic or renal impairment, geriatric patients) should be considered for each drug in the fixed combination.²⁶²

Specific Populations

Pregnancy

Category X.^{101 104 105 106 107 121 262} (See Contraindications under Cautions.)

In utero exposure of females to diethylstilbestrol (DES [no longer commercially available in US]) is associated with increased risk of vaginal adenosis, squamous cell dysplasia of the cervix, and clear-cell vaginal cancer in later life.^b

In utero exposure of males to DES is associated with an increased risk of genital abnormalities and possibly testicular cancer later in life.^b

Women who receive DES during pregnancy may be at increased risk of breast cancer; causal relationship unproven.^b

Lactation

Administration of estrogens to nursing women has been associated with decreased amounts and lower quality of milk.^{101 104 105 106 107 121 262} Detectable amounts of estrogens have been identified in milk of women receiving these drugs.^{101 104 105 106 107 121 262} Caution advised.^{101 104 105 106 107 121} Conjugated estrogens/bazedoxifene in fixed combination not recommended for use in nursing women.²⁶²

Pediatric Use

Estrogen therapy has been used for induction of puberty in adolescents with some forms of pubertal delay.¹⁰¹ Safety and efficacy of estrogens in children not otherwise established.^{101 104 105 107 121}

Use estrogen therapy with caution and careful monitoring if bone growth is not yet complete, since estrogens may cause premature epiphyseal closure.¹⁰¹

Estrogen therapy in prepubertal girls induces premature breast development and vaginal cornification and may induce vaginal bleeding.¹⁰¹ Estrogen therapy in boys may modify the normal pubertal process.¹⁰¹

Geriatric Use

No substantial differences in safety in women ≥65 years of age compared with younger women; increased incidence of stroke and invasive breast cancer reported in women≥75 years of age compared with younger women.^{101 104 105 107}

Conjugated estrogens/bazedoxifene in fixed combination not recommended for use in women ≥75 years of age.²⁶²

Possible increased risk of developing probable dementia in women ≥65 years of age. (See Dementia under Cautions.)^{101 104 105 107}

Clinical studies of estrogens alone or in combination with a progestin did not include sufficient numbers of patients ≥65 years of age to determine whether geriatric patients respond differently than younger patients.^{101 104 105 107}

Hepatic Impairment

Estrogens may be poorly metabolized in patients with hepatic impairment.^{101 104 105 106 107 121} (See Contraindications under Cautions.)

Caution advised in patients with a history of cholestatic jaundice associated with previous estrogen use or with pregnancy; discontinue if jaundice recurs.^{101 104 105 106 107 121}

Renal Impairment

Use with caution.^{101 104 105 107 121} (See Fluid Retention under Cautions.)

Common Adverse Effects

Abdominal pain, asthenia, flatulence, leg cramps, pruritus, vaginal hemorrhage, vaginitis, vaginal moniliasis.^{101 107}

Drug Interactions

Appears to be metabolized partially by CYP3A4.^{101 104 105 106 107 121}

Drugs Affecting Hepatic Microsomal Enzymes

CYP3A4 inhibitors: Potential pharmacokinetic interaction (increased plasma estrogen concentrations).^{101 104 105 106 107 121}

CYP3A4 inducers: Potential pharmacokinetic interaction (decreased plasma estrogen concentrations).^{101 104 105 106 107 121}

Specific Drugs and Foods

Estrogens, Conjugated Pharmacokinetics

Absorption

Bioavailability

Conjugated estrogens are well absorbed through mucous membranes and from the GI tract.^{101 104 105 106 107 121}

Food

Conjugated estrogens USP: High-fat meal does not affect extent of oral absorption.¹⁰⁷

Synthetic conjugated estrogens A: Effect of food unknown.¹⁰⁶

Synthetic conjugated estrogens B: Effects of food unknown.¹²¹

Distribution

Extent

Widely distributed; highest concentrations found in sex hormone target organs.^{101 104 105 106 107 121}

Plasma Protein Binding

50–80%.^b

Elimination

Metabolism

Metabolized in the liver; the kidney, gonads, and muscle tissue involved to some extent.^b Estrogens metabolized partially by CYP3A4.^{101 104 105 106 107 121}

Extensive metabolic conversion takes place in the liver (e.g., estradiol converted to estrone, both converted to estriol).^{101 104 105 106 107 121}

Estrogens undergo enterohepatic recirculation via sulfate and glucuronide conjugation in the liver, biliary secretion of conjugates into the intestine, and hydrolysis in the gut followed by reabsorption.^{101 104 105 106 107 121}

Elimination Route

Estrogens and their metabolites excreted mainly in urine.^{101 104 106 107 121}

Half-life

Conjugated estrogens: 10–28 hours.^{101 106 107}

Stability

Storage

Oral

Tablets

20–25°C (may be exposed to 15–30°C).^{101 106 107 121}

Parenteral

Powder for Injection

2–8°C.¹⁰⁴

Vaginal

Cream

20–25°C (may be exposed to 15–30°C).¹⁰⁵

Compatibility

Parenteral

Stated to be incompatible with protein hydrolysate, ascorbic acid, or any solution with an acid pH.¹⁰⁴

Solution Compatibility104

Drug Compatibility

Actions

• Conjugated estrogens USP is a mixture of conjugated equine estrogens obtained from natural sources and occurring as the sodium salts of the water-soluble estrogen sulfates blended to represent the average composition of material derived from pregnant mare’s urine.¹⁰¹ It is a mixture of sodium estrone sulfate and sodium equilin sulfate that also contains 17α-dihydroequilin, 17α-estradiol, 17β-dihydroequilin, equilenin, 17α-dihydroequilenin, 17β-dihydroequilenin, δ^8,9-dehydroestrone, and 17β-estradiol.¹⁰¹

• Synthetic conjugated estrogens A is a mixture of conjugated estrogens prepared synthetically from plant sources (i.e., soy and yams).¹⁰⁶ It contains the sodium salts of water-soluble estrogen sulfates blended into a 9-component mixture of estrone sulfate and sodium equilin sulfate as well as the concomitant components 17α-dihydroequilin, 17α-estradiol, 17β-dihydroequilin, 17α-dihydroequilenin, 17β-dihydroequilenin, equilenin, and 17β-estradiol as sodium sulfate conjugates.¹⁰⁶

• Synthetic conjugated estrogens B is a mixture of conjugated estrogens prepared synthetically from plant sources.^{121 122} It contains the sodium salts of water-soluble estrogen sulfates blended into a 10-component mixture of estrone sulfate and sodium equilin sulfate as well as the concomitant components 17α-dihydroequilin, 17α-estradiol, 17β-dihydroequilin, 17α-dihydroequilenin, 17β-dihydroequilenin, equilenin, 17β-estradiol, and δ^8,9-dehydroestrone as sodium sulfate conjugates.¹²¹ This mixture contains the 10 estrogenic substances present in currently available commercial preparations of conjugated estrogens USP.¹²¹

• Exogenous estrogens elicit, to varying degrees, all the pharmacologic responses usually produced by endogenous estrogens.^a

Advice to Patients

• Importance of providing patient a copy of the manufacturer’s patient information.^{101 104 105 106 107 121}

• Risk of cancer of the uterus in postmenopausal women.^{101 104 105 106 107 121} Importance of reporting any unusual vaginal bleeding to clinicians.^{101 104 105 106 107 121}

• Risk of MI, stroke, breast cancer, and venous thromboembolism.^{101 104 105 106 107 121} Importance of not using estrogens to prevent heart disease, MI, or strokes.^{101 104 105 106 107 121}

• Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.^{101 104 105 106 107 121}

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and herbal supplements, as well as concomitant illnesses.^{101 104 105 106 107 121}

• Importance of informing patients of other important precautionary information.^{101 104 105 106 107 121} (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

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