Estropipate; Estrogens, Esterified (Monograph)

Brand names: Menest, Ogen, Ortho-Est
Drug class: Estrogens
ATC class: G03CA07
VA class: HS300
CAS number: 7280-37-7

Introduction

Steroidal estrogens.^{106 107 108}

Uses for Estropipate; Estrogens, Esterified

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

Estrogen Replacement Therapy

Management of moderate to severe vasomotor symptoms associated with menopause.^{106 107 108} Esterified estrogens also is used in fixed combination with methyltestosterone in women who do not respond adequately to estrogens alone;¹⁰⁸ FDA is reevaluating this combination.^{100 101}

Management of vulvar and vaginal atrophy associated with menopause.^{106 107} If estrogens are used solely for this indication, consider use of topical vaginal preparations.^{106 107}

Osteoporosis

Prevention of postmenopausal osteoporosis.^{106 l m w x y ll} 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.^{106 j k l m n w x y cc ll}

Estrogens are effective for prevention of osteoporosis but are associated with a number of adverse effects.¹⁰⁶ If prevention of postmenopausal osteoporosis is the sole indication for therapy, consider alternative therapy (e.g., alendronate, raloxifene, risedronate).¹⁰⁶

Has been effective in the treatment of osteoporosis in postmenopausal women.^{w x dd ee ff} Formerly recommended as first-line therapy; however, recommendations on appropriate use of HRT have been revised based on WHI study findings.^{ss tt vv} (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.^{w x y z aa bb jj tt ww yy zz}

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.^ss

Corticosteroid-induced Osteoporosis

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

Hypoestrogenism

Treatment of hypoestrogenism secondary to hypogonadism, castration, or primary ovarian failure.^{106 107}

Metastatic Breast Carcinoma

Palliative treatment of metastatic breast cancer in selected women and men.¹⁰⁷ One of several second-line agents.^a

Prostate Carcinoma

Palliative treatment of advanced androgen-dependent prostate carcinoma.¹⁰⁷

Cardiovascular Risk Reduction† [off-label]

ERT or HRT does not decrease the incidence of cardiovascular disease.^{106 107 108 d g gg tt uu yy zz ccc} 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).^{d g ss tt vv yy zz ggg}

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]}.^xx Estrogens have not been shown to prevent progression of Alzheimer’s disease, and American Academy of Neurology recommends that estrogens not be used for treatment of Alzheimer’s disease.^oo

Initiation of ERT or HRT in women ≥65 years of age not associated with an improvement in cognitive function.^{aaa eee fff} Some women receiving ERT or HRT (specifically conjugated estrogens 0.625 mg in conjunction with medroxyprogesterone acetate 2.5 mg daily or conjugated estrogens 0.625 mg daily) experience detrimental effects.^{aaa bbb eee fff} Incidence of probable dementia in women receiving ERT or HRT was higher than that in women receiving placebo.^{bbb eee} Use of ERT or HRT to prevent dementia or cognitive decline in women ≥65 years of age is not recommended.^{eee fff}

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.^b (See Lactation under Cautions.)

Pregnancy

Not effective for any purpose during pregnancy; use contraindicated in pregnant women.^{106 107 108} (See Pregnancy under Cautions.)

Estropipate; Estrogens, Esterified Dosage and Administration

General

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

ERT is appropriate in women who have undergone a hysterectomy (avoids unnecessary exposure to progestins).^{106 107 108}

Administration

Administer estropipate and esterified estrogens orally.^{106 107 108}

Estrogen therapy generally is administered in a continuous daily dosage regimen or, alternatively, in a cyclic regimen.^{106 107 108} When administered cyclically, estrogen usually is given once daily for 3 weeks followed by 1 week without the drug; regimen is repeated as necessary.^{106 107 108}

Oral Administration

Administer orally one or more times daily.^{106 107 108}

When estropipate or esterified estrogens is used for management of vasomotor symptoms, initiate treatment at any time in women who have not menstruated within the previous 2 months; if patient is menstruating, start cyclic administration on day 5 of cycle.^{106 107}

Dosage

Individualize dosage according to the condition being treated and the tolerance and therapeutic response of the patient.^{106 107 108}

To minimize risk of adverse effects, use the lowest possible effective dosage.^{106 107 108 c} Because of the potential increased risk of cardiovascular events, breast cancer, and venous thromboembolic events, limit estrogen and estrogen/progestin therapy to the lowest effective doses and shortest duration of therapy consistent with treatment goals and risks for the individual woman.^{106 107 108}

Periodically reevaluate estrogen and estrogen/progestin therapy (i.e., at 3- to 6-month intervals).^{106 107 108}

Adults

Estrogen Replacement Therapy

Vasomotor Symptoms

Oral

Estropipate: 0.75–6 mg daily in a cyclic regimen.¹⁰⁶

Esterified estrogens: 1.25 mg daily in a cyclic regimen.¹⁰⁷

Esterified estrogens in fixed combination with methyltestosterone: Esterified estrogens 0.625 mg with methyltestosterone 1.25 mg daily in a cyclic regimen (3 weeks on, 1 week off).¹⁰⁸ Alternatively, esterified estrogens 1.25 mg with methyltestosterone 2.5 mg daily in a cyclic regimen.¹⁰⁸

Vulvar and Vaginal Atrophy

Oral

Estropipate: 0.75–6 mg daily in a cyclic regimen.¹⁰⁶

Esterified estrogens: 0.3–≥1.25 mg daily in a cyclic regimen.¹⁰⁷

Osteoporosis

Prevention in Postmenopausal Women

Oral

Estropipate: 0.75 mg daily in a cyclic regimen (25 days on, 6 days off).¹⁰⁶

Hypoestrogenism

Female Hypogonadism

Oral

Estropipate: 1.5–9 mg daily for 3 weeks followed by 8–10 days without the drug; if menstruation does not occur by the end of the 8- to 10-day drug-free period, repeat the same dosage schedule.¹⁰⁶ Number of courses required to induce menstruation varies depending on endometrial responsiveness.¹⁰⁶ If satisfactory withdrawal bleeding does not occur, may administer an oral progestin concomitantly during the third week of the cycle.¹⁰⁶

Esterified estrogens: 2.5–7.5 mg daily in divided doses for 20 days, followed by 10 days without the drug.¹⁰⁷ Number of courses required to induce menstruation varies depending on endometrial responsiveness.¹⁰⁷ If menstruation does not occur by the end of the first complete cycle, repeat the same dosage schedule.¹⁰⁷ If menstruation occurs before the end of the 10-day drug-free period, initiate estrogen-progestin regimen with esterified estrogens 2.5–7.5 mg given daily in divided doses for 20 days; administer oral progestin during the last 5 days of esterified estrogens administration.¹⁰⁷ If menstruation begins before the estrogen-progestin regimen is completed, discontinue therapy and then reinstitute on the fifth day of menstruation.¹⁰⁷

Female Castration or Primary Ovarian Failure

Oral

Estropipate: 1.5–9 mg daily for 3 weeks, followed by 8–10 days without the drug.¹⁰⁶ Adjust dosage according to severity of symptoms and therapeutic response.¹⁰⁶

Esterified estrogens: 1.25 mg daily in a cyclic regimen.¹⁰⁷ Adjust dosage according to severity of symptoms and therapeutic response.¹⁰⁷

Metastatic Breast Carcinoma

Oral

Esterified estrogens: 10 mg 3 times daily for ≥3 months.¹⁰⁷

Prostate Carcinoma

Oral

Esterified estrogens: 1.25–2.5 mg 3 times daily.¹⁰⁷

Cautions for Estropipate; Estrogens, Esterified

Contraindications

• Undiagnosed abnormal genital bleeding.^{106 107 108}

• Known or suspected breast cancer or history of breast cancer (except when used for palliative treatment of metastatic disease in appropriately selected individuals).^{106 107 108}

• Known or suspected estrogen-dependent neoplasia.^{106 107 108}

• Active DVT or pulmonary embolism; history of DVT or pulmonary embolism.^{106 107 108}

• Active or recent (within past year) arterial thromboembolic disease (e.g., stroke, MI).^{106 107 108 b}

• Liver disease or impairment.^{106 107 108}

• Known or suspected pregnancy.^{106 107 108}

• Known hypersensitivity to the drug or any ingredient in the formulation.^{106 107 108}

Warnings/Precautions

Warnings

Cardiovascular Disorders

Estrogen/progestin therapy associated with increased risk of MI, stroke, DVT, and pulmonary embolism.^{106 107 108 c} Estrogen therapy associated with increased risk of stroke and DVT.^c (See Boxed Warning.) Discontinue estrogens immediately if any of these events occur or are suspected.^{106 107 108} Use of ERT or HRT is not advised in women with a history of stroke or transient ischemic attacks.^ddd (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).^{106 107 108} (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.^{hh 106 107 108}

Endometrial Cancer

Use of unopposed estrogen therapy in women who have a uterus is associated with increased risk of endometrial cancer.^{106 107 108} Clinical surveillance and evaluation are essential.^{106 107 108} Perform diagnostic tests to rule out malignancy in women with undiagnosed, persistent or recurring abnormal vaginal bleeding.^{106 107 108}

Incidence of endometrial hyperplasia is reduced substantially when progestins are used concomitantly.^{106 107 108 o s t u v}

Breast Cancer

HRT associated with an increased risk of breast cancer.^{106 107 108 p q r ii jj kk}

All postmenopausal women should receive yearly breast examinations by a clinician and perform monthly self-examinations.^{106 107 108} Schedule periodic mammography based on patient age and risk factors.^{106 107 108}

Dementia

ERT or HRT in women ≥65 years of age has been associated with increased risk of developing probable dementia.^{106 107 108 aaa bbb eee fff} Whether these findings apply to younger women is unknown.^{106 107 108 aaa bbb} (See Alzheimer’s Disease under Uses.)

Gallbladder Disease

ERT associated with increased risk of gallbladder disease requiring surgery.^{106 107 108}

Hypercalcemia

Estrogens may cause severe hypercalcemia in patients with breast cancer and bone metastases.^{106 107 108} Discontinue the drug and initiate appropriate therapy to reduce serum calcium concentrations if hypercalcemia occurs.^{106 107 108}

Ocular Effects

Retinal thrombosis reported.^{106 107 108} Discontinue pending examination if sudden partial or complete loss of vision, or sudden onset of proptosis, diplopia, or migraine occurs.^{106 107 108} Discontinue estrogen if papilledema or retinal vascular lesions noted on examination.^{106 107 108}

General Precautions

Elevated BP

Rarely, substantial increases in BP attributed to idiosyncratic reactions to estrogen.^{106 107 108} ERT generally is not associated with elevated BP.^{106 107 108 e f h i} Monitor BP at regular intervals.^{106 107 108 e f h i}

Hypertriglyceridemia

Estrogen therapy may be associated with increases in plasma triglyceride concentrations resulting in pancreatitis in women with increased serum lipids.^{106 107 108}

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).^{106 107 108}

Hypocalcemia

Use with caution in patients with severe hypocalcemia.^{106 107 108}

Ovarian Cancer

Long-term estrogen therapy associated with increased incidence of ovarian cancer in some epidemiologic studies.^{106 107 108 mm nn} Other studies did not show a clinically important association.^{106 107 108}

Endometriosis

Estrogens may exacerbate endometriosis.^{106 107 108}

Malignant transformation of residual endometrial implants reported rarely in women receiving unopposed estrogen following hysterectomy.^{106 107 108} Consider the addition of progestin in women with residual endometriosis following hysterectomy.^{106 107 108}

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.^{106 107 108}

Combination Therapy

When esterified estrogens is used in fixed combination with methyltestosterone or estrogens are used in conjunction with a progestin, consider the precautions, cautions, and contraindications of the concomitant agent.^{106 107 108}

Specific Populations

Pregnancy

Category X.^{106 107 108} (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.^{106 107 108} Detectable amounts of estrogens have been identified in milk of women receiving these drugs.^{106 107 108} Caution advised.^{106 107 108}

Pediatric Use

Estrogen therapy has been used for induction of puberty in adolescents with some forms of pubertal delay.^b Safety and efficacy of estrogens in children not otherwise established.^{106 107 108}

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

Geriatric Use

Insufficient experience with esterified estrogens in fixed combination with methyltestosterone (Estratest, Estratest HS) in geriatric patients to determine whether geriatric patients respond differently than younger women.¹⁰⁸ Select dosage with caution because of age-related decreases in hepatic, renal, and/or cardiac function and potential concomitant disease and drug therapy.¹⁰⁸

Possible increased risk of developing probable dementia in women ≥65 years of age.^{106 107 108} (See Dementia under Cautions.)

Hepatic Impairment

Estrogens may be poorly metabolized in patients with hepatic impairment.^{106 107 108} (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.^{106 107 108}

Renal Impairment

Use with caution.^{106 107 108} (See Fluid Retention under Cautions.)

Common Adverse Effects

Vaginal hemorrhage, vaginal moniliasis.^{106 107 108}

Drug Interactions

Appears to be metabolized partially by CYP3A4.^{106 107 108}

Drugs Affecting Hepatic Microsomal Enzymes

CYP3A4 inhibitors: Potential pharmacokinetic interaction (increased plasma estrogen concentrations).^{106 107 108}

CYP3A4 inducers: Potential pharmacokinetic interaction (decreased plasma estrogen concentrations).^{106 107 108}

Specific Drugs and Foods

Estropipate; Estrogens, Esterified Pharmacokinetics

Absorption

Bioavailability

Estrogens are well absorbed from the GI tract.^{106 107 108}

Distribution

Extent

Widely distributed;^b highest concentrations found in sex hormone target organs.^{106 107 108}

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.^{106 107 108}

Extensive metabolic conversion (i.e., estradiol converted to estrone, both converted to estriol) takes place in the liver.^{106 107 108}

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.^{106 107 108}

Elimination Route

Estrogens and their metabolites are excreted mainly in urine.^{106 107 108}

Stability

Storage

Oral

Tablets

<30°C.^{106 108}

Actions

• Estropipate is estrone solubilized as the sulfate and stabilized with piperazine.¹⁰⁶

• Esterified estrogens is a mixture of the sodium salts of the sulfate esters of the estrogenic substances excreted by pregnant mares.¹⁰⁷

• 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.^{106 107 108}

• Risk of cancer of the uterus in postmenopausal women.^{106 107 108} Importance of reporting any unusual vaginal bleeding to clinicians.^{106 107 108}

• Risk of MI, stroke, breast cancer, and venous thromboembolism.^{106 107 108} Importance of not using estrogens to prevent heart disease, MI, or strokes.^{106 107 108}

• Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.^{106 107 108}

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as concomitant illnesses.^{106 107 108}

• Importance of informing patients of other important precautionary information.^{106 107 108} (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.

Most preparations containing androgenic anabolic steroid hormones are subject to control under the Federal Controlled Substances Act of 1970, as amended by the Anabolic Steroids Control Act of 1990 and 2004, as schedule III (C-III) drugs.^{102 104} However, manufacturers of certain preparations containing androgenic anabolic steroids (principally combinations that also include estrogens) have applied for and obtained for their product(s) an exemption from the record-keeping and other regulatory requirements of the Federal Controlled Substances Act.^{103 105} Because regulatory requirements for a given preparation containing an androgenic anabolic steroid may be subject to change under the provisions of the Act, contact the manufacturer when specific clarification about a preparation’s status is required.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

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