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.

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.

Estrogen Replacement Therapy

Management of moderate to severe vasomotor symptoms associated with menopause. Esterified estrogens also is used in fixed combination with methyltestosterone in women who do not respond adequately to estrogens alone; FDA is reevaluating this combination.

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

Osteoporosis

Prevention of postmenopausal osteoporosis. 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.

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

Has been effective in the treatment of osteoporosis in postmenopausal women. Formerly recommended as first-line therapy; however, recommendations on appropriate use of HRT have been revised based on WHI study findings. (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.

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.

Corticosteroid-induced Osteoporosis

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

Hypoestrogenism

Treatment of hypoestrogenism secondary to hypogonadism, castration, or primary ovarian failure.

Metastatic Breast Carcinoma

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

Prostate Carcinoma

Palliative treatment of advanced androgen-dependent prostate carcinoma.

Cardiovascular Risk Reduction† [off-label]

ERT or HRT does not decrease the incidence of cardiovascular disease. 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).

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]}. 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.

Initiation of ERT or HRT in women ≥65 years of age not associated with an improvement in cognitive function. 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. Incidence of probable dementia in women receiving ERT or HRT was higher than that in women receiving placebo. Use of ERT or HRT to prevent dementia or cognitive decline in women ≥65 years of age is not recommended.

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. (See Lactation under Cautions.)

Pregnancy

Not effective for any purpose during pregnancy; use contraindicated in pregnant women. (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. 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.

ERT is appropriate in women who have undergone a hysterectomy (avoids unnecessary exposure to progestins).

Administration

Administer estropipate and esterified estrogens orally.

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

Oral Administration

Administer orally one or more times daily.

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.

Dosage

Individualize dosage according to the condition being treated and the tolerance and therapeutic response of the patient.

To minimize risk of adverse effects, use the lowest possible effective dosage. 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.

Periodically reevaluate estrogen and estrogen/progestin therapy (i.e., at 3- to 6-month intervals).

Adults

Estrogen Replacement Therapy

Vasomotor Symptoms

Oral

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

Esterified estrogens: 1.25 mg daily in a cyclic regimen.

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). Alternatively, esterified estrogens 1.25 mg with methyltestosterone 2.5 mg daily in a cyclic regimen.

Vulvar and Vaginal Atrophy

Oral

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

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

Osteoporosis

Prevention in Postmenopausal Women

Oral

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

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. Number of courses required to induce menstruation varies depending on endometrial responsiveness. If satisfactory withdrawal bleeding does not occur, may administer an oral progestin concomitantly during the third week of the cycle.

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

Female Castration or Primary Ovarian Failure

Oral

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

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

Metastatic Breast Carcinoma

Oral

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

Prostate Carcinoma

Oral

Esterified estrogens: 1.25–2.5 mg 3 times daily.

Cautions for Estropipate; Estrogens, Esterified

Contraindications

• Undiagnosed abnormal genital bleeding.

• Known or suspected breast cancer or history of breast cancer (except when used for palliative treatment of metastatic disease in appropriately selected individuals).

• Known or suspected estrogen-dependent neoplasia.

• Active DVT or pulmonary embolism; history of DVT or pulmonary embolism.

• Active or recent (within past year) arterial thromboembolic disease (e.g., stroke, MI).

• Liver disease or impairment.

• Known or suspected pregnancy.

• Known hypersensitivity to the drug or any ingredient in the formulation.

Warnings/Precautions

Warnings

Cardiovascular Disorders

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

Endometrial Cancer

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

Incidence of endometrial hyperplasia is reduced substantially when progestins are used concomitantly.

Breast Cancer

HRT associated with an increased risk of breast cancer.

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

Dementia

ERT or HRT in women ≥65 years of age has been associated with increased risk of developing probable dementia. Whether these findings apply to younger women is unknown. (See Alzheimer’s Disease under Uses.)

Gallbladder Disease

ERT associated with increased risk of gallbladder disease requiring surgery.

Hypercalcemia

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

Ocular Effects

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

General Precautions

Elevated BP

Rarely, substantial increases in BP attributed to idiosyncratic reactions to estrogen. ERT generally is not associated with elevated BP. Monitor BP at regular intervals.

Hypertriglyceridemia

Estrogen therapy may be associated with increases in plasma triglyceride concentrations resulting in pancreatitis in women with increased serum lipids.

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).

Hypocalcemia

Use with caution in patients with severe hypocalcemia.

Ovarian Cancer

Long-term estrogen therapy associated with increased incidence of ovarian cancer in some epidemiologic studies. Other studies did not show a clinically important association.

Endometriosis

Estrogens may exacerbate endometriosis.

Malignant transformation of residual endometrial implants reported rarely in women receiving unopposed estrogen following hysterectomy. Consider the addition of progestin in women with residual endometriosis following hysterectomy.

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.

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.

Specific Populations

Pregnancy

Category X. (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.

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

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

Lactation

Administration of estrogens to nursing women has been associated with decreased amounts and lower quality of milk. Detectable amounts of estrogens have been identified in milk of women receiving these drugs. Caution advised.

Pediatric Use

Estrogen therapy has been used for induction of puberty in adolescents with some forms of pubertal delay. Safety and efficacy of estrogens in children not otherwise established.

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

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. Select dosage with caution because of age-related decreases in hepatic, renal, and/or cardiac function and potential concomitant disease and drug therapy.

Possible increased risk of developing probable dementia in women ≥65 years of age. (See Dementia under Cautions.)

Hepatic Impairment

Estrogens may be poorly metabolized in patients with hepatic impairment. (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.

Renal Impairment

Use with caution. (See Fluid Retention under Cautions.)

Common Adverse Effects

Vaginal hemorrhage, vaginal moniliasis.

Drug Interactions

Appears to be metabolized partially by CYP3A4.

Drugs Affecting Hepatic Microsomal Enzymes

CYP3A4 inhibitors: Potential pharmacokinetic interaction (increased plasma estrogen concentrations).

CYP3A4 inducers: Potential pharmacokinetic interaction (decreased plasma estrogen concentrations).

Specific Drugs and Foods

Estropipate; Estrogens, Esterified Pharmacokinetics

Absorption

Bioavailability

Estrogens are well absorbed from the GI tract.

Distribution

Extent

Widely distributed; highest concentrations found in sex hormone target organs.

Plasma Protein Binding

50–80%.

Elimination

Metabolism

Metabolized in the liver; the kidney, gonads, and muscle tissue involved to some extent. Estrogens metabolized partially by CYP3A4.

Extensive metabolic conversion (i.e., estradiol converted to estrone, both converted to estriol) takes place in the liver.

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.

Elimination Route

Estrogens and their metabolites are excreted mainly in urine.

Stability

Storage

Oral

Tablets

<30°C.

Actions

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

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

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

Advice to Patients

• Importance of providing patient a copy of the manufacturer’s patient information.

• Risk of cancer of the uterus in postmenopausal women. Importance of reporting any unusual vaginal bleeding to clinicians.

• Risk of MI, stroke, breast cancer, and venous thromboembolism. Importance of not using estrogens to prevent heart disease, MI, or strokes.

• Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as concomitant illnesses.

• Importance of informing patients of other important precautionary information. (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. 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. 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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