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Mechanism of Action
US Drug Names
Initially, 0.3 mg PO once daily. May titrate if needed. Use lowest effective dose. Few patients need up to 1.25 mg/day PO. Doses of less than 0.45 mg/day may be appropriate for patients with vaginal/vulvar symptoms only. Continuous, unopposed estrogen administration is acceptable in women without a uterus. In women with an intact uterus, estrogen may be given cyclically (e.g., 25 days of month then 5 days off) or combined with a progestin for at least 10 to 14 days per month to minimize the risk of endometrial hyperplasia. However, taking estrogens with progestins may have additional health risks for the patient; risk must be determined individually. In patients with an intact uterus, therapy is initiated arbitrarily if the patient has not menstruated for 2 months or more. If the patient is menstruating, the dose is initiated on day 5 of a cycle. Reassess every 3 to 6-months to determine if continued systemic hormone therapy is appropriate.   In patients with only vaginal or urogenital symptoms, consider vaginal treatment alone.    The North American Menopause Society (NAMS) Guidelines support the initiation of hormone replacement therapy (HRT) around the time of menopause if no contraindications to use exist and use is acceptable to the individual patient, as hormone therapy is the most effective treatment for vasomotor and genitourinary symptoms and has been shown to prevent bone loss and fracture. Early initiation of HRT and continuation of use at until the median age of menopause (52 years) is recommended in women with premature natural or surgically induced menopause. HRT for vasomotor symptoms and/or increased risk for bone loss around the time of menopause may be considered in those women aged younger than 60 years or who are fewer than 10 years from menopause onset.  For women who initiate HRT more than 10 or 20 years from menopause onset or are aged 60 years or older, the benefit-risk ratio is less favorable due to known risks for HRT (e.g., stroke, myocardial infarction, venous thromboembolism, dementia, urinary incontinence), and guidelines generally recommend against use in these women. Decisions regarding whether to continue systemic HRT in women aged older than 60 years should be made on an individual basis for quality of life, persistent vasomotor symptoms, or prevention of bone loss and fracture, with consideration given to alternative treatments for prevention of bone loss and other health issues.  Some women receiving oophorectomy for cancer-related concerns may be able to pursue hormone replacement to improve menopause-like symptoms following surgery. Some data suggest that the short-term treatment of vasomotor and menopause-symptoms in women receiving prophylactic oophorectomy due to BRCA 1/2 gene mutation-related cancer risks does not increase the risk for other cancers, particularly in women less than 45 years of age at time of surgery; larger studies are needed to confirm these findings and optimal treatment guidelines.
Initially, 0.5 grams vaginally once daily for 21 days; then, no treatment for 7 days. May titrate up to 2 grams/day vaginally depending on response. Repeat cyclically. Use the lowest effective dose. Reassess need for hormonal treatment every 3 to 6-months. For moderate to severe dyspareunia, 0.5 grams vaginally twice weekly (e.g., every Monday and Thursday) may be sufficient in some patients; otherwise, consider the usual vaginal dose. When isolated genitourinary symptoms caused by menopause are present, treatment guidelines recommend low-dose vaginal estrogens over systemic estrogens as first-line therapy.
Initiate at 0.3 mg PO once daily, given continuously, with no interruption in therapy, or cyclically. Use the lowest effective dose based on clinical and bone mineral density response. Few patients require 1.25 mg/day PO or more. Continuous unopposed estrogen administration is acceptable for women without a uterus. In women with an intact uterus, consider adding a progestin to reduce the risk of endometrial hyperplasia. Supplement calcium and vitamin D if dietary intake is inadequate. Reassess the appropriateness of hormone therapy every 3 to 6-months; carefully consider non-estrogen medication. In postmenopausal women with low bone mineral density, there is good evidence that standard-dose estrogen therapy reduces the risk for osteoporotic fractures, including hip, spine, and all non-spine fractures; however, estrogens are not generally recommended as a first-line prevention tactic due to the known risks of estrogen treatment (e.g., thromboembolism, cerebrovascular events) relative to other treatments. Women who need osteoporosis prophylaxis who are younger than 60 years or who are within 10 years of menopause onset may be given consideration for estrogen therapy, based on individual assessment of risk vs. benefit. Beyond the age of 60 years, other agents are preferred due to the known risks associated with hormonal therapy. Consider each woman's net balance of individual benefits and harms. If estrogen with or without a progestin is prescribed, use the lowest effective dose for the shortest duration that is consistent with an individual's treatment goals and risks. Estrogens can be used in conjunction with other medications for osteoporosis (e.g., bisphosphonates, denosumab, or teriparatide) based on clinical needs and judgment, when necessary. Estrogen therapy should not be used in patients with known osteoporosis; the risks outweigh the moderate benefit seen in postmenopausal women with established osteoporosis.    
0.3 mg or 0.625 mg PO once daily, administered cyclically (e.g., 3 weeks on and 1 week off). Adjust dose based on the severity of symptoms and responsiveness of the endometrium. In clinical studies, doses as low as 0.15 mg/day PO have induced breast development in patients with delayed puberty. The dosage may be gradually titrated upward at 6- to 12-month intervals as needed to achieve appropriate bone age advancement and eventual epiphyseal closure. The number of estrogen cycles needed to produce cyclical monthly bleeding will depend on the responsiveness of the patient's endometrium. Dosage cycles are often repeated for 3- to 6- months to establish a normal menstruation cycle. A 2-month hiatus often follows establishment of menses to assess if the patient can maintain normal menstrual cycles without further hormonal therapy. If menses does not resume, medication cycles may be repeated. Data suggest that chronic dosing with 0.625 mg/day PO of conjugated estrogens is sufficient to induce cyclic menses with sequential progestin treatment and to maintain bone mineral density after skeletal maturity is achieved.
1.25 mg PO once daily, administered cyclically (e.g., 3 weeks on and 1 week off). Adjust dosage, upward or downward, according to severity of symptoms and response of the patient. For maintenance, use lowest effective dose cycle that provides symptom control. Estrogen replacement therapy is considered standard of care to reduce chronic health risks and to improve quality of life. In women with an intact uterus, the addition of progestin therapy to the estrogen helps prevent endometrial hyperplasia; hormone replacement may induce cyclic vaginal bleeding again, but won't restore ovarian function, and infertility is treated with other means. Maintenance treatment can continue until the average age of natural menopause, if the patient desires.
25 mg IV or IM as a single dose. May repeat this dose in 6 to 12 hours, if necessary. The intravenous route is preferred for a more rapid response; inject IV slowly to reduce flushing. The use of conjugated estrogens parenterally does not preclude the use of other appropriate measures. 
Use the same dosing as for adult patients: 25 mg IV or IM as a single dose. May repeat this dose in 6 to 12 hours, if necessary. The intravenous route is preferred for a more rapid response; inject IV slowly to reduce flushing. The use of conjugated estrogens parenterally does not preclude the use of other appropriate measures. While FDA-approval for use in adolescents has not been specifically established, adolescent females have been included in clinical trials and use is part of standard medical management options in this population when acute care is needed. 
10 mg PO 3 times per day for at least 3 months. Estrogens have been used historically for this indication; in modern medicine, some estrogens are used as salvage endocrine therapy for metastatic disease. 
1.25 mg to 2.5 mg PO 3 times per day, usually for 3 months. The effectiveness of therapy can be judged by serial PSA determinations as well as by symptomatic improvement of the patient. A response to estrogen treatment, if it will occur, will usually be noted within 3 months. If the patient responds, estrogen therapy is continued until a significant advancement of the disease occurs. 
Dependent on indication for therapy.
Not indicated in prepubescent females.
Contraindicated in the presence of known liver dysfunction or hepatic disease of any type.
Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.
Conjugated estrogens are traditionally a mixture of the water soluble salts of sulfate esters from estrone, equilin, 17 alpha-dihydroequilin, and other related steroids. Traditionally conjugated estrogens are derived from pregnant equine urine (e.g., Premarin). The estrogens include the sodium salts of estrone sulfate, equilin sulfate, 17alpha- and 17beta-dihydroequilin sulfate, 17alpha- and 17beta-estradiol sulfate, 17alpha- and 17beta-dihydroequilenin sulfate, and equilenin sulfate; the exact composition of the equine urine-derived mixture is uncertain. The synthetic conjugated estrogens, A product (e.g., Cenestin) is derived from yam and soy plants and contains 9 synthetic estrogenic substances. The synthetic conjugated estrogens, B product (e.g., Enjuvia), is plant-derived, and includes the active estrogenic component delta 8,9-dyhydroestrone sulfate. The different conjugated estrogens products are not considered to be bioequivalent at this time. However, there is no evidence that 'natural' estrogens are more or less efficacious or safe than 'synthetic' estrogens given at equiestrogenic doses. Conjugated estrogens are used primarily as hormone replacement therapy (HRT) to treat moderate to severe vasomotor symptoms and genitourinary symptoms associated with menopause, and for the prevention of osteoporosis. Conjugated estrogens are also used for numerous abnormalities related to gonadotropin hormone dysfunction. Conjugated estrogens were first marketed in 1938; parenteral, oral and vaginal dose forms are available. Conjugated estrogens, A was approved by the FDA in March 1999. Conjugated estrogens, B was approved by the FDA in May 2004. In December 2008, the FDA approved synthetic conjugated estrogens A vaginal cream.
For storage information, see the specific product information within the How Supplied section.
Hazardous Drugs Classification
Uterine bleeding pattern changes and other genitourinary effects occur commonly during chronic, systemic conjugated estrogens therapy in postmenopausal women and is most common with oral replacement therapy; non-cyclic vaginal breakthrough bleeding is reported in 2% to 14% of patients. Amenorrhea is common and desirable in many postmenopausal women with an intact uterus and is not considered an adverse effect when estrogens are given continuously with a progestin; however, continued amenorrhea in a premenopausal woman may signal a lack of therapeutic response to the estrogen. Withdrawal bleeding, similar to menstrual bleeding, occurs with cyclic progestin administration, and is usually of shorter duration than regular menses. Changes in vaginal bleeding pattern and breakthrough bleeding or spotting have been noted with estrogens with or without progestins and are commonly reported. Metrorrhagia (3% to 11%) and pelvic pain or dysmenorrhea (4% to 12%) are infrequent. Changes in uterine bleeding patterns will usually taper and stabilize within 3 to 6 months. Infrequent genitourinary effects reported with conjugated estrogens use include dysmenorrhea or pelvic pain (reported in 1% to 8% of postmenopausal women), vaginal discharge (leukorrhea, roughly 3% to 7%), vaginitis or vaginal candidiasis (5% to 7%) and libido increase (less than 5%). The vaginal cream may cause vaginal irritation, burning or genital pruritus on application in less than 5% of patients. Less frequent (1% or less) adverse reactions to conjugated estrogens include changes in cervical ectropion, cervical secretion changes, cervical dysplasia, or libido decrease. Unusual vaginal bleeding or other pelvic symptoms that persist beyond 6 months should be evaluated by a health care professional. For example, continued and unexpected changes in bleeding patterns may indicate a change in uterine leiomyomatas (fibroids) or cervicitis, if present. Women should report unusual symptoms to their healthcare professionals, and follow advice for annual pelvic examinations and periodic Papanicolaou smears.
Breast changes that may occur with conjugated estrogen therapy include mastalgia (breast pain) and breast tenderness, which occur in 8% to 12% of women on chronic estrogen HRT. Breast enlargement, breast discharge, galactorrhea, and fibrocystic breast changes have been reported with estrogens and/or progestin therapy. Gynecomastia may occur in men on estrogen therapy. Patients should report breast changes, lumps, or breast discharge to their health care professionals. All women should receive yearly breast examinations by a healthcare provider and perform monthly breast self-examinations. In addition, mammography examinations should be scheduled based on patient age, risk factors, and prior mammogram results.
Gastrointestinal effects from conjugated estrogens administration are typically mild and relatively limited. Common side effects with conjugated estrogen use include diarrhea (0—7%), dyspepsia (9—11%), flatulence (4—7%) and nausea (6—12%). Some GI complaints may attenuate with continued administration. In larger doses, estrogens may cause vomiting and nausea may be significant. Other reported effects in < 5% of patients include abdominal pain, cramps or bloating, hypertriglyceridemia, and an increased incidence of gallbladder disease. With chronic use, abdominal pain can indicate biliary obstruction, and result in cholestatic jaundice. Estrogens enhance hepatic lipoprotein uptake and inhibit bile acid synthesis, resulting in increased concentration of cholesterol in the bile which can lead to cholelithiasis. Gallbladder disease and cholecystitis are 2- to 4-fold as frequent in women taking hormone replacement therapy (HRT) compared with controls. Rare adverse reactions (< 1%) include hepatitis (and elevated hepatic enzymes), enlargement of hepatic hemangiomas, ischemic colitis (bowel ischemia, no incidence reported), or pancreatitis. Patients with familial hyperlipoproteinemia may be at greater risk of pancreatitis while on estrogen therapy, which may greatly increase their serum triglycerides. Estrogens may induce peliosis hepatis, a very rare consequence of taking estrogens and combined oral contraceptives that is characterized by the presence of blood-filled spaces. Persistent or severe abdominal symptoms should be evaluated by a medical professional. Conjugated estrogens should be discontinued in any patient developing jaundice, cholestasis, or severe abdominal pain, and the patient should be evaluated.
Deep and superficial venous thrombosis, pulmonary embolism, thrombophlebitis, myocardial infarction, and stroke have been reported with estrogens and/or progestin therapy. The use of estrogens in postmenopausal women, with or without a progestin, carries a risk for thromboembolism, and cardiovascular events such as myocardial infarction (MI) or stroke. Detailed information regarding what is known about thromboembolic and cardiovascular risk in postmenopausal women is available in the boxed warnings and precautions section of the product labeling for the products, as these risks must be considered prior to use of HRT in women, and with consideration to age and other risk factors for these events. Risks vary with the use of estrogen-alone vs. use of estrogen with progestin therapy. Should any of these events occur or be suspected, discontinue the estrogen or estrogen-progestin therapy immediately.  
Conjugated estrogens can cause sodium and fluid retention and peripheral vasodilation, resulting in edema or mild weight gain. They should be prescribed cautiously to patients in whom edema formation would be detrimental. Estrogens also can slightly increase blood pressure, occasionally causing hypertension. Data indicate in most patients the change is not clinically significant. In a small number of case reports, substantial increases in blood pressure have been attributed to idiosyncratic reactions to estrogens. During clinical trials with various conjugated estrogens, such reactions occurred in < 5% or patients.  In the PEPI trial, postmenopausal women 45—65 years of age randomized to any hormone replacement therapy regimen containing conjugated estrogens experienced increases in both systolic and diastolic blood pressure of 3—5% after the first year of treatment, but the increases were not statistically different from placebo.
Headache has been reported in greater than 5% of patients receiving conjugated estrogens by any route, and has been reported in patients receiving chronic HRT. A severe headache may be a warning sign of a serious adverse event such as a stroke or retinal problems (e.g., thrombosis) in the eye. Discontinue the estrogen pending examination if there is sudden partial or complete loss of vision or sudden onset of migraine. If examination reveals a serious event, estrogens should be permanently discontinued. In some women, headache patterns are hormonally influenced. A number of changes can occur when a woman initiates HRT and include 1) migraines can appear for the first time, 2) a change in frequency, severity and duration of migraine headaches may be seen, or 3) an improvement or decrease in the occurrence of migraine headaches. When initiating therapy an individual's headache pattern should be observed and if migraines worsen consider discontinuing therapy.
Nervous system and mood disturbances occur in some women taking conjugated estrogens for hormonal replacement therapy. These changes can include mental depression (5—7%), dizziness (1—7%), fatigue or asthenia (1.4—8%), nervousness or anxiety (2—5%) or insomnia (2.9—7%). Paresthesias (0—6%) have also been reported. Less common central nervous system events (<5%) include chorea, emotional lability, irritability, exacerbation of epilepsy, and dementia. Possible growth potentiation of a benign meningioma may occur.
Conjugated estrogens and other estrogens used for hormone replacement can cause a variety of dermatological reactions; most occur in <5% of patients. Melasma and chloasma, in the form of tan or brown patches, may develop on the forehead, cheeks, temples and upper lip. These patches may persist after the drug is discontinued. Other infrequent reactions include urticaria, erythema nodosum, alopecia, hirsutism, or rash (unspecified). Erythematous eruptions, with or without pruritus, may also occur. In some cases estrogens may induce or aggravate an existing acne vulgaris or cause an acneiform rash. An injection site reaction with pain and redness may be associated with parenteral use.
Retinal thrombosis has been reported in patients receiving estrogens such as conjugated estrogens. Discontinue medication pending examination if there is sudden visual impairment either partial or complete or a sudden onset of proptosis, diplopia, or migraine. If examination reveals papilledema, visual loss, or retinal vascular lesions, permanently discontinue estrogens. Exogenous estrogen use can cause a conical cornea to develop from steepening or increased curvature of the cornea, caused by thinning of the stroma. Patients with contact lenses may develop intolerance to their lenses.
Conjugated estrogens and medroxyprogesterone combinations can cause impaired carbohydrate metabolism and impaired glucose tolerance, leading to hyperglycemia in some women taking HRT. In the PEPI trial, fasting glucose levels were lower, and mean 2-hour glucose levels were 8% higher, in combined HRT treated women versus placebo in all treatment arms. The effects appeared to be consistent across demographic, clinical, and lifestyle variables. Limited clinical studies of estrogen regimens have not noted significant alterations in glucose metabolism in healthy post-menopausal women. However, altered glucose tolerance secondary to decreased insulin sensitivity may be important for patients with hyperglycemia or diabetes mellitus. They should be observed for changes in glucose tolerance when initiating or discontinuing conjugated estrogens therapy.
Conjugated estrogens are known to cause teratogenesis during pregnancy and are in FDA category X. Increased risk of a wide variety of fetal abnormalities, including modified development of sexual organs, cardiovascular anomalies and limb defects, have been reported following the use of estrogens in pregnant women. The use of diethylstilbestrol, DES is well known for creating disturbances in the reproductive systems of both male and female offspring; similar disturbances are reported to occur in female offspring of rats exposed to other estrogens during gestation. In any patient in whom pregnancy is suspected, pregnancy should be ruled out before continuing the use of conjugated estrogens.
Cases of anaphylactoid reactions with or without angioedema, requiring emergency medical treatment, have been reported during post marketing use of conjugated estrogen oral tablets. Reported symptoms include hives, pruritis, swollen lips-tongue-face, bronchospasm, abdominal pain, or vomiting. Angioedema involving the tongue, larynx, face, hands, and feet requiring medical intervention has occurred post marketing. Patients who develop these symptoms following treatment should discontinue use not be re-challenged with oral conjugated estrogen. Other potential events related to hypersensitivity can include erythema multiforme, urticaria and other rashes. 
Some women taking conjugated estrogens or other estrogens for HRT notice tenderness, swelling, or minor bleeding of their gums, which may lead to gingivitis. Proper attention to oral care and regular dental visits are recommended.
There is an association of unopposed estrogen therapy and endometrial hyperplasia in women with an intact uterus. Unopposed estrogen therapy can promote endometrial hyperplasia in approximately 10% of patients with an intact uterus, and thus increase the risk of endometrial cancer. Adding a progestin to estrogen therapy has been shown to reduce, but not eliminate, the risk of endometrial hyperplasia, which may be a precursor to endometrial cancer. With concurrent progestin use (cyclically or continuously), the incidence of endometrial hyperplasia due to conjugated estrogens is estimated to be 1% or less. Clinical surveillance of all women using estrogen-alone or estrogen plus progestin therapy is important. Adequate diagnostic measures, including directed or random endometrial sampling when indicated, should be undertaken to rule out malignancy in postmenopausal women with undiagnosed persistent or recurring abnormal vaginal bleeding. The reported endometrial cancer risk among unopposed estrogen users is about 2- to 12-times greater than in non-users, and appears dependent on duration of treatment and on estrogen dose. Most studies show no significant increased risk associated with use of estrogens for less than 1 year. The greatest risk appears associated with prolonged use, with increased risks of 15-to 24-fold for 5 to 10 years or more, and this risk has been shown to persist for at least 8 to 15 years after estrogen therapy is discontinued. There is no evidence that the use of natural estrogens results in a different endometrial risk profile than synthetic estrogens of equivalent estrogen dose.     
Numerous epidemiologic studies have examined the effects of estrogen and estrogen-progestin hormone replacement therapy (HRT) on the development of new primary malignancy (e.g., breast cancer, endometrial cancer, ovarian cancer) in postmenopausal women. Detailed clinical study information regarding what is known about cancer risk in postmenopausal women is available in the boxed warnings and precautions section of the product labeling for the products, as these risks must be considered prior to use of HRT in women, and with consideration to age and other risk factors for these events. The risk for endometrial cancer is increased in women who take unopposed estrogen. Adding a progestin to estrogen therapy has been shown to reduce, but not eliminate, the risk of endometrial hyperplasia, which may be a precursor to endometrial cancer. Proper surveillance is important. At diagnosis endometrial cancers in estrogen recipients are generally of an earlier stage and a lower grade and show less myometrial invasion than tumors in women who have not used estrogen. The Women's Health Initiative (WHI) estrogen plus progestin study reported increased risks of invasive breast cancer in patients taking combined estrogen-progestin HRT vs. placebo. The potential risk of breast cancer may increase with longer duration of use. Women who used hormonal therapy for menopausal symptoms also had an increased risk for ovarian cancer, but data are still uncertain if risk is associated with a specific duration of use.         
Hormone replacement therapy (HRT), both estrogen/progestin combination therapy and estrogen alone therapy, fails to prevent mild impaired cognition (memory loss) and is positively associated with the risk of developing dementia in women 65 years and older; do not use HRT to prevent or treat dementia or preserve cognition (memory). When data from the 2 populations in the WHIMS estrogen-alone and estrogen plus progestin ancillary studies were pooled as planned in the WHIMS protocol, the reported overall relative risk for probable dementia was 1.76 (95% CI 1.19 to 2.60, p = 0.005). Since both ancillary studies were conducted in women 65 to 79 years of age, it is unknown whether these findings apply to younger postmenopausal women.   In the Women’s Health Initiative Memory Study (WHIMS) estrogen plus progestin ancillary study, a population of 4,532 postmenopausal women 65 to 79 years of age was randomized to daily CE (0.625 mg) plus MPA (2.5 mg) or placebo. After an average follow-up of 4 years, 40 women in the CE plus MPA group and 21 women in the placebo group were diagnosed with probable dementia. The relative risk of probable dementia for CE plus MPA versus placebo was 2.05 (95% CI, 1.21 to 3.48). The absolute risk of probable dementia for CE plus MPA versus placebo was 45 vs. 22 cases per 10,000 women-years. In the WHIMS estrogen-alone ancillary study of WHI, a population of 2,947 hysterectomized women 65 to 79 years of age was randomized to daily CE (0.625 mg)-alone or placebo. After an average follow-up of 5.2 years, 28 women in the estrogen-alone group and 19 women in the placebo group were diagnosed with probable dementia. The relative risk of probable dementia for CE-alone versus placebo was 1.49 (95% CI, 0.83 to 2.66). The absolute risk of probable dementia for CE-alone versus placebo was 37 versus 25 cases per 10,000 women-years.
In women with a history of cardiovascular disease, the use of estrogen and progestin combination therapy increases the risk of developing urinary incontinence. Patients in the HERS study who did not have urinary incontinence prior to the studies initiation were observed to determine if hormone replacement therapy was helpful in preventing urinary incontinence. The study found that women who received estrogen/progestin therapy were almost twice as likely as patients receiving placebo to develop urge incontinence and 3 times as likely to develop stress incontinence after 1 year of treatment. At 4 years, the effect of hormone replacement therapy became even more pronounced, increasing the risk to 3.23 for urge incontinence and to 4.81 for stress incontinence. The applicability of these findings to women who use estrogen alone is unclear.
Musculoskeletal adverse events associated with conjugated estrogens include back pain (13-14%), arthralgia (3.5—14%), leg muscle cramps (3—7%), and myalgia (5—9%). Rates of these reactions are often similar to those seen in patients taking placebo. In some cases, muscle cramps may be indicative of an exacerbation of hypocalcemia (pre-existing condition). Arthralgia may be aggravated by estrogen-induced fluid retention.
Miscellaneous adverse events associated with conjugated estrogens include porphyria. Respiratory reactions may include increased cough, exacerbations of asthma (bronchospasm), pharyngitis, rhinitis, or sinusitis, or mild upper respiratory infection; rates of respiratory reactions are similar to those observed with placebo.
Estrogen administration may lead to severe hypercalcemia in patients with breast cancer and bone metastases. If hypercalcemia occurs, discontinue the estrogen and take appropriate measures to reduce the serum calcium concentration.
Do not use conjugated estrogens products in patients with a known hypersensitivity to the hormones or any of the specific product ingredients; conjugated estrogens are contraindicated in patients with known anaphylactic reactions or history of angioedema to the drug. Cases of both anaphylactic reactions and angioedema have been reported in patients taking estrogens, including conjugated estrogens. Events have developed in minutes and have required emergency medical treatment. Exogenous estrogens may also induce or exacerbate symptoms of angioedema, particularly in women with hereditary angioedema, which can be hormonally sensitive. Conjugated estrogens vaginal cream contains benzyl alcohol and should be used with caution in those with benzyl alcohol hypersensitivity; allergic-type reactions, including bronchospasm or other bronchial events, may occur in certain susceptible individuals.    
Estrogens are generally contraindicated in patients with a history of, or known or suspected breast cancer. The use of estrogen-alone and estrogen plus progestin has been reported to result in an increase in abnormal mammograms, requiring further evaluation. All women taking estrogen with or without a progestin should receive an annual clinical breast examination, perform monthly self-examinations, and have regular mammograms as recommended by their health care professional based on patient age, risk factors, and prior mammogram results.    Since the 1970's, numerous epidemiological studies have examined the association of estrogens or combined hormone replacement therapy (HRT) and breast cancer (new primary malignancy). The most important randomized clinical trial providing information about breast cancer in estrogen-alone users is the Womens Health Initiative (WHI) substudy of conjugated estrogens (CE, 0.625 mg/day)-alone. In the WHI estrogen-alone substudy, after an average follow-up of 7.1 years, daily estrogen monotherapy was not associated with an increased risk of invasive breast cancer [relative risk (RR) 0.80].  The most important randomized clinical trial providing information about breast cancer in patients taking combined estrogen-progestin HRT regimens is the WHI substudy of CE (0.625 mg/day) plus MPA (2.5 mg/day).  After a mean follow-up of 5.6 years, the WHI estrogen plus progestin substudy reported an increased risk of invasive breast cancer in women who took daily CE plus MPA vs. placebo. In this substudy, prior use of estrogen-alone or estrogen plus progestin therapy was reported by 26 percent of the women. The relative risk of invasive breast cancer was 1.24, and the absolute risk was 41 versus 33 cases per 10,000 women-years, for CE plus MPA compared with placebo. Among women who reported prior use of hormone therapy, the relative risk of invasive breast cancer was 1.86, and the absolute risk was 46 vs. 25 cases per 10,000 women-years for CE plus MPA compared with placebo. Among women who reported no prior use of hormone therapy, the relative risk of invasive breast cancer was 1.09, and the absolute risk was 40 vs. 36 cases per 10,000 women-years for CE plus MPA compared with placebo. In the same WHI substudy, invasive breast cancers were larger, were more likely to be node positive, and were diagnosed at a more advanced stage in the combined HRT group compared with the placebo group. Metastatic disease was rare, with no apparent difference between the 2 groups. Other prognostic factors, such as histologic subtype, grade and hormone receptor status did not differ between the 2 groups. Consistent with the WHI clinical trial, observational studies have also reported an increased risk of breast cancer for estrogen plus progestin therapy, and a smaller increased risk for estrogen-alone therapy, after several years of use. The risk increased with duration of use, and appeared to return to baseline over about 5 years after stopping treatment (only the observational studies have substantial data on risk after stopping). Observational studies also suggest that the risk of breast cancer was greater, and became apparent earlier, with combined HRT as compared to estrogen-alone therapy. However, these studies have not found significant variation in the risk of breast cancer among different estrogen plus progestin combinations, doses, or routes of administration.    While estrogen therapy may be used rarely for the palliative treatment of advanced breast cancer in men and women, estrogen administration may lead to severe hypercalcemia in patients with breast cancer and bone metastases. If hypercalcemia occurs, use of the drug should be stopped and appropriate measures taken to reduce the serum calcium level.   
Conjugated estrogens are contraindicated in the presence of estrogen-responsive tumors, including ovarian cancer. The Women's Health Initiative (WHI) estrogen plus progestin substudy reported a statistically non-significant increased risk of ovarian cancer in women taking combined hormone replacement therapy (HRT). After an average follow-up of 5.6 years, the relative risk for ovarian cancer for estrogen (conjugated estrogens, CE) plus a progestin (medroxyprogesterone, MPA) versus placebo was 1.58 (95% CI, 0.77 to 3.24). The absolute risk for CE plus MPA versus placebo was 4 versus 3 cases per 10,000 women-years. A meta-analysis of 17 prospective and 35 retrospective epidemiology studies found that women who used HRT for menopausal symptoms had an increased risk for ovarian cancer. The primary analysis, using case-control comparisons, included 12,110 cancer cases from the 17 prospective studies. The relative risk associated with current use of hormonal therapy was 1.41 (95% CI, 1.32 to 1.5); there was no difference in the risk estimates by duration of the exposure (less than 5 years [median of 3 years] vs. greater than 5 years [median of 10 years] of use before the cancer diagnosis). The relative risk associated with combined current and recent use (discontinued use within 5 years before cancer diagnosis) was 1.37 (95% CI, 1.27 to 1.48), and the elevated risk was significant for both estrogen-alone and estrogen plus progestin products. The exact duration of hormone therapy use associated with an increased risk of ovarian cancer, however, is unknown.   
Estrogen therapy is contraindicated in patients with known estrogen-dependent malignancies. There is an association of unopposed estrogen therapy and endometrial cancer in women with an intact uterus. Adding a progestin to estrogen therapy has been shown to reduce the risk of endometrial hyperplasia, which may be a precursor to endometrial cancer. Clinical surveillance of all women using estrogen-alone or estrogen plus progestin therapy is important. Adequate diagnostic measures, including directed or random endometrial sampling when indicated, should be undertaken to rule out malignancy in postmenopausal women with undiagnosed persistent or recurring abnormal vaginal bleeding. The reported endometrial cancer risk among unopposed estrogen users is about 2- to 12-times greater than in non-users, and appears dependent on duration of treatment and on estrogen dose. Most studies show no significant increased risk associated with use of estrogens for less than 1 year. The greatest risk appears associated with prolonged use, with increased risks of 15-to 24-fold for 5 to 10 years or more, and this risk has been shown to persist for at least 8 to 15 years after estrogen therapy is discontinued. There is no evidence that the use of natural estrogens results in a different endometrial risk profile than synthetic estrogens of equivalent estrogen dose. With concurrent progestin use (cyclically or continuously), the incidence of endometrial hyperplasia due to conjugated estrogens is estimated to be 1% or less.     
Estrogens are contraindicated in the presence of vaginal cancer, cervical cancer, uterine cancer, or other estrogen-responsive tumors. Clinical surveillance of all women using estrogen-alone or estrogen plus progestin therapy is important; all women receiving estrogen treatment should have an annual pelvic examination and other diagnostic or screening tests, such as cervical cytology, as clinically indicated or as generally recommended based on age, risk factors, and other individual needs. Because estrogens influence the growth of endometrial tissues, use conjugated estrogens cautiously in women with endometriosis or uterine leiomyomata (uterine fibroids). A few cases of malignant transformation of residual endometrial growths have been reported in women treated post-hysterectomy with estrogen-alone therapy. For women known to have residual endometriosis post-hysterectomy, the addition of a progestin should be considered to reduce the risk of endometrial tissue growth.   
Estrogens are contraindicated in patients with an active or past history of stroke, thrombophlebitis, thromboembolism, thromboembolic disease, or myocardial infarction (MI). An increased risk of cerebrovascular disease (stroke) and deep venous thrombosis (DVT) has been reported with unopposed estrogen therapy. An increased risk of thromboembolism, including pulmonary embolism (PE), DVT, stroke and myocardial infarction (MI) has been reported with estrogen plus progestin hormone replacement therapy (HRT). Should any of these events occur or be suspected, discontinue conjugated estrogens immediately.    Estrogens are also contraindicated for patients with known protein C deficiency, protein S deficiency, or antithrombin deficiency or other known thrombophilic disorders associated with increased risk of venous thrombosis. Other risk factors for arterial vascular disease (e.g., hypertension, diabetes, tobacco smoking, hypercholesterolemia, and obesity) and/or venous thromboembolism (VTE) [e.g., personal history or family history of VTE, obesity, or systemic lupus (SLE)] should be monitored and managed appropriately.    A positive relationship between estrogen use and an increased risk for thromboembolism has been demonstrated. In the WHI estrogen-alone substudy, the risk of VTE (DVT and PE) was increased for women receiving daily unopposed estrogen compared to placebo (30 vs. 22 per 10,000 women-years), although only the increased risk of DVT reached statistical significance (23 vs. 15 per 10,000 women years). The increase in VTE risk was demonstrated during the first 2 years. In the WHI estrogen plus progestin substudy, a statistically significant 2-fold greater rate of VTE was reported in women receiving estrogen plus progestin HRT compared to women receiving placebo (35 vs. 17 per 10,000 women-years). Statistically significant increases in risk for both DVT (26 vs. 13 per 10,000 women-years) and PE (18 vs. 8 per 10,000 women-years) were also demonstrated. The increase in VTE risk was demonstrated during the first year and persisted.  Estrogens with or without progestins should not be used for the prevention of cardiac disease or cardiovascular disease (e.g., coronary artery disease). In the Women's Health Initiative (WHI) estrogen-alone substudy, no overall effect on coronary heart disease (CHD) events (defined as non-fatal MI, silent MI, or CHD death ) was reported in women receiving conjugated estrogen-alone compared to placebo. Subgroup analyses of women 50 to 59 years of age suggest a statistically non-significant reduction in CHD events (CE-alone vs. placebo) in women with less than 10 years since menopause (8 vs. 16 per 10,000 women-years). In the WHI estrogen plus progestin substudy, there was a statistically non-significant increased risk of CHD events reported in women receiving daily estrogen plus progestin compared to women receiving placebo (41 vs. 34 per 10,000 women-years). An increase in relative risk was demonstrated in year 1, and a trend toward decreasing relative risk was reported in years 2 through 5.  Studies have also shown no cardiovascular benefit to the use of estrogens or estrogen-progestin therapy for secondary prevention in women with documented cardiac disease or CHD.  Estrogens also increase the risk for stroke. In the WHI estrogen-alone substudy, a statistically significant increased risk of stroke was reported in women 50 to 79 years of age receiving estrogen-alone compared to women in the same age group receiving placebo (45 vs. 33 per 10,000 women-years). The increase in risk was demonstrated in the first year and persisted. Subgroup analyses of women 50 to 59 years of age suggest no increased risk of stroke for those women receiving estrogen-alone versus those receiving placebo (18 vs. 21 per 10,000 women-years). In the WHI estrogen plus progestin substudy, a statistically significant increased risk of stroke was reported in women 50 to 79 years of age receiving estrogen plus progestin HRT compared to women in the same age group receiving placebo (33 vs. 25 per 10,000 women-years). The increase in risk was demonstrated after the first year and persisted. Women over the age of 65 years were at increased risk for non-fatal stroke.  Patients with hypertension should be monitored closely for increases in blood pressure if estrogens are administered. In a small number of case reports, substantial increases in blood pressure have been attributed to idiosyncratic reactions to estrogen therapy. In a large, randomized, placebo controlled clinical trial, a generalized effect of estrogens on blood pressure was not seen. Estrogens may cause some degree of fluid retention. Women with conditions that might be influenced by this factor, such as a cardiac disease, warrant careful observation when estrogens are prescribed.    In men treated with estrogens for palliation of prostate or breast cancer, estrogens have increased the risk of nonfatal MI, PE, and thrombophlebitis.
If feasible, estrogen therapy should be discontinued at least 4 to 6 weeks before any surgery associated with an increased risk of thromboembolism, or during any periods of prolonged immobilization. The decision on when to resume estrogens after such procedures or conditions would be based on the perceived additional thromboembolic risk from estrogen use and the need for estrogen therapy; resume only after the patient is fully ambulatory. In addition, women taking conjugated estrogens should be advised to move about periodically during travel involving prolonged immobilization.   
Conjugated estrogens are contraindicated during pregnancy. There appears to be little or no increased risk of birth defects in children born to women who have used estrogens and progestins as an oral contraceptive inadvertently during early pregnancy. However, increased risk of a wide variety of fetal abnormalities, including modified development of sexual organs, cardiovascular anomalies and limb defects, have been reported following the chronic use of estrogens in pregnant women. There is no FDA-approved indication for the use of conjugated estrogens in pregnancy.   
Caution should be used if a breast-feeding mother is receiving conjugated estrogens; in general, these products should not be used during lactation. Estrogen administration to nursing women has been shown to decrease the quantity and quality of the breast milk. Detectable amounts of estrogens have been identified in the breast milk of women receiving estrogen-alone therapy. Estrogens are not approved by the FDA for the treatment of postpartum breast engorgement.   
Estrogens are contraindicated in the presence of hepatocellular cancer, hepatic adenoma, or in severe hepatic disease of any type. Estrogens may be poorly metabolized in women with impaired liver function. For women with a history of cholestatic jaundice associated with past estrogen use or with pregnancy, caution should be exercised, and in the case of recurrence, estrogens should be discontinued. Estrogens should also be used cautiously in patients with acute intermittent, or variegate hepatic porphyria, which can be exacerbated. Estrogens have been reported during trials to increase the risk of gallbladder disease (e.g., cholestasis, cholelithiasis and cholecystitis) by roughly 2- to 4-fold in postmenopausal women; use with caution in patients with a history of gallbladder disease.    
Patients with systemic lupus erythematosus (SLE) may have increased risk for thromboembolism and should be managed appropriately when estrogen therapy is considered.    Approximately 85% of patients diagnosed with systemic lupus erythematosus (SLE) are females, giving support to the notion that hormonal influences, especially estrogen, contribute to the pathophysiology of SLE. Accordingly, hormone replacement therapy (HRT) has been reported to induce, unmask, and exacerbate lupus; case reports, anecdotal data, and the prospective Nurses Health Study indicate that a temporal relationship between HRT and lupus exist. However, several retrospective studies dispute a relationship between estrogens and lupus, and the SELENA trial, a large prospective, randomized clinical trial evaluating the safety of estrogen therapy (both as oral contraceptives and HRT in postmenopausal women) in patients with SLE has been completed and is being analyzed. Determining the risk of estrogen therapy in SLE patients is important as postmenopausal women with lupus can benefit from HRT; not only does it offer relief from postmenopausal symptoms (vasomotor symptoms, genital symptoms, and emotional lability), but it has the additional benefit of protecting patients from bone fracture and postmenopausal or drug-induced (i.e., chronic corticosteroid or cyclophosphamide therapy) osteoporosis. Women with hypercoagulable states are at increased risk of venous thromboembolism when taking HRT; given the increased prevalence of hypercoagulable states in patients with SLE (in particular antiphospholipid antibodies), the use of HRT in this population may be even more risky as the incidence of strokes, heart attacks, and blood clots is increased in general in women taking HRT. Unfortunately, definitive recommendations regarding the use of HRT in patients with SLE are not available. The results of the SELENA trial should provide evidence regarding the use of HRT in this population. 
In women with pre-existing hypertriglyceridemia, estrogen therapy may be associated with elevations of plasma triglycerides leading to pancreatitis. Consider discontinuation of estrogen treatment if pancreatitis occurs.   
Retinal vascular thrombosis has been reported in women receiving estrogens. Any visual disturbance should be examined by an ophthalmologist. Discontinue the estrogen pending examination if there is sudden partial or complete loss of vision, or a sudden onset of proptosis, diplopia, or migraine with visual changes. If examination reveals papilledema or retinal vascular lesions, estrogens should be permanently discontinued.    Estrogen therapy may cause an exacerbation of migraine or a change in headache patterns and should be used with caution in women with migraine. Patients who complain of migraine with focal neurologic visual changes should be evaluated, and in some patients, such changes may indicate cerebrovascular events. Estrogens can increase the curvature of the cornea and may lead to intolerance of contact lenses.
Patients with risk factors for arterial vascular disease (e.g., diabetes mellitus), which may increase the risk for thromboembolism, should be monitored and managed appropriately during estrogen therapy. Patients with diabetes mellitus should be observed for changes in glucose tolerance when initiating or discontinuing estrogen therapy, since estrogen therapy may exacerbate diabetes. Altered glucose tolerance secondary to decreased insulin sensitivity has been reported.   
Use estrogens with caution in patients with thyroid disease, particularly hypothyroidism. Estrogens can increase thyroid-binding globulin (TBG) levels. Patients with normal thyroid function can compensate for the increased TBG by making more thyroid hormone, thus maintaining free T4 and T3 serum concentrations in the normal range. Patients dependent on thyroid hormone replacement therapy who are also receiving estrogens may require increased doses of their thyroid replacement therapy. These patients should have their thyroid function monitored in order to maintain their free thyroid hormone levels in an acceptable range.   
Because estrogens may cause fluid retention, conditions that might be affected by fluid retention, such as heart disease or renal disease, require careful observation. Estrogen therapy may also cause an exacerbation of asthma, seizure disorder, and hepatic hemangiomas in some patients and should be used with caution in women with these conditions.   
Mood disorders, like depression, may be aggravated in women taking exogenous estrogens or progestins. Women with a history of depression may need special monitoring. If significant depression occurs, the hormone replacement therapy should be discontinued.
Estrogen therapy should be used with caution in women with hypoparathyroidism as estrogen-induced hypocalcemia may occur.   
Hormone replacement therapy (HRT), both estrogen/progestin combination therapy and estrogen alone therapy, has been found to fail to prevent mild cognitive impairment (memory loss) and to increase the risk of dementia in women 65 years and older.    Administration of HRT should generally be avoided in women 65 years of age and older, and HRT should not be used to prevent or treat dementia or preserve cognition (memory). Overall risk vs. benefit should be considered along with the goals of use of HRT for the individual patient when considering whether to continue HRT in a geriatric woman over 65 years of age.   According to the Beers Criteria, oral and topical patch forms of estrogens with or without progestins are considered potentially inappropriate medications (PIMs) for use in geriatric patients and should be avoided due to evidence of carcinogenic potential (i.e., breast and endometrium) and lack of cardiovascular or cognitive protective effects in older women. According to the Beers Criteria, oral, topical patch, or other systemic forms of estrogens (with or without progestins), are considered potentially inappropriate medications (PIMs) for use in geriatric patients and should be avoided due to evidence of carcinogenic potential (i.e., breast and endometrium) and lack of cardiovascular or cognitive protective effects in older women. Additionally, the Beers expert panel recommends avoiding oral or transdermal estrogen in elderly women with any type of urinary incontinence due to lack of efficacy. The Beers expert panel considers use of vaginal estrogens acceptable for the management of dyspareunia, recurrent lower urinary tract infections, and other vaginal/vulvar symptoms.
The safety and efficacy of estrogens have not been established in neonates, infants or children. Estrogens are not indicated in children because estrogens promote epiphysial closure. In young children, overdose of estrogens have not been reported to cause serious ill effects. However, nausea is common. Vaginal withdrawal bleeding may occur in female children exposed to estrogens in large doses. Estrogen therapy has been used for the induction of puberty in adolescents with some forms of pubertal delay; however, if estrogen is administered to adolescent patients whose bone growth is not complete, these patients should be monitored periodically for bone maturation and effects on epiphyseal centers.    Premarin vaginal cream contains benzyl alcohol; inadvertent exposure to benzyl alcohol is associated with 'gasping syndrome' in neonates.
The primary source of estrogens in premenopausal women is the ovary, which normally secretes 0.07 to 0.5 mg of estradiol daily, depending on the phase of the menstrual cycle. After menopause estrone is the primary circulating estrogen; it is derived from the peripheral conversion of androstenedione by an aromatase enzyme found in adipose tissues. Estrone is converted to small amounts of estradiol in peripheral tissues. Estrogens increase the rate of synthesis of DNA, RNA, and some proteins. Exogenous estrogens elicit all of the actions of endogenous estrogens. Estrogens are responsible for the growth and development of female sex organs and the maintenance of sex characteristics including growth of axillary and pubic hair, and shaping of body contours and skeleton. At the cellular level, estrogens increase cervical secretions, cause proliferation of the endometrium, and increase uterine tone. Paradoxically, prolonged administration of estrogen can shrink the endometrium. During the preovulatory or nonovulatory phase of the menstrual cycle, withdrawal of estrogen can initiate menstruation; in the ovulatory phase, however, the decrease in progesterone secretion is the more significant factor causing menstruation.
Estrogens have a weak anabolic effect and also can affect bone calcium deposition and accelerate epiphysial closure. Estrogens appear to prevent osteoporosis associated with the onset of menopause, they generally do not reverse bone density loss that has already developed. Estrogens generally have a favorable effect on blood lipids, reducing LDL- and increasing HDL-cholesterol concentrations on average, by 15%. Serum triglycerides increase with estrogen administration. Estrogens increase the rate of synthesis of many proteins, including thyroid binding globulin and several clotting factors. Estrogens reduce levels of antithrombin III, and increase platelet aggregation. Estrogens also enhance sodium and fluid retention.
Unopposed estrogen has been associated with increased risk of endometrial cancer in menopausal women with an intact uterus; concomitant progestin therapy reduces, but does not eliminate, this risk. However, combination hormone replacement therapy (HRT) may add additional health risks for some women, as evidenced by the HERS trials , the Women's Health Initiative study , and other investigations. In particular, the Women's Health Initiative (WHI) study reported an increased risk of myocardial infarction, stroke, dementia, invasive breast cancer, and venous thromboembolism in patients taking combination HRT and an increased risk of stroke, dementia, and venous thromboembolism in patients taking estrogen only HRT; an increased risk of invasive breast cancer was not evident in women taking estrogen only. Because of these findings, patients should be prescribed estrogen HRT or estrogen-progestin HRT for the shortest duration consistent with the treatment goals. Estrogen HRT with or without a progestin is not indicated and should not be used to prevent coronary artery disease or other cardiovascular disease. The risks and benefits of HRT must be determined for a woman individually.
In men with advanced prostate cancer, estrogens exert their effect by inhibition of the hypothalamic-pituitary axis through negative feedback. This results in decreased secretion of luteinizing hormone (LH). Decreased testosterone production from the Leydig cells in the testes occurs, which may decrease tumor growth and lower prostate specific antigen (PSA) levels. Improvement in bone metastasis may also occur. In the past, high-dose estrogen therapy was also used in selected men and postmenopausal women with inoperable, progressive breast cancer. Since the development of selective estrogen receptor modifiers (SERMs), high-dose estrogen therapy for the palliative treatment of breast cancer is rarely used today.
Conjugated estrogens are administered orally, intramuscularly, intravenously, intravaginally, or by local vulvar application. Conjugated estrogens bind primarily to albumin; unconjugated estrogens bind both to albumin and sex-hormone-binding globulin. Similar to that of endogenous estrogens, conjugated estrogens are widely distributed throughout the body and are found in higher concentration in the sex hormone target organs.
Metabolism occurs in the same manner as endogenous estrogens. There is a dynamic equilibrium of metabolic interconversions; most transformations take place in the liver. Conjugated estrogens are metabolized primarily in the liver to glucuronide and sulfate conjugates of estradiol, estrone, and estriol. These products are eliminated in the urine. A portion of the conjugates are excreted into the intestine through the biliary system; hydrolysis in the gut allows for enterohepatic recirculation of the estrogens. In postmenopausal women, a significant portion of the sulfate conjugates exist as estrone sulfate, which serves as a reservoir for the formation of the more active estrogens, estradiol and estriol. The apparent terminal half life of conjugated estrone is 4—18.5 hours and the half-life of conjugated equilin is 4—17 hours.
Affected cytochrome P450 isoenzymes: none
Conjugated estrogens are rapidly absorbed from the GI tract after oral administration; the tablets are designed to release the estrogens slowly over a period of several hours.
Conjugated estrogens are absorbed systemically when given by the vaginal route. The degree of systemic absorption via the vaginal route is dependent on the frequency of use, dose prescribed, and degree of vaginal mucosal atrophy present.
The pharmacokinetics of conjugated estrogens have not been studied in patients with hepatic impairment. In general, estrogen use is not recommended in patients with severe hepatic disease or jaundice.
The pharmacokinetics of conjugated estrogens have not been studied in patients with renal impairment.
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