Estrogens (Conjugated A/Synthetic)Pronunciation
(ES troe jenz, KON joo gate ed, aye, sin THET ik)
Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product
Cenestin: 0.3 mg [DSC] [contains fd&c blue #2 aluminum lake, fd&c yellow #10 aluminum lake, polysorbate 80]
Cenestin: 0.45 mg [DSC] [contains fd&c yellow #6 (sunset yellow), polysorbate 80]
Cenestin: 0.625 mg [DSC] [contains fd&c red #40 aluminum lake, polysorbate 80]
Cenestin: 0.9 mg [DSC] [contains polysorbate 80]
Cenestin: 1.25 mg [DSC] [contains fd&c blue #2 aluminum lake, polysorbate 80]
Brand Names: U.S.
- Cenestin [DSC]
- Estrogen Derivative
Conjugated A/synthetic estrogens contain a mixture of 9 synthetic estrogen substances, including sodium estrone sulfate, sodium equilin sulfate, sodium equilenin sulfate, sodium 17 alpha-dihydroequilin sulfate, sodium 17 alpha-dihydroequilenin sulfate, sodium 17 alpha-estradiol sulfate, sodium 17 beta-estradiol sulfate, sodium 17 beta-dihydroequilin sulfate, and sodium 17 beta-dihydroequilenin sulfate. Estrogens are responsible for the development and maintenance of the female reproductive system and secondary sexual characteristics. Estradiol is the principle intracellular human estrogen and is more potent than estrone and estriol at the receptor level; it is the primary estrogen secreted prior to menopause. Following menopause, estrone and estrone sulfate are more highly produced. Estrogens modulate the pituitary secretion of gonadotropins, luteinizing hormone, and follicle-stimulating hormone through a negative feedback system; estrogen replacement reduces elevated levels of these hormones in postmenopausal women.
Well absorbed over a period of several hours
Hepatic via CYP3A4; estradiol is converted to estrone and estriol; also undergoes enterohepatic recirculation; estrone sulfate is the main metabolite in postmenopausal women
Urine (primarily estriol, also as estradiol, estrone, and conjugates)
Sex hormone-binding globulin (SHBG) and albumin
Use: Labeled Indications
Vasomotor symptoms associated with menopause: Treatment of moderate-to-severe vasomotor symptoms associated with menopause
Vulvar and vaginal atrophy associated with menopause: Treatment of moderate-to-severe vulvar and vaginal atrophy associated with menopause
Limitations of use: When used solely for the treatment of vulvar and vaginal atrophy, topical vaginal products should be considered.
Angioedema or anaphylactic reaction to estrogen conjugated A synthetic or any component of the formulation; undiagnosed abnormal genital bleeding; DVT or PE (current or history of); active or history of arterial thromboembolic disease (eg, stroke, MI); breast cancer (known, suspected or history of); estrogen-dependent tumor (known or suspected); hepatic impairment or disease; known protein C, protein S, antithrombin deficiency or other known thrombophilic disorders; pregnancy
Documentation of allergenic cross-reactivity for estrogens is limited. However, because of similarities in chemical structure and/or pharmacologic actions, the possibility of cross-sensitivity cannot be ruled out with certainty.
Note: Cenestin has been discontinued in the US for more than 1 year.
General dosing guidelines: When treating postmenopausal women, use estrogens for the shortest duration possible at the lowest effective dose consistent with treatment goals. Reevaluate patients as clinically appropriate to determine if treatment is still necessary. Consider use of an estrogen with a progestin in postmenopausal women with a uterus. Women who have had a hysterectomy generally do not need a progestin; however one may be needed if there is a history of endometriosis.
Vasomotor symptoms associated with menopause: Oral: Initial: 0.45 mg once daily. Adjust dose based upon patient response.
Vulvar and vaginal atrophy associated with menopause: Oral: 0.3 mg once daily
Refer to adult dosing.
Dosing: Renal Impairment
There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied); use with caution.
Dosing: Hepatic Impairment
There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied). Use is contraindicated with hepatic dysfunction or disease.
Administer at the same time each day. Hazardous agent; use appropriate precautions for handling and disposal (NIOSH 2014 [group 2]).
Store at 20°C to 25°C (68°F to 77°F); excursions are permitted to 15°C to 30°C (59°F to 86°F).
Ajmaline: Estrogen Derivatives may enhance the adverse/toxic effect of Ajmaline. Specifically, the risk for cholestasis may be increased. Monitor therapy
Anastrozole: Estrogen Derivatives may diminish the therapeutic effect of Anastrozole. Avoid combination
Anthrax Immune Globulin (Human): Estrogen Derivatives may enhance the thrombogenic effect of Anthrax Immune Globulin (Human). Monitor therapy
Anticoagulants: Estrogen Derivatives may diminish the anticoagulant effect of Anticoagulants. More specifically, the potential prothrombotic effects of some estrogens and progestin-estrogen combinations may counteract anticoagulant effects. Management: Carefully weigh the prospective benefits of estrogens against the potential increased risk of procoagulant effects and thromboembolism. Use is considered contraindicated under some circumstances. Refer to related guidelines for specific recommendations. Consider therapy modification
Antidiabetic Agents: Hyperglycemia-Associated Agents may diminish the therapeutic effect of Antidiabetic Agents. Monitor therapy
Ascorbic Acid: May increase the serum concentration of Estrogen Derivatives. Monitor therapy
Bosentan: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy
C1 inhibitors: Estrogen Derivatives may enhance the thrombogenic effect of C1 inhibitors. Monitor therapy
Cannabis: May decrease the serum concentration of CYP1A2 Substrates. Monitor therapy
Chenodiol: Estrogen Derivatives may diminish the therapeutic effect of Chenodiol. Management: Monitor clinical response to chenodiol closely when used together with any estrogen derivative. Monitor therapy
CloZAPine: CYP1A2 Inhibitors (Weak) may increase the serum concentration of CloZAPine. Monitor therapy
Corticosteroids (Systemic): Estrogen Derivatives may increase the serum concentration of Corticosteroids (Systemic). Monitor therapy
CYP1A2 Inducers (Strong): May increase the metabolism of CYP1A2 Substrates. Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Consider therapy modification
CYP3A4 Inducers (Moderate): May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy
CYP3A4 Inducers (Strong): May increase the metabolism of CYP3A4 Substrates. Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Consider therapy modification
Cyproterone: May decrease the serum concentration of CYP1A2 Substrates. Monitor therapy
Dabrafenib: May decrease the serum concentration of CYP3A4 Substrates. Management: Seek alternatives to the CYP3A4 substrate when possible. If concomitant therapy cannot be avoided, monitor clinical effects of the substrate closely (particularly therapeutic effects). Consider therapy modification
Dantrolene: Estrogen Derivatives may enhance the hepatotoxic effect of Dantrolene. Monitor therapy
Deferasirox: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy
Dehydroepiandrosterone: May enhance the adverse/toxic effect of Estrogen Derivatives. Avoid combination
Enzalutamide: May decrease the serum concentration of CYP3A4 Substrates. Management: Concurrent use of enzalutamide with CYP3A4 substrates that have a narrow therapeutic index should be avoided. Use of enzalutamide and any other CYP3A4 substrate should be performed with caution and close monitoring. Consider therapy modification
Exemestane: Estrogen Derivatives may diminish the therapeutic effect of Exemestane. Avoid combination
Hemin: Estrogen Derivatives may diminish the therapeutic effect of Hemin. Avoid combination
Herbs (Estrogenic Properties): May enhance the adverse/toxic effect of Estrogen Derivatives. Monitor therapy
Hyaluronidase: Estrogen Derivatives may diminish the therapeutic effect of Hyaluronidase. Management: Patients receiving estrogens (particularly at larger doses) may not experience the desired clinical response to standard doses of hyaluronidase. Larger doses of hyaluronidase may be required. Consider therapy modification
Immune Globulin: Estrogen Derivatives may enhance the thrombogenic effect of Immune Globulin. Monitor therapy
Indium 111 Capromab Pendetide: Estrogen Derivatives may diminish the diagnostic effect of Indium 111 Capromab Pendetide. Avoid combination
Lenalidomide: Estrogen Derivatives may enhance the thrombogenic effect of Lenalidomide. Monitor therapy
Mitotane: May decrease the serum concentration of CYP3A4 Substrates. Management: Doses of CYP3A4 substrates may need to be adjusted substantially when used in patients being treated with mitotane. Consider therapy modification
NSAID (COX-2 Inhibitor): May enhance the thrombogenic effect of Estrogen Derivatives. NSAID (COX-2 Inhibitor) may increase the serum concentration of Estrogen Derivatives. Monitor therapy
Ospemifene: Estrogen Derivatives may enhance the adverse/toxic effect of Ospemifene. Estrogen Derivatives may diminish the therapeutic effect of Ospemifene. Avoid combination
Pomalidomide: May enhance the thrombogenic effect of Estrogen Derivatives. Management: Canadian pomalidomide labeling recommends caution with use of hormone replacement therapy and states that hormonal contraceptives are not recommended. US pomalidomide labeling does not contain these specific recommendations. Consider therapy modification
ROPINIRole: Estrogen Derivatives may increase the serum concentration of ROPINIRole. Monitor therapy
Siltuximab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy
Somatropin: Estrogen Derivatives may diminish the therapeutic effect of Somatropin. Shown to be a concern with oral hormone replacement therapy in postmenopausal women. Management: Monitor for reduced growth hormone efficacy. A larger somatropin dose may be required to reach treatment goal. This interaction does not appear to apply to non-orally administered estrogens (e.g., transdermal, vaginal ring). Consider therapy modification
St John's Wort: May decrease the serum concentration of CYP3A4 Substrates. Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Consider therapy modification
Teriflunomide: May decrease the serum concentration of CYP1A2 Substrates. Monitor therapy
Thalidomide: Estrogen Derivatives may enhance the thrombogenic effect of Thalidomide. Monitor therapy
Theophylline Derivatives: Estrogen Derivatives may increase the serum concentration of Theophylline Derivatives. Exceptions: Dyphylline. Monitor therapy
Thyroid Products: Estrogen Derivatives may diminish the therapeutic effect of Thyroid Products. Monitor therapy
Tipranavir: Estrogen Derivatives may enhance the dermatologic adverse effect of Tipranavir. The combination of tipranavir/ritonavir and ethinyl estradiol/norethindrone was associated with a high incidence of skin rash. Tipranavir may decrease the serum concentration of Estrogen Derivatives. Management: Women using hormonal contraceptives should consider alternative, non-hormonal forms of contraception. Consider therapy modification
TiZANidine: CYP1A2 Inhibitors (Weak) may increase the serum concentration of TiZANidine. Management: Avoid these combinations when possible. If combined use cannot be avoided, initiate tizanidine at an adult dose of 2 mg and increase in 2-4 mg increments based on patient response. Monitor for increased effects of tizanidine, including adverse reactions. Consider therapy modification
Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy
Ursodiol: Estrogen Derivatives may diminish the therapeutic effect of Ursodiol. Monitor therapy
Reduced response to metyrapone test observed with conjugated estrogens (equine).
Central nervous system: Headache (11% to 68%), paresthesia (8% to 33%), dizziness (11%), pain (11%)
Gastrointestinal: Abdominal pain (9% to 28%), nausea (9% to 18%)
Genitourinary: Mastalgia (29%), endometrial hyperplasia (19%), uterine hemorrhage (14%)
Infection: Infection (2% to 14%)
Neuromuscular & skeletal: Back pain (14%)
Respiratory: Upper respiratory tract infection (13%)
1% to 10%:
Central nervous system: Anxiety (6%), hypertonia (6%)
Endocrine & metabolic: Weight gain (6%)
Gastrointestinal: Dyspepsia (10%), vomiting (7%), constipation (6%), diarrhea (6%)
Genitourinary: Vaginitis (8%)
Neuromuscular & skeletal: Leg cramps (10%)
Respiratory: Rhinitis (6% to 8%), cough (6%)
Miscellaneous: Fever (1%)
Concerns related to adverse effects:
• Breast cancer: [US Boxed Warning]: Based on data from the Women’s Health Initiative (WHI) studies, an increased risk of invasive breast cancer was observed in postmenopausal women using conjugated estrogens (CE) in combination with medroxyprogesterone acetate (MPA). This risk may be associated with duration of use and declines once combined therapy is discontinued (Chlebowski, 2009). The risk of invasive breast cancer was decreased in postmenopausal women with a hysterectomy using CE only, regardless of weight. However, the risk was not significantly decreased in women at high risk for breast cancer (family history of breast cancer, personal history of benign breast disease) (Anderson, 2012). An increase in abnormal mammogram findings has also been reported with estrogen alone or in combination with progestin therapy. Estrogen use may also lead to severe hypercalcemia in patients with breast cancer and bone metastases; discontinue estrogen if hypercalcemia occurs. Use is contraindicated in patients with known or suspected breast cancer.
• Dementia: [US Boxed Warning]: Estrogens with or without progestin should not be used to prevent dementia. In the Women’s Health Initiative Memory Study (WHIMS), an increased incidence of probable dementia was observed in women ≥65 years of age taking CE alone or in combination with MPA.
• Endometrial cancer: [US Boxed Warning]: The use of unopposed estrogen in women with a uterus is associated with an increased risk of endometrial cancer. The addition of a progestin to estrogen therapy may decrease the risk of endometrial hyperplasia, a precursor to endometrial cancer. Adequate diagnostic measures, including endometrial sampling if indicated, should be performed to rule out malignancy in postmenopausal women with undiagnosed abnormal vaginal bleeding. There is no evidence that the use of natural estrogens results in a different endometrial risk profile than synthetic estrogens at equivalent estrogen doses. The risk of endometrial cancer appears to be dose and duration dependent; risk appears to be greatest with use ≥5 years and may persist following discontinuation of therapy.
• Endometriosis: Estrogens may exacerbate endometriosis. Malignant transformation of residual endometrial implants has been reported posthysterectomy with unopposed estrogen therapy. Consider adding a progestin in women with residual endometriosis posthysterectomy.
• Inherited thrombophilia: Women with inherited thrombophilias (eg, protein C or S deficiency) may have increased risk of venous thromboembolism (DeSancho, 2010; van Vlijmen, 2011). Use is contraindicated in women with protein C, protein S, antithrombin deficiency, or other known thrombophilic disorders.
• Lipid effects: Estrogen compounds are generally associated with lipid effects such as increased HDL-cholesterol and decreased LDL-cholesterol. Triglycerides may also be increased in women with preexisting hypertriglyceridemia; discontinue if pancreatitis occurs.
• Ovarian cancer: Postmenopausal estrogens with or without progestins may increase the risk of ovarian cancer; however, the absolute risk to an individual woman is small. Although results from various studies are not consistent, risk does not appear to be significantly associated with the duration, route, or dose of therapy. In one study, the risk decreased after 2 years following discontinuation of therapy (Mørch, 2009). Although the risk of ovarian cancer is rare, women who are at an increased risk (eg, family history) should be counseled about the association (NAMS, 2012).
• Retinal vascular thrombosis: Estrogens may cause retinal vascular thrombosis; discontinue if migraine, loss of vision, proptosis, diplopia, or other visual disturbances occur; discontinue permanently if papilledema or retinal vascular lesions are observed on examination.
• Asthma: Use caution in patients with asthma; may exacerbate disease.
• Carbohydrate intolerance: May have adverse effects on glucose tolerance; use caution in women with diabetes.
• Cardiovascular disease: [US Boxed Warning]: Estrogens with or without progestin should not be used to prevent cardiovascular disease. Using data from the Women’s Health Initiative (WHI) studies, an increased risk of deep vein thrombosis (DVT) and stroke has been reported with CE and an increased risk of DVT, stroke, pulmonary emboli (PE) and myocardial infarction (MI) has been reported with CE with MPA in postmenopausal women 50 to 79 years of age. Additional risk factors include diabetes mellitus, hypercholesterolemia, hypertension, SLE, obesity, tobacco use, and/or history of venous thromboembolism (VTE). Risk factors should be managed appropriately; discontinue use immediately if adverse cardiovascular events occur or are suspected. Use is contraindicated in women with active DVT or PE (or a history of these conditions) or in women with active or recent arterial thromboembolic disease (stroke and MI), or a history of these conditions.
• Diseases exacerbated by fluid retention: Use with caution in patients with diseases which may be exacerbated by fluid retention, including cardiac or renal dysfunction.
• Epilepsy: Use caution with epilepsy; may exacerbate disease.
• Gallbladder disease: Use of postmenopausal estrogen may be associated with an increased risk of gallbladder disease requiring surgery.
• Hepatic dysfunction: Estrogens are poorly metabolized in patients with hepatic dysfunction. Use caution with a history of cholestatic jaundice associated with prior estrogen use or pregnancy. Discontinue if jaundice develops or if acute or chronic hepatic disturbances occur. Use is contraindicated with hepatic impairment or disease.
• Hepatic hemangiomas: Use with caution in patients with hepatic hemangiomas; may exacerbate disease.
• Hereditary angioedema: Exogenous estrogens may exacerbate angioedema symptoms in women with hereditary angioedema.
• Hypoparathyroidism: Use caution with hypoparathyroidism; estrogen-induced hypocalcemia may occur.
• Migraine: Use caution with migraine; may exacerbate disease.
• Porphyria: Use with caution in patients with porphyria; may exacerbate disease.
• Renal impairment: Use with caution in patients with renal impairment.
• SLE: Use with caution in patients with SLE; may exacerbate disease.
Concurrent drug therapy issues:
• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.
• Thyroid replacement therapy: Estrogens may increase thyroid-binding globulin (TBG) levels leading to increased circulating total thyroid hormone levels. Women on thyroid replacement therapy may require higher doses of thyroid hormone while receiving estrogens.
• Surgical patients: Whenever possible, estrogens should be discontinued at least 4 to 6 weeks prior to elective surgery associated with an increased risk of thromboembolism or during periods of prolonged immobilization.
• Hazardous agent: Use appropriate precautions for handling and disposal (NIOSH 2014 [group 2]).
• Laboratory changes: The use of estrogens and/or progestins may change the results of some laboratory tests (eg, coagulation factors, lipids, glucose tolerance, binding proteins). The dose, route, and the specific estrogen/progestin influences these changes. In addition, personal risk factors (eg, cardiovascular disease, smoking, diabetes, age) also contribute to adverse events; use of specific products may be contraindicated in women with certain risk factors.
• Risks vs benefits: [US Boxed Warning]: Estrogens with or without progestin should be used for the shortest duration possible at the lowest effective dose consistent with treatment goals and risks for the individual woman. Patients should be reevaluated as clinically appropriate to determine if treatment is still necessary. Available data related to treatment risks are from Women’s Health Initiative (WHI) studies, which evaluated oral CE 0.625 mg with or without MPA 2.5 mg relative to placebo in postmenopausal women. Other combinations and dosage forms of estrogens and progestins were not studied. Outcomes reported from clinical trials using CE with or without MPA should be assumed to be similar for other doses and other dosage forms of estrogens and progestins until comparable data becomes available. Women who are early in menopause, who are in good cardiovascular health, and who are at low risk for adverse cardiovascular events can be considered candidates for estrogen with or without progestin therapy for the relief of menopausal symptoms (ACOG 565, 2013). Use of a transdermal product should be considered over an oral agent in women requiring systemic therapy who have risk factors for venous thromboembolism or coronary heart disease (ACOG 556, 2013; Schenck-Gustafsson, 2011; Tremollieres, 2011).
• Vulvar and vaginal atrophy use: Moderate-to-severe symptoms of vulvar and vaginal atrophy include vaginal dryness, dyspareunia, and atrophic vaginitis. When used solely for the treatment of vulvar and vaginal atrophy, topical vaginal products should be considered (NAMS, 2012; NAMS, 2013).
Yearly physical examination that includes blood pressure and Papanicolaou smear, breast exam, mammogram. Monitor for signs of endometrial cancer in female patients with uterus. Adequate diagnostic measures, including endometrial sampling, if indicated, should be performed to rule out malignancy in all cases of undiagnosed abnormal genital bleeding. Monitor for loss of vision, sudden onset of proptosis, diplopia, migraine; signs and symptoms of thromboembolic disorders; glycemic control in patients with diabetes; lipid profiles in patients being treated for hyperlipidemias; thyroid function in patients on thyroid hormone replacement therapy.
Menopausal symptoms: Periodically assess need for continued therapy
Note: Monitoring of FSH and serum estradiol is not useful when managing vasomotor symptoms associated with menopause or vulvar and vaginal atrophy.
In general, the use of estrogen and progestin as in combination hormonal contraceptives have not been associated with teratogenic effects when inadvertently taken early in pregnancy. This product is contraindicated for use during pregnancy.
• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)
• Patient may experience flatulence, hair loss, bloating, dark patches on face, leg cramps, abdominal cramps, flu-like symptoms, increased hunger, joint pain, insomnia, loss of strength and energy, weight gain, back pain, or dark spots on face. Have patient report immediately to prescriber signs of liver problems (dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or jaundice), signs of severe cerebrovascular disease (change in strength on one side is greater than the other, difficulty speaking or thinking, change in balance, or vision changes), signs of DVT (edema, warmth, numbness, change in color, or pain in the extremities), angina, shortness of breath, coughing up blood, severe headache, severe nausea, vomiting, severe dizziness, passing out, vision changes, bulging eyes, contact lens discomfort, lump in breast, breast soreness or pain, nipple discharge, vaginal bleeding, vaginitis, depression, burning or numbness feeling, mood changes, edema, anxiety, polyuria, or memory impairment (HCAHPS).
• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.
Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.
More about conjugated estrogens
- Estrogens (Conjugated B/Synthetic) (Wolters Kluwer)
- Estrogens (Conjugated/Equine, Systemic) (Wolters Kluwer)