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Estradiol Cypionate(ess-tra-dye-ole)ECP®Hormonal Agent (Estrogen)Prescriber HighlightsNatural estrogen salt used primarily to induce estrus; has been used as an abortifacient (but rarely recommended today).Contraindications: Pregnancy (abortifacient, teratogen); the FDA has stated that the use of ECP in food animals is illegal.Adverse Effects: In cats & dogs: Bone marrow toxicity, cystic endometrial hyperplasia, and pyometra.In male animals, feminization may occur; in females, signs of estrus may occur.Drug InteractionsUses/IndicationsFor mares, indications for the use of estradiol include enhancing estrus behavior and receptivity in ovariectomized mares and to treat estrogen-responsive incontinence. Historically, estradiol cypionate has been used as an abortifacient agent in cattle, cats and dogs, but estrogens are no longer recommended by most theriogenologists for use as an abortifacient in small animals and the FDA stated (April 5, 2006): “The use of ECP in food-producing animals is illegal, and manufacturing and compounding of ECP for such use is illegal.”Pharmacology/ActionsThe most active endogenous estrogen, estradiol possesses the pharmacologic profile expected of the estrogen class. Estrogens are necessary for the normal growth and development of the female sex organs and in some species contribute to the development and maintenance of secondary female sex characteristics. Estrogens cause increased cell height and secretions of the cervical mucosa, thickening of the vaginal mucosa, endometrial proliferation, and increased uterine tone.Estrogens have effects on the skeletal system. They increase calcium deposition, accelerate epiphyseal closure, and increase bone formation. Estrogens have a slight anabolic effect and can increase sodium and water retention.Estrogens affect the release of gonadotropins from the pituitary gland. This can cause inhibition of lactation, ovulation, and androgen secretion.PharmacokineticsNo specific information was located regarding the pharmacokinetics of estradiol in veterinary species. In humans, estrogen in oil solutions after IM administration are absorbed promptly and absorption continues over several days. Esterified estrogens (e.g., estradiol cypionate) have delayed absorption after IM administration. Estrogens are distributed throughout the body and accumulate in adipose tissue. Elimination of the steroidal estrogens occurs principally by hepatic metabolism. Estrogens and their metabolites are primarily excreted in the urine, but are also excreted into the bile where most are reabsorbed from the GI.Contraindications/Precautions/WarningsEstradiol is contraindicated during pregnancy as it can cause fetal malformations of the genitourinary system and induce bone marrow depression in the fetus.Estradiol cypionate should not be used to treat estrogen–responsive incontinence in small animals; other estrogens (DES, conjugated estrogens) are less toxic.In cases of prolonged corpus luteum in cows, a thorough uterine exam should be completed to determine if endometritis or a fetus is present.In ferrets, estradiol is reportedly very toxic to bone marrow.Adverse EffectsEstrogens have been associated with severe adverse reactions in small animals. In cats and dogs, estrogens are considered toxic to the bone marrow and can cause blood dyscrasias. Blood dyscrasias are more prevalent in older animals and if higher dosages are used. Initially, a thrombocytosis and/or leukocytosis may be noted but thrombocytopenia and leukopenia will gradually develop. Changes in a peripheral blood smear may be apparent within two weeks after estrogen administration. Chronic estrogen toxicity may be characterized by a normochromic, normocytic anemia, thrombocytopenia, and neutropenia. Bone marrow depression may be transient and begin to resolve within 30-40 days or may persist or progress to a fatal aplastic anemia.Estrogens may cause cystic endometrial hyperplasia and pyometra. After therapy is initiated, an open-cervix pyometra may be noted 1-6 weeks after therapy.Estrogens may induce mammary neoplasia.When used chronically in male animals, feminization may occur. In females, signs of estrus may occur and persist for 7-10 days.In cattle, prolonged estrus, genital irritation, decreased milk-flow, precocious development, and follicular cysts may develop after estrogen therapy. These effects may be secondary to overdosage and dosage adjustment may reduce or eliminate them.Reproductive/Nursing SafetyEstradiol is contraindicated during pregnancy. In humans, the FDA categorizes this drug as category X for use during pregnancy (Studies in animals or humans demonstrate fetal abnormalities or adverse reaction; reports indicate evidence of fetal risk. The risk of use in pregnant women clearly outweighs any possible benefit.) In a separate system evaluating the safety of drugs in canine and feline pregnancy (Papich 1989), this drug is categorized as class: D (Contraindicated. These drugs have been shown to cause congenital malformations or embryotoxicity.)Estrogens have been shown to decrease the quantity and quality of maternal milk.Overdosage/Acute ToxicityNo reports of inadvertent acute overdosage in veterinary patients were located; see Adverse Effects above.Drug InteractionsThe following drug interactions have either been reported or are theoretical in humans or animals receiving estradiol and may be of significance in veterinary patients. Unless otherwise noted, use together is not necessarily contraindicated, but weigh the potential risks and perform additional monitoring when appropriate.Azole Antifungals (fluconazole, itraconazole, ketoconazole, etc.): May increase estrogen levels.Corticosteroids: Enhanced glucocorticoid effects may result if estrogens are used concomitantly with corticosteroid agents. It has been postulated that estrogens may either alter the protein binding of corticosteroids and/or decrease their metabolism; corticosteroid dosage adjustment may be necessary when estrogen therapy is either started or discontinued.Macrolide Antibiotics (erythromycin, clarithromycin, etc.): May increase estrogen levels.Phenobarbital: May decrease estrogen activity if administered concomitantly.Rifampin: May decrease estrogen activity if administered concomitantly.ST. John’s Wort: May decrease estrogen activity if administered concomitantly.Warfarin: Oral anticoagulant activity may be decreased if estrogens are administered concurrently; increases in anticoagulant dosage may be necessary if adding estrogens.Laboratory ConsiderationsEstrogens in combination with progestins (e.g., oral contraceptives) have been demonstrated in humans to increase thyroxine-binding globulin (TBG) with resultant increases in total circulating thyroid hormone. Decreased T3 resin uptake also occurs, but free T4 levels are unaltered. It is unclear if estradiol affects these laboratory tests in veterinary patients.DosesDogs:For pregnancy avoidance after mismating (extra-label): Note: This drug is rarely used or recommended for this indication today as there are safer, more effective treatments. 44 micrograms/kg (0.044 mg/kg) IM once; during day 4 estrus to day 2 of diestrus, toxic at ≥100 micrograms/kg. (Wiebe et al. 2009)Cats:For pregnancy avoidance after mismating (extra-label): Note: This drug is rarely used or recommended for this indication today as there are safer, more effective treatments. 250 micrograms/kg (0.25 mg/kg) IM once 6 days after coitus; or 0.25 mg/cat IM at 40 hours after coitus. (Wiebe et al. 2009)Cattle:The FDA has stated that the use of ECP in food-producing animals is illegal.Horses:To enhance estrus behavior and receptivity in ovariectomized mares (extra-label): 5 – 10 mg (total dose) IM once. (Dascanio 2009)For treatment of mares with estrogen-responsive incontinence (extra-label): 4 – 10 micrograms/kg estradiol cypionate IM daily for three days and then every other day. Some mares will improve, but does not “cure.” (Schott II et al. 2003)MonitoringWhen therapy is either at high dosages or chronic, see adverse effects for more information. Done at least monthly:Packed Cell Volumes (PCV).White blood cell counts (CBC).Platelet counts; Baseline, one month after therapy, and repeated two months after cessation of therapy if abnormal.Liver function tests.Client InformationInjectable estrogen that should only be given by veterinarians.Chemistry/SynonymsEstradiol is a naturally occurring steroidal estrogen. Estradiol cypionate is produced by esterifying estradiol with cyclopentanepropionic acid, and occurs as a white to practically white, crystalline powder. It is either odorless or may have a slight odor and has a melting range of 149-153°C. Less than 0.1 mg/mL is soluble in water and 25 mg/mL is soluble in alcohol. Estradiol cypionate is sparingly soluble in vegetable oils.Estradiol may also be known as: beta-oestradiol, dihydrofolliculin, dihydrotheelin, dihydroxyoestrin, estradiolum, NSC-9895, NSC-20293 (alpha-estradiol), and oestradiol; many trade names are ***** ***** may also be known as: oestradiol cyclopentylpropionate, oestradiol cypionate, Delestrogen®, Depo-Estradiol®, Depogen®, Dura-Estrin®, ECP®, E-Cypionate®, Estra-D®, Estrace®, Estro-Cyp®, Estroject®, depGynogen®, Femtrace®, or Gynodiol®.Storage/StabilityEstradiol cypionate should be stored in light-resistant containers at temperatures of less than 40°C, preferably at room temperature (15-30°C); avoid freezing.Commercially available injectable solutions of estradiol cypionate are sterile solutions in a vegetable oil (usually cottonseed oil); they may contain chlorobutanol as a preservative.Compatibility/Compounding ConsiderationsIt is not recommended to mix estradiol cypionate with other medications.In the USA it is illegal to compound estradiol for use in food producing animals.Dosage Forms/Regulatory StatusVeterinary-Labeled Products:There are several estradiol-containing implants for use in beef cattle.Human-Labeled Products:Estradiol Cypionate in Oil for Injection: 5 mg/mL in 5 mL vials; Depo-Estradiol®; (Rx)Estradiol Valerate in Oil for Injection: 10 mg/mL, 20 mg/mL & 40 mg/mL in 5 mL multi-dose vials; Delestrogen®, generic; (Rx)Estradiol Tablets: 0.5 mg, 1 mg, 1.5 mg, & 2 mg micronized estradiol; Estrace®, generic; (Rx)Revisions/ReferencesMonograph revised/updated January 2014.Dascanio, J. (2009). Hormonal Control of Reproduction. Proceedings: ABVP. accessed via Veterinary Information Network; vin.comSchott II, H. & E. Carr (2003). Urinary incontinence in horses. Proceedings: ACVIM Forum. accessed via Veterinary Information Network; vin.comWiebe, V. J. & J. P. Howard (2009). Pharmacologic Advances in Canine and Feline Reproduction. Topics in Companion Animal Medicine 24(2): 71-99.January 1, 2005 (published) | January 1, 2015 (revised)