Elephant specific information, if available, is in blue.

Chemistry – Estradiol 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.

 

Storage/Stability/Compatibility – Estradiol 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.

 

It is not recommended to mix estradiol cypionate with other medications.

 

Pharmacology – The 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, inhibition of ovulation and inhibition of androgen secretion.

 

Uses/Indications – For mares, indications for the use of estradiol include, induction of estrus during the non-breeding or breeding seasons and to enhance the mare’s uterine de­fense mechanism. Estradiol cypionate has also been used as an abortifacient agent (see warnings below) in cattle, cats and dogs.

 

One product (ECP® — Upjohn) approved for use in breeding cattle, indications listed in its package insert for use in bovine medicine include:

To correct anestrus (absence of heat period) in the absence of follicular cysts in some cases.

To treat cattle having persistent corpus luteum due to certain causes.

To expel purulent material from the uterus in pyometra of cows.

To stimulate uterine expulsion of retained placentas and mummified fetuses.

 

Pharmacokinetics – No 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 is reabsorbed from the GI.

 

Contraindications/Precautions – Estradiol is contraindicated during pregnancy. It has been demonstrated to cause fetal malformations of the genitourinary system and to induce bone marrow depression in the fetus.

 

In cases of prolonged corpus luteum in cows, thorough uterine exam should be completed to determine if endometritis or a fetus is present

 

Adverse Effects/Warnings – Estrogens have been associated with severe adverse reac­tions in small animals; see the Adverse Effects section in the DES monograph (prior to this one) for more information.

 

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.

 

Overdosage – No reports of inadvertent acute overdosage in veterinary patients was located; see Adverse Effects above.

 

Drug Interactions – Rifampin may decrease estrogen activity if administered concomitantly. This is presumably due to microsmal enzyme induction with resultant increase in estrogen metabolism. Other known enzyme inducers (e.g., phenobarbital, phenylbuta­zone, etc.), may have a similar effect, but clinical significance is unclear. 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. Oral anticoagulant activity may be decreased if estrogens are administered concur­rently. Increases in anticoagulant dosage may be necessary if adding estrogens.

 

Drug/Laboratory Interactions – Estrogens 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. Decrease T3 resin uptake also occurs, but free T4 levels are unaltered. It is unclear if estradiol affects these laboratory tests.

 

Doses –

Horses:

For induction of estrus during the non-breeding season:

a)   10 mg estradiol cypionate will result in estrus 2-3 days after treatment (Squires and McKinnon 1987)

 

For induction of estrus in mares with “silent heat” during breeding season:

a)   1 mg estradiol (Squires and McKinnon 1987)

 

To enhance the mare’s uterine defense mechanism:

a)   1 – 2 mg estradiol daily for 3-5 days (Squires and McKinnon 1987)

 

Elephants:

a) The administration of 10 mg estradiol cypionate IM followed by the 200 IU oxytocin IV

on day 15 postpartum and an additional 10 IU oxytocin the following day facilitated the

removal of a retained placenta in an Asian cow. (Murray, et.al. 1996).

 

Elephant References:

a) Murray,S., Bush,M., and Tell,L.A. 1996. Medical management of postpartum problems in an Asian elephant (Elephas maximus) cow and calf. Journal of Zoo and Wildlife Medicine 27:(2):255-258  Abstract: An 18-yr old female Asian elephant (Elephas maximus) gave birth to a 120-kg female calf following 22 mo of gestation.  Immediately after parturition, the cow became agitated and aggressive towards the calf.  Before the keepers were able to safely intervene and remove the calf, the cow stepped on the calf’s head and right front leg.  Within 30 min, the cow calmed down, allowing the calf’s safe reintroduction under close keeper supervision and control.  The cow had a retained placenta, poor mammary development, and low milk production.  The calf’s injuries, in combination with the cow’s low milk production, impeded the calf’s ability to nurse and gain weight.  Within 10 days, the calf lost 10% of its weight.  Serum protein electrophoresis indicated failure of passive transfer of maternal immunoglobulin.  On day 10, the calf received a transfusion of concentrated immunoglobulin extracted and concentrated from the cow’s previously banked plasma.  On day 13, the calf developed a urinary tract infection, as diagnosed by white blood cells and bacteria in the urine.  Following immunoglobulin administration and antibiotic therapy, clinical signs slowly resolved and the calf gained weight.  The cow passed the fetal membranes during parturition, but the placenta was retained.  Despite prophylactic systemic antibiotics and vaginal flushing, the cow became depressed and developed a leukocytosis and anemia.  A mucopurulent vaginal discharge and ventral edema were noted on day 3, and milk production was minimal.  Because decreased milk production has been reported as a common sequel to retained placenta, efforts were focused on removing the placenta.  Intermittent oxytocin therapy on days 2-14 did not result in expulsion of the placenta and produced only transient abdominal contractions and minimal increases in milk letdown.  On day 15, 10 mg estradiol cypionate was administered i.m. followed by 200 IU oxytocin i.v. (in 2 L of saline over 75 minutes).  An additional 100 IU oxytocin (in 1 L of saline over 30 minutes) was administered i.v. on day 16.  The friable placenta was palpable within the vaginal vault on day 17.  The remaining placenta was removed by gentle traction applied by a modified weighted pressure cuff.  Once the placenta was removed, the cow’s clinical problems slowly resolved and the calf continued to gain weight.

Monitoring Parameters – When therapy is either at high dosages or chronic; see adverse effects for more information.

Done at least monthly:

1)   Packed Cell Volumes (PCV)

2)   White blood cell counts (CBC)

3)   Platelet counts

Baseline, one month after therapy, and repeated 2 months after cessation of therapy if abnormal:

1)   Liver function tests

 

Dosage Forms/Preparations/FDA Approval Status/Withholding Times –

 

Veterinary-Approved Products:

Estradiol Cypionate in Oil for Injection 2 mg/ml in 50 ml vials

ECP® (Upjohn), Generic; (Rx)  Approved for use in cattle. No slaughter withdrawal times were located for these products.

 

Human-Approved Products:

Estradiol Cypionate in Oil for Injection 5 mg/ml in 5 & 10 ml vials )

Generic; Many trade names; (Rx)