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Placentitis: Clinical Signs and Diagnosis

Clinical signs include those observed in mares with pending abortion. Udder development, premature lactation, and cervical softening are often seen before the mare aborts. Vaginal discharge may or may not proceed abortions. Once clinical signs develop, the disease has reached an advanced stage and treatment may not always be successful.

Evaluation of the equine placenta should routinely be performed after abortion or parturition. In aborting mares with an ascending placentitis, the pathologic lesions are characteristic. An area of the chorion adjacent to the cervical star is depleted of chorionic villi and is thickened, discolored, and covered by fibronecrotic exudate (). Placentitis caused by N. actinomycete causes characteristic lesions at the ventral aspect of the base of the gravid horn and nongravid horn at the junction between the body and the horn of the placenta. The chorionic surface is thickened and covered with brown-red, thick, mudlike material. Placentitis caused by a hematogenous route of infection shows less characteristic multifocal lesions of the chorionic surface of the placenta. A thorough inspection of the placenta is necessary to ensure that any existing lesions are found. Examination of the placenta postpartum provides excellent information on disease processes or dysfunctions that could have affected the well being of an aborted fetus, or that may potentially cause illness in the neonatal foal. However, this examination does not aid the clinician in decisions that are aimed to prevent abortion or neonatal diseases of the foal. Evaluation of the placenta in the pregnant mare must be performed by the use of ultrasonography and endocrine tests.

Ultrasonographic Evaluation of the Equine Placenta

Transabdominal Ultrasonography

Ultrasonographic examinations of the placenta in mares that are considered to be at risk for abortion during late gestation can be performed by a transabdominal approach (Figure 5.24-2). With a 5- or 7.5-MHz sector scanner, four quadrants of the placenta should be examined; right cranial, right caudal, left cranial, and left caudal. With this technique, mares with normal pregnancies should have a rrunimal combined thickness of the uterus and the placenta (CTUP) of 7.1 +/-1.6 mm, and a maximal CTUP of 11.5 +/-2.4 mm. Pregnancies with an increased CTUP have been associated with the delivery of abnormal foals. The caudal portion of the allantochorion cannot be imaged with transabdominal ultrasonography, which prevents the clinician from diagnosing ascending placentitis in its early stages. However, placental thickening and partial separation of the allantochorion from the endometrium may be observed with transabdominal ultrasonography in mares that have placentitis originating from a hematogenous infection. In addition, a pocket of hyperechoic fluid can be seen at the base of the lowest area of the gravid uterus in mares with placentitis caused by N. actinomycete. Mares that graze on endophyte-infected fescue often experience retained placenta, premature separation of the allantochorion, and increased allantochorion weight and thickness. A significant increase in uteroplacental thickness and premature separation of the allantochorion has been found on transabdominal ultrasonographic examination of endophyte-infected mares. However, the thickness was not observed until an average of 8 hours before the onset of labor.

Transrectal Ultrasonography

Transrectal ultrasonography of the caudal allantochorion in late gestational mares provides an excellent image of the placenta close to the cervical star (). A 5-MHz linear transducer should be positioned 1 to 2 inches cranial of the cervical-placental junction, and then moved laterally until the middle branch of the uterine artery is visible at the ventral aspect of the uterine body. The CTUP should then be measured between the middle branch of the uterine artery and the allantoic fluid (). The clinician has to make sure that the amniotic membrane is not adjacent to the allantochorion, because this may result in a falsely increased CTUP. The CTUP should be measured in the ventral part of the uterine body. The CTUP in the dorsal part of the uterus is often thicker than in the ventral part of the uterus. In addition, placental parts of the dorsal uterus have often been found to be edematous in normal pregnant mares during the last month of gestation (). Normal values for CTUP are illustrated in Table Normal Upper Limits for the Combined Thickness of the Uterus and the Placenta during Late Gestation. An abnormal thickness and partial separation of the allantochorion from the endometrium has been observed on ultrasonographic examination in mares with clinical signs of ascending placentitis (). A CTUP greater than 8 mm between day 271 and 300, less than 10 mm between day 301 and 330, and greater than 12 mm after day 330 has been associated with placental failure and pending abortion. In advanced stages, the space between the uterus and the placenta is filled with hyperechoic fluid.

Table Normal Upper Limits for the Combined Thickness of the Uterus and the Placenta during Late Gestation

Cestational Period CTUP
151-270 days <5 mm
271-300 days <7 mm
301-330 days <9 mm
331 + <12 mm

Although transrectal and transabdominal ultrasonographic examination of the placenta is useful to detect early signs of some placental pathology, the clinician should keep in mind that placental changes resulting in periparturient problems can be subtle and not readily detected on ultrasonographic examination.

Endocrine Monitoring of the Placenta

Progesterone

The equine placenta is part of an endocrine fetal-placental interaction that synthesizes and metabolizes progestogens. This endocrine function of the placenta is important for maintenance of pregnancy after the endometrial cups and the secondary corpora lutea disappear at approximately day 150 of gestation. Mares with advanced stages of placentitis or placental separation may have increased plasma concentrations of progestogens as a result of stress to the fetal placental unit. In contrast, circulating progestogens have been reported to fall below normal after fetal hypoxia and infection with equine herpesvirus. Although increased concentrations of plasma progesterone during mid and late gestation would suggest placentitis, therapeutic decisions should not be made on the basis of one sample. Serial blood samples need to be obtained from an individual mare in order to detect a clinically useful trend in progesterone concentrations. Fetal-placental progesterone is rapidly metabolized to 5-pregnanes, and the metabolites may not be recognized by commercial progesterone assays. Therefore maternal serum progesterone concentrations in late pregnant mares do not accurately reflect the conditions in the uterus. Monthly blood sampling of mares at risk of abortion showed no differences in plasma progesterone concentrations in mares with impending abortion and mares with normal pregnancies.

Estrogen

Both estradiol and conjugated estrogen (estrone sulfate) are elevated during late pregnancy in mares. Estrone sulfate in maternal serum is thought to be a marker of fetal well-being. However estrogens have not been useful to detect early signs of placentitis.

Relaxin

Relaxin is produced by the equine placenta and can be detected in peripheral blood plasma from day 80 of gestation and throughout the pregnancy. The role of relaxin during pregnancy is not fully understood, but some evidence exists that placental relaxin production is compromised in mares at risk of aborting their fetuses. No commercial test for equine relaxin is currently available, and more research needs to be performed to evaluate the usefulness of plasma relaxin as a clinical tool to diagnose placentitis and to monitor the efficacy of treatment strategies.

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Oocyte Transfer

Oocyte transfer is the placement of a donor’s oocyte into the oviduct of a recipient. The recipient can be inseminated within the uterus or within the oviduct. Placement of the oocyte and sperm within the recipient’s oviduct is more accurately termed gamete intrafallopian transfer (GIFT).

The first successful oocyte transfer was done in 1989; however, the technique was not used for commercial transfers until the late 1990s. Oocyte transfer is currently used to produce offspring in subfertile mares in which embryo transfer is not successful because of various reproductive problems. These problems include ovulatory failure, oviductal blockage, recurrent or severe uterine infections, and cervical tears or scarring. In some cases, the cause of reproductive failure cannot be diagnosed; however, oocyte transfer can be successful.

Sychronization Of Donors And Recipients

Oocytes are collected from preovulatory follicles between 24 and 36 hours after the administration of human chorionic gonadotropic (hCG; 1500-2500 IU, IV) to a donor mare or between 0 and 14 hours before anticipated ovulation. Criteria for hCG administration are as follows:

• Follicles greater than 35 mm in diameter

• Relaxed cervical and uterine tone

• Uterine edema or estrous behavior present for 2 or more days

Some mares, especially older mares, do not consistently respond to hCG. In these cases, this author uses a combination of the gonadotropin-releasing hormone (GnRH) analog, deslorelin acetate (2.1 mg implant; Ovuplant), followed by an injection of hCG (2000 IU, IV) between 4 and 5 hours later.

Oocytes collected 36 hours after hCG administration to the donor are transferred immediately into a recipient’s oviduct. Oocytes collected 24 hours after drug administration to the donor are cultured in vitro for 12 to 16 hours before transfer. The advantage of collection of oocytes between 32 and 36 hours after hCG administration to the donor is that the oocytes do not require culture in vitro. However, donors could ovulate follicles before oocytes are collected. The collection and culture of oocytes at 24 hours after hCG administration to the donor are often easier to schedule; the oocyte can be collected in the afternoon and transferred the next morning. This method requires expensive equipment and training for tissue culture, however. In a modification of these procedures, oocytes are collected 24 hours after hCG and immediately transferred into the recipient’s oviduct to allow maturation to complete within the oviduct. With this latter method, recipients are inseminated 16 hours after transfer.

Oocyte Collection

Oocytes are usually collected by one of two methods. In one method, the ovary is held per rectum against the ipsilateral flank of the mare. A puncture is made through the skin and a trocar is advanced into the abdominal cavity. The ovary is held against the end of the trocar while a needle is advanced through the trocar and into the follicular antrum.

In this author’s laboratory oocytes are collected by using transvaginal, ultrasound-guided follicular aspirations. For this procedure, a linear or curvilinear ultrasound transducer is used with the transducer housed in a casing with a needle guide. Before the procedure, the rectum is evacuated and the vulvar area is cleaned. The mare is sedated (xylazine HC1, 0.4 mg/kg, and butorphanol tartrate, 0.01 mg/kg, IV) and a substance to relax the rectum (propantheline bromide, 0.04 mg/kg, IV) is administered. A twitch is applied. The probe is covered with a nontoxic lubricant and placed within the anterior vagina lateral to the posterior cervix and ipsilateral to the follicle to be aspirated. The follicle is positioned per rectum and stabilized with the apex of the follicle juxtaposed to the needle guide. A needle is advanced through the needle guide to puncture the vaginal and follicular walls. In this author’s laboratory, a 12-gauge, double-lumen needle is used (Cook Veterinary Products, Spencer, Ind.). The follicular fluid is aspirated from the follicle by using a pump set at a pressure of -150 mm Hg. After removal of follicular fluid, the lumen of the follicle is lavaged with 50 to 100 ml of flush (typically modified Dulbecco’s phosphate-buffered solution or Emcare [ICP, Auckland, New Zealand]) that contains fetal calf serum (1%) or bovine serum albumin (0.4%) and heparin (10 IU/ml).

Equipment used to handle the oocyte is warmed to 38.5° C before use because the oocyte is sensitive to temperature changes. On collection, the follicular aspirate and flush are poured into large search dishes and examined under a dissecting microscope to locate the oocyte. Aspirations of preovulatory follicles are often bloody because the follicle has increased vascularity as ovulation approaches. The oocyte is approximately 100 μm in diameter and is surrounded by a large mass of nurse ceils — the cumulus complex. Cumulus cells, or the corona radiata, appear as a ring surrounding the oocyte. When the oocyte matures, the cumulus complex becomes less distinct. The corona radiata appears clear in the bloody flush solution and can be observed by the naked eye.

Oocyte Evaluation And Culture

On collection, cumulus oocyte complexes (COC) are evaluated for cumulus expansion (graded from compact to fully expanded) and for signs of atresia. Oocytes are determined to be in a stage of atresia when the COC is clumped and/or sparse, the corona radiata is fully expanded, or when the ooplasm is shrunken and dark or severely mottled. Oocytes with a fully expanded cumulus (marked separation of cumulus cells with expansion of the corona radiata) are considered mature and are transferred as soon as possible into a recipient’s oviduct. Oocytes with a moderately expanded cumulus complex (translucent COC with moderate separation of cumulus cells and incomplete expansion of corona radiata) are cultured before transfer. On occasion, the donor does not respond to hCG and the follicle does not begin to mature. Consequently, the granulosa cells that line the follicle are collected in small, compact sheets, and the oocyte is frequently not retrieved. If an immature (compact COC with little or no separation of cumulus cells) oocyte is collected, special culture conditions are required, including a maturation medium with additions of hormones and growth factors.

On identification and evaluation, the oocyte is washed and placed in a transfer or collection medium. A commonly used medium for the culture of maturing oocytes is tissue culture medium (TCM) 199 with additions of 10% fetal calf serum, 0.2 mM pyruvate, and 25 mg/ml gentamicin sulfate. A carbon dioxide (C02) incubator must be used to establish the proper culture conditions of 38.5° C in an atmosphere of 5% or 6% C02 and air.

Oocyte Transfer

Mares that will receive oocytes should be young (preferably 4-10 years of age) with a normal reproductive tract. Oocytes are transferred surgically; therefore, adequate exposure of the ovary is essential to facilitate transfers. Mares with short, thick flanks and short broad ligaments are not good candidates for recipients. Both cycling and noncycling mares have been used as oocyte recipients. When cyclic mares are used, they must be synchronized with the donor; thus, hCG is administered to the estrous donor and recipient at the same time of day. Before the mare can be used as a suitable recipient, her own oocyte must be aspirated. Anestrus and early transitional mares are suitable noncyclic recipients. During the breeding season, a high dose of a GnRH analog or injections of progesterone and estrogen (150 mg progesterone and 10 mg estradiol) can be administered to reduce follicular development in potential recipients. Noncyclic recipients are given injections of estradiol (2-5 mg daily for 3-7 days) before transfer and progesterone (150-200 mg daily) after transfer. In mares that are not having estrus cycles, pregnancies must be maintained through the use of exogenous progesterone.

Oocytes are transferred through a flank laparotomy into standing sedated mares. Recipients are placed in a stock and a presurgical sedative (xylazine HC1, 0.3 mg/kg, and butorphanol tartrate, 0.01 mg/kg, IV) is administered. The surgical area is clipped, scrubbed, and blocked with a 2% lidocaine solution. Immediately before surgery, additional sedation is administered (detomidine HC1, 9 mg/kg, and butorphanol tartrate, 0.01 mg/kg, IV). An incision is made through the skin approximately midway between the last rib and tuber coxae, and the muscle layers are separated through a grid approach. The ovary and oviduct are exteriorized through the incision. The oocyte is pulled into a fire-polished, glass pipette, and the pipette is carefully threaded into the infundibular os of the oviduct and advanced approximately 3 cm. The oocyte is transferred with less than 0.05 ml of medium.

Insemination Of Recipients

In a commercial oocyte transfer program, use of stallions with good fertility is essential. Cooled and transported semen is often provided. When fresh semen from fertile stallions and oocytes from young mares was used in different experiments, insemination of the recipient only before (12 hours) or only after (2 hours) oocyte transfers resulted in embryo development rates of 82% (9/11) and 57% (8/14), respectively. In a commercial oocyte program, mares were older with histories of reproductive failure and cooled semen from numerous stallions of variable fertility was used. Pregnancy rates when recipients were inseminated before or before and after oocyte transfer were significantly higher than when recipients were only inseminated after transfer (18/45, 40%; 27/53, 51% and 0/10, respectively). These results suggest that the insemination of a recipient before transfer with 5 X 108 to 1 x 109 progressively motile sperm from a fertile stallion is sufficient. However, if fertility of the stallion is not optimal, insemination of the recipient before and after transfer may be beneficial.

After insemination and transfer, the recipient’s uterus is examined by ultrasonography to detect intrauterine fluid collections. The uterine response to insemination often appears to be more severe when recipients are inseminated after transfer than when they are inseminated only before transfer. The uterus is evaluated and treated once or twice daily until no fluid is imaged. Recipients with accumulations of intrauterine fluid are treated similar to ovulating mares, with administration of oxytocin or prostaglandins to stimulate uterine contractions or with uterine lavage and infusion.

Future Of Oocyte Transfer

Oocyte transfer has proved to be a valuable method of obtaining pregnancies from mares that cannot carry their own foal or produce embryos for transfer. Because the mare does not have to ovulate or provide a suitable environment for fertilization or embryo development, the oocyte donor is only required to develop a preovulatory follicle with a viable oocyte.

The transfer of oocytes and a low number of sperm (200,000 motile sperm) into the oviduct of recipients has been successful. Pregnancies could be produced with GIFT when sperm numbers are limited, such as from subfertile stallions and from sex-selected or frozen sperm.

Through the use of this technique at this author’s laboratory, pregnancies have been recently produced from oocytes that were frozen and thawed and from oocytes that were collected from the excised and shipped ovaries of dead mares. These advances provide excellent methods to preserve the genetics of valuable mares.

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Selection And Management Of Recipients

Selection and management of recipient mares for an embryo transfer program is the most important factor affecting pregnancy rates. On farms handling only one or two donors, recipient mares may be purchased from local backyard horse owners who are familiar with the mare’s reproductive history. However, acquiring a large number of recipient mares requires that mares be purchased from local sale barns. Thus the reproductive history of these mares is unknown. In either case the recipient mare should meet the following criteria: 900 to 1200 pounds; 3 to 10 years of age; and broken to halter. The effect of size of recipient on the subsequent size of the foal has not truly been determined. However, the size of the donor mare should be matched with the recipient as nearly as possible. This may be difficult when obtaining embryos from large warmbloods or draft horses.

Typically nonlactating mares are easier to use in an embryo transfer program than a mare that is lactating. If a lactating mare is not being used, the animals should not be used as recipients until at least the second postpartum cycle. Numerous types of recipient mares can be used: ovarian-intact cycling mares; ovariectomized mares; mares in anestrus; and mares during the transitional period. This author prefers to use ovarian intact normal cycling mares. However, pregnancy rates using ovariectomized, progesterone-treated mares have been shown to be similar to ovarian-intact mares.

Occasionally, early in the year a scarcity of normal cycling mares occurs. The alternative at that time of the year is to use either an anestrous mare or a transitional mare. In this author’s experience transitional mares are more appropriate to use than truly anestrous mares. Mares in transition should be selected based on the presence of endometrial folds. This indicates that estrogen is being secreted. Transitional mares can then be placed on progesterone at the time of the donor mares ovulation. The suggested progestin treatment for either ovariectomized mares or transitional mares includes altrenogest (Regumate) daily or 150 mg of progesterone injected daily. With the use of ovariectomized mares, progesterone treatment must continue until the placenta begins to produce progesterone at approximately 100 to 120 days. With transitional mares, progesterone treatment may be terminated once the mare has ovulated and developed secondary corpora lutea during early gestation.

The recipient mare should be examined by rectal palpation and ultrasonography before purchase. The external genitalia are observed for normal conformation. Those mares with poor external conformation that may predispose them to wind sucking are generally rejected. Mares are then palpated per rectum and the size and tone of the uterus, cervix, and ovary are determined. The uterus and ovary are then examined with ultrasonography. Evidence of pathology such as uterine fluid, uterine cyst, ovarian abnormalities, or the presence of air or debris in the uterus would render the mare unsuitable for purchase as an embryo recipient. In addition, any mare found to be pregnant is not purchased unless the pregnancy is less than 30 days.

Approximately 15% to 20% of the mares initially presented are rejected. Mares that pass the initial examination are given a breeding soundness exam similar to the exam of the donor mare. Recipients are vaccinated for influenza, tetanus, and rhinopneumonitis and are quarantined from other mares for at least a period of 30 days. Those mares that are in thin condition are fed a concentrate ration and a free-choice alfalfa hay. The majority of recipients are purchased in late fall and placed on a 16-hour lighting regimen beginning December 1. Starting approximately February 1, mares are palpated and examined with ultrasonography twice per week until a follicle greater than 35 mm is obtained. Mares with follicles greater than 30 mm are examined daily with ultrasonography until ovulation. Ideally, recipient mares should have one or two normal estrous cycles prior to being used as a recipient. Mares are excluded as potential recipients if they consistently have erratic or abnormal estrous cycles.

Hormonal manipulation of the recipient mare’s estrous cycle is an important component of an embryo transfer program. The degree of hormonal manipulation is dependent upon the size of the embryo transfer operation. Smaller operations that deal with only one or two donors use more hormonal manipulation than larger operations that may have a large number of donors and recipients. Small operations should place the donor and one or two recipients on progesterone for 8 to 10 days and then administer prostaglandins on the last day of treatment. The progesterone can either be altrenogest used daily or injectable progesterone at a level of 150 mg daily for the same length of time. It is not uncommon to use a combination of progesterone and estrogen (150 mg progesterone, 10 mg estradiol-17β) daily for 8 to 10 days followed by prostaglandins.

The donors and recipients will ovulate 7 to 10 days after prostaglandin treatment. Generally, having the recipient ovulate either 1 day before or up to 3 days after the donor mare is desirable. This can be accomplished by using hCG (Chorulon) or GnRH (Ovuplant) to induce ovulation in either the recipient or donor mare to provide optimal synchrony of ovulation. In a larger embryo transfer station it is common to manipulate the cycle by using only prostaglandins, hCG, or GnRH. Typically the ovulation dates of the recipient are recorded and once a donor mare ovulates then a recipient is selected that has ovulated either 1 day before or up to 3 days after the donor. If a mare is not used as the recipient she is then given prostaglandins 9 or 10 days after her ovulation and induced to return to estrus.

Each recipient mare is given a final examination 5 days after ovulation before to being used as the recipient. Mares are classified as acceptable, marginal, or nonacceptable based on this 5-day exam. The 5-day exam includes palpation per rectum for uterine and cervical tone, and ultrasonography of the uterus and ovaries. An acceptable recipient should have a round, tubular, firm uterus and a closed cervix. She also would have the absence of endometrial folds, a normal sized uterus, and the presence of a visible corpus luteum. Mares generally are placed in the marginal category based on a decrease in uterine tone or cervical tone or perhaps the presence of grade 1 endometrial folds. Unacceptable recipients typically have poor uterine tone, a soft-open cervix, or presence of endometrial folds and/or fluid in the uterus. A retrospective examination of this author’s commercial embryo transfer program has revealed that the 5-day check is the best predictor of whether or not a recipient mare will become pregnant.

Embryos are transferred either surgically by flank incision or nonsurgically. Most of the embryo transfer stations are now using nonsurgical transfer methods. The details of the transfer methods are presented in the subsequent chapter. Mares are examined with ultrasonography for pregnancy detection 4 or 5 days after transfer. Mares that are diagnosed pregnant are reexamined on days 16, 25, 35, and 50. Mares not confirmed pregnant on the initial examination (day 12) are reexamined 2 days later. If the ultrasound scan continues to be negative the mare is considered not pregnant and given prostaglandin to induce estrus. Unless the embryo was extremely small (<150 microns) the majority of mares that are to be pregnant have a visible vesicle at 12 days of gestation. Those mares in which the vesicle does not appear until 14 or 16 days of gestation have delayed embryonic development and are more likely to suffer early embryonic loss. The initial ultrasound examination allows the breeder to decide whether to rebreed the donor and attempt a second embryo recovery. The ultrasound exam at 25 days determines whether a fetus is present with a viable heartbeat. The majority of losses that do appear in embryo transfer recipients occur between days 12 and 35. However, early embryonic loss before 50 days of gestation appears to be no greater in embryo transfer recipients than other pregnant mares that are inseminated with either fresh or cooled semen. Mares that fail to become pregnant after an embryo transfer are generally used a second time but not a third. The pregnancy rates on mares receiving an embryo on a second attempt are no different than those that receive an embryo only one time and become pregnant.

Pregnant recipients should be fed a maintenance ration similar to other broodmares during the first two thirds of gestation and then administered extra energy in the form of concentrate rations during the final one third of pregnancy. Recipients should be monitored closely around the time of impending parturition. Management procedures identical to those used for foaling broodmares should be used. No greater difficulty in foaling embryo transfer recipients than normal broodmares has been found. The influence of the size of the recipient versus size of donor on ease of foaling has not been adequately studied, although this does not appear nearly as critical in horses as it does in cattle.

In summary, a relatively high pregnancy rate can be anticipated in an embryo transfer program if management of the donor and recipient mares are maximized. Attention should be given to selection of both donor and recipient, nutrition, proper monitoring of the donor and recipient with palpation per rectum and ultrasonography, careful assessment of the recipient, and management of the recipient after embryo transfer. Day 12 pregnancy rates for either fresh or cooled semen should be 75% to 80% and those at 50 days of gestation should be 65% to 70%.

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Enlarged Ovaries

Anovulatory Follicles

Large, anovulatory follicles are a normal finding during the spring and fall transition periods. Anovulatory follicles can exceed 10 cm in diameter and may persist for several weeks. The cause is likely to be abnormal estrogen production by the follicle and/or insufficient release of pituitary gonadotropin to induce ovulation. Often the ultrasonographic image reveals scattered free-floating echogenic spots as a result of the presence of blood in the follicular fluid (hemorrhagic follicles). In others are echogenic fibrous bands resulting from gelatinization of the hemorrhagic fluid. Although human chorionic gonadotropin (2500 IU IV) or a GnRH implant may induce ovulation, in most cases the treatment is ineffective. Fortunately most of these anovulatory follicles spontaneously regress within 1 to 4 weeks. Breeding a mare in anticipation of ovulation of a persistent follicle is unwise because fertility of the aged oocyte is likely to be poor.

Clinicians should be aware that not all palpable and ultrasonographically imaged structures around the ovary have to be follicles. Fossa cysts and parovarian (fimbrial) cysts can be found in many mares as an incidental finding.

These structures tend to arise from remnants of the embryonic (mullerian and wolffian) duct systems. If they are of a significant size they should be noted on the mare’s breeding records, but they generally are not associated with any reduction in fertility. Theoretically an excessively large cyst could interfere with ovulation or oocyte transport.

Hematoma

During the physiologic breeding season in a healthy, non-pregnant mare, a surge of luteinizing hormone from the anterior pituitary results in rupture of the mature follicle (ovulation). Normally some hemorrhage from blood vessels in the theca layer occurs, and this results in a soft, intermediate structure — the corpus hemorrhagicum. Immediately after ovulation a depression may be palpable, but this is soon replaced by the developing corpus luteum. The theca cells and invading granulosa cells become luteinized such that the serum progesterone level is elevated until endometrial prostaglandin brings about luteolysis.

A hematoma is the most likely explanation for a unilateral ovarian enlargement during the physiologic breeding season. Excessive postovulatory hemorrhage is not uncommon. The former follicle can become distended markedly. Treatment is not indicated because the structure is essentially an abnormally large corpus hemorrhagicum. Behavior will be normal. The mare continues to have regular estrous cycles, and the opposite ovary remains functional. Serum hormone levels are normal. The hematoma resolves over a period of several weeks, and normal ovarian function can be expected to return in most cases.

Pregnancy

Although an ovarian tumor could begin development during pregnancy, the most likely explanation for ovarian enlargement and abnormal behavior during this time is normal physiologic events. Secondary corpora lutea tend to cause bilateral ovarian enlargement after approximately day 40 of gestation. Expressions of estrus and stallion-like or just aggressive behavior can occur during pregnancy. The large fetal gonads are a significant source of testosterone. Obviously progesterone from the corpora lutea and progestins from the placenta are present. By 2 to 3 months of gestation, testosterone levels can exceed 100 pg/ml and then continue to rise until about 6K months. The testosterone concentrations then gradually decline to basal levels at parturition.

Granulosa Cell Tumors

In a normal ovary the granulosa cells line the inside of follicles, whereas the theca cells surround the outside of the follicle. The theca cells produce testosterone. Both the granulosa and theca cells are involved in the steroidogenic pathway that leads to estradiol production. The granulosa cells also produce the protein hormone, inhibin.

The granulosa cell tumor (GCT) is the most common tumor of the equine ovary. These tumors tend to be unilateral, slow growing, and benign. In fact, they can develop during pregnancy. If a GCT is detected at the foal heat, it may be possible to remove the ovary and have the mare bred back later that season. This depends on the time of year that the mare foals and also the degree of follicular suppression present in the contralateral ovary.

Although GCTs are steroidogenically active, the hormonal milieu can vary from case to case. This affects the amount of follicular activity on the contralateral ovary and the type of behavior being exhibited. Typically the opposite ovary is small and inactive, but occasionally a GCT presents on one ovary while a corpus luteum is on the other. Owners may report that the mare has failed to exhibit estrous behavior (prolonged anestrus) or that it is continuously displaying signs of being in estrus (nympho-mania). A dangerous side effect in some mares is aggressive behavior towards the handler. These mares tend to exhibit stallion-like behavior and may develop a crested neck and clitoral hypertrophy if the tumor has been present for some time.

Loss of the characteristic kidney-bean shape is usually a good indication that a tumor may be present in a small ovary (). Often the ovary is too large to be palpated thoroughly. In both instances the characteristic multicystic (honeycomb) image on an ultrasound examination can support the diagnosis (). Occasionally the GCT may present as a large unilocular cyst ().

The ultrasonographic diagnosis can be supported by hormonal assays if necessary (Table Hormonal Concentrations in Mares with a Granulosa Cell Tumor). Most GCT appear to secrete sufficient inhibin to suppress pituitary release of follicle-stimulating hormone (FSH), and this probably explains the typical suppression of follicular activity on the contralateral ovary. If a significant theca cell component exists in the tumor then the serum testosterone level is elevated, and these mares are more likely to be aggressive and exhibit stallion-like behavior. Although progesterone levels tend to be low (<1 ng/ml) in affected mares, in some instances cyclic activity may continue in the presence of a GCT.

Table Hormonal Concentrations in Mares with a Granulosa Cell Tumor

Hormone Diagnostic Level Incidence
Testosterone More than 50 to 100 pg/ml 50%-60% of cases
Inhibin More than 0.7 ng/ml -90% of cases

Indications for removal of these benign tumors include breeding purposes, behavioral problems, and in some cases colic episodes. Diagnosis must be certain because a histopathologic diagnosis of normal ovarian tissue can be difficult to explain to an owner once the ovary has been removed. Veterinarians must explain to owners that not all behavioral problems are ovarian in origin. An endometrial biopsy and cervical evaluation are recommended if the mare is to be used for breeding purposes. Although the abnormal hormonal environment can cause reversible changes in the density of the endometrial glands, chronic degenerative changes including fibrosis limit the mare’s ability to carry a foal to term. The affected ovary can be removed by several surgical approaches, depending on the size of the GCT and the preference of the surgeon. Options for ovariectomy include laparoscopy, colpotomy, and flank and ventral midline laparotomy. The time until subsequent ovulation on the remaining ovary can vary tremendously, and owners should be advised that it might take up to 6 to 8 months.

Other Ovarian Tumors

Although they are rare, teratomas are the next most common ovarian tumor after a GCT. They are also unilateral but are not hormonally active and do not alter the mare’s behavior. The opposite ovary remains active and the mare exhibits normal estrous activity during the physiologic breeding season. A teratoma is a germ cell tumor and may contain cartilage, bone, hair, mucus, and other tissues. The surface of the ovary tends to be sharp and irregular on palpation, and the varying density of the aberrant tissues causes abnormal shadows on the ultrasound image (). Although an ovarian teratoma generally is thought of as being benign, this author has reported on one malignant case that had metastasized to several organs.

Even more rare tumors of the equine ovary include cystadenomas and dysgerminomas. Cystadenomas tend to be benign, whereas dysgerminomas may be malignant. They are both unilateral and hormonally inactive. Thus the contralateral ovary and behavior are normal. The ultrasonographic image of a cystadenoma can resemble that of multiple follicular activity. The same considerations for surgical removal apply as for GCT.

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Horses

Foal Heat-Breeding

Commercial horse breeding farms operate under the same economic rules as other forms of intensive livestock production. Use of stallions must be efficient, and mares must produce the greatest number of foals possible. This requires intensive management. The primary reason for foal heat-breeding is to increase the efficiency of the production unit.

The performance of a herd of mares should be measured not only by the final conception rate but also by how efficiently that pregnancy rate was achieved. This can be measured by the number of breedings per conception and by noting when in the breeding season each mare becomes pregnant. A set of criteria can be established such that the performance of individual mares and the herd can be measured against the ideal. The criteria can be flexible and should be tailored to meet the economic objectives of the operation. For example, the time at which the farm would like the earliest foal to be born is determined by the management practices of that farm and by the requirements of a particular breed registry. Once these criteria are established, a management goal can be set. In central Kentucky the main commercial business is the production and sale of Thoroughbred yearlings. Thus a workable criterion is that no mare is bred before the fifteenth of February. Optimal fertility dictates that no mare is bred before the tenth day after foaling. That means that all maiden, barren, and January foaling mares should be bred as close to the fifteenth of February as possible. All other foaling mares are bred on or soon after the tenth day from foaling. Of course, this schedule is not always possible, nor in many instances is it advisable. However, if management strives to meet these goals, the net result will be that the farm can push foaling dates to the front of the season. This shift will result in increased production from the mare herd. It can be readily seen that foal heat-breeding plays an important part in such a strategy because it keeps the interval between foaling dates to a minimum.

Selection Of Mares

Determining An Appropriate Time To Breed The Mare

Mares that are normal and eligible to be bred on the foal heat can then be monitored for follicular development and bred at the optimal time. Several studies have shown that time of ovulation is critical to the success of foal heat-breeding. Mares that ovulate before ten days after foaling have a much lower pregnancy rate than do mares that ovulate at 10 days or later. Therefore if ovulation occurs too early, it is better not to breed the mare even if she is deemed suitable for mating. The performance of the herd will be better if these mares are not bred at the foal heat and then are managed so that they can be bred at the earliest time possible after this first ovulation.

If a decision has been made to skip the foal heat, these mares may be bred earlier by using prostaglandin to cause regression of the corpus luteum. The prostaglandin can be given at day six or seven postovulation, and the mare will often be ready to breed six or seven days later. This will shorten the time from foaling to breeding by about a week compared to allowing the mare to return to heat naturally. Mares that have a uterine infection, have fluid in their uteri, or have poor uterine involution after foaling often will also benefit from prostaglandin therapy. The early return to estrus appears to have a cleansing effect on the reproductive tract of these mares. It also gives the veterinarian a chance to continue therapy if necessary.

Some managers use hormonal therapy to delay the onset of the first estrus and thus ensure that the ovulation will occur ten days or more after foaling. Two methods are used to achieve this delay. One is with the use of oral altrenogest, and the other with the use of injectable progesterone and estradiol. Although the altrenogest (0.044 mg/kg) is the simplest and most readily available product, it is also the least precise. The progesterone (150 mg) estradiol-17β (10 mg) in oil combination provides more precise control of follicular development but must be given by daily injections and thus can cause some muscle soreness. Irrespective of the method chosen, beginning treatment on the first day postfoaling is important. If treatment is begun later — after follicular development has commenced — it may be difficult to suppress this growth, and some mares will continue through the therapy and ovulate. Mares that are successfully managed in this manner can be made to ovulate at day ten, twelve, or even later from foaling. Some investigators believe that this can be helpful. However, a controlled study in which this author participated showed very little benefit over the intensive management of foal heat alone.

Care Of The Mare After Breeding

Mares bred on foal heat should be examined the day after breeding — not only to confirm ovulation but also to ensure that the uterus has not retained a significant amount of fluid. If an ultrasound examination reveals an echogenic fluid accumulation, the mare should be treated with oxytocin to help promote elimination of this fluid. If a large volume of fluid is present, it may be advisable to lavage the uterus. Postbreeding antibiotic infusion may also be indicated in foal heat mares — more so than at other times. If the mare requires a Caslick operation, it should be performed at this time. The mare is less forgiving at the foal heat than during later estrous periods. Thus attention to detail is especially important.

Foal heat-breeding is a useful management tool, but it must be done carefully and with thought. Indiscriminate foal heat-breeding can often be detrimental to the mare and thus make the overall management program less efficient.

Categories
Horses

Pharmacologic Induction Of Estrus

It is clear that use of artificial lighting is the most successful and most widely employed method for jump-starting the breeding season. However, is there hope for a pharmacologic approach that does not require rewiring the farm? The short answer is that there is hope — but not necessarily promise.

Careful study of Table Physiologic Events of Vernal Transition in Chronologic Order reveals the problem to be surmounted in order for a mare to reinitiate estrous cyclicity. Luteinizing hormone (LH) secretion from the pituitary is, for all practical purposes, limiting throughout anestrus and vernal transition. These authors have shown that the gene for production of the LH subunits is not detectable in the pituitaries of anestrus mares. It is this reduction or outright lack of LH that appears to be responsible for the anovulatory vernal transition follicles. The reduction in pituitary LH appears to continue even after hypothalamic gonadotropin-releasing hormone (GnRH) secretion is renewed. That may explain the mixed results when GnRH is administered to mares in vernal transition in attempts to stimulate ovulation. Studies that employed this strategy several years ago were promising, but positive results likely reflected treatment given to mares further along in vernal transition. Similarly, studies using synthetic progestins to “stimulate” early onset of estrous cyclicity may have employed mares further along in vernal transition.

Dopamine Antagonist and Seasonality in Horses

In species such as sheep, evidence indicates that dopamine plays an inhibitory role on the hypothalamic-pituitary axis (HPA) during the nonbreeding season. Specifically, gonad-otropin secretion decreases during the nonbreeding season because of a neuronal inhibition of GnRH secretion via dopaminergic input. The inhibition of the HPA occurs only during anestrous and is estrogen-dependent.

Although a direct relationship between dopamine secretion and suppression of the equine HPA has not been demonstrated to date, dopamine concentrations in cerebrospinal fluid are highest in mares during anestrus. Thus recent interest in studying the effects of various dopamine antagonists on the equine hypothalamic-pituitary-gonadal axis and their subsequent effects on the timing of the breeding season in mares has been considerable.

The first dopamine antagonist to be tested was sulpiride at a dose of 0.5 mg/kg, orally every 12 hours. This dose caused a significant advance of the onset of the breeding season. Similarly, when domperidone (1.1 mg/kg once daily orally), another dopamine antagonist, was administered to horses during early vernal transition, it resulted in a significant advance of the onset of the breeding season over that in control mares. The primary difference between sulpiride and domperidone is that sulpiride crosses the blood-brain barrier, whereas domperidone does not.

The reported effect of dopamine antagonist on accelerating the onset of the breeding season in mares has been further evaluated to determine what effect, if any, the antagonist has on the hypothalamic-pituitary axis. Brendemuehl and Cross (2000) treated anestrous mares with domperidone beginning on January 15 and reported no effect on FSH, LH, nor estradiol secretion. However, Brendemuehl and Cross (see readings list) reported a significant advance in the onset of the breeding season in those mares treated with domperidone (51 days versus 130 days). Similarly, unpublished data from laboratory of the authors of this chapter reported that anestrous pony mares treated with sulpiride twice daily for 2 weeks during winter anestrus were not different from control mares with respect to LH and GnRH secretion. Therefore the data suggest that dopamine antagonist may accelerate the onset of the breeding season in vernal transition mares but not through activation of the hypothalamic-pituitary axis. Recent work by Daels and colleagues (2000) reported that treatment of anestrous mares with daily sulpiride plus extended photoperiod and ambient temperature resulted in an advance of the onset of the breeding season. However, when mares were treated with sulpiride alone and maintained under natural photoperiod and natural temperatures, no difference in date of the first ovulation of the year was found. It is important to note that no data on the fertility of the reported “early” ovulations exist.

Although the current evidence that suggests that dopamine antagonist may be helpful in manipulating the timing of the first ovulation of the year in mares is promising, variation in results may again suggest that treatment efficacy depends to some extent on the photic status of the mare. As in many experimental treatments, timing of treatment may be critical relative to photic exposure (anestrous versus vernal transition). These authors have proposed the idea of a “photic gate,” which means that some neural mechanism(s) require exposure to stimulatory photoperiods before pharmacologic initiation of estrous cyclicity can be accomplished.

Categories
Horses

Treatment of Cutaneous Lymphosarcoma

Glucocorticoids remain the mainstay of treatment of cutaneous T cell-rich, B cell lymphoma. Tumor regression is typically noted following the systemic administration of dexamethasone (0.02-0.2 mg/kg IV, IM or PO q24h) or prednisolone (1-2 mg/kg PO q24h). In these authors’ experience, dexamethasone proves more effective than prednisolone in treating lymphosarcoma. Once cutaneous lesions have regressed in size and number, the glucocorticosteroid dose can be gradually tapered. However, a rapid decrease or discontinuation of glucocorticosteroid administration may result in recurrence of cutaneous lesions. Relapses are anecdotally reported to be sometimes more refractory to treatment. Long-term maintenance therapy may be required in these cases. These authors prefer to use a dose of 0.04 mg/kg of dexamethasone (approximately 20 mg for an average-size horse) once daily until significant regression of tumors has occurred; the dose then is reduced to 0.02 mg/kg daily and then to every 48 hours. Intralesional injections of betamethasone or triamcinolone can also be performed with success; this may be impractical when presented with a large number of cutaneous lesions. Topical application of corticosteroid preparations may result in clinical improvement in cases with ulceration; however, results of its use have not been reported. In addition to im-munosuppression, laminitis is a potential side effect of corticosteroid administration.

Exogenous progestins may demonstrate an antiproliferative effect on lymphosarcoma tumors. The exact mechanism of action has not been determined; however, it is believed to be due to the presence of progesterone receptors, which have been demonstrated on both neoplastic and normal equine lymphoid tissues. Progestogens also have glucocorticoid-like activity, which may also account for the response observed in some cases of lymphosarcoma. In one study, progesterone receptors were identified on 67% of the subcutaneous lymphosarcoma tumors that were evaluated (primarily representing T cell-rich, B cell tumors). In the mare diagnosed with simultaneous cutaneous histiolymphocytic lymphosarcoma and a granulosatheca cell ovarian tumor, partial regression of the skin lesions occurred following a ten-day course of the synthetic progestin, altrenogest (0.044 mg/kg q24h PO). A temporary response was also observed after unilateral ovariectomy. The ovarian tumor stained positive for estradiol and led the authors to believe it was estrogen-secreting. The authors speculated that the steroid hormones secreted by the ovarian tumor may have influenced growth of the T cell-rich, B cell tumors by leading to low progesterone concentrations. Anecdotal reports of tumor regression during pregnancy also exist. In one mare with cutaneous T cell lymphosarcoma, regression of nodules was noted after surgical excision, a single intralesional injection of betamethasone (0.04 mg/kg), and an 8-day course of the oral progestogen, megestrol acetate (0.2 mg/kg q24h). Surgical excision may be efficacious in cases in which a single or a small number of cutaneous nodules exists.

The administration of autologous tumor cell vaccines may benefit horses with cutaneous lymphosarcoma. In one report, tumor regression was achieved by using a combination of low-dose cyclophosphamide and autologous tumor cells infected with vaccinia virus. Cyclophosphamide is thought to potentiate the immune response by decreasing suppressor T cell activity. Infection of tumor cells with the vaccinia virus was performed to augment the host antitumor immune response. The treatment protocol included intravenous administration of cyclophosphamide (300 mg/m2) via a jugular catheter over a period of 2 to 3 minutes on days 1 and 36. Immunization with tumor-cell vaccine was performed on days 4 and 21. Response to immunostimulation was confirmed by development of a delayed-type hypersensitivity response to autologous tumor cells injected intradermally in the horse. Potential side effects of cyclophosphamide administration in other species include immunosuppression, enterocolitis, myelosuppression, and hemorrhagic cystitis. No side effects were noted in the horse in this report.

Treatment of epitheliotropic (cutaneous T cell lymphosarcoma) in horses remains speculative because of a paucity of reported cases. Surgical excision of small lesions may be curative. Retinoids and vitamin A analogs inhibit malignant lymphocyte proliferation in human and canine patients with epitheliotropic lymphosarcoma. No reports of the use of retinoids in horses have been published. However, these authors noted no gross or histologic improvement in treating one case of equine epitheliotropic lymphosarcoma with retinoid cream. Side effects included local erythema and signs of irritation after repeated applications.

Investigations as to the effectiveness of radiation therapy and systemic chemotherapy in the management of equine cutaneous lymphosarcoma are needed. Local therapy that consists of intralesional injection of cutaneous nodules with cisplatin has been used successfully in horses with a small number of lesions. Combination chemotherapy that consists of cytosine arabinoside, chlorambucil or cyclophosphamide, prednisone, and vincristine has been reported for use in horses with multicentric lymphosarcoma, as has L-asparaginase.

Categories
Veterinary Drugs

Drugs Acting On The Reproductive System

  • Drugs used to promote gonadal function
  • Sex hormones
  • Prostaglandins
  • Myometrial stimulants
  • Myometrial relaxants
  • Prolactin antagonists
  • Non-hormonal abortificants
  • Drugs for uterine infections

Many drugs are used at different stages of the oestrous cycle to manage the response of the reproductive system; these are summarised in Table Drags affecting the reproductive system.

Table Drags affecting the reproductive system

Indications Species Drug
Synchronisation and regulation of the oestrous cycle and ovulation Horses Altrenogest, Buserelin, Cloprostenol, Dinoprost, Luprostiol
Cattle Buserelin, Cloprostenol, Dinoprost, Etiproston, Gonadorelin, Luprostiol, Progesterone (Eazi-Breed CIDR), Progesterone + estradiol benzoate (Prid)
Sheep, Goats Flugestone acetate, Medroxyprogesterone acetate
Pigs Altrenogest
Stimulation of the onset of cyclical ovarian activity Horses Altrenogest, Buserelin, Chorionic gonadotrophin, Cloprostenol, Deslorelin, Dinoprost, Luprostiol, Serum gonadotrophin
Cattle Buserelin, Chorionic gonadotrophin, Cloprostenol, Dinoprost, Etiproston, Gonadorelin, Luprostiol, Progesterone, Progesterone + estradiol benzoate (Prid), Serum gonadotrophin
Sheep, Goats Flugestone acetate, Medroxyprogesterone acetate, Melatonin, Serum gonadotrophin
Pigs Altrenogest, Chorionic gonadotrophin + serum gonadotrophin (PG600)
Dogs Chorionic gonadotrophin, Serum gonadotrophin
Rabbits Buserelin
Superovulation Cattle Chorionic gonadotrophin, Menotrophin, Serum gonadotrophin, Follicle stimulating hormone (porcine, ovine, recombinant)
Misalliance and pregnancy termination Horses Cloprostenol, Dinoprost, Luprostiol
Cattle Cloprostenol, Dinoprost, Etiproston, Luprostiol
Dogs Aglepristone, Cabergoline, Estradiol benzoate
Induction of parturition Horses Cloprostenol, Dinoprost, Luprostiol
Cattle Cloprostenol, Dexamethasone, Dinoprost, Etiproston, Luprostiol
Sheep Dexamethasone
Pigs Cloprostenol, Dinoprost, Luprostiol
Overt pseudopregnancy Horses (type 1 only) Cloprostenol, Dinoprost
Goats Cloprostenol, Dinoprost
Dogs Cabergoline, Methyltestosterone, Proligestone, Testosterone esters (Durateston)
Suppression of ovarian activity Dogs Medroxyprogesterone acetate, Megestrol acetate, Methyltestosterone, Proligesterone, Testosterone esters (Durateston)
Cats Megestrol acetate, Proligesterone

 

Drugs used to promote gonadal function

Gonadotrophins

Gonadotrophin-releasing hormones

Melatonin

Melatonin advances the time of onset of cyclical ovarian activity in the ewe and doe goat by mimicking the natural production of melatonin by the pineal gland. This gives improved reproductive performance in sheep flocks mated early in the season. A single dose of 18 mg, in a modified-release formulation, is implanted behind the ear. This is carried out 30 to 40 days before the introduction of the ram. It is important that ewes are kept completely separate from rams and also male goats for no less than 30 days after implantation.

In the UK, for Suffolk and Suffolk cross-breeds, the drug should be administered from mid-May to late June, for ram introduction in late June and July. For Mule and Half-bred flocks, melatonin should be administered from early June to late July, for ram introduction from mid-July to late August.

MELATONIN

Indications. Induction of ovulation

Contra-indications. Sexually immature animals

Warnings. Use of drug in ewes suckling lambs at foot may not give optimum results. The drug should not be used at times other than recommended, see notes above

Dose:

Sheep: by subcutaneous administration, 1 implant

PML Regulin (Ceva) UK Implant, m/r, melatonin 18 mg, for sheep

Withdrawal Periods.

Sheep: slaughter withdrawal period nil, milk withdrawal period nil

Sex hormones

Prostaglandins

Myometrial stimulants

Myometrial relaxants

Prolactin antagonists

Pregnancy in bitches is maintained by the presence of corpora lutea; if they regress, pregnancy will be terminated. The presence of corpora lutea is probably dependent upon the luteotrophic support of pituitary-derived prolactin during the second half of the luteal phase of metoestrus and pregnancy.

The prolactin inhibitor cabergoline exerts its effect by inhibiting prolactin release by direct stimulation of dopamine receptors in prolactin-releasing cells in the anterior pituitary. As a consequence, the corpora lutea regress. Towards the end of metoestrus, as the corpora lutea start to regress, there is a concomitant rise in prolactin which is responsible for the overt signs of pseudopregnancy such as behavioural signs and mammary development and lactation. Cabergoline reduces prolactin release and is used for the treatment of overt pseudopregnancy in the bitch. Bromocriptine is a potent dopamine receptor agonist (dopamine receptor stimulant), which inhibits prolactin release from the anterior pituitary gland. Bromocriptine commonly causes side-effects such as vomiting, anorexia, and behavioural changes, which may be severe. Metergoline is a serotonin agonist with actions similar to bromocriptine; it is used to suppress lactation.

CABERGOLINE

Indications. Pseudopregnancy; suppression of lactation; termination of pregnancy ; behavioural modification

Contra-indications. Pregnant animals unless pregnancy termination required; lactating animals unless suppression of lactation required; use directly after surgery while animal still recovering from anesthesia

Side-effects. Transient hypotension, occasionally vomiting or anorexia, transient drowsiness

Warnings. Drug Interactions.

Dose: Doe goats, to suppress lactation, by mouth, 5 micrograms/kg

Dogs: by mouth, 5 micrograms/kg once daily for 4-6 days.

May be mixed with food

Prescription-only medicine: Galastop (Ceva) UK

Oral solution, cabergoline 50 micrograms/mL, for dogs (3 drops = cabergoline 5 micrograms)

Non-hormonal abortificants

Lotrifen is a phenyltriazole isoquinoline which causes embryopathy and abortion in many species such as rats, hamsters, guinea pigs, and dogs. It is most effective in dogs when administered around 20 days of gestation and it is used in dogs for pregnancy termination. The mode of action is unclear: the drug may be embryotoxic, it may reduce blood supply to the gravid uterus, or modify the animal’s immune response.

Drugs for uterine infections

Bacteria will contaminate the uterus of most individuals after normal parturition. However these micro-organisms will soon be eliminated by natural defence mechanisms. The bacteria may originate from the environment and are opportunist pathogens or may be specific venereal pathogens; failure to eliminate them due to impaired defence mechanisms will result in infection. In addition, trauma associated with dystocia and heavy bacterial contamination are also likely to predispose to infection. Uterine infection may be acute, frequently involving all layers of the uterine wall (metritis) or chronic, usually involving the endometrium (endometritis). The former may be fatal. Treatment of metritis includes the use of systemic antimicrobials such as potentiated sulphonamides, oxytetracycline, or semisynthetic penicillins, NSAIDs, and supportive therapy. Chronic infection involving the endometrium can be treated by the intra-uterine infusion of broad-spectrum antimicrobials, administered at the usual therapeutic dosage. In the cow, if a corpus luteum is present, endometritis is best treated by administration of prostaglandin F2alpha or an analogue. In bitches, cystic endometrial hyperplasia and pyometra most commonly occur in the luteal phase of the oestrous cycle (metoestrus). In animals with ‘open’ pyometra with dilated cervix and vaginal discharge, dinoprost is administered at a dose of 250 micrograms/kg for at least 5 days. It is contra-indicated in bitches with very enlarged uteri, animals with heart conditions, and patients with ‘closed’ pyometra. Side-effects occur within 15 minutes of administration and include panting, salivation, vomiting, and whimpering. These symptoms are transient and cease within one hour.

In the UK, the Horserace Betting Levy Board publishes Codes of Practice on contagious equine metritis (CEM) Klebsiella pneumoniae, Pseudomonas aeruginosa; equine viral arteritis (EVA); and equid herpesvirus-1 (EHV-1), which include recommendations for disease prevention and control in breeding horses.

Prescription-only medicine: Metricure (Intervet) UK

Intra-uterine suspension, cephapirin (as cephapirin benzathine) 500 mg, for cattle; dose applicator

Withdrawal Periods.

Cattle: slaughter 2 days, milk withdrawal period nil

Dose:

Cattle: by intra-uterine administration, contents of one applicator. May be repeated after 7-14 days

Prescription-only medicine: Utocyl (Novartis) UK

Pessaries, benzylpenicillin 62.7 mg, formosulphathiazole 1.75 g, streptomycin (as sulfate) 50 mg, for cattle

Withdrawal Periods.

Cattle: slaughter 2 days, milk withdrawal period nil

Dose:

Cattle: by intra-uterine administration, 6 pessaries for prophylaxis only

Categories
Veterinary Drugs

Sex hormones

Oestrogens

Oestrogens are responsible physiologically for initiating behavioural signs of oestrus, preparing the female reproductive tract for fertilisation and developing the secretory tissue of the mammary gland. They also have anabolic activity.

Oestrogens are used in the treatment of misalliance in the bitch. They act by inhibiting the transport of the fertilised ova down the oviducts, in addition to causing hypertrophy of the uterine mucosa. Urinary incontinence in the spayed bitch may also be controlled with oestrogens.

In males, oestrogens are used in the treatment of excess libido, anal adenoma, and, with caution, for prostate hyperplasia.

The use of stilbenes, such as diethylstilbestrol (with the following exception), is prohibited in food-producing animals because they have been found to be carcinogenic in humans under some circumstances. Administration is allowed, if prior steps are taken to ensure that the treated animal and its products are not available for human or animal consumption. This exemption allows the administration of authorised-human products to farm animals for research purposes and also to companion and laboratory animals. Oestrogens may cause aplastic anaemia in dogs and cats and cystic endometrial hyperplasia in bitches. Overdosage can cause severe inhibition of pituitary function and cystic ovaries, particularly in cattle and pigs; repeated administration to treat misalliancee can cause coagulopathy in bitches.

DIETHYLSTILBESTROL

(Stilboestrol)

Indications. See under Dose; urinary incontinence; behavioural modification

Contra-indications. See notes above

Warnings. Overdosage may cause severe inhibition of pituitary function, anaemia and thrombocytopenia, squamous metaplasia of the prostate, cystic endometrial hyperplasia

Dose:

Dogs: prostatic hyperplasia, anal adenoma, by mouth, up to 1 mg daily, reducing to maintenance dose

Prescription-only medicine: © Diethylstilbestrol (Non-proprietary) UK

Tablets, diethylstilbestrol 1 mg, 5 mg

ESTRADIOL

(Oestradiol)

Indications. See Dose under preparation details; urinary incontinence

Contra-indications. Cats

Warnings. Oestrogens, particularly if used repeatedly, may cause aplastic anaemia, coagulopathies, increased risk of cystic endometrial hyperplasia, and pyometra in bitches; owners should be warned that pregnancy may not be terminated in 5% of treated bitches

Dose:

Dogs: misalliance, by subcutaneous or intramuscular injection, 10 micrograms/kg administered on day 3, day 5, and (if required) day 7 after mating

Prescription-only medicine: Mesalin (Intervet) UK

Injection (oily), estradiol benzoate 200 micrograms/mL, for dogs

ETHINYLESTRADIOL

(Ethinyloestradiol)

Indications. See notes above and under Dose

Side-effects. Feminisation

Warnings. Overdosage may cause severe inhibition of pituitary function, anaemia and thrombocytopenia, squamous metaplasia of the prostate, cystic endometrial hyperplasia

Dose: By mouth.

Dogs. Males: prostatic hyperplasia, anal adenoma, 50-100 micrograms daily. If feminisation occurs, cease treatment. Recommence therapy at half original dose

Prescription-only medicine: @ Ethinylestradiol (Non-proprietary) UK

Tablets, ethinylestradiol 10 micrograms, 50 micrograms, 1 mg

Progestogens

Antiprogestogens

Antiprogestogens are used to terminate pregnancy in bitches. They act in a number of different ways. Dopamine receptor agonists, such as bromocriptine and cabergoline exert their effect by reducing prolactin levels, and hence progesterone secretion by the corpora lutea. Some enzyme inhibitors such as epostane prevent the conversion of pregnenolone to progesterone. Both these groups reduce plasma-progesterone concentration, which is necessary for the maintenance of pregnancy. Aglepristone is a progesterone receptor antagonist, which blocks the effect of progesterone on the target tissues; progesterone concentrations in the peripheral circulation are not affected. Aglepristone is used to terminate pregnancy in bitches up to 45 days after mating. Termination of pregnancy should be confirmed by examination of animals 10 days after treatment and at least 30 days after mating. A partial abortion may occur in some bitches with retention of one or more puppies, which may become macerated. In animals treated after day 20 of gestation, abortion is accompagnied by physiological signs of parturition such as fetal expulsion, slight anorexia, and mammary congestion. An early return to oestrus is seen in animals treated with aglepristone with the oestrus to oestrus interval being shortened by one to three months.

AGLEPRISTONE

Indications. Pregnancy termination in bitches

Contra-indications. Hypersensitivity to aglepristone

Side-effects. Transient pain at injection site

Warnings. Owners should be warned that partial abortion may occur in 5% of bitches; early return to oestrus after treatment; physiological signs of parturition seen in bitches treated after day 20 of gestation; may cause abortion in humans and women should take care to avoid accidental self-injection

Dose:

Dogs: by subcutaneous injection, 10 mg/kg. Repeat after 24 hours

Prescription-only medicine: Alizin (Virbac) UK

Injection, (oily), aglepristone 30 mg/mL, for dogs

Accidental self-injection with oil-based injections can cause severe pain and intense swelling, which may result in ischaemic necrosis and loss of a digit. Prompt medical attention is essential. A copy of the warning given in the package leaflet or data sheet should be shown to the doctor (or nurse) on duty.

Androgens

Compound hormonal preparations

A combination of hormones is used to induce a preseasonal ovulation, synchronise oestrus in a group of animals, or enable prediction of the time of oestrus. Some compound preparations are also used in the treatment of ovarian cysts or for the control of clinical signs of pseudopregnancy. Their use is unlikely to produce satisfactory results in animals in deep anoestrus, immature animals, animals with genital-tract abnormalities, or when breeding problems have resulted from severe nutritional deficiency or other stresses.

Prescription-only medicine: PG 600 (Intervet) UK

Injection, powder for reconstitution, chorionic gonadotrophin 200 units, serum gonadotrophin 400 units, for pigs more than 5 months of age

Withdrawal Periods.

Pigs: slaughter withdrawal period nil

Contra-indications. Injection into subcutaneous fat

Side-effects. Anaphylactic reactions

Dose: Sows, gilts: anoestrus, suboestrus, by intramuscular injection, 5 mL of reconstituted solution

Sows, post weaning: to promote early postpartum oestrus, by intramuscular injection, 5 mL of reconstituted solution within 2 days of weaning Note. Gilts more than 5 months of age, a single dose normally results in fertile oestrus within 5 days

Prescription-only medicine: Prid (Ceva) UK

Intravaginal device, progesterone 1.55 g, estradiol benzoate 10 mg, for cows, mature heifers

Withdrawal Periods.

Cattle: milk withdrawal period nil

Note. For 24 hours after insertion, animals must not be sent for slaughter and at all times the intravaginal device should be removed at least 6 hours before slaughter

Contra-indications. Immature heifers; cows calved less than 30 days except when using at 21 days onwards for late calving herds where, in healthy cows, early service is required; pregnant cattle; genital tract infections

Dose:

Cattle: anoestrus, suboestrus, synchronisation of oestrus, by intravaginal administration, 1 device. Remove after 12 days, and follow by insemination either 2 times, at 48 hours and 72 hours, or once at 56 hours, after removal. May be used in conjunction with serum gonadotrophin and prostaglandin For analogues

Categories
Complementary Medicine

Alopecia

Definition and cause

Alopecia is one of the most common conditions seen by veterinarians. It is often a result of multiple underlying causes with the secondary ramification of loss of hair. The broad categories of alopecia are (1) genetic predisposition, and (2) acquired, such as inflammatory, infectious (bacterial, fungal), immune-mediated, hormonal imbalances, parasitic, and secondary to other diseases such as hypothyroidism, Cushing’s, etc..

Medical therapy rationale, drug(s) of choice, and nutritional recommendations

Therapy for alopecia relies upon the proper and accurate diagnosis, because the underlying cause dictates the course of therapy. Please refer to other sections in this book for underlying causes and their appropriate therapies.

Anticipated prognosis

Because alopecia is most often secondary to multiple underlying causes, the prognosis varies with the primary cause.

Integrative veterinary therapies

An integrative approach to alopecia starts with a determination of the underlying cause. If the cause can be identified and addressed, the alopecia usually resolves.

The use of nutrients, nutraceuticals, medicinal herbs, and combination homeopathics that help balance gland function, reduce inflammation, and prevent cellular degeneration should be part of the therapeutic approach to alopecia.

Nutrition

General considerations / rationale

When searching for the underlying cause and proper diagnosis, a medical and physiological blood evaluation should be included as part of the clinician’s diagnostic protocol. This nutrition-based information gives clinicians the ability to formulate therapeutic nutritional protocols that address the local lesions as well as underlying organ conditions that may be ultimately responsible for the surface condition. For example, identifying early thyroid and pituitary weakness and supporting their function with appropriate nutrients, antioxidants, and gland support can help re-establish a normal coat. (See site, Nutritional Blood Testing for more information.)

Appropriate nutrients

Nutritional / gland therapy: Glandular hypothalamus, pituitary, and lymph provide intrinsic nutrients that nourish and help neutralize cellular immune inflammation and help improve organ function (see Gland Therapy, site, for a more detailed explanation).

Zinc: Zinc is a mineral that particularly benefits metabolism and skin health. Zinc-responsive dermatosis is a common deficiency disease in animals; it is found often in huskies, malamutes, and large-breed puppies.

Essential fatty acids: Research has been conducted on the importance of essential fatty acids in the daily diet, and on the clinical management of various degenerative diseases. The importance of the ratio between omega-6 and omega-3 fatty acids has been substantiated. Research on polyun-saturated fatty acids has shown their beneficial and antipruritic affects on skin.

Chinese herbal medicine

General considerations / rationale

According to traditional Chinese medicine theory, alopecia is a result of Yin and Blood deficiency in the Liver and Kidney, accompanied by blockage of the meridians. The Liver and Kidney control the Blood. The fur is the end of the Blood, according to traditional Chinese medicine (traditional Chinese medicine). Without Blood and fluids (Yin), there is no fluid to nourish the skin. Similarly, if the meridians are blocked, nourishment cannot get to the skin to allow the fur to grow. Without nourishment, the follicles become inactive.

The etiology of the Yin and Blood deficiency must be corrected to heal the patient. In Western practice this means that not only is the hair loss treated, but the cause of the alopecia must also be addressed. To modern practitioners, this means any immune dysfunction, pathogen infection, or hormonal imbalance must be corrected.

Appropriate Chinese herbs

Actractylodes (Cang zhu): Has antiinflammatory effects. Experimentally, it has been shown to ameliorate swelling caused by treatment with xylene, carrageenin, and acetic acid. It also inhibits Staphylococcus aureus and some dermatophytes.

Angelica (Bai zhi): Has demonstrated antiinflammatory properties in mice, which suggests efficacy in any inflammatory type of alopecia.

Angelica root (Dang gui): Was used in 40 patients with alopecia areata, an immune-mediated skin disease in which the follicles are attacked, leading to baldness or hair loss on the entire body. In this trial, all 40 patients had improvement in their symptoms.

Buffalo horn shavings (Shui niu jiao): Has antiinflammatory effects. It has been shown to decrease experimentally induced edema in the ears and feet of mice. It may help promote cellular immunity. It increases the leukocyte count, which may help in cases of infectious alopecia.

Bupleurum (Chai hu): Stimulates both humoral and cellular immunity in mice, which may help in cases of alopecia of infectious etiology. In addition it has been shown to inhibit various bacteria. Bupleurum has antiinflammatory effects, as was demonstrated in a mouse model using dimethyl-benzene-induced ear swelling.

Cnidium (Chuan xiong): Stimulates the cellular immunity. It increases phagocytic function of macrophages. It also stimulates the humoral immune system. It can also promote the formation of sheep red blood cells (SRBC) antibody in mice.

Dandelion (Pu gong ying): Has demonstrated antibacterial efficacy against many bacteria, including Staph aureus and beta-hemolytic streptococci.

Earthworm (Di long): Has immunostimulant properties. It improves macrophage function. It also promotes wound healing. Earthworm was shown to enhance the production of fibroblasts and capillaries in experimentally induced wounds in rabbits. It also increased the healing rate of the skin.

Fleece flower root (He shou wu): Increases thyroid hormone secretion. This may be beneficial in cases of hypothyroid-induced alopecia. Furthermore, it has been shown to inhibit a variety of bacteria including Staphylococcus aureus. It may prove efficacious in cases of bacterial pyoderma.

Honeysuckle (Jin yin hua): Has demonstrated antibacterial properties. This is due in large part to the action of chlorogenic acid and isochlorogenic acid. Among the bacteria these compounds inhibit are Staphylococcus aureus, beta-hemolytic streptococci, and E coli.

Kochia (Di fu pi): Has been shown to inhibit some dermatophytes.

Licorice (Gan cao): Has demonstrated a complex effect on the immune system. It has shown the ability to both stimulate and inhibit the phagocytic activity of macrophages. It also contains glycyrrhizin and glycyrrhetinic acid, which have approximately 10% of the corticosteroid activity of cortisone and decrease the permeability of blood vessels and interfere with histamine action. These actions suggest that licorice may be useful in allergic, immune-mediated, and infectious alopecia. In addition it has antibiotic effects on different bacteria including Staphylococcus aureus.

Mint (Bo he): Has demonstrated antiinflammatory properties. This may make it useful in inflammation-mediated alopecic condition.

Mouton (Mu dan pi): Reduces inflammation. In mice it was shown to decrease dimethylbenzene-induced inflammation in the ear. It also may treat bacterial dermatitis. It has a direct inhibitory effect on multiple strains of bacteria including Staphylococcus aureus and beta-hemolytic streptococci. It has been shown to enhance phagocytosis of peripheral neutrophils on Staphylococcus aureus.

Platycodon (Jie geng): Prevents allergic reactions and decreases capillary permeability. It has been shown to promote the secretion of corticosterone in rats, which suggests that it is indicated in cases of allergic pyoderma.

Poria (Fu ling): Inhibits Staphylococcus aureus, among other bacteria (Nanjing College of Pharmacy).

Rehmannia (Sheng di huang): Increases the level of estradiol in females and testosterone in male rats. This may be applicable in cases of hormone-responsive alopecia. It also has antiinflammatory properties. It reduces swelling and inflammation.

Schizonepeta (Jing jie): Decreases the signs in cases of pruritic rashes and itching.

Scutellaria (Huang qin): Contains biacalin, which has antibiotic activity against Stapylococcus aureus, b-hemolytic streptococcus, as well as other bacteria and some dermatophytes. Biacilin can have synergistic effects with ampicillin, amoxicillin, methacillin, and cefotaxime. It can help overcome B lactam resistance. Biacalein has an added benefit of suppressing inflammation. It has been shown experimentally to decrease swelling induced by dimethyl-benzene and formaldehyde. While decreasing inflammation, it also enhances cellular immunity. It enhances production of IL2, which stimulates the cellular immune system.

Siegesbeckia (Xi xian cao): Possesses antiinflammatory properties. It has been shown to decrease swelling in rats. It decreases both humoral and cellular immunity in mice, which suggests that it may be of use in immune-mediated cases of alopecia. Furthermore, it has antibiotic actions and may be of benefit in bacterial etiologies.

Siler (Fang feng): Has been shown to inhibit various bacteria, including Staphylococcus aureus.

Silkworm (Jiang can): Has antibiotic effects. It has been shown to affect Stapylococcus aureus and other bacteria.

White peony (Bai shao): Has antibiotic properties against a variety of bacterian including both Staphylococcus aureus and beta-hemolytic streptococci. It also inhibits some dermatophytes. It contains Paeoniflorin, which is a strong antiinflammatory. These capabilities may make it useful for bacterial, fungal, allergic, and immune-mediated alopecia.

Xanthium (Cang er zi): Decreases histamine-mediated increases in capillary permeability. This indicates that it may be of use in allergy-mediated alopecic conditions.

Homotoxicology

General considerations / rationale

Alopecia can occur as a consequence of Inflammation, Deposition, Impregnation, Degeneration, or Dedifferen-tiation phase disorders. Proper diagnosis is needed to select therapy. In Inflammation Phase disorders, simply treating the primary cause usually results in regrowth of hair. In deeper homotoxicoses, hair growth may be delayed or may not occur.

Appropriate homotoxicology formulas

(Also see other protocols such as Cushing’s, hypothyroidism, pancreatic insufficiency, etc).

Cutis compositum: Stimulates healing and detoxification of the skin.

Aesculus homaccord: Supports vascular repair.

BHI-Hair and -Skin: Used for alopecia, dandruff, acne, poor toenails, dry hair coat, postvaccinal hair loss, and hair loss after severely debilitating disease.

BHI-Skin: Treats eczema, rashes and redness, blisters, and cold sores.

Cerebrum compositum: Supports cerebral tissues.

Coenzytne compositum: Provides metabolic support.

Galium-Heel: Used for cellular and matrix drainage and detoxification, and after vaccination reactions.

Hepar compositum: Supports hepatic tissue.

Lymphomyosot: Provides lymph drainage and support.

Ovarium compositum: Treats endocrine alopecia in females.

Placenta compositum: Used to improve vascularization of extremities.

Psorinoheel: Phase remedy in Excretion and Impregnation phase disorders, intense pruritus of elbows and legs, warts, and excretion of malodorous material.

Pulsatilla compositum: Used for type two regulation rigidity.

Selenium homaccord: Used in conjunction with Psorinoheel.

Solidago compositum: Provides support of renal tissues.

Sulfur Heel: Provides general support of mesenchymal structures.

Testis compositum: Supports endocrine alopecias in males.

Thuja homaccord: Used in post vaccinal alopecia.

Thyroidea compositum: Provides endocrine support and deep detoxification and matrix drainage.

Tonsilla compositum: Supports endocrine and central controls.

Traumeel S: Used for type one regulation rigidity and after inflammatory skin issues such as allergies or vaccination reactions.

Ubichinon compositum: Provides metabolic support.

Ypsiloheel: Used for central regulation.

Authors’ suggested protocols

Nutrition

Pituitary / hypothalamus / pineal and skin support formula: 1 tablet for every 25 pounds of body weight BID. When indicated, lymph and thyroid support formulas may be added.

Zinc: 15 mg for every 25 pounds of body weight SID.

Eskimo fish oil: One-half to 1 teaspoon per meal for cats. 1 teaspoon for every 35 pounds of body weight for dogs.

Omega-3,-6,-9: 1 capsule for every 25 pounds of body weight with food.

Chinese herbal medicine

The authors recommend a full diagnostic work-up to determine the cause of alopecia because it is a symptom, not a diagnosis. For most causes of alopecia the authors recommend a combination of DermGuard and Immuno-Derm at a dose of 1 capsule of each herbal supplement per 10 to 20 pounds twice daily.

DermGuard contains angelica (Bai zhi), angelica root (Dang gui), aurantium fruit (Zhi qiao), bupleurum (Chai hu), cicada (Chan tui), cnidium (Chuan xiong), honeysuckle (Jin yin hua), licorice (Gan cao), mint (Bo he), moutan (Mu dan pi), platycodon (Jie geng), poria (Fu ling), schizonepeta (Jing jie), scutellaria (Huang qin), siegesbeckia (Xi xian cao), siler (Fang feng), silkworm (Jiang can), and xanthium fruit (Cang er zi).

ImmunoDerm contains atractylodes (Cang zhu), angelica root (Dang gui), buffalo horn shavings (Shui niu jiao), bupleurum (Chai hu), dandelion (Pu gong ying), earthworm (Di long), fleece flower root (He shou wu), honeysuckle (Jin yin hua), kochia (Di fu zi), licorice (Gan cao), moutan (Mu dan pi), oldenlandia (Bai hua she cao), poria (Fu ling), rehmannia — raw (Sheng di huang), scutellaria (Huang qin), siegesbeckia (Xi xian cao), tokoro (Bi xie), white peony (Bai shao), and xanthium fruit (Cang er zi).

Homotoxicology (Dose: 10 drops PO for 50-pound dog; 5 drops PO small dog or cat)

Symptom formula: Psorinoheel, Selenium homaccord, Galium-Heel, BHI-Hair and Skin, and Sulfur-Heel mixed together and given BID PO. In acute cases, Traumeel or BHI-Hair and Skin as single agents may suffice.

Deep detoxification formula: Thyroidea compositum, Solidago compositum, and Hepar compositum given every three days. Cutis compositum given every seven days.

Product sources

Nutrition

Pituitary / hypothalamus / pineal, skin, lymph and thyroid support formulas: Animal Nutrition Technologies. Alternatives: Derma Strength — Vetri Science Laboratories; Canine Dermal and Thyroid Support — Standard Process Veterinary Formulas.

Omega-3,-6,-9: Vetri Science. Alternatives: Eskimo fish oil — Tyler Encapsulations; flax oil — Barlean’s Organic Oils; hemp oil — Nature’s Perfect Oil; Ultra EFA — Rx Vitamins for Pets.

Chinese herbal medicine

Derm Guard and ImmunoDerm: Natural Solutions, Inc.

Homotoxicology

BHI / Heel Corporation