Categories
Drugs

Altrenogest (Regu-Mate, Matrix)

Oral Progestin

Highlights Of Prescribing Information

Progestational drug used in horses to suppress estrus or maintain pregnancy when progestin deficient; used in swine to synchronize estrus

May be used in dogs for luteal deficiency or as a treatment to prevent premature delivery

Many “handling” warnings for humans (see below)

Very sensitive to light

What Is Altrenogest Used For?

Altrenogest (Regu-Mate) is indicated (labeled) to suppress estrus in mares to allow a more predictable occurrence of estrus following withdrawal of the drug. It is used clinically to assist mares to establish normal cycles during the transitional period from anestrus to the normal breeding season often in conjunction with an artificial photoperiod. It is more effective in assisting in pregnancy attainment later in the transition period. Some authors () suggest selecting mares with considerable follicular activity (mares with one or more follicles 20 mm or greater in size) for treatment during the transitional phase. Mares that have been in estrus for 10 days or more and have active ovaries are also considered excellent candidates for progestin treatment.

Altrenogest is effective in normally cycling mares for minimizing the necessity for estrus detection, for the synchronization of estrus, and permitting scheduled breeding. Estrus will ensue 2-5 days after treatment is completed and most mares ovulate between 8-15 days after withdrawal. Altrenogest is also effective in suppressing estrus expression in show mares or mares to be raced. Although the drug is labeled as contraindicated during pregnancy, it has been demonstrated to maintain pregnancy in oophorectomized mares and may be of benefit in mares that abort due to sub-therapeutic progestin levels.

The product Matrix is labeled for synchronization of estrus in sexually mature gilts that have had at least one estrous cycle. Treatment with altrenogest results in estrus (standing heat) 4-9 days after completion of the 14-day treatment period.

Altrenogest has been used in dogs for luteal insufficiency and as a treatment to prevent premature delivery.

Pharmacology/Actions

Progestins are primarily produced endogenously by the corpus luteum. They transform proliferative endometrium to secretory endometrium, enhance myometrium hypertrophy and inhibit spontaneous uterine contraction. Progestins have a dose-dependent inhibitory effect on the secretion of pituitary gonadotropins and have some degree of estrogenic, anabolic and androgenic activity.

Pharmacokinetics

In horses, the pharmacokinetics of altrenogest have been studied (). After oral dosing of 44 mg/kg PO, peak levels usually occur within 15-30 minutes post-dose; 24 hours post-dose, levels were below the level of quantification. Elimination half-lives are approximately 2.5-4 hours. Altrenogest appears to be primarily eliminated in the urine. Peak urine levels occur 3-6 hours after oral dosing. Urine levels were detectable up to 12 days post-administration.

Before you take Altrenogest

Contraindications / Precautions / Warnings

The manufacturer (Regu-Mate — Intervet) lists pregnancy as a contraindication to the use of altrenogest, however it has been used clinically to maintain pregnancy in certain mares (see Dosages below). Altrenogest should also not be used in horses intended for food purposes.

Adverse Effects

Adverse effects of altrenogest appear to be minimal when used at labeled dosages. One study () found negligible changes in hematologic and most “standard” laboratory tests after administering altrenogest to 4 groups of horses (3 dosages, 1 control) over 86 days. Occasionally, slight changes in Ca++, K+, alkaline phosphatase and AST were noted in the treatment group, but values were only slightly elevated and only noted sporadically. No pattern or definite changes could be attributed to altrenogest. No outward adverse effects were noted in the treatment group during the trial.

Use of progestational agents in mares with chronic uterine infections should be avoided as the infection process maybe enhanced.

Overdosage / Acute Toxicity

The LD50 of altrenogest is 175-177 mg/kg in rats. No information was located regarding the effects of an accidental acute overdose in horses or other species.

How to use Altrenogest

Altrenogest dosage for dogs:

For luteal insufficiency:

a) Document luteal insufficiency and rule out infectious causes of pregnancy loss. Best to avoid during first trimester. Give equine product (Regumate) at 2 mL per 100 lbs of body weight PO once daily. Monitor pregnancy with ultrasound. Remember that exogenous progesterone is the experimental model for pyometra in the bitch, so monitor carefully. ()

b) For luteal insufficiency, pre-term labor: 0.1 mL per 10 lb body weight PO once daily. ()

c) To maintain pregnancy if tocolytics (e.g., terbutaline) do not control myometrial contractility: 0.088 mg/kg once daily (q24h). Must be withdrawn 2-3 days prior to predicted whelp date. ()

Altrenogest dosage for horses:

To suppress estrus for synchronization:

a) Administer 1 mL per 110 pounds body weight (0.044 mg/ kg) PO once daily for 15 consecutive days. May administer directly on tongue using a dose syringe or on the usual grain ration. (Package insert; Regu-Mate — Intervet)

b) 0.044 mg/kg PO for 8-12 days ()

To maintain pregnancy in mares with deficient progesterone levels:

a) 22-44 mg daily PO ()

b) 0.044 mg/kg PO once daily. Three options for treatment: 1) treatment until day 60 of pregnancy or greater AND measurement of endogenous progesterone level of >4 ng/mL; 2) treatment until day 120 of pregnancy; or 3) treatment until end of pregnancy. ()

To maintain pregnancy in mares with placentitis: a) 10-20 mL (22-44 mg) daily PO () To suppress estrus (long-term): a) 0.044 mg/kg PO daily ()

Altrenogest dosage for swine:

For synchronization of estrous in sexually mature gilts that have had at least one estrous cycle:

a) Follow label directions for safe use. Administer 6.8 mL (15 mg) per gilt for 14 consecutive days. Apply as a top-dressing on a portion of gilt’s daily feed allowance. Estrous should occur 4-9 days after completing treatment. (Package insert; Matrix — Intervet)

Client Information

■ The manufacturer (Regu-Mate, Matrix — Intervet) lists the following people as those who should not handle the product:

1. Women who are or suspect that they are pregnant

2. Anyone with thrombophlebitis or thromboembolic disorders or with a history of these events

3. Anyone having cerebrovascular or coronary artery disease

4. Women with known or suspected carcinoma of the breast

5. People with known or suspected estrogen-dependent neoplasias

6. Women with undiagnosed vaginal bleeding

7. People with benign or malignant tumor that developed during the use of oral contraceptives or other estrogen containing products

■ Altrenogest can be absorbed after skin contact and absorption can be enhanced if the drug is covered by occlusive materials (e.g., under latex gloves, etc.). If exposed to the skin, wash off immediately with soap and water. If the eyes are exposed, flush with water for 15 minutes and get medical attention. If the product is swallowed, do not induce vomiting and contact a physician or poison control center.

■ This medication is prohibited from use in an extra-label manner to enhance food and/or fiber production in animals

Chemistry / Synonyms

An orally administered synthetic progestational agent, altrenogest has a chemical name of 17 alpha-Allyl- 17beta-hydroxyestra-4,9,11-trien-3-one.

Altrenogest may also be known as: allyl trenbolone, A-35957, A-41300, RH-2267, or RU-2267, Regu-Mate, or Matrix.

Storage / Stability

Altrenogest oral solution should be stored at room temperature. Altrenogest is extremely sensitive to light; dispense in light-resistant containers.

Dosage Forms / Regulatory Status

Veterinary-Labeled Products:

Altrenogest 0.22% (2.2 mg/mL) in oil solution in 150 mL and 1000 mL bottles; Regu-Mate (Intervet); (Rx). Approved for use in horses not intended for food. This medication is banned in racing animals in some countries.

Altrenogest 0.22% (2.2 mg/mL) in 1000 mL bottles; Matrix (Intervet); (OTC, but extra-label use prohibited). Approved for use in sexually mature gilts that have had at least one estrous cycle. Gilts must not be slaughtered for human consumption for 21 days after the last treatment. The FDA prohibits the extra-label use of this medication to enhance food and/or fiber production in animals.

Human-Labeled Products: None

Categories
Horses

Stallion Behavior Problems

This post briefly outlines several of the most common behavior problems of breeding stallions. These problems include self-mutilation, inadequate libido, rowdy breeding behavior, specific erection dysfunction, mounting and thrusting difficulties, frenzied hyperactive behavior, and specific ejaculation dysfunction. Also briefly outlined is the common problem of residual stallionlike behavior in geldings.

Inadequate Libido

Specific stallion libido problems include slow starting novices, slow or sour experienced stallions, and specific aversions or preferences. Although certain genetic lines tend to be shy or quiet breeders, the majority of inadequate libido in stallions is man-made in the sense that it is the result of domestic rearing, training, or breeding conditions. Stallions that have been disciplined for showing sexual interest in mares during their performance career, discouraged from showing spontaneous erection and masturbation, or mishandled during breeding under halter are at risk of libido problems. When exposed to a mare for teasing, stallions such as these may simply stand quietly, may appear anxious and confused, or may savage the mare.

Most stallions with such experience-related libido problems respond well to behavior therapy alone or in combination with anxiolytic medication. These stallions typically respond best to continued exposure to mares, initially with minimal human presence, and then with gradual introduction of quiet, respectful, patient, positive reinforcement-based handling. These stallions appear to respond favorably to reassurance for even small increments of improvement. Tolerance of minor misbehavior rather than punishment is often the most effective strategy with low-libido stallions. The anxiolytic diazepam (0.05 mg/kg through slow IV 5-7 min before breeding) is useful in about half of such cases as an adjunct to behavior modification.

Some libido problems are hormone-related, with androgens on the low side of the normal range. These stallions will likely improve with management aimed at increasing exposure to mares and reduced exposure to other stallions. This will typically increase androgen levels, general confidence, as well as sexual interest and arousal. Gonadotropin-releasing hormone (GnRH; 50 μg SQ 2 hr and again 1 hr before breeding) can be useful to boost libido in stallions, particularly in those with low normal levels. In rare cases when more rapid improvement is required to rescue a breeding career, treatment with testosterone can effectively jump-start a slow novice without apparent significant adverse effects on spermatogenesis. Current recommendations are 0.1 to 0.2 mg/kg aqueous testosterone SQ every other day for as long as 2 weeks, with frequent assay of circulating testosterone not to exceed 4 ng/ml.

Specific Erection Dysfunction

Libido-independent erection dysfunction is rare in stallions. The majority of erection dysfunction that does occur is related to traumatic damage of the corpora cavernosa that results in insufficient or asymmetric tumescence (lateral or ventral deviations) that impairs insertion. In some instances, penile injury appears to impair sensory and or proprioceptive feedback from the penis, delaying ejaculation, coupling, or organized thrusting. Common causes include stallion ring injuries, drug-related paralyzed penis and paraphimosis, kick injuries, and self-serve breeding dummy accidents.

An interesting and often confusing type of erection dysfunction involves the folding back of the penis within the prepuce. The behavioral hallmark of this situation is a stallion that appears aroused and ready to mount, without a visible erection. The stallion may also appear uncomfortable or intermittently distracted, pinning the ears, kicking toward the groin, and/or stepping gingerly on the hind legs. Close observation reveals a rounded, full-appearing prepuce, with the skin stretched taut. Resolution usually requires removal of the stallion from the mare until the penis detumesces. Once the penis is fully withdrawn, application of a lubricating ointment to the prepuce facilitates subsequent normal protrusion. This situation tends to repeat occasionally over time, particularly in stallions with profuse smegma production or with dryness of the penis and sheath from frequent cleansing.

Mounting And Thrusting Difficulties

A significant percentage of breeding dysfunction appears to involve neurologic or musculoskeletal problems that affect the stallion’s ability to mount and thrust. Many such stallions can continue breeding with therapy aimed to reduce discomfort and accommodate disabilities during breeding, including adjustments to the breeding schedule aimed at reducing the total amount of work. This author has found that long-term treatment with oral phenylbutazone (2-3 mg/kg orally twice daily) often works well to keep such stallions comfortable for breeding. Certain debilitated stallions can benefit from semen collection while standing on the ground.

Specific Ejaculation Dysfunction

Although any libido, erection, or mounting and thrusting problem can result in failure to ejaculate, stallions also exist in which the dysfunction seems to be specific to ejaculation. Specific ejaculation problems can include apparent

failure of the neural ejaculatory apparatus, physical or psychologic pain associated with ejaculation, and genital tract pathology. Goals of therapy are to address as many contributing conditions as possible, as well as to optimize handling and breeding conditions and maximize musculoskeletal fitness and libido to enhance the stallion’s ability to overcome ejaculatory difficulty. Imipramine hydrochloride (0.5-1.0 mg/kg orally 2 hr before breeding) can effectively reduce the ejaculatory threshold.

Rowdy Breeding Behavior

Rowdy, misbehaved breeding stallions in most cases represent a human-animal interaction problem. Most problems can be overcome with judicious, skillful, respectful re-training. Even strong, vigorous, and misbehaved stallions can be brought under control by using consistent positive and negative reinforcement, with very little or no severe punishment. Re-training can be done in a safe and systematic manner without abuse or commotion, usually within a few brief sessions. Some of the most challenging, rowdy stallions may benefit from vigorous exercise under saddle or ground work immediately before breeding. This practice not only fatigues the stallion but also establishes a pattern of the stallion taking direction from a handler. For similar reasons, this author recommends an intensive schedule for breeding shed retraining, with as many as several breedings per day. With fatigue and reduced urgency to breed, many stallions seem more able to abide direction and learn a routine. With rapid repetition, stallions seem to more readily understand the routine. Tranquilization is generally not recommended. Levels of sedation that improve controllability without compromising musculoskeletal stability or ejaculatory function are difficult to achieve. Tranquilizing agents commonly used in stallions, such as xylazine or detomidine, can both facilitate and inhibit erection and ejaculation depending on dose.

Frenzied Behavior

Distinct from simple rowdiness, some stallions are hyperactive or even frenzied. This is typically greater during the breeding season. Some will spend nearly their entire time budget frantically “climbing the walls,” or running a fence line. In general frenzied breeding stallions can benefit from more roughage and less grain in the diet, organized physical work and pasture exercise, and consistent housing in a quiet area. Careful observation (particularly video surveillance) can be useful to identify environmental conditions and events that set off episodes or tend to quiet a stallion. In extreme cases, pasturing directly with mares can effectively quiet or sensibly occupy a frenzied stallion. L-Tryptophan supplementation (1-2 g twice daily in feed) can have a calming effect on such stallions. Tranquilization for this purpose is not recommended in breeding stallions because of risk of paralyzed penis and paraphimosis.

Self-Mutilation

Although not unique to stallions, self-mutilation is a severe and relatively uncommon fertility limiting and/or life-threatening problem. This behavior typically takes the form of self-biting of the flank, chest, or limbs, with violent spinning, kicking, and vocalization. Self-mutilation in horses appears to occur in two distinct forms. One appears to be a severe reaction to irritation or pain, and would be similar in males or females. The self-biting is typically targeted toward the site of discomfort. Another form occurs in males and is reminiscent of stallion intermale aggression. The behavior is targeted at the typically intermale sites of aggression — the groin, flank, knees, chest, and hocks. The sequence of the behavior follows closely to that of two males fighting, with sniffing and nipping of the groin, vocalization, stamping with a fore leg, kicking out with a hind leg, and then taking occasional larger bites from anywhere on the opponent’s body.

Episodes often appear to be stimulated by sight, sound, or smell (feces or oily residues) of another stallion. For some stallions, episodes are set off by sniffing their own excrement or oily residues on stall walls or doorways. Current recommendations to control episodes are as follows: (1) physically protect the stallion from injury by padding walls or limbs, blanketing, and muzzling as effective; (2) aggressively evaluate the housing and social environment to identify exacerbating and ameliorating conditions that may be manipulated for greatest relief; (3) reduce concentrates and increase grass and hay in the diet to increase feeding time and eliminate highly palatable meals (feeding tends to distract and occupy the stallion; concentrate meals tend to increase stereotypic behavior); (4) apply odor-masking agents (Vicks or Acclimate) around the nares; and (5) provide as much organized exercise as possible, also to distract the stallion.

Residual Stallionlike Behavior In Geldings

Castration, regardless of age or previous sexual experience, does not always eliminate stallionlike behavior in horses. If given the opportunity, as many as half of geldings will show stallionlike behavior to mares, many will herd mares, and even mount and appear to breed. Similarly, although castration does tend to “mellow” most horses, it does not eliminate general misbehavior. Traditional behavior modification is usually much more effective in the control of sexual and aggressive behavior in a gelding under saddle or in-hand than it is with an intact stallion. Also, treatment aimed at quieting sexual and aggressive behavior, such as progesterone (e.g., altrenogest, 50-75 mg orally daily), is typically more effective in geldings than in intact stallions. Elimination of stallionlike herding and teasing at pasture is difficult. Separation from mares is recommended.

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Horses

Placental Hydrops

Hydrops is a rare condition in the mare, with hydroallantois occurring more commonly than hydramnios. Hydroallantois causes rapid abdominal enlargement during the last trimester of pregnancy (), and a sudden increase in the volume of allantoic fluid during a period of 10 to 14 days. The pathophysiology of hydroallantois in the mare remains unknown. Some authors have suggested that the increase in fluid is a placental problem caused either by increased production of fluid or decreased transplacental absorption. Others have proposed that the etiology is related to placentitis and heritability. In these authors’ experience, examination of the fetus and fetal membranes have rarely demonstrated any consistent abnormality. One mare had diffuse mild placentitis (with leptospirosis) and another had histologic evidence of vasculitis when an endometrial biopsy was taken within 2 days of delivery of the fetus.

Mares may present with anorexia, tachycardia, severe ventral edema/plaques, abdominal discomfort, and labored breathing caused by pressure on the diaphragm. They typically have difficulty walking and often become recumbent. Uterine rupture may occur in advanced cases. Other complications associated with the excessive weight of the uterine contents include prepubic tendon rupture and development of abdominal wall and inguinal hernias.

Rectal palpation is diagnostic and reveals a huge, taut, fluid-filled uterus. The fetus cannot be balloted. Transrectal ultrasound imaging shows hyperechogenic allantoic fluid. The fetus is seldom observed as a result of the depth of the enlarged uterus. Transabdominal ultrasound will confirm the presence of excessive echogenic allantoic fluid and this approach does permit evaluation of fetal viability (movement and a heart rate of 80-100 bpm).

Treatment of Placental Hydrops

During the last few years the medical facility at these authors’ clinic has seen an increase in the number of hydroallantois cases presented to the clinic. Once the diagnosis of hydroallantois is confirmed, fetal viability is determined, and udder development and the milk electrolytes are assessed to estimate the level of fetal maturity. Those mares that present early in gestation may undergo elective termination of pregnancy by IM injection of cloprostenol (500 μg, 2 ml IM ql2h until delivery). Cases that occur later in gestation, or those with profound abdominal enlargement, may have large volumes of fluid within the uterus and require controlled drainage of the fluid before expulsion of the fetus. The reason for the controlled drainage is that excessive uterine distention alters total body fluid balance and venous return to the right heart. Sudden loss of this large volume of fluid may result in hypovolemic shock. The effect of the fluid loss is exacerbated by the sudden expansion of the abdominal venous circulation once the uterine weight is reduced. In the short term, abdominal support (i.e., belly band), IV fluids, steroids, broad-spectrum antibiotics, and antiinflammatory medication will provide systemic support for the mare. Slow siphoning of the allantoic fluid is then attempted. Once the size of the distended uterus has been reduced, the authors have used oxytocin (20 IU IV given repeatedly or 50 IU in a saline drip) or cloprostenol (two doses of 500 μg, 30 minutes apart) to promote fetal expulsion. In these authors’ experience, cloprostenol has provided a smooth progression of labor, with stage 2 occurring 30 to 60 minutes after the second dose. Mares that present within the last 2 to 4 weeks of pregnancy may be managed by partial drainage. The aim in these cases is to maintain the pregnancy for as long as possible in order for additional fetal maturation to occur.

The technique for drainage involves several considerations. Location (stocks or stall) is determined by individual preference and the condition of the mare. The process takes 2 to 3 hours, so comfort is a factor. The clinician should initiate supportive care by placing an IV catheter and administering a slow infusion of a crystalloid fluid. A tail wrap and sterile surgical preparation of the mare’s perineum is essential. The equipment includes a 24- to 32-French sharp thoracic trocar catheter, a two-way plastic adapter, sterile plastic tubing, a sterile sleeve, and buckets to collect the allantoic fluid. Smaller-sized catheters will take longer for fluid removal. The technique involves sterile passage of the catheter through the vagina and cervix, and sharp puncture of the chorioallantois. The sharp trocar is removed and the two-way adapter is used to connect the catheter to the tubing. The catheter is held in place by the clinician’s arm within the vagina. Controlled gradual drainage can then be performed into the buckets. Some pericervical separation of the placenta is common.

Several mares have been successfully treated in these authors’ hospital with this technique. In a few cases (6) that were within 2 to 4 weeks of term, maintenance of the pregnancy has been attempted after partial drainage of the allantoic compartment. These mares were treated with additional antimicrobial therapy, antiinflammatory medications (flunixin meglumine, pentoxifylline), agents with possible tocolytic activity (isoxsuprine, clenbuterol, albuterol), and altrenogest. In cases where partial drainage is attempted, fetal death may occur as a result of fetal asphyxia that results from varying degrees of placental separation. Iatrogenic fetal infection, secondary to contamination of the placental fluids during drainage, is also a problem. In most cases attempted to date, the fetus has become infected with Escherkhia coli and subsequently died. One mare died after 72 hours as a result of rupture of a uterine artery. The fetus in that mare had remained alive and exhibited normal parameters when monitored by transabdominal ultrasound.

Owners should be advised that the fetus is usually lost in mares with hydroallantois. However, early recognition of the problem, and prompt intervention, provides a good prognosis for the mare both physically and reproductively. Complications that should be anticipated when managing a mare with hydroallantois include hypovolemic shock, dystocia, and retention of the fetal membranes. The hypovolemia requires rapid volume expansion with use of large volume crystalloid infusion (as high as 40 ml/kg) alone, or in combination with hypertonic saline (4 ml/kg). The use of colloid fluids such as hetastarch (10 ml/kg) might also be beneficial. Dystocia may be associated with incomplete cervical dilation and uterine inertia. Malpositioning and malpostures are common. Therefore manual assistance to deliver the foal is necessary. Management of retained fetal membranes is discussed elsewhere in this text (see “Retained Fetal Membranes”). Because it is possible that a heritable component to this condition exists, breeding to a different stallion may be prudent.

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Horses

Placentitis

The equine placenta consists of the allantochorion, the allantoamnion, and the umbilical cord. The chorionic portion of the allantochorion is attached to the endometrium by microcotyledons that are present throughout the uterus, with the exception of a small area at the internal os of the cervix called the cervical star. The allantochorion supports the fetus in utero. This structure provides respiratory and nutrient exchange between the mare and the fetus and is an endocrine organ for maintenance and normal development of the fetus. The “free floating” allantoamnion allows the fetus to move freely within the uterus. The only attachment between the fetus and the allantoamnion is at the umbilicus. The umbilicus contains two umbilical arteries, one umbilical vein, and the urachus. The length of the cord and the length of the allantoic and amniotic portions can vary, but is normally 50 to 100 cm long.

Pregnancy loss during late gestation can be the result of fetal illness, placental dysfunction, maternal illness, or a combination of these factors. A functional placenta is necessary for a normal development of the fetus. Any insult or disruption of normal anatomy or physiology of the placenta may result in placental insufficiency and abortion. Compromised placental anatomy or function is the most common cause of abortions in late gestational mares. Placental insufficiency may be noninfectious (e.g., twin pregnancy) or infectious. Effective management of twin pregnancies has reduced this cause of abortion, and placentitis has become one of the most common cause of abortion in late gestational mares.

Placentitis: Etiology

The most common route of infection is believed to be ascension through the cervix. An ascending infection may be the result of a failure of the external genital barriers to protect the uterus from bacterial or fungal invasion (e.g., defective perineal conformation, nonfunctional vestibulovaginal fold, or cervical lacerations). The possibility of bacterial contamination entering the uterus at the time of breeding or the presence of a preexisting low-grade endometritis with clinical signs that develop several months later has not been critically investigated. The characteristic location of the lesions away from the cervix in mares with placentitis caused by a Nocardioform actinomycete raises the question of whether the microorganism may enter the uterus before, or at the time of breeding, without causing a clinical problem until later during the pregnancy. Hematogenously spread placentitis occurs but is considered to be less common than an ascending route of infection.

The most commonly isolated microorganisms from mares with placentitis are Streptococcus zooepidemicus, Escherichia coli, Pseudomonas aeruginosa, Klebsiella pneumoniae, Nocardioform actinomycete, Aspergillus spp., and Candida organisms. The mechanism of abortion as a result of placentitis is not fully understood, but it most likely involves infection of the fetus, hormonal changes, the release of inflammatory mediators, and deprivation of the fetus of nutrients.

Placentitis: Clinical Signs and Diagnosis

Placentitis: Treatment And Prevention

Treatment of mares with placentitis should focus on elimination of the infectious agents, reduction of the inflammatory response, and reduction of the increased myometrial contractility in response to the ongoing inflammation. No controlled studies have been reported on the efficacy of treatments for mares with placentitis, and the following recommendations are based on clinical experience and extrapolation from other species.

Urine pooling, cervical lesions, and poor perineal conformation should be corrected to prevent an ascending route of infection during pregnancy. Mares with abnormal placental findings on ultrasonographic examination or clinical signs of placentitis should be treated with broad-spectrum antibiotics, antiinflammatories (flunixin meglumine, 1.1 mg/kg ql2h; or phenylbutazone, 4 mg/kg ql2h), and tocolytics (altrenogest, 0.088 mg/kg q24h; or clenbuterol, 0.8 μg/kg ql2h). Pentoxifylline (7.5 mg/kg PO ql2h) is thought to increase oxygenation of the placenta through an increased deformability of red blood cells. A bacterial culture should be obtained in mares with vaginal discharge for isolation of a causative agent and sensitivity to antibiotics. After foaling or abortion, the uterus of the mare should be cultured and the mare should be treated for endometritis if the culture is positive.

Mares have been reported to deliver normally developed foals several weeks or even months after successful treatment of placentitis. No current diagnostic method exists, however, to predict how the compromised uterine environment in a mare with placentitis will affect the development of her fetus in individual cases.

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Horses

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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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.

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Horses

Twins

The diffuse microcotyledonary placentation of the mare makes it highly unlikely that a twin pregnancy will be carried to term. If the twin pregnancy is maintained until the latter part of gestation the placenta cannot meet the nutrient demands of the rapidly growing fetuses. Death of one or both fetuses is followed by abortion, with the characteristic avillous areas on the fetal membranes confirming the amount of placental disruption (). Twin abortions in the last few months of gestation are likely to cause a dystocia. The live birth of twin foals is extremely uncommon, and many of these neonates do not survive. The mares are prone to fetal membrane retention and may be difficult to rebreed. Thus it is not surprising that the equine breeding industry has always tried to avoid twin pregnancies. This chapter will review the management options that are currently available.

Monitoring Follicular Development And Ovulation

A high incidence of twin ovulations occurs in some breeds, such as Thoroughbreds and warmbloods, and mares that tend to double ovulate can be expected to do this repeatedly. Thus a mare with a tendency to double-ovulate should have this information noted prominently on her breeding record. Most twin pregnancies arise from such double ovulations. Owners need to appreciate that these double ovulations are generally asynchronous and may be separated by a couple of days. If a fertile stallion was used to breed the mare on the first ovulation, it is possible that viable sperm will still be present in the reproductive tract when the second oocyte arrives. This possibility must be remembered when scanning mares for pregnancy at 14 to 16 days. At that time, it is good practice to scan the ovaries for evidence of luteal tissue from a second ovulation.

In the past, one strategy that was employed when a veterinarian palpated two large (>30 mm) follicles was to wait to breed until the next cycle. This approach wasted valuable days in the breeding season, and many of these mares would repeat the same follicular process during the next cycle. An alternate approach was to hope that the second follicle would continue to develop for 10 to 12 hours after the first detected ovulation. Because the ovulated oocyte is unlikely to be viable at this time, a delayed breeding could be performed in anticipation of the second ovulation. Today the preferred strategy is to breed all eligible mares — irrespective of the number of preovulatory follicles. The widespread adoption of early ultrasonographic pregnancy examinations has permitted the focus to be placed on embryonic vesicle reduction once the presence of a twin pregnancy has been confirmed.

Manual Reduction

The increasing size of the embryonic vesicle, coupled with the increasing tone of the early pregnant uterus, tends to fix the conceptus at the base of one uterine horn by day 16. It is essential that the ultrasound scan of the uterus be thorough, with a complete examination of the length of both horns plus the uterine body as far back as the cervix. This is especially important before day 16 because the vesicle moves freely within the lumen of both horns and the uterine body. The advantage of these early scans is that if twin vesicles are detected it will be easier to manually separate them before day 16. Successful elimination of one vesicle is more likely at that time because the uterine walls are thin, and minimal pressure is required to crush a vesicle. A definite “pop” can be felt when the vesicle ruptures, but success should always be confirmed by ultrasound.

The downside to this approach is that an early embryonic vesicle can easily be confused with an endometrial cyst. The embryo itself does not become readily identifiable until the fourth week of pregnancy. Thus it is good practice to note the size and location of any cysts at the time the mare is being examined for breeding. However, it is not an uncommon occurrence that the veterinarian doing the early (14-16 days) pregnancy scan will be examining the mare for the first time. If no record of cyst size and location exists, it is virtually impossible to differentiate twin vesicles from a singleton and a cyst with a single examination. This is especially true because asynchronous ovulations are likely to result in considerable size discrepancy between the two vesicles. Under these circumstances it may be best to measure each suspect vesicle and note its location. A second scan in 1 to 2 days should note a size increase in any normally growing vesicle (~4 mm/day). Only then can a confident decision be made about attempting to “pinch” one of the growing vesicles. Unfortunately this delay may make separation of unilaterally fixed vesicles more difficult because of their ongoing growth and the increased uterine tone.

Manual reduction of bilaterally fixed vesicles requires less manipulation than with unilateral twins. It is a relatively easy procedure, and success rates exceeding 90% are not uncommon if the vesicle is crushed before day 16. If the vesicles are unilaterally fixed, the clinician should attempt to move the more proximal vesicle away towards the tip of the uterine horn. At this location the manual reduction procedure is less likely to disrupt the remaining vesicle. The vesicle can be crushed by pinching it between the thumb and fingers. Alternately, the vesicle is squeezed against the mare’s pelvis until it ruptures. If the twins can be separated before crushing, the success rate may be similar to that for reduction of bilateral twins. If the unilateral twins cannot be separated or are greater than 20 days’ gestation, the success rate is lower. The extra pressure used to eliminate a twin vesicle after fixation is the reason many clinicians will accompany reduction with antiinflammatory medications and progestin therapy. The likelihood of success improves with experience, and some clinicians develop a reputation for being especially adept at the procedure. Obviously the nature of the mare is an important factor, and those that strain excessively can make the procedure extremely difficult. If the unilateral vesicles are not detected until after day 20, manipulations can easily result in the disruption of both vesicles. The best option in these cases may be to wait and see whether natural reduction occurs.

Natural Reduction

Almost three quarters (70%) of twin embryonic vesicles become fixed unilaterally; only 30% of twin vesicles become fixed bilaterally. The advantage of this probability is that natural reduction to a single pregnancy is far more likely with unilaterally fixed vesicles. Over 80% of unilaterally fixed twins are likely to naturally reduce to a singleton, with over half of these occurring between days 16 and 20. On the other hand, the majority of bilaterally fixed vesicles will continue to develop. Late in the season these odds play an important part in any informed discussion about management options. Early in the season most veterinarians will opt to attempt reduction, knowing that if both vesicles are lost that it will still be possible to rebreed the mare. Close to the end of the season an unsuccessful attempt at reduction may preclude the mare from being rebred. If natural reduction does not occur by day 30, the advent of transvaginal reduction has opened a window for later attempts at reduction. If this fails, owners may opt to put the mare under lights and breed her early next season rather than be locked into a pattern of late foals.

Pregnancy Termination With Prostaglandin

If natural reduction does not occur, terminating the pregnancy with a prostaglandin injection is always possible. This will cause lysis of the corpora lutea that resulted from the double ovulation, and the precipitous decline in progesterone will bring the mare back into estrus. However, this treatment must be given before day 35. Once the endometrial cups form it may take repeated injections to terminate the pregnancy, and the mare is unlikely to return to estrus until the cups are sloughed. The endometrial cups originate from specialized fetal trophoblast cells. They secrete equine chorionic gonadotropin (eCG), a hormone that causes the development of accessory corpora lutea and thus augments the progesterone level in support of the early pregnancy.

Transvaginal Ultrasound-Guided Allantocentesis

Although the advent of transrectal ultrasonography has dramatically improved the ability of veterinarians to make an early diagnosis of twin pregnancies, diagnostic errors still occur. This could be due to an early pregnancy diagnosis when the second vesicle was too small to detect, incomplete examination of the entire uterus, poor image quality, or an inability of the clinician to differentiate two embryonic vesicles that are closely apposed to each other. If natural reduction does not occur or the diagnosis of twins is not confirmed until after 30 days, transvaginal aspiration of one vesicle is an option. The results are best if the procedure is performed before day 35. Although spontaneous reduction of twin pregnancies can occur even after day 40, the probability is low. Natural twin reduction is more likely to occur if an obvious size discrepancy is present between the two vesicles at this time.

If a transvaginal reduction is to be attempted, the mare should be treated with flunixin meglumine. Many clinicians will also administer oral altrenogest. Because sedation causes significant uterine relaxation, most clinicians use a lidocaine enema to reduce straining. The transvaginal aspiration technique employs a 5.0- or 7.5-MHz endovaginal curvilinear transducer. The transducer and casing should be cold-disinfected or sterilized before use. The assembled unit is then placed in a sterile transducer cover that has been filled with sterile lubricating gel. The transducer is advanced aseptically until it is seated lateral to the cervix. The clinician then grasps the pregnancy per rectum and advances a sterile 60-cm, 18-gauge spinal needle with an echogenic tip along the needle guide in the transducer casing. A dotted line on the ultrasound screen can be used to select a path for the needle entry into the embryonic vesicle. A sharp jab of the needle penetrates the vaginal wall, peritoneal lining, uterus, and ultimately the allantoic or yolk sac. A 60-ml syringe is attached to the needle, and the embryonic fluid aspirated. Aspiration should be stopped when danger of damaging the adjacent vesicle of unilateral twins arises. If a bilateral twin is being eliminated, the needle can be moved within the vesicle until all detectable fluid has been aspirated. The success rate is better for bilateral twin reductions. Death of the remaining twin is most likely to occur within 2 weeks of the procedure. Although reports are scarce, preliminary data suggest that experienced operators may achieve a live singleton birth in about one third of cases.

Transabdominal Ultrasound-Guided Fetal Cardiac Puncture

In advanced twin pregnancies, attempting reduction by a transabdominal approach is possible. Fetal intracardiac injection of potassium chloride is effective but requires accurate placement of the KC1 into the fetal heart. Best results are obtained when the pregnancy is between 115 and 130 days. At this stage experienced operators can achieve a 50% success rate. Procaine penicillin G can cause fetal death when injected into either the fetal thorax or abdomen, but the effect is not instantaneous. The advantage of the latter treatment is that it does not require precise placement of the injection into the fetal heart. Mares should be started on oral altrenogest, systemic antibiotics, and flunixin meglumine on the day of the procedure. The antibiotic coverage and antiinflammatory medication should be continued for 3 days.

A 3.0-MHz transducer can be used to image the 90- to 130-day fetus in the caudal abdomen, just cranial to the udder (Figure 5.9-2). Once the mare has been sedated, the uterus will relax, and the location of the fetuses will shift cranially. A sedative/analgesic combination that works well for this procedure is acepromazine (10 mg), xylazine (100 mg), and butorphanol (10 mg). The smallest and/or most easily accessible fetus is selected for reduction. The ventral abdomen should be surgically prepared, and local anesthetic infiltrated at the puncture site. Some clinicians are adept at a “free-hand” injection technique, whereby the fetus is injected by merely observing the ultrasound image. Others prefer to use an ultrasound transducer that is fitted with a biopsy guide. An 18-gauge, 6- to 8-inch spinal needle with stylet can be used for most fetal injections. The distance from the skin surface to the fetus determines the length of the needle that is required. Specialized needles with echogenic tips are available to provide better visualization via ultrasound. Once the location of the selected twin’s thorax is confirmed, the needle is introduced through the prepared skin, abdominal wall, and uterus. If procaine penicillin G is to be injected, the needle may puncture either the fetal thorax or abdomen. Up to 20 ml is typically injected into the fetus. Fetal death should be confirmed the following day.

Although the benefits of supplemental progestin therapy are debatable, many clinicians suggest that the mare be medicated for at least 2 weeks if the initial twin reduction has been successful. It is essential that fetal viability be checked regularly because supplemental progestin therapy may prevent elimination of the dead fetuses if both die. Most abortions will occur within 1 to 2 months after the reduction procedure. Survival of the remaining twin seems to depend somewhat on the amount of endometrial surface that was its domain before the reduction. If the operator is experienced in the technique, between 30% and 60% of cases can be expected to deliver a singleton foal, although the ultimate size and viability may be suboptimal. The eliminated twin in these cases can be seen as a mummified remnant contained within an invaginated pouch that protrudes into the allantoic space of the viable foal’s fetal membranes.

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Horses

Endometrial Cysts

Endometrial cysts are often cited as a cause of infertility; however, a cause-and-effect relationship has not been clearly established. The proportion of mares with endometrial cysts increases with age. Mares over 11 years of age are more than four times as likely to have endometrial cysts as younger mares and a majority of mares over 17 years of age will have endometrial cysts. Reports that associate endometrial cysts with a lower pregnancy rate or increased embryonic loss fail to account for the effect of advancing age. When confounding effects such as parity and age are controlled for, the assumption that cysts cause infertility is not supported. When confounding factors were accounted for in the analysis of nearly 300 mares, endometrial cysts did not have a statistically significant effect on establishing or maintaining pregnancy, although the time of initial pregnancy diagnosis was not strictly controlled in that study. Another report by a different group of researchers which controlled for the time of pregnancy diagnosis similarly found no difference in pregnancy loss between mares with cysts and those without cysts, although mares with endometrial cysts tended to have a lower day-40 pregnancy rate.

A quantitative effect of cysts on fertility appeared to exist because an effect was not evident until a mare had numerous cysts or until the cysts were very large. However, even then the effect of endometrial cysts on fertility was much less than that seen with delayed uterine clearance or intrauterine fluid accumulation. A quantitative effect of endometrial cysts could be due to interference with embryonic mobility. It is well known that the equine embryo undergoes a period of mobility after entering the uterus, finally becoming fixed in place at approximately 16 or 17 days’ gestation. If mobility is restricted during this period and the embryo is not permitted to contact a sufficient portion of the endometrium, maternal recognition of pregnancy may not occur, thus resulting in luteolysis and embryonic loss.

Rather than being viewed as a cause of infertility, endometrial cysts should be considered an indication of underlying pathologic changes in the uterus. Endometrial cysts are of lymphatic origin, and their occurrence may be associated with a disruption of lymphatic function.

Diagnosis of Endometrial Cysts

Endometrial cysts are best diagnosed with ultrasonography. Cysts can be identified as hypoechoic, immovable structures with a clear border in the lumen of the uterus, as opposed to intraluminal fluid, which is movable and has a less distinct shape or border. Endometrial cysts are usually multiple and are most commonly found at the base of the uterine horns. Cysts may change in size and number between estrus and pregnancy.

Endometrial cysts can complicate early pregnancy diagnosis. Often an endometrial cyst can be similar in size and appearance to an early conceptus. Cysts that appear spherical can often be shown to have a more irregular shape if the ultrasound probe can be reoriented in relation to the cyst. To make early pregnancy diagnosis easier and more reliable, the size and location of endometrial cysts should be recorded with a diagram or by storing ultra-sonographic images during a prebreeding examination. Even so, pregnancy examination may need to be repeated or confirmation delayed in some mares with endometrial cysts ().

Treatment of Endometrial Cysts

In most cases of endometrial cysts, no treatment is necessary, other than recording their size and location for future reference during pregnancy examination. However, if the cysts are sufficient in size or number to pose a potential threat to embryonic migration, treatment can be aimed at facilitating establishment of pregnancy by providing exogenous progestogen.

Progestogen, usually in the form of altrenogest (0.044 mg/kg PO daily), can maintain pregnancy even when the signal for maternal recognition of pregnancy is lacking. Numerous studies have shown the ability of altrenogest to maintain pregnancy after luteolysis or in ovariectomized mares. It should be emphasized that, if progestogen therapy is deemed necessary, the correct dose and frequency of administration is required or the effort is wasted. For example, weekly injections of progesterone in oil or monthly medroxyprogesterone is insufficient to maintain pregnancy and therefore would not be beneficial in mares with large or numerous endometrial cysts.

Alternatively, the cysts may be removed surgically. Laser surgery is an ideal method if the equipment is available. Ligation and transection of the stalk of pedunculated cysts is an alternative. Merely puncturing and draining the cyst or incising its wall will not provide long-term remission.

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Horses

Cutaneous Lymphosarcoma

Clinical manifestations of lymphosarcoma in horses include cutaneous, multicentric, thymic, and alimentary forms. Cutaneous lymphosarcoma can exist as a primary disease entity limited to skin and subcutaneous tissues or concurrently with visceral involvement. Horses of all ages have been diagnosed with lymphosarcoma, with the majority being between the ages of 4 and 9 years. No clear age, sex, or breed predisposition has been identified specifically for the cutaneous form of lymphosarcoma, but some authors have reported a higher incidence in mares. The most common form of cutaneous lymphosarcoma is T cell-rich, B cell lymphoma within the subcutis and dermis. A less common form involving the epidermis with variable extension into the dermis and subcutaneous tissues is termed epitheliotropic (cutaneous T cell lymphosarcoma or mycosis fungoides).

Cutaneous Lymphosarcoma: Etiology

The etiology of equine cutaneous lymphosarcoma is unknown. Although a pleomorphic coryneform bacterium was isolated from the cutaneous masses of two horses, the importance of this isolate is unknown, as no etiologic agent is determined in the majority of lymphosarcoma cases. Inoculation of normal horses with large doses of this organism failed to produce any clinical signs. Viruslike particles were identified by electron microscopy in a foal with multicentric lymphoma. The foal died shortly after birth, and no causal relationship was documented.

Cutaneous Lymphosarcoma: Clinical Signs

Cutaneous lymphosarcoma can be categorized into T cell-rich, B cell lymphoma or epitheliotropic forms based on the extent of cutaneous infiltration and the cell types involved. T cell-rich, B cell lymphoma defines a mixed population of lymphocytes and reactive histiocytes within the dermis and subcutis. Previously described as histiolymphocytic lymphosarcoma, several cases have been described recently as T cell-rich, B cell lymphomas through the use of morphologic evaluation, immunophenotyping, and cell proliferation markers. This form of lymphosarcoma is characterized clinically by solitary or multiple well-demarcated dermal and subcutaneous nodules located on any region of the body. These masses are usually covered by haired and intact skin, although they may ulcerate secondary to necrosis as they enlarge. The nodules are typically firm and nonpainful and may vary in size from millimeters to several centimeters in diameter. The cutaneous lesions may appear suddenly, although they more often slowly progress. Spontaneous periods of rapid growth followed by episodes of partial to full remission occur. Concurrent involvement of the nasopharyngeal mucosa may be present in some horses. Such cases may be presented for stridor, exercise intolerance, or nasal discharge.

T cell-rich, B cell lymphoma may demonstrate hormone sensitivity. Partial regression of skin lesions has coincided with hormonal fluctuations associated with the estrous cycle and pregnancy. One report describes a mare that was diagnosed with concurrent cutaneous lymphosarcoma and a granulosa-theca cell ovarian tumor. In addition to cutaneous lesions, aggressive stallion-like behavior and abnormal hormone assay results (elevated serum testosterone and inhibin concentrations) were present in this mare. Progesterone receptors were demonstrated on neoplastic B cells, and temporary regression of the subcutaneous masses occurred following removal of the ovarian mass. Previous partial regression of the subcutaneous lesions in this horse had also coincided with the administration of a synthetic progestin, altrenogest.

Epitheliotropic lymphosarcoma, also known as mycosis fungoides or cutaneous T cell lymphoma, is infiltration of neoplastic T lymphocytes within the epidermis, with variable extension into underlying tissues. Lesions display varying degrees of ulceration, alopecia, scaling, lichenification, and erythema. Secondary bacterial infection may result in purulent discharge, and pruritus may be present.

Horses with cutaneous lymphosarcoma may also present with weight loss, lethargy, inappetence, intermittent fever, lymphadenopathy, and peripheral edema in addition to skin lesions. Signs of respiratory disease, recurrent colic, weight loss, and/or diarrhea may be observed if concurrent multicentric, thymic, or alimentary forms are present. Exophthalmos, blepharitis, chemosis, epiphora, and conjunctivitis may occur secondary to neoplastic involvement of the periorbital tissues. Careful ocular examinations often reveal infiltration of the palpebral conjunctiva and eyelids, uveitis, corneoscleral and third eyelid masses, as well as retrobulbar involvement.

Clinicopathologic Findings

Hematologic and biochemical findings in horses with the cutaneous form of lymphosarcoma are often unremarkable. Nonspecific abnormalities may occur with concurrent systemic forms of lymphoma and include anemia, neutrophilia, hyperfibrinogenemia, hyperglobulinemia, hypoalbuminemia, and hypercalcemia. Leukemia and alterations in peripheral lymphocyte morphology in cases of primary cutaneous lymphosarcoma are rare. A mild elevation of creatine kinase was noted in one report and was attributed to neoplastic infiltration of adjacent muscle.

Serum concentrations of immunoglobulins M, G, and A (IgM, IgG, and IgA) vary in horses with systemic lymphosarcoma and may be elevated or deficient. Selective IgM deficiency has been noted in horses with extracuta-neous involvement. However, two recent retrospective studies found that IgM deficiency was neither specific nor sensitive for lymphosarcoma. Monoclonal gammopathies may be noted in horses with diffuse lymphoma. These immunologic changes may not be present in horses with primary cutaneous lymphosarcoma.

Diagnosis of Cutaneous Lymphosarcoma

The differential diagnoses for cutaneous lymphosarcoma include nodular skin diseases — such as nodular necrobiosis (eosinophilic granuloma), mycobacteriosis, hypodermiasis, fibroma, sarcoid, melanoma, chronic urticaria, mastocytosis, fungal granuloma, basal cell tumor, lipoma, panniculitis, and cutaneous amyloidosis. Squamous cell carcinoma and lymphangitis should be considered as diagnostic rule-outs in cases with ulcerative lesions. Definitive diagnosis requires histopathologic or cytologic confirmation. Neoplastic cells have been reported to infiltrate associated fascial and muscle tissue in both T cell-rich, B cell lymphoma and epitheliotropic forms of cutaneous lymphosarcoma. Histopathology is preferred over fine needle aspiration of lymph nodes in cases with peripheral lymphadenopathy because cytology alone may not be definitive. Cutaneous amyloidosis has been reported in horses with lymphosarcoma, including one with cutaneous lymphoma.

Immunophenotyping, or immunohistochemical analysis directed against cell markers, allows for further classification of tumors into B cell or T cell categories. Monoclonal antibodies against surface glycoproteins, surface and cytoplasmic domains, and CD3 and CD5 markers have been used. Epitheliotropic lymphosarcoma in the horse is rare but appears to be of T cell origin. Histiolymphocytic tumors have been previously classified as B cell or T cell in origin. However, recent work in the morphologic and immunohistochemical classification of equine lymphomas has suggested that the histiolymphocytic form comprises neoplastic B cells; a concurrent component of reactive but nonneoplastic T cells also exists, thereby classifying these masses as T cell-rich, B cell tumors. Large numbers of nonneoplastic T cells could result in an erroneous diagnosis of a T cell tumor. The role of histiocytes in such masses is unclear. T cell-rich, B cell lymphosarcoma defines neoplastic B cells interspersed within a large population of well-differentiated, benign T cells and variable numbers of histiocytes. Further characterization of T cell subpopulations as CD4 or CD8 in horses with cutaneous lymphosarcoma has not been described.

Hematologic and serum biochemical evaluations are adjunctive diagnostics in horses with cutaneous lymphosarcoma. Ultrasonographic evaluation of cutaneous lesions and regional lymph nodes may prove useful in assessment of the extent of neoplastic involvement. A thorough diagnostic examination — including rectal palpation, abdominal and thoracic ultrasonography, abdominocentesis, xylose absorption, thoracic radiography, and transtracheal and thoracocentesis cytology — should be tailored to individual cases for evaluation of internal neoplastic involvement. Endoscopy should be performed to evaluate for nasopharyngeal masses in horses that display upper respiratory signs. Bone marrow aspiration or biopsy may be indicated if leukemia, leukopenia, pancytopenia, or abnormal peripheral lymphocyte morphology are noted. Thorough examination of the reproductive tract and submission of hormone assays (testosterone, inhibin, progesterone) are indicated in mares that display behavioral abnormalities consistent with a granulosatheca cell tumor.

Treatment of Cutaneous Lymphosarcoma

Prognosis

Primary cutaneous lymphosarcoma carries a fair to good prognosis; many horses survive for several years. In contrast, cutaneous lymphosarcoma associated with visceral involvement is often rapidly progressive and poorly responsive to therapy, thus resulting in a guarded prognosis for life. The prognosis for horses with extensive epitheliotropic lymphosarcoma remains guarded.

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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.