DRUG USE IN EQUINE REPRODUCTION

  1. INDUCTION OF OVULATION DURING ANESTRUS

    1. Lighting

      Mares are commonly kept under lights during winter months to initiate cycling early in the year. Cycling commences 8-10 weeks after the lighting program has begun. Thus if one aims to have horses cycling in February, lighting must be initiated in November. Ideal photoperiod is about 16 hours of light, and lights should be turned on in the evening. Extending the photo period by turning lights on before dawn is less effective. The horse requires 2 foot-candles of light. This can be achieved using a 200 watt bulb over a stall in which the mare is no greater than 8 feet from the light source.

    2. GnRH and its agonists

      Cycling can be induced by GnRH administration. However, single injections are ineffective; GnRH must be delivered in a pulsatile fashion or by sustained release. Pulsatile release of GnRH by osmotic pumps is effective to induce ovulation, but the approach is costly and complicated. Silastic implants containing potent GnRH agonists such as Buserelin, Goserelin or Deslorelin are partially effective at inducing ovulation in acyclic mares. The GnRH agonist "ovuplant" is currently available.

  2. COPING WITH TRANSITION

    1. Altrenogest

      Veterinarians are often asked to suppress transitional estrus and to hasten onset of ovulation in transitional mares. The oral progestogen altrenogest (Regumate) is marketed partly for this purpose. Progestogens inhibit LH release during prolonged administration. Following their withdrawal there is a rebound LH surge which theoretically drives ovulation. Administration of Regumate at the recommended dose (0.044 mg/kg per os SID) effectively suppresses behavioral estrus. To hasten ovulation, the recommended course of 10-15 days is effective only in late transition (when the mare might be about to ovulate anyway). A large follicle (>35mm) should therefore be present on the ovary to achieve hastened ovulation. Progesterone in oil (150 mg IM daily) is a cheaper but less convenient alternative. Response is variable, but on the average mares come into heat in 3-6 days and ovulate in 10-12 days following withdrawal.

    2. Human Chorionic Gonadotropin

      A single injection of HCG may be used late in transition to hasten ovulation if a large follicle is present. if successful, ovulation will occur within 48 hours. However, success is not assured, and mares may lapse back into transition.

  3. MANIPULATION OF THE ESTROUS CYCLE IN CYCLING MARES

    1. Induction of ovulation with HCG

      HCG is commonly used in cycling mares to induce ovulation. Ovulation occurs 24-48 hours following administration of 1500 -3300 I.U. IV or IM if a growing, dominant follicle greater than 35 mm is present. 2500 I.U. is a common dose. Given early in estrus, ovulation usually occurs 36-42 hour post injection. HCG is not effective in large follicles that are regressing. HCG is most commonly used post insemination, to hasten ovulation, and to minimize number of inseminations. Fresh stallion semen survives longer than 48 hours in the uterus, so HCG induced ovulation occurs within the life span of the semen. If semen longevity is believed to be poor, the clinician may elect to give HCG prior to insemination. Our current protocol for frozen semen insemination includes insemination 36 hours after an injection of HCG, if ovulation has not already occurred by then. Anti HCG antibodies do occur following repeated (4-5) injections of HCG. They do not interfere with normal ovulation, but efficacy of HCG may be reduced. High doses of HCG ( >4500 I.U. ) cause reduced pregnancy rates.

    2. Short cycling with prostaglandins

      Shortening the length of diestrus is used widely in managing brood mares. It allows spreading or grouping of mares for breeding, and shortens the waiting period following missed ovulations. Exogenous prostaglandin administered to the diestrus mare lyses the CL, causing return to estrus. We currently use IM injection of 5 mg to 10 mg dinoprost tromethamine (Lutalyse).The CL resists prostaglandin in the first 4-5 days post ovulation, but becomes responsive after this time in most horses. Best response is achieved when administered between day 6 and 9 post ovulation. Predicting the response to prostaglandin depends on degree of follicular development at the time of injection. In the absence of a dominant follicle, prostaglandin leads to estrus in about 2-4 days and ovulation in 6-12 days. If a large follicle (35 mm or greater) is present, estrus may occur in as early as 24 hours, and ovulation shortly thereafter, or the mare may ovulate without showing signs of estrus (prostaglandin analogs can themselves induce ovulation). Palpation of mares prior to prostaglandin injection, and diligent teasing is necessary to cope with variable responses. Normal side effects of Lutalyse injection include transitory sweating and mild colic which usually completely resolve within an hour of injection.

    3. Medical uses of prostaglandins

      Some medical conditions of the mare require luteolysis. These include persistent corpus luteum, and pyometra. Persistent corpora lutea may result from a diestrus ovulation occurring immediately prior to prostaglandin release. The immature CL which then develops is not responsive to the normal luteolytic release of PGF2a . This CL may persist indefinitely, in the absence of a subsequent prostaglandin release. The condition is usually treated with a single luteolytic dose of prostaglandin. Pyometra in the horse is usually caused by impaired myometrial contractility or cervical blockage. However, inflammatory exudate sometimes accumulates in the uterus when a CL is present on one or both ovaries. Induction of estrus by lysis of the CL will assist uterine clearance in these mares.

    4. Suppression of estrus

      Estrous behavior is sometimes a problem in show mares. Altrenogest (0.044 mg/kg SID PO) is effective in suppressing estrous behavior in mares, and is partly marketed for this purpose. Progesterone in oil (150 mg BID IM) may be a cheaper alternative. If the horse is in estrus at the start of treatment, estrus behavior is usually suppressed in 2-3 days. Anabolic steroids, such as stanazolol (Winstrol) or boldenone undecyclate (Equipoise) are administered as performance enhancers. Although these steroids effectively suppress estrus, long term administration may lead to objectionable stallion like behavior, and prolonged suppression of ovarian function. Anabolic steroids are not recommended for horses intended for reproduction.

    5. Synchronization of estrus

      Synchronization of estrus is a requirement for donors and recipients in embryo transfer programs, and may be helpful in scheduling breedings. Progestogens may be used to synchronize estrus (altrenogest 0.044 mg/kg sid PO or 150 mg progesterone in oil for 8-12 days). Following withdrawal prostaglandin is administered, and estrus occurs in about 3-6 days and ovulation in 8-15 days. The variable time to ovulation arises from progestogens' inability to inhibit follicular. development (remember that progesterone does not inhibit FSH secretion in the mare). The addition of estradiol 17 b to the protocol inhibits follicular development and improves synchrony. The most effective protocol for synchronizing estrus in mares consist of daily progestin (altrenogest 0.044 mg/kg sid PO or 150 mg progesterone in oil sid IM ) with daily estrogen (10 mg estradiol 17 b ) for 10 days. Prostaglandin is given on the last day, and mares will ovulate within 10-12 days of the last treatment.

    6. Induction of estrous behavior

      Collection of semen from a stallion frequently requires an estrous mare. Ovariectomized mares given 1 to 4 mg IM of estradiol cyprionate (ECP) will show heat in 6-20 hours. Exogenous estradiol will not induce estrus in ovarian intact mares if a corpus luteum is present. ECP (single injection of 1 mg estradiol cyprionate) has been used to induce estrous behavior in silent heat mares when breeding must occur by live cover. Exogenous estrogens should be used with caution due to potential side effects.

  4. PREGNANCY MAINTENANCE

    1. Prevention of prostaglandin release

      Unwanted, luteolytic release of prostaglandin may terminate early pregnancy. Possible stimuli to cause prostaglandin release include endotoxemia (eg from colic), cervical manipulation (eg transcervical placement of an embryo), or uterine manipulation (manual twin reduction). Flunixin meglumine is frequently helpful in preventing prostaglandin release, especially if given in advance. In potentially endotoxic situations, flunixin meglumine should be included early, if not prophylactically, in treatment of pregnant mares less than 90 days of gestation. After day 70 the fetal-placental unit begins to synthesize progestogens, and luteal sources of progesterone become gradually less critical, overtaken between 100 and 120 days by placental sources, and completely disappearing by day 180. Thus the luteolytic danger of endotoxemia becomes less as gestation advances.

    2. Progestogens

      Progestogen supplementation to mares suffering an endotoxic insult in the first 90 days of gestation is a wise and necessary precaution. Because luteolysis may have occurred, supplementation needs to be extended at least through 90 days, if not to 120 days. Altrenogest is a convenient but expensive source of oral progestogens. Mares without any history of endotoxemia may be presented for progestogen supplementation for pregnancy maintenance. The value of progestogen supplementation in these mares is a controversial one. Although circulating progesterone levels of less than 4 ng/ml are suggestive of luteal insufficiency, the need for progestogen supplementation of such mares has not yet been established. Assessment of cervical tone may be helpful in deciding whether progestogen supplementation is necessary. Altrenogest is an expensive product; if it is used for pregnancy maintenance, regular pregnancy examination will prevent wasteful supplementation of a non-pregnant mare. Alternative sources of progestogens for pregnancy maintenance include repositol progesterone (500-1000 mg IM every 7 days) and depo-provera (200-250 mg every 8 -14 days, available from Upjohn).

  5. TERMINATION OF UNWANTED PREGNANCY

    For a variety of reasons a veterinarian might be called to terminate an unwanted pregnancy. Twins and obvious fetal monsters may be clear indications, plus dam considerations which would make carrying a foal to term a dangerous option. Owners sometimes elect to terminate healthy pregnancies due to undesirable matings. It is valuable to review techniques of pregnancy termination since they depend on the endocrinology of pregnancy maintenance.

    1. Day 0 to 5

      Essentially impossible, since the CL is refractory to prostaglandins. Saline lavage is ineffective since the embryo is still in the oviduct.

    2. Day 5 to 35

      Single luteolytic dose of prostaglandin is effective. Mare should cycle back normally, and can be rebred.

    3. Day 35 to 160

      After formation of the endometrial cups, response to a single dose of prostaglandins is variable, but repeated doses (sid or bid for 3-5 days) should be effective before day 70. Return to cyclicity is variable given due to presence of the endometrial cups. Estrous cycles may be irregular. As pregnancy advances, efficacy of prostaglandin will continue to decrease as the placenta becomes the primary source of progestogens.

    4. Day 160 to 310

      Neither prostaglandins nor corticosteroids will induce abortion during this period. Oxytocin does not become effective until after day 310.

  6. INDUCTION OF PARTURITION

    Underlying induction of parturition is the concept of fetal readiness for birth. As pregnancy advances to 330 days, termination of pregnancy becomes possible, but survivability of the neonate becomes the issue of major importance. Parameters for fetal maturity will not be reviewed in detail here, but electrolyte concentrations in mammary secretions should be as follows: calcium > 40 mg/dl sodium:potassium ratio inverted (potassium greater).

    1. Prostaglandins

      At about 320-330 days prostaglandins become effective in terminating pregnancy. However, they vary greatly with respect to fetal readiness for birth:

      1. Prostaglandin F 2 a

        Single injection can terminate pregnancy in approximately 3.5 hours, but foal will not survive unless other parameters of readiness for birth are met. Response is variable, and complications frequently reported.

      2. Fluprostenol

        Effective in induction of parturition if the foal is ready for birth. Ineffective in terminating pregnancy if foal is not ready. Foaling takes place within 1-6 hours, which is a disadvantage compared to oxytocin.

    2. Oxytocin

      The drug of choice for induction of parturition. Will terminate pregnancy after 310 days, regardless of fetal maturity, so fetal readiness for birth must be determined. Low doses (eg 2.5 - 10 units) give smoother delivery than larger doses (> 40 units). Can be repeated every 20 minutes. Foaling usually begins in 15-30 minutes and is complete within 1 hour.

    3. Corticosteroids

      Although effective in other species, they are essentially ineffective in inducing parturition or terminating pregnancy in the mare.

  7. THERAPY FOR EQUINE ENDOMETRITIS

    Therapy for uterine infections is controversial. The following are some considerations to bear in mind as you form your own opinions on the subject.

    1. Intrauterine antibiotics

      Anti biotics are used widely to treat endometritis. Because the caudal genital tract contains bacteria, it is almost impossible to introduce antibiotics into the uterus without introducing some bacteria. In addition, mares are recontaminated with vaginal and clitoral flora at breeding, culture, or insemination. These are excellent circumstances for selection of antibiotic resistant organisms. Intrauterine yeast infections are common sequelae of extensive use of intrauterine antibiotics. In addition, the ability of mares, even susceptible mares, to self clear is substantial. Heavy growth of an organism from culture at the onset of estrus may be eliminated in a few days with no antimicrobial therapy. Antibiotics, such as gentocin, may disrupt uterine defenses. Indications for specific antimicrobial therapy should probably include isolation of the same organism in heavy growth on 2 successive occasions.

    2. Saline lavage

      Saline by itself is bactericidal. Intrauterine lavage with saline is as effective as intrauterine penicillin in reducing numbers of intrauterine streptococci. Removal of intrauterine fluid and exudate by lavage is an valuable preventative and treatment for equine endometritis, regardless of the organism. Although by nature invasive and potentially irritating, it is usually well tolerated by the reproductive tract.

    3. Oxytocin

      Uterine defenses require that intraluminal fluid be removed, and that the walls of the uterus be brought into close apposition. Oxytocin achieves this without invading the uterus. Repeated dosage is easy and safe. 10 IU IV or 20 IU IM is a common dose. Ultrasonographic monitoring post breeding allows one to judge the need for oxytocin or lavage on a mare by mare basis.