The mare is seasonally polyestrus. The proportion of cycling mares is highest in the summer months in both the Northern and Southern Hemispheres. However, a small fraction of mares will continue to cycle throughout the year.1,2 During winter, most mares are in a reproductively quiescent state, with small inactive ovaries. Winter anestrus is characterized by reduced pituitary production of follicle stimulating hormone (FSH) and luteinizing hormone (LH) and reduced secretion of hypothalamic gonadotrophin-releasing hormone (GnRH). After the winter solstice, increasing hours of daylight result in an increase in production and secretion of GnRH and a resultant increase in the pituitary hormones FSH and LH.3 Most mares will enter a phase of transition between winter anestrus and normal cyclicity known as vernal transition. This phase is dominated by rises in FSH and waves of follicular development which are not accompanied by ovulation.1,2 Vernal transition can persist for many weeks in which large follicles develop and the mare demonstrates fluctuations in sexual receptivity. Once the first ovulation occurs, mares usually resume normal cyclicity until the end of the physiologic breeding season. The characteristics of the autumnal transition from cyclicity to anestrus are similar to the vernal transition. Estrus is the behavioral expression of sexual receptivity in the mare, and typically accompanies the follicular phase of the reproductive cycle.4 Diestrus is the phase of the cycle in which the mare is not receptive, and typically accompanies the luteal phase of the cycle.4 In normally cycling mares, each ovulation occurs approximately 21 days apart, and mares typically display estrus for 5–9 days, with ovulation occurring 1–2 days prior to the cessation of estrus.2,4–6 Hormonal concentrations of estradiol and luteinizing hormone rise during estrus.7 Serum progesterone concentration rises within 24–36 hours after ovulation and causes cessation of estrous behavior.6 In the absence of progesterone, estradiol-17β is responsible for the behavioral and physiological changes that accompany estrus in mares.4,8–10 Rarely, seasonally anovulatory mares, ovariectomized mares and pregnant mares have been reported to show behavioral signs of estrus which is thought to arise from the effects of hormones secreted by the adrenal cortex.11,12 Owners or trainers might seek advice of a veterinarian in managing estrus in mares. Estrus is perceived to impede performance or disrupt training through the presence of back or hindquarter pain, increased aggression, ears back and tail swishing during riding or handling, submissive behavior or overt expression of estrus, such as winking, crouching and urinating.13 It must be recognized that some problems which are perceived to be associated with estrus are not estrous behaviors. In some mares, problems attributed to the reproductive hormones are actually observed in the diestrous phase of the cycle. 14 In many situations, the manner in which the problem behavior is expressed is not specific to estrus and could be confused with other problems such as lameness, lack of training, or poor environmental enrichment. Behaviors which can easily be confused with estrus expression include submissive behaviors, urogenital discomfort and stallion-like behavior.15 In estrus, mares usually express behaviors towards stallions, but these can also be directed at geldings. Typical signs include a relaxed, raised tail, ears neutral or forwards, leaning inwards, adoption of breeding posture, urinating and clitoral winking (see Fig. 59.1).8 Submissive behaviors are distinct from estrous behaviors in that they typically involve leaning away from perceived threats, urinating and swishing the tail. Some mares experience pain in the peri-ovulatory period, and this can range in intensity from mild discomfort on manual rectal palpation of the ovary, to back pain or overt colic.8,16 In women, changing levels of estrogen and progesterone within the menstrual cycle can influence non-reproductive body systems such as the musculoskeletal system. These effects include changes in pain perception, muscle recovery and tendon distensibility.17–19 Therefore it is plausible that performance in mares could be affected by the stage of the reproductive cycle. Research looking specifically at this area in mares is lacking. The following procedures should be considered as part of a veterinary examination: • general physical examination with particular consideration to ruling out other causes of a change in performance (musculoskeletal pain or disease involving another body system) • observation of mare behavior when exposed to an intact stallion • transrectal palpation and ultrasonographic examination of the genital tract at a time when the mare is showing behavior suggestive of estrus • measurement of blood concentrations of reproductive hormones such as progesterone, estradiol, testosterone and inhibin. This is particularly important if a granulosa cell tumour is a differential diagnosis for behavioral problems. Diagnostic confirmation is reliant on observing typical estrous behavior along with ultrasonographic and biochemical features consistent with estrus. Ultrasonographic features of estrus are described in detail elsewhere, but generally include the presence of one or more dominant follicles (>25 mm diameter) on the ovary, the absence of a functional corpus luteum on the ovary, and uterine edema with observation of uterine folding (see Figs 59.2 and 59.3).4 Rectal palpation would be expected to reveal a soft cervix and this would also be visible on vaginal speculum examination. Reliably, progesterone will be <1 ng/ml in a mare in estrus and >1 ng/ml in diestrus. Blood concentrations for some hormones can vary widely depending on the assay used and the time of day the sample was taken. A concentration of estradiol in the range 20–45 pg/ml is consistent with estrus. An inhibin concentration >0.7 ng/ml or a testosterone concentration >100 pg/ml are consistent with a granulosa cell tumour. An ideal estrus control product should be highly effective at suppressing signs of estrus, easily administered, rapidly absorbed, require infrequent dosing and be safe for both animals and people.20 It should have no residual effect on fertility, should not affect performance, and should allow treated animals to begin a breeding career following withdrawal of treatment. There should ideally be no restriction on use of the product by rules controlling athletic horse events. The FEI publishes a list of prohibited or restricted substances at www.fei.org. Advice should be sought from other jurisdictions as to their rules for racing or competition as these can vary widely between countries and between different organizing bodies within the same country. As described, ovarian function and expression of reproductive behavior are based on feedback mechanisms within the hypothalamo–pituitary–ovarian axis. Manipulation of the various points within this axis can allow for suppression of estrous behavior alone or both estrous behavior and ovulation. The primary methods for suppression of behavior include administration of exogenous progesterone or progestins, extending the duration of corpora lutea function, suppressing ovarian follicular activity and ovariectomy.15 Display of estrous behavior in mares is reliant more on the absence of progesterone than on the presence of estrogen.8,10 Exogenous administration of efficacious progestagens inhibits estrous behavior and delays ovulation.21,22 Natural progesterone and altrenogest are the progestagens with demonstrated efficacy.23,24 Many other synthetic progestagens have been proven to not be effective in suppressing estrus or ovulation21,22 or in maintaining pregnancy.25–27 The failure of many synthetic progestagens to induce an effect in mares might be due to a lack of binding to progesterone receptors in this species. Progesterone in oil administered daily at a rate of 100 mg or more is effective in suppressing behavioral signs of estrus in mares.23 However, the requirement for daily intramuscular injection and the propensity of the formulation to induce injection site reactions renders it impractical for use in performance mares and fillies. Administration of a long-acting, compounded formulation of 1.5 g progesterone maintains serum levels of progesterone above 1.0 ng/ml, sufficient to suppress estrous behavior, for approximately 10 days28 and a compounded formulation of 600 mg (BioRelease P4 LA300) maintained serum progesterone above 1.0 ng/ml for approximately 7 days.29 Whilst these formulations show promise in that they alleviate the need for daily injection, consideration should be given to the potential for injection site reactions with repeated use in performance mares.15,28 Progesterone implants designed for use in other species, such as Synovex S (Fort Dodge Animal Health) designed for use in steers, are unlikely to contain sufficient quantities of progesterone to suppress estrus in mares. The administration of 80 Synovex S pellets, a total dose of 2000 mg progesterone and 200 mg estradiol per mare, did not suppress estrus.30 Intravaginal progesterone-releasing sponges are effective in suppressing behavioral oestrus in mares and have been used in breeding programs.31–33 However, in addition to being unsightly and potentially uncomfortable, the devices would need to be replaced weekly and potentially harmful effects of a prolonged intravaginal device on future reproductive potential have not been investigated. Therefore these devices are not recommended for controlling estrous behavior in performance mares. Altrenogest (Regu-Mate®, Intervet, Millsboro, DE) is a synthetic progestin registered for use in horses for suppressing estrus. It is likely to be the most commonly used pharmacological agent for this purpose across the world. Daily oral administration of altrenogest (0.044 mg/kg) to mares effectively inhibits behavioral estrus.34 The threshold concentration of altrenogest required to suppress estrous behavior is lower than that required to suppress LH release and ovulation.22 Continued expression of estrous behavior has been observed in mares treated with altrenogest and this therapeutic failure could be due to incorrect dosing (half-life is short and dosing needs to be at 24-hour intervals not 7 a.m. one day and 7 p.m. the next), failure in administration, errors in estrus detection, treatment during estrus and individual variability in responsiveness to the treatment. In mares treated for 88 days, altrenogest effectively suppressed estrus with no evidence of adverse effects.24 Mares receiving long-term altrenogest treatment demonstrated normal fertility when bred following withdrawal of the drug.24 There is a risk that progestin therapy could promote uterine infection due to maintenance of a closed cervix. Consideration should be given to this potentially adverse effect when administering long-term progestin therapy. The use of long-acting injectable altrenogest formulations has become popular in some countries for their ease of use and affordability. Several different formulations are available. The BioRelease MP 500 formulation, containing a total of 500 mg of altrenogest, provided the most prolonged suppression of estrus in one study.22 Mares receiving BioRelease MP 500 ovulated a mean of 33.5 days after luteolysis was induced with prostaglandin F2α, compared to 8.8 days in control mares receiving 225 mg or 450 mg of altrenogest, respectively.22 A further observation in this study was that several mares receiving BioRelease MP 500 did not show estrus at the time of ovulation and for variable periods up to 49 days after injection.22 When considering the use of altrenogest in performance mares, trainers can be reassured that the product does not have any effect on body mass, condition score or dominance hierarchies, which was used as a model for aggression.35 Of concern when handling oral formulations of altrenogest, is that the product is readily absorbed through human skin and there are anecdotal reports of the product interfering with the reproductive cycle and lactation in women. Therefore strict recommendations should be made for personnel to wear impervious gloves when handling the product. Other synthetic progestagens infrequently administered to horses include medroxyprogesterone acetate (Depo-Provera, Pharmacia), hydroxyprogesterone caproate (also labeled as hydroxyprogesterone hexanoate), chlormadinone acetate, norgestomet and melengestrol acetate. Several studies have found medroxyprogesterone acetate ineffective for suppressing estrus21,22 or for maintaining pregnancy after prostaglandin F2α-induced luteolysis.25 Hydroxyprogesterone caproate/hexanoate failed to maintain pregnancy and did not block the return to estrus in pregnant mares without a functional corpus luteum.25,26 Limited evidence suggests chlormadinone acetate ineffective for suppression of estrus in mares.36 Norgestomet is also ineffective for suppressing estrus37 or maintaining pregnancy.25 Therefore, the use of these products at the dosages studied cannot be recommended for suppression of estrus in performance mares. Melengestrol acetate, administered orally at a dose rate of 15 or 20 mg once daily did not suppress estrus.23 However, a more recent study suggested that at a dose rate of 100–150 mg orally once daily, this product could have an effect in mares.38 Establishment of pregnancy prevents the secretion of prostaglandin F2α from the endometrium, and thus a progesterone-secreting corpus luteum (CL) is maintained on the ovary. Maternal recognition of pregnancy in the mare is reliant on the presence of a mobile embryo within the uterus prior to day 14 post-ovulation. Prolonged luteal function can be maintained despite loss of the pregnancy if the embryo is terminated by manual crushing (via transrectal ultrasonography) on day 16–22 post-ovulation.39 Following this procedure, the corpus luteum is maintained, and estrus suppressed for at least 60 days.39 Although this method appears to be highly efficacious, it requires considerable investment in first establishing a pregnancy and might be considered unethical by some horse owners. Intrauterine balls, made of glass or polypropylene, can mimic the effect of an embryo in stimulating maternal recognition of pregnancy, suppression of prostaglandin F2α and CL maintenance.40,41 Using aseptic technique, a sterile glass ball (www.glassmarble.com) is manually placed through the cervix into the uterine body within 24 hours after ovulation, when the cervix should still be soft and open, but beginning to close. A 35 mm ball was retained in 12/12 mares, whereas a 25 mm ball was retained in only 6/12 mares.41 Of 18 mares that retained the ball, estrus was suppressed in 7 (39%).41 The duration of estrus suppression following placement of the ball ranged from 76 to 109 days.41 This study also observed spontaneous prolonged luteal function, which is a well-recognized phenomena in mares, in 4/50 control cycles.41 Removal of the glass ball is recommended when estrus suppression is no longer needed. The ball can be retrieved via a combination of per rectum and per vagina manipulation. Water-filled polypropylene intrauterine balls were also effective in prolonging the luteal phase in 9/12 mares.40 Evidence suggests that placement of these intrauterine devices does not have an adverse effect on fertility.40,41 However, there are anecdotal reports of the marbles fracturing in the uterus, with potentially severe consequences.15 Placement of the intrauterine devices could be a relatively inexpensive, although somewhat unreliable, non-pharmacological method of long-term estrus suppression in mares. Administration of 60 IU oxytocin IM twice daily in early diestrus (days 7–14 after ovulation) induces a prolonged luteal phase and maintains serum progesterone above 1.0 ng/ml for greater than 30 days.42 The exact mechanism behind the effectiveness of this protocol is not certain, but it is thought to block the oxytocin-induced prostaglandin F2α release from the endometrium which normally induces luteolysis.42 Vanderwall also reports that once-daily intramuscular administration of 60 IU oxytocin during this phase of the cycle is as effective as the twice-daily protocol first described.15,42 Whilst the effect on estrus behavior was not studied directly, the endogenous progesterone levels maintained were high enough to suppress behavioral estrus. The researchers also suggested that the prolonged luteal phase could be terminated by the administration of prostaglandin F2α.42 No adverse effects were observed in any of the mares receiving oxytocin for prolongation of the luteal phase. However, consideration should be given to the propensity of oxytocin to induce mild colic in horses,43 and other effects on smooth and striated muscle. Notwithstanding, this protocol could be considered as a long-term method of suppressing estrus in performance mares. A recent study, designed to investigate the role of estrogen on maternal recognition of pregnancy, revealed that infusion of plant oil into the uterine lumen in late diestrus prolonged the luteal phase.44 The effect was most reliable when performed on day 10 post-ovulation, and infusion of a 1 ml dose of either fractionated coconut oil with estradiol (10 mg/ml), fractionated coconut oil or peanut oil prolonged the luteal phase in 11/12 treated mares.44 In mares which responded to the treatment, endogenous progesterone concentrations were maintained above 1 ng/ml for 30 days, at which point luteolysis was achieved by the administration of prostaglandin F2α. The mechanism by which plant oils suppressed luteolysis is not clear. The authors proposed that fatty acids present in the oil interrupted prostaglandin synthesis or release from the endometrium.44 The failure of mineral oil to induce a similar response suggests that a physical effect of the oil in the endometrium was not responsible for prolonged luteostasis.44
Reproductive management of the athletic horse
The mare
Normal estrus
Suppression of estrus in mares
Pharmacologic suppression of estrus
Progestagens
Pregnancy
Intrauterine balls
Oxytocin
Intrauterine oil
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