2009: The heat is on: what's new for suppression of estrus in mares The heat is on: what’s new for suppression of estrus in mares 1 D. K. Vanderwall 2 Department of Clinical Studies, New Bolton Center, School of Veterinary Medicine, University 3 of Pennsylvania, Kennett Square, PA, USA 4 5 Abstract 6 Therapeutic suppression of estrus in mares is routinely performed when exhibition of 7 estrous behavior is deemed undesirable or it interferes with intended uses such as recreational 8 and/or performance activities. Various modalities are available for suppression of estrus in 9 mares, each with its own advantages, disadvantages and efficacy (or lack of). This paper will 10 review currently available methods of suppressing estrous behavior in mares, which includes 11 administration of exogenous progesterone/progestins, extending the duration of corpora luteal 12 function, suppressing ovarian follicular activity and ovariectomy. Particular emphasis will be 13 placed on recent studies supporting or refuting the effectiveness of these methods of blocking 14 estrus, so the clinician can identify the most suitable and efficacious method of suppressing 15 estrus for horse owners and their animals. 16 17 Keywords: Equine, mare, estrus, estrous behavior, therapeutics 18 19 Introduction 20 A relatively common complaint of horse owners and trainers is variable performance in 21 mares related to the estrous cycle.1 Similarly, approximately 90% of over 750 veterinarians 22 507 responding to a survey had the clinical impression the estrous cycle impacted the performance of 23 mares, and the most frequently reported clinical sign associated with an effect of the 24 reproductive cycle on performance was attitude change, while other signs included tail swishing, 25 difficulty to train, squealing, “horsing”, excess urination, kicking, and a decrease in 26 performance.2 In some cases undesirable behavior has been associated with estrus and in other 27 cases with diestrus.3 It is important to note that some problematic behaviors displayed by mares 28 that are thought to be associated with estrus, are in fact not estrous behaviors; in particular, 29 submissive behavior may be most easily confused with estrous behavior. Submissive behavior 30 includes leaning away from perceived threats, swishing/ringing the tail and actively squirting 31 urine, which collectively can give the impression of estrus.4 In contrast to submissive behavior, 32 true estrous behavior includes leaning towards the stallion (or other stimulus), a relaxed lifting 33 motion of the tail, stationary/squatting stance and passive urination (full stream or small amounts 34 in spurts).4 In some mares the signs of true estrous behavior are so strong as to directly impair 35 performance; for example, even under saddle some mares may “break down” and show estrus in 36 response to being around other horses and/or other stimuli.4 In other mares, the condition may 37 be much more subtle, simply causing owners and trainers to report the mare is less cooperative 38 or attentive during estrus.1 39 In an effort to evaluate the potential for an effect of stage of estrous cycle on the behavior 40 of mares, Hedberg et al.5 conducted two behavior tests (novel object and isolation) on 12 mares 41 once when they were in estrus and once during diestrus in a cross-over design. Five of the mares 42 served as controls, while the other seven mares were classified as “problem” mares based on 43 their owner’s perception of estrus-related behavioral problems. There were no significant 44 508 differences in the behavioral responses between estrus and diestrus within the control and 45 “problem” groups, nor were there differences in the behavioral responses between the two 46 groups of horses; however, as the authors note, the sample size was small and a cross-over study 47 design may not have been the most appropriate experimental design. Therefore, further work in 48 this area is warranted. 49 Ideally, a complaint of an estrous cycle-related behavior/performance problem in a mare 50 should be systematically evaluated in order to determine if the problematic behavior is or is not 51 related to a specific phase of the cycle (i.e., estrus or diestrus). A team approach to evaluating 52 and addressing the problem involving behavioral and reproductive expertise may be beneficial.6 53 In situations where there is evidence that the problematic behavior is associated with estrus, 54 suppression of estrus may be warranted. It is also common to suppress estrus in situations where 55 the signs of estrous behavior are simply perceived to be associated with performance problems or 56 to preemptively block the behavior to preclude the possibility of an adverse effect of estrus on 57 performance. This paper will review currently available methods of suppressing estrous 58 behavior in mares, with particular emphasis on recent data that support or refute various methods 59 of blocking estrus. The following methods of suppressing estrous behavior will be discussed: 1) 60 administration of exogenous progesterone/progestins, 2) extending the duration of corpora luteal 61 (CL) function, 3) suppressing ovarian follicular activity and 4) ovariectomy. 62 Administration of exogenous progesterone/progestins 63 Progesterone 64 It was first demonstrated in the 1960's that daily intramuscular administration of 100 mg 65 progesterone in oil (0.2 mg/kg) effectively suppressed signs of estrus in mares.7 Intramuscular 66 509 administration of 100 mg progesterone in oil to ovariectomized mares produced peak systemic 67 blood levels of approximately 2 ng/mL, which then declined to 1 ng/mL or less 24 hours later.8 68 Progesterone in oil is available from several compounding pharmacies; however, the need for 69 daily administration and the potential for soreness at the site of injection are limitations to its use. 70 It has also been demonstrated that intramuscular administration of a compounded long-acting 71 formulation of progesterone containing a total dose of 1.5 g progesterone will maintain blood 72 levels of progesterone above 1.0 ng/mL for approximately 10 days,9 which is a sufficient level of 73 progesterone to block estrous behavior;7,8 however, the potential for soreness at the injection site 74 is a limitation to its use, particularly in performance horses. 75 Altrenogest 76 Altrenogest (Regu-Mate®, Intervet/Schering-Plough Animal Health, Millsboro, DE, 77 USA) is a synthetic progestin approved for use in horses for suppressing estrus, and is widely 78 considered to be the “gold-standard” method of inhibiting estrous behavior. Daily oral 79 administration of altrenogest at a dose of 0.044 mg/kg (1 mL per 110 lbs of body weight) is very 80 efficacious for suppressing estrus in mares;10,11 however, the need for daily administration is a 81 drawback to its use. It was recently reported that intramuscular administration of a compounded 82 preparation containing 225 mg or 450 mg of altrenogest in a sustained-release vehicle blocked 83 estrous behavior for approximately 12 and 15 days, respectively, while administration of 500 mg 84 altrenogest in lactide-glycolide microparticles suppressed estrous behavior for approximately 30 85 days.12 86 Medroxyprogesterone acetate 87 510 Although there are anecdotal reports on the use of the synthetic progestin 88 medroxyprogesterone acetate (MPA) for estrus suppression in mares, it was recently reported 89 that intramuscular administration of an initial dose of 1,600 mg MPA followed by 400 mg once 90 weekly for five weeks did not suppress estrous behavior in mares.13 Similarly, administration of 91 1,000 mg MPA in an aqueous suspension did not prolong the return to estrus compared to 92 control mares.12 On a related note, MPA was unable to maintain pregnancy in mares following 93 induced luteolysis when 1,000 mg was administered intramuscularly every seven days.14 94 Therefore, the use of MPA for suppression of estrus cannot be advocated. 95 Hydroxyprogesterone caproate 96 Although it has not been tested for its efficacy for suppressing estrous behavior in mares, 97 McKinnon et al. demonstrated that intramuscular administration of 500 mg hydroxyprogesterone 98 caproate every other day was unable to maintain pregnancy in ovariectomized mares.15 99 Similarly, the same synthetic progestin, repackaged as hydroxyprogesterone hexanoate, though 100 labeled for pregnancy maintenance was unable to maintain pregnancy in mares when 500 mg 101 was administered intramuscularly every four days following induced luteolysis.14 Therefore, the 102 use of hydroxyprogesterone caproate for suppression of estrus cannot be advocated. 103 Melengestrol acetate 104 Melengestrol acetate (MGA), a synthetic progestin, is labeled as a feed additive for estrus 105 suppression in cattle. However, when fed to mares at 10 or 20 mg/day for up to 15 days, it failed 106 to block estrus.7 It has been suggested higher doses (>100 mg/day) may be effective for 107 suppression of estrus in mares,16 which may be plausible, since it was recently reported that oral 108 administration of 100 mg or 150 mg MGA to mares during the spring transitional phase 109 511 significantly hastened the onset of ovulatory activity compared to control mares indicating 110 apparent biological activity of higher doses of MGA.17 Therefore, further work to evaluate the 111 effect of higher doses of MGA on estrous behavior is warranted. 112 Implants 113 A variety of implants containing various progestins, labeled and marketed for use in other 114 species, have been used in mares with the intent of suppressing estrus. The most widely used 115 implant has been Synovex S® (Fort Dodge Animal Health, Ft. Dodge, IA, USA), which contains 116 200 mg progesterone and 20 mg estradiol benzoate in each dose of eight pellets. McCue et al. 117 were unable to suppress estrus or cyclicity in mares that received 80 Synovex S® pellets.18 118 Similarly, although not critically tested for its ability to suppress estrous behavior, Scheffrahn et 119 al. reported that following subcutaneous placement of a implant containing 6.0 mg of the 120 synthetic progestin norgestomet in six mares, two of the mares displayed estrous behavior two 121 days before the implants were removed 10 days after placement. 19 On a related note, placement 122 of five subcutaneous implants containing a total of 15 mg norgestomet was unable to maintain 123 pregnancy in mares following induced luteolysis.14 Therefore, at this time, there is no evidence 124 that implants containing progesterone/progestins have efficacy for suppression of estrus in 125 mares, so their use cannot be advocated. 126 Extending CL function 127 Intra-uterine glass marble 128 One alternative to the use of exogenous progesterone/progestins for estrus suppression is 129 intrauterine insertion of a glass ball to extend CL function, which allows continued secretion of 130 endogenous progesterone to block estrus. Nie et al. reported that placement of a 25 or 35 mm 131 512 sterile glass ball into the uterine body immediately following ovulation resulted in prolonged CL 132 function in seven of 18 (39%) mares that retained the glass ball after insertion (six of 12 mares 133 expelled the glass marble).20 In mares that developed prolonged CL function following 134 placement of the glass ball, CL function was maintained for approximately 90 days, during 135 which time progesterone levels remained above 1.0 ng/mL and estrous behavior was not 136 exhibited. In non-treated control mares, spontaneous prolongation of CL function occurred in 137 four of 32 (13%) mares. Although placement of a glass ball appeared to be an efficacious means 138 of blocking estrous behavior for an extended period of time, it should be noted that in addition to 139 the 11 mares that retained the glass ball and never developed extended CL function (i.e., 140 continued to cycle normally), three of the seven glass ball treated mares with extended CL 141 function had one or two estrous cycles of normal duration after placement of the glass ball before 142 CL function was prolonged. Therefore, on a “per-cycle” basis the incidence of prolonged CL 143 function was only 11% (7/62 cycles) in the glass ball treated mares compared to 8% (4/50 144 cycles) in the non-treated control mares, which was not significantly different between groups. 145 Because of its variable efficacy among mares, and the need to physically remove the glass ball 146 when the resumption of cyclical reproductive activity is desired, placement of an intrauterine 147 glass ball does not appear to be an optimal method of suppressing estrous behavior in mares. 148 In a more recent study, Rivera del Alamo et al. examined the effect of intrauterine 149 placement of a 20 mm water-filled polyproplylene ball on the duration of CL function in mares 150 with the specific objective of investigating two potential mechanisms by which CL function is 151 extended: 1) the intrauterine device induces mild endometrial inflammation that completely 152 blocks or markedly attenuates prostaglandin (PG) F2α secretion (i.e., prevents high magnitude 153 513 luteolytic pulses) or 2) the physical presence of the device (movement and/or contact with the 154 endometrium) directly mimics the inhibitory effect of a conceptus on PGF2α secretion.21 155 Corpora luteal function was extended in nine of 12 mares (75%) with an average duration of 57 156 days compared to zero of 12 control mares in which the average duration of CL function was 16 157 days. In six of the nine mares with extended CL function, small accumulations of intrauterine 158 fluid (≤10 mm x 20 mm) were identified during the luteal phase, but no neutrophils or bacteria 159 were recovered on uterine swabs when they were examined during the subsequent estrus. In 160 addition, changes in uterine biopsy scores for inflammation and glandular dilation pre- and post-161 treatment were similar for control and uterine device mares (with or without extended CL 162 function); therefore, there was no evidence the intrauterine device induced an inflammatory 163 response in the uterus. Based on intensive blood sampling and measurement of PGF2α 164 metabolite (PGFM) levels in the systemic circulation on days 11 to 16 post-ovulation in four 165 control and eight uterine device mares, PGF2α secretion was attenuated in mares with prolonged 166 CL function, with the exception of two mares; one mare showed a single PGFM peak and 167 another showed two isolated PGFM peaks. Because there was no evidence of inflammatory 168 changes caused by the intrauterine device, the authors concluded the physical presence of the 169 device in the uterine lumen somehow mimicked the effect of a conceptus by impairing 170 endometrial secretion of PGF2α; however, the exact mechanism remains unknown. 171 Administration of exogenous oxytocin 172 In contrast to using an intrauterine device to extend CL function, administration of 173 exogenous oxytocin during diestrus is an alternative method of blocking luteolysis to prolong CL 174 function. Endogenous oxytocin secretion is involved in regulating prostaglandin PGF2α 175 514 secretion from the endometrium during spontaneous luteolysis in the mare,22,23 and although 176 administration of exogenous oxytocin to mares around the time of luteolysis (i.e., days 11 to 15 177 post-ovulation) stimulates an acute onset of PGF2α secretion, 24-26 when oxytocin is administered 178 in the mid-luteal phase prior to the expected time of luteolysis (i.e., before day 10 post-ovulation) 179 it does not induce PGF2α secretion and often disrupts luteolysis causing prolonged CL 180 function.25 181 Experimentally, continuous infusion of oxytocin using a subcutaneous osmotic minipump 182 from day eight to 20 post-ovulation blocked luteolysis in four of five mares, whereas luteolysis 183 occurred at the expected time in all four control mares that received saline infusion.27 Although 184 it successfully induced prolonged CL function, continuous infusion of oxytocin to disrupt 185 luteolysis would not be a practical method of long-term suppression of estrous behavior. More 186 recently, Vanderwall et al. showed that twice daily intramuscular administration of 60 units of 187 oxytocin on days seven to 14 post-ovulation was an efficacious method of disrupting luteolysis, 188 since it caused prolonged CL function through day 30 post-ovulation in six treated mares (Figure 189 1), whereas six saline-treated control mares underwent luteolysis by day 16 post-ovulation 190 (Figure 2).28 Progesterone levels fell below 1.0 ng/mL between days 30 and 40 in two of the 191 mares with prolonged CL function, while the other four mares maintained progesterone levels 192 above 3.0 ng/mL through day 40 when blood sampling was discontinued. The cessation of CL 193 function before day 40 in two mares may have reflected a seasonal effect on CL function, since 194 the study was completed at the end of the physiological breeding season when gonadotropin 195 secretion wanes, and CL function (i.e., progesterone secretion) is dependent upon adequate 196 support from endogenous gonadotropin secretion.29-31 A follow-up study (Vanderwall et al., 197 515 unpublished) was then performed to compare use of the same dose of oxytocin (60 units) given 198 twice daily compared to once daily on days seven to 14 post-ovulation; CL function was 199 maintained for 50 days post-ovulation in five of seven mares treated twice daily, five of eight 200 mares treated once daily and in one of seven untreated control mares. There was no difference 201 (P>0.05) in the proportion of mares with extended CL function between once daily and twice 202 daily administration of oxytocin, whereas collectively oxytocin treatment increased (P<0.05) the 203 proportion of mares with extended CL function. An advantage of using exogenous oxytocin 204 treatment to prolong CL function is that it can be readily reversed by the administration of a 205 luteolytic dose of PGF2α, in contrast to the need to physically remove an intrauterine device as 206 described above. 207 Inducing late-diestrus ovulation 208 In 2006, Hedberg et al. described the results of a preliminary study in which their 209 objective was to prolong the luteal phase in mares by using human chorionic gonadotropin 210 (hCG) to induce a late-diestrus ovulation to produce a new CL that would be too immature to 211 respond to the luteolytic effects of endogenous PGF2α secretion at the end of diestrus (i.e., day 212 14 to 15 after the initial ovulation).32 Mares were randomly assigned to control (n=4) and 213 experimental groups (n=5), and beginning on approximately day eight after ovulation (or last 214 signs of estrous in three mares) their ovaries were examined with transrectal ultrasonography 215 every other day to determine the size(s) of their diestrus follicles. When a diestrus follicle ≥30 216 mm was detected, control mares were treated with saline and the experimental mares were 217 treated with 3,000 IU hCG IM. After treatment the mares were followed with transrectal 218 ultrasonography for up to 72 hours or until ovulation was detected, and then once weekly for 219 516 three weeks. Beginning on the day of treatment, blood samples were collected twice weekly for 220 at least one month and then once weekly for another two to four months for progesterone 221 determination. If a mare did not develop a diestrus follicle ≥30 mm during the first diestrus 222 period, they were monitored for a second, and if necessary a third diestrus period. 223 Three of the nine mares developed a follicle ≥30 mm during the first diestrus period, 224 four mares during the second diestrus period and one mare in the third diestrus period. One 225 experimental mare never developed a diestrus follicle that was ≥30 mm during the three diestrus 226 periods that were monitored, and therefore, could not be treated with hCG. Overall, three out of 227 the four (75%) experimental mares treated with hCG ovulated within 72 hours after treatment 228 with hCG, which resulted in luteal phases that lasted for 58 to 82 days after treatment. None of 229 the control mares ovulated during the luteal phase; however, one control mare had a 230 spontaneously prolonged luteal phase during both a non-treated cycle in which she never 231 developed a diestrus follicle ≥30 mm (CL function was terminated with exogenous PGF2α) and 232 during the subsequent cycle in which she was treated with saline when she had a large diestrus 233 follicle (that did not ovulate). 234 Although, based on this study, the use of hCG to induce a late-diestrus ovulation looks 235 promising for prolonging CL function, it is important to note that as described above, for some 236 mares (five out of nine) it required multiple estrous cycles to develop a diestrus follicle ≥30 mm. 237 In addition, one mare never developed a large diestrus follicle during the three cycles that were 238 monitored, which precluded her from receiving the hCG treatment. Therefore, in addition to the 239 effort (and expense) of monitoring mares in order to evaluate their suitability for treatment, the 240 fact that some mares may not develop a large enough diestrus follicle to warrant treatment, the 241 517 use of hCG to induce a late-diestrus ovulation does not appear to be a reliable, “on-demand” 242 method of blocking estrous behavior in mares. It is interesting to note that although the use of 243 hCG was apparently efficacious for inducing ovulation of diestrus follicles ≥30 mm in diameter 244 in this study by Hedberg et al.,32 previous work by Glazar et al.33 demonstrated that 245 administration of the GnRH agonist deslorelin acetate failed to induce ovulation and/or 246 luteinization of diestrus follicles > 30 mm in diameter. 247 Pregnancy 248 Pregnancy is another means of suspending cyclicity by taking advantage of the natural 249 ability of the conceptus to block luteolysis and maintain CL function/progesterone secretion. 250 Although efficacious, this method has obvious disadvantages that may make it undesirable for 251 many horse owners. In addition to the time and expense necessary to establish pregnancy, is the 252 need to eventually terminate pregnancy (unless an offspring is ultimately desired). Lefranc and 253 Allen reported that manual transrectal rupture of the conceptus between days 16 and 22 of 254 gestation in 11 mares resulted in continued CL function for at least 60 days in all of the mares, 255 during which time they did not display estrous behavior.34 Although efficacious, as noted above, 256 terminating a normal, healthy pregnancy may be untenable to many horse owners. 257 Suppressing ovarian follicular activity 258 When considering the use of suppression of ovarian follicular activity as a method of 259 blocking estrous behavior in mares, it is important to recognize that mares are unique among 260 domestic animals, because in addition to the ovarian-derived estrogen-induced signs of estrous 261 behavior that occur when progesterone is at a basal level, many seasonally anovulatory (and 262 ovariectomized) mares exhibit paradoxical estrous behavior associated with hormone secretion 263 518 from the adrenal cortex.35,36 The intensity of this type of “unseasonable” estrous behavior was 264 judged to be equivalent to the behavior intact cycling mares display during the initial and 265 terminal days of estrus, but less intense than the behavior displayed near ovulation.35 Such 266 behavioral receptivity to a stallion outside the breeding/ovulatory season that is independent of 267 ovarian estrogen secretion may have developed as a means of maintaining social bonds between 268 a harem stallion and his mares.35,37 This phenomenon has important implications for the clinical 269 management of estrous behavior in mares, since simply suppressing ovarian follicular activity 270 (or removing the ovaries) and its attendant estrogen production may not ensure the elimination of 271 estrous behavior. 272 Down-regulation of the hypothalamic-pituitary-ovarian axis with gonadotropin releasing 273 hormone (GnRH) analogs 274 Although a subcutaneous implant containing the potent GnRH analog deslorelin acetate 275 (Ovuplant®, Fort Dodge Animal Health) was initially developed and found to be efficacious for 276 inducing timed ovulation for the breeding management of mares,38,39 it soon became evident the 277 implant caused prolonged anovulatory intervals in some mares.40-42 Subsequent work 278 demonstrated the deslorelin implant caused reduced circulating FSH concentrations and absence 279 of the mid-cycle FSH peak that was associated with a prolonged inter-ovulatory interval.43 280 Although problematic for the breeding management of mares, the down-regulating effect of the 281 deslorelin implant on pituitary function has been used clinically to suppress ovarian activity; for 282 example, placement of two deslorelin implants suppressed follicular development in mares used 283 as recipients for oocyte transfer.44 Fitzgerald et al. reported suppressing ovulation for 30-90 days 284 in 15 of 20 mares that were treated with a subcutaneous implant containing another GnRH 285 519 analog (goserelin acetate).45 Collectively, these data indicate that treating mares with a potent 286 GnRH analog may be efficacious for suspending cyclicity and suppressing estrus in mares for 287 extended periods of time. However, as noted previously, since anovulatory mares can show 288 estrous behavior, suppressing follicular activity may not ensure a complete absence of estrous 289 behavior. 290 Immunologic 291 Immunizing a mare against GnRH would eliminate the stimulus for gonadotropin release 292 from the pituitary resulting in suspension of cyclicity. Tshewang et al. reported successfully 293 suspending ovarian activity and suppressing estrus for 25-30 weeks in mares after treating with a 294 GnRH vaccine.46 All of the vaccinated mares recovered from the effect of immunization with 295 normal cyclicity and estrous behavior. Over the next two seasons, each mare also conceived and 296 produced a normal foal. Subsequent studies have confirmed the efficacy of vaccination against 297 GnRH for suppressing ovarian follicular activity; however, not surprisingly, some of the 298 vaccinated mares continued to show estrous behavior in spite of their anovulatory state. It is 299 important to note, that in one study47 one vaccinated mare had not resumed normal ovarian 300 activity two years after initial vaccination; therefore, although most mares appear to regain 301 ovarian activity within a reasonable period of time post vaccination, some mares may not, which 302 could be particularly problematic. Although a GnRH vaccine is not currently available in North 303 America, commercial preparations are available in Europe and Australia (Equity®; Pfizer 304 Australia Pty Ltd, West Ryde, NSW, Australia). 305 Ovariectomy 306 520 Bilateral ovariectomy may be warranted in some circumstances for permanently 307 eliminating ovarian activity in mares. Although the ovaries can be removed through a ventral 308 abdominal or flank laparotomy, laparoscopy or a colpotomy, at this time the latter two methods 309 are most commonly utilized.48,49 In an initial report, Hooper et al. described the outcome of the 310 use of bilateral ovariectomy for treatment of objectionable behavior during estrus in 17 mares; 311 they found that after surgery owners reported that behavior was no longer a problem in 14 mares 312 (82%), while the remaining three mares continued to show estrous behavior.48 Of the 23 mares 313 in that study that underwent bilateral ovariectomy for any reason, eight (35%) continued to show 314 estrous behavior after surgery. In a recent report, Kamm and Hendrickson evaluated clients’ 315 perspectives on the outcome following the use of laparoscopic ovariectomy for behavioral and 316 medical problems in mares.49 Overall, client satisfaction (rated as very satisfied or satisfied) 317 with bilateral ovariectomy as a treatment for behavioral problems was 78% (18 of 23 of mares). 318 Assessment of outcomes for specific behavioral problems showed that aggression problems 319 improved in 86% of cases; general disagreeable demeanor improved in 81%; excitability 320 improved in 75%; kicking and biting at other horses improved in 73%; problems in training 321 improved in 72%; frequent urination improved in 64%; and problems with other horses 322 improved in 64% of cases. The most common source of dissatisfaction for owners of patients 323 with behavioral problems was lack of behavioral change after surgery, including continued signs 324 of estrous behavior. Although ovariectomy offers the advantage of being a potentially 325 permanent solution to a cycle-related behavior/performance problem, there are significant 326 disadvantages as well. The procedure is relatively expensive, though when compared to repeated 327 hormonal treatments, the cost may, in fact, be comparable. There are also risks associated with 328 521 the surgical procedure, though newer laparoscopic procedures have significantly reduced 329 them.48,49 The permanency of the procedure can also be a significant disadvantage because all 330 possibility for future reproduction is eliminated. And as noted above, because of the potential 331 for paradoxical estrous behavior, removing the ovaries may not ensure cessation of estrous 332 behavior. Therefore, this option should be weighed carefully before proceeding. One way of 333 evaluating the potential effectiveness of ovariectomy for a behavioral problem is to evaluate the 334 mare’s behavior during either a natural (i.e., seasonal) or induced anovulatory state (e.g., down-335 regulation with a GnRH agonist); if the problem is not resolved or at least significantly improved 336 during the anovulatory state, it is unlikely ovariectomy will be any more efficacious. 337 Summary 338 The primary indication for suppressing estrous behavior in mares is cycle-related 339 behavior/performance problems during estrus. When evaluating an owner/trainer complaint of 340 an estrous cycle-related problem in a mare, it should first be determined if the problematic 341 behavior is or is not related to a specific phase of the estrous cycle. In order to thoroughly 342 evaluate the mare, additional expertise may be needed in the form of consultation with or 343 referrals to behavior and/or reproduction experts. Once a behavior/performance problem is 344 confidently defined as being related to estrus, the previously discussed methods (with proven 345 efficacy) of suppressing estrous behavior can be considered for use. Each method has 346 advantages and potential disadvantages, that should be weighed for each individual 347 animal/owner/trainer. 348 References 349 522 1. McDonnell S:. Estrus cycle-related performance problems. J Equine Vet Sci 350 1997;17:196. 351 2. Jorgensen JS, Vivrette S, Correa M,et al: Significance of the estrous cycle on athletic 352 performance in mares. Proc Annu Conv Am Assoc Equine Practnr 1996;42:98-100. 353 3. McDonnell SM: Evaluation and modification of mare behavior problems. Proc Annu Mtg 354 Soc Therio 1993; p. 185-189. 355 4. McDonnell S: Performance problems in mares. The Horse; April 2000:61-70. 356 5. Hedberg Y, Dalin AM, Ohagen P, et al: Effect of oestrous-cycle stage on the response of 357 mares in a novel object test and isolation test. Reprod Domest Anim 2005;40:480-488. 358 6. McDonnell SM: Is it psychological, physical, or both? Proc Annu Conv Am Assoc 359 Equine Pract 2005;51:231-238. 360 7. Loy RG, Swan SM: Effects of exogenous progestogens on reproductive phenomena in 361 mares. J Anim Sci 1966;25:821-826. 362 8. Hawkins DL, Neely DP, Stabenfeldt GH: Plasma progesterone concentrations derived 363 from the administration of exogenous progesterone to ovariectomized mares. J Reprod 364 Fertil 1979 Suppl 27;211-216. 365 9. Vanderwall DK, Marquardt JL, Woods GL: Use of a compounded long-acting 366 progesterone formulation for equine pregnancy maintenance. J Equine Vet Sci 367 2007;27:62-66. 368 10. Squires EL, Stevens WB, McGlothlin DE, et al: Effect of an oral progestin on the estrous 369 cycle and fertility of mares. J Anim Sci 1979;49:729-735. 370 523 11. Webel SK, Squires EL: Control of the oestrous cycle in mares with altrenogest. J Reprod 371 Fertil 1982 Suppl 32;193-198. 372 12. Storer WA, Thompson DL, Jr., Gilley RM, et al: Evaluation of injectable sustained 373 release progestin formulations for suppression of estrus and ovulation in mares. J Equine 374 Vet Sci 2009;29:33-36. 375 13. Gee EK, McCue PM, DeLuca CA, et al: Efficacy of medroxyprogesterone acetate in 376 suppression of estrous behavior and follicular activity in cycling mares. Theriogenology 377 2008;70:588 (abstract). 378 14. McKinnon AO, Lescun TB, Walker JH, et al: The inability of some synthetic 379 progestagens to maintain pregnancy in the mare. Equine Vet J 2000;32:83-85. 380 15. McKinnon AO, Tarrida Del Marmol Figueroa S, Nobelius AM, et al: Failure of 381 hydroxyprogesterone caproate to maintain pregnancy in ovariectomized mares. Equine 382 Vet J 1993;25:158-160. 383 16. Neely DP: Progesterone/progestin therapy in the broodmare. Proc Annu Conv Am Assoc 384 Equine Pract 1988;34:203-218. 385 17. Lopez-Bayghen C, Zozaya H, Ocampo L, et al: Melengestrol acetate as a tool for 386 inducing early ovulation in transitional mares. Acta Vet Hung 2008;56:125-131. 387 18. McCue PM, Lemons SS, Squires EL, et al: Efficacy of Synovex-S implants in 388 suppression of estrus in the mare. J Equine Vet Sci 1997;17:327-329. 389 19. Scheffrahn NS, Wiseman BS, Vincent DL, et al: Reproductive hormone secretions in 390 pony mares subsequent to ovulation control during late winter. Theriogenology 391 1982;17:571-585. 392 524 20. Nie GJ, Johnson KE, Braden TD, et al: Use of an intra-uterine glass ball protocol to 393 extend luteal function in mares. J Equine Vet Sci 2003;23:266-273. 394 21. Rivera Del Alamo MM, Reilas T, Kindahl H, et al: Mechanisms behind intrauterine 395 device-induced luteal persistence in mares. Anim Reprod Sci 2008;107:94-106. 396 22. Vanderwall DK, Silvia WJ, Fitzgerald BP: Concentrations of oxytocin in the 397 intercavernous sinus of mares during luteolysis: temporal relationship with 398 concentrations of 13,14-dihydro-15-keto-prostaglandin F2a. J Reprod Fertil 399 1998;112:337-346. 400 23. Shand N, Irvine CHG, Turner JE, et al:. A detailed study of hormonal profiles in mares at 401 luteolysis. J Reprod Fertil 2000 Suppl 56;271-279. 402 24. Betteridge KJ, Renard A, Goff AK: Uterine prostaglandin release relative to embryo 403 collection, transfer procedures and maintenance of the corpus luteum. Equine Vet J 1985 404 Suppl 3;25-33. 405 25. Goff AK, Pontbriand D, Sirois J: Oxytocin stimulation of plasma 15-keto-13,14- dihydro 406 prostaglandin F-2a during the oestrous cycle and early pregnancy in the mare. J Reprod 407 Fertil 1987 Suppl 35;253-260. 408 26. Starbuck GR, Stout TA, Lamming GE, et al: Endometrial oxytocin receptor and uterine 409 prostaglandin secretion in mares during the oestrous cycle and early pregnancy. J Reprod 410 Fertil 1998;113:173-179. 411 27. Stout TAE, Lamming GE, Allen W:. Oxytocin administration prolongs luteal function in 412 cyclic mares. J Reprod Fertil 1999;116:315-320. 413 525 [8. Vanderwall DK, Rasmussen DM, Woods GL: Effect of repeated administration of 414 oxytocin during diestrus on duration of function of corpora lutea in mares. J Am Vet Med 415 Assoc 2007;231:1864-1867. 416 29. Pineda MH, Ginther OJ, McShan WH: Regression of corpus luteum in mares treated with 417 an antiserum against an equine pituitary fraction. Am J Vet Res 1972;33:1767-1773. 418 30. Pineda MH, Garcia MC, Ginther OJ: Effect of antiserum against an equine pituitary 419 fraction on corpus luteum and follicles in mares during diestrus. Am J Vet Res 420 1973;34:181-183. 421 31. Bergfelt DR, Ginther OJ: Embryo loss following GnRH-induced ovulation in anovulatory 422 mares. Theriogenology 1992;38:33-43. 423 32. Hedberg Y, Dalin AM, Santesson M, et al: A preliminary study on the induction of 424 dioestrous ovulation in the mare--a possible method for inducing prolonged luteal phase. 425 Acta Vet Scand 2006;48:12. 426 33. Glazar BS, McCue PM, Bruemmer JE, et al: Deslorelin on Day 8 or 12 postovulation 427 does not luteinize follicles during an artificially maintained diestrous phase in the mare. 428 Theriogenology 2004;62:57-64. 429 34. Lefranc AC, Allen WR: Nonpharmacological suppression of oestrus in the mare. Equine 430 Vet J 2004;36:183-185. 431 35. Asa CS, Goldfoot DA, Garcia MC, et al: Sexual behavior in ovariectomized and 432 seasonally anovulatory pony mares (Equus caballus). Horm Behav 1980;14:46-54. 433 36. Asa CS, Goldfoot DA, Carcia MC, et al: Dexamethasone suppression of sexual behavior 434 in the ovariectomized mare. Horm Behav 1980;14:55-64. 435 526 37. Crowell-Davis SL: Sexual behavior of mares. Horm Behav 2007;52:12-17. 436 38. Meinert C, Silva JFS, Kroetz I, et al: Advancing the time of ovulation in the mare with a 437 short-term implant releasing the GnRH analogue deslorelin. Equine Vet J 1993;25:65-68. 438 39. McKinnon AO, Nobelius AM, Tarrida Del Marmol Figueroa S, et al: Predictable 439 ovulation in mares treated with an implant of the GnRH analogue deslorelin. Equine Vet 440 J 1993;25:321-323. 441 40. Johnson CA, Thompson DL, Jr., Kulinski KM, et al: Prolonged interovulatory interval 442 and hormonal changes in mares following the use of OvuplantTM to hasten ovulation. J 443 Equine Vet Sci 2000;20:331-336. 444 41. Morehead JA, Blanchard TL. Clinical experience with deslorelin (OvuplantTM) in a 445 Kentucky Thoroughbred broodmare practice (1999). J Equine Vet Sci 2000;20:358-402. 446 42. Vanderwall DK, Juergens TD, Woods GL. Reproductive performance of commercial 447 broodmares after induction of ovulation with HCG or OvuplantTM (Deslorelin). J Equine 448 Vet Sci 2001;21:539-542. 449 43. Farquhar VJ, McCue PM, Nett TM, et al: Effect of deslorelin acetate on gonadotropin 450 secretion and ovarian follicle development in cycling mares. J Am Vet Med Assoc 451 2001;218:749-752. 452 44. Carnevale EM, Checura CH, Coutinho da Silva MA, et al: Use of deslorelin acetate to 453 suppress follicular activity in mares used as recipients for oocyte transfer. 454 Theriogenology 2001;55:358 (abstract). 455 45. Fitzgerald BP, Peterson KD, Silvia PJ. Effect of constant administration of a 456 gonadotropin-releasing hormone agonist on reproductive activity in mares: preliminary 457 527 evidence on suppression of ovulation during the breeding season. Am J Vet Res 458 1993;54:1746-1751. 459 46. Tshewang U, Dowsett KF, Knott LM, et al: Preliminary study of ovarian activity in fillies 460 treated with a GnRH vaccine. Aust Vet J 1997;75:663-667. 461 47. Imboden I, Janett F, Burger D, et al: Influence of immunization against GnRH on 462 reproductive cyclicity and estrous behavior in the mare. Theriogenology 2006;66:1866-463 1875. 464 48. Hooper RN, Taylor TS, Varner DD, et al: Effects of bilateral ovariectomy via colpotomy 465 in mares: 23 cases (1984-1990). J Am Vet Med Assoc 1993;203:1043-1046. 466 49. Kamm JL, Hendrickson DA. Client's perspectives on the effects of laparoscopic 467 ovariectomy on equine behavioral and medical problems. J Equine Vet Sci 2007;27:435-468 438. 469 470 471 528 Figure 1. Serum progesterone concentrations from the day of ovulation (day 0) through day 472 40 after ovulation in six mares treated with 60 units oxytocin intramuscularly 473 twice daily on days seven to 14 after ovulation (reprinted with permission from 474 JAVMA 2007;231:1864-1867). 475 476 Figure 2. Serum progesterone concentrations from the day of ovulation (day 0) through day 477 40 after ovulation in six mares treated with 3 mL sterile saline intramuscularly 478 twice daily on days seven to 14 after ovulation (reprinted with permission from 479 JAVMA 2007;231:1864-1867). 480 529 << /ASCII85EncodePages false /AllowTransparency false /AutoPositionEPSFiles true /AutoRotatePages /All /Binding /Left /CalGrayProfile (Dot Gain 20%) /CalRGBProfile (sRGB IEC61966-2.1) /CalCMYKProfile (U.S. Web Coated \050SWOP\051 v2) /sRGBProfile (sRGB IEC61966-2.1) /CannotEmbedFontPolicy /Warning /CompatibilityLevel 1.4 /CompressObjects /Tags /CompressPages false /ConvertImagesToIndexed true /PassThroughJPEGImages true /CreateJobTicket false /DefaultRenderingIntent /Default /DetectBlends true /DetectCurves 0.0000 /ColorConversionStrategy /CMYK /DoThumbnails false /EmbedAllFonts true /EmbedOpenType false /ParseICCProfilesInComments true /EmbedJobOptions true /DSCReportingLevel 0 /EmitDSCWarnings false /EndPage -1 /ImageMemory 1048576 /LockDistillerParams false /MaxSubsetPct 100 /Optimize true /OPM 1 /ParseDSCComments true /ParseDSCCommentsForDocInfo true /PreserveCopyPage true /PreserveDICMYKValues true /PreserveEPSInfo true /PreserveFlatness false /PreserveHalftoneInfo false /PreserveOPIComments false /PreserveOverprintSettings true /StartPage 1 /SubsetFonts true /TransferFunctionInfo /Apply /UCRandBGInfo /Preserve /UsePrologue false /ColorSettingsFile () /AlwaysEmbed [ true ] /NeverEmbed [ true ] /AntiAliasColorImages false /CropColorImages false /ColorImageMinResolution 300 /ColorImageMinResolutionPolicy /OK /DownsampleColorImages false /ColorImageDownsampleType /Average /ColorImageResolution 300 /ColorImageDepth -1 /ColorImageMinDownsampleDepth 1 /ColorImageDownsampleThreshold 1.50000 /EncodeColorImages false /ColorImageFilter /DCTEncode /AutoFilterColorImages true /ColorImageAutoFilterStrategy /JPEG /ColorACSImageDict << /QFactor 0.76 /HSamples [2 1 1 2] /VSamples [2 1 1 2] >> /ColorImageDict << /QFactor 0.15 /HSamples [1 1 1 1] /VSamples [1 1 1 1] >> /JPEG2000ColorACSImageDict << /TileWidth 256 /TileHeight 256 /Quality 30 >> /JPEG2000ColorImageDict << /TileWidth 256 /TileHeight 256 /Quality 30 >> /AntiAliasGrayImages false /CropGrayImages false /GrayImageMinResolution 300 /GrayImageMinResolutionPolicy /OK /DownsampleGrayImages false /GrayImageDownsampleType /Average /GrayImageResolution 300 /GrayImageDepth -1 /GrayImageMinDownsampleDepth 2 /GrayImageDownsampleThreshold 1.50000 /EncodeGrayImages false /GrayImageFilter /DCTEncode /AutoFilterGrayImages true /GrayImageAutoFilterStrategy /JPEG /GrayACSImageDict << /QFactor 0.76 /HSamples [2 1 1 2] /VSamples [2 1 1 2] >> /GrayImageDict << /QFactor 0.15 /HSamples [1 1 1 1] /VSamples [1 1 1 1] >> /JPEG2000GrayACSImageDict << /TileWidth 256 /TileHeight 256 /Quality 30 >> /JPEG2000GrayImageDict << /TileWidth 256 /TileHeight 256 /Quality 30 >> /AntiAliasMonoImages false /CropMonoImages false /MonoImageMinResolution 1200 /MonoImageMinResolutionPolicy /OK /DownsampleMonoImages false /MonoImageDownsampleType /Average /MonoImageResolution 300 /MonoImageDepth -1 /MonoImageDownsampleThreshold 1.50000 /EncodeMonoImages false /MonoImageFilter /FlateEncode /MonoImageDict << /K -1 >> /AllowPSXObjects false /CheckCompliance [ /None ] /PDFX1aCheck false /PDFX3Check false /PDFXCompliantPDFOnly false /PDFXNoTrimBoxError true /PDFXTrimBoxToMediaBoxOffset [ 0.00000 0.00000 0.00000 0.00000 ] /PDFXSetBleedBoxToMediaBox true /PDFXBleedBoxToTrimBoxOffset [ 0.00000 0.00000 0.00000 0.00000 ] /PDFXOutputIntentProfile () /PDFXOutputConditionIdentifier () /PDFXOutputCondition () /PDFXRegistryName () /PDFXTrapped /False /CreateJDFFile false /Description << /ENU ([Based on 'No Compression'] [Based on 'No Compression wbleeed'] [Based on '[High Quality Print]'] Use these settings to create Adobe PDF documents for quality printing on desktop printers and proofers. Created PDF documents can be opened with Acrobat and Adobe Reader 5.0 and later.) >> /Namespace [ (Adobe) (Common) (1.0) ] /OtherNamespaces [ << /AsReaderSpreads false /CropImagesToFrames false /ErrorControl /WarnAndContinue /FlattenerIgnoreSpreadOverrides false /IncludeGuidesGrids false /IncludeNonPrinting false /IncludeSlug false /Namespace [ (Adobe) (InDesign) (4.0) ] /OmitPlacedBitmaps false /OmitPlacedEPS false /OmitPlacedPDF false /SimulateOverprint /Legacy >> << /AddBleedMarks false /AddColorBars false /AddCropMarks false /AddPageInfo false /AddRegMarks false /BleedOffset [ 0 0 0 0 ] /ConvertColors /NoConversion /DestinationProfileName () /DestinationProfileSelector /NA /Downsample16BitImages true /FlattenerPreset << /PresetSelector /MediumResolution >> /FormElements false /GenerateStructure true /IncludeBookmarks false /IncludeHyperlinks false /IncludeInteractive false /IncludeLayers false /IncludeProfiles true /MarksOffset 6 /MarksWeight 0.250000 /MultimediaHandling /UseObjectSettings /Namespace [ (Adobe) (CreativeSuite) (2.0) ] /PDFXOutputIntentProfileSelector /NA /PageMarksFile /RomanDefault /PreserveEditing true /UntaggedCMYKHandling /LeaveUntagged /UntaggedRGBHandling /LeaveUntagged /UseDocumentBleed false >> << /AllowImageBreaks true /AllowTableBreaks true /ExpandPage false /HonorBaseURL true /HonorRolloverEffect false /IgnoreHTMLPageBreaks false /IncludeHeaderFooter false /MarginOffset [ 0 0 0 0 ] /MetadataAuthor () /MetadataKeywords () /MetadataSubject () /MetadataTitle () /MetricPageSize [ 0 0 ] /MetricUnit /inch /MobileCompatible 0 /Namespace [ (Adobe) (GoLive) (8.0) ] /OpenZoomToHTMLFontSize false /PageOrientation /Portrait /RemoveBackground false /ShrinkContent true /TreatColorsAs /MainMonitorColors /UseEmbeddedProfiles false /UseHTMLTitleAsMetadata true >> ] >> setdistillerparams << /HWResolution [2400 2400] /PageSize [612.000 792.000] >> setpagedevice