IN-DEPTH: REPRODUCTIVE ENDOCRINOLOGY


CL function by altering the dose, route of adminis- tration, and/or duration of treatment. In 2012, Gee et al38 reported that five of six mares (83%) treated with 10 units of oxytocin intravenously once daily on days 7 to 14 had prolonged CL function compared with only one of six (17%) and two of six (33%) mares treated with 10 units oxytocin or saline intramuscu- larly, respectively. The apparent inability of 10 units of oxytocin administered intramuscularly to prolong CL function indicates the threshold intra- muscular dose of oxytocin needed to disrupt luteoly- sis and prolong CL function is between 10 and 60 units. In all of the oxytocin-treated mares that de- veloped prolonged CL function, estrous behavior was inhibited throughout the period of extended CL function, demonstrating the clinical efficacy of oxy- tocin treatment for estrus suppression. In a 2013 study, Keith et al39 initiated intramuscular treat- ment with 60 units of oxytocin on day 8 and com- pared three different durations of treatment (2, 4, or 6 days). Administration of oxytocin on days 8 to 10, 8 to 12, and 8 to 14 induced prolonged CL function in three of seven (43%), four of seven (57%) and six of seven (86%) mares, respectively, compared with none of seven (0%) control mares. The proportion of mares with prolonged CL function increased (P  0.01) as the number of days of oxytocin administra- tion increased, confirming the need to continue oxy- tocin treatment until the expected time of luteolysis (ie, day 14) for maximum effectiveness. Also in 2013, Bare et al40 compared the estrous cycle char- acteristics of mares treated with oxytocin or the synthetic oxytocin analog carbetocin on days 7 to 14 after ovulation. Carbetocin has a circulating half- life after intravenous administration 2.5 times lon- ger than oxytocin (17.2 minutes versus 6.8 minutes, respectively).41 Oxytocin-treated mares received 60 units of oxytocin intramuscularly once daily, whereas carbetocin-treated mares received 1.19 mg carbetocin intramuscularly, which, on the basis of its pharmacokinetics, is equivalent to 60 units of oxytocin. Compared with nontreated control cy- cles, administration of oxytocin increased the inter- estrus and inter-ovulatory intervals (P  0.01), whereas carbetocin shortened the inter-estrus and inter-ovulatory intervals (P  0.01), essentially “short-cycling” the mares. Therefore, with the use of this dose and treatment schedule, carbetocin was not efficacious for prolonging CL function. In nonpregnant mares, the ability of the endome-


trium to secrete PGF2in response to oxytocin (en- dogenous or exogenous) increases markedly between days 10 and 15 after ovulation concomitantly with an increase in the concentration of oxytocin recep- tors33,42 and PGF2synthetic enzymes25 in the en- dometrial cells. In contrast, before day 10, the concentration of endometrial oxytocin receptors33,42 and PGF2 synthetic enzymes25 are low, which ef- fectively blocks the ability of oxytocin to stimulate PGF2secretion. We hypothesized that when oxy- tocin treatment is initiated before day 10 after ovu-


346 2013  Vol. 59  AAEP PROCEEDINGS


lation, it prevents luteolysis by inhibiting the rise in endometrial oxytocin receptor concentration that would otherwise permit endogenous oxytocin-in- duced PGF2 secretion at the time of luteolysis; however, there was no difference in endometrial oxytocin receptor concentrations between saline- treated control mares and oxytocin-treated mares on day 15, which does not support that hypothesis.36 More recently, it was demonstrated that oxytocin treatment suppresses PGF2 secretion by prevent- ing upregulation of endometrial gene expression of COX-2,39 which, as noted previously, appears to be the mechanism by which intrauterine placement of a polypropylene ball inhibits luteolysis and prolongs CL function.24 Also, it seems clear from the results of Bare et al40 that carbetocin (with use of the dose and treatment schedule in their study) does not have the same effect. Collectively, the studies described above provide convincing evidence that administration of exoge- nous oxytocin on days 7 (or 8) to 14 after ovulation is an effective method of disrupting luteolysis to pro- long CL function that can be used as a means of suppressing estrous behavior in mares. An advan- tage of using oxytocin treatment to prolong CL func- tion is that it can be readily reversed by simply administering a luteolytic dose of PGF2to initiate resumption of cyclical reproductive activity, in con- trast to the need to physically remove an intrauter- ine glass ball. Disadvantages of the oxytocin protocol include the need to determine the exact day of ovulation before initiating treatment and poten- tial difficulties associated with its use in mares with a needle aversion (ie, “needle-shy”). Although the dose of oxytocin is fairly high (60 units), no differ- ence in body temperature, heart rate, or respiratory rate was noted before and after treatment; however, mild sweating, urticaria around the injection site, and mild diarrhea were noted in some mares.40 Notably, there was no evidence of abdominal cramp- ing and/or transient signs of colic,40 which suggests the myometrium is much less responsive to oxytocin during mid- to late-diestrus than it is during other physiologic states (eg, immediately post-partum).


6. Inducing a Late-Diestrus Ovulation


In 2006, Hedberg et al43 described the results of a preliminary study in which their objective was to prolong the luteal phase in mares with the use of human chorionic gonadotropin (hCG) to induce a late-diestrus ovulation to produce a new CL that would be too immature to respond to the luteolytic effects of endogenous PGF2secretion at the end of diestrus (ie, day 14 to 15 after the initial “primary” ovulation). Mares were randomly assigned to con- trol (n  4) and experimental groups (n  5), and, beginning on approximately day 8 after ovulation (or last signs of estrous in 3 mares), their ovaries were examined with transrectal ultrasonography every other day to determine the size(s) of their diestrus follicles. When a diestrus follicle 30 mm was de-


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