EQUINE VETERINARY EDUCATION / AE / MAY 2007 215 Tutorial Article Management of the transition period: hormone therapy P. M . M CCUE*, N. L. LOGAN AND C. MAGEE Equine Reproduction Laboratory, Colorado State University, Fort Collins, Colorado 80523, USA. Keywords: horse; equine transition; hormone therapy; reproduction Introduction TABLE 1: Medications and dosage regimens that have been used in the management of transitional mares Economic pressures exist in the broodmare industry to produce Medication Brand name Dosage foals early in the year. Consequently, owners want to begin breeding mares in North America by the middle of February at Altrenogest Regumate 0.044 mg/kg bwt, per os, a time when fertile matings are prevented by the seasonal s.i.d. absence of follicular activity. Exposure of mares to an artificial Buserelin (GnRH agonist) Compounded 10–100 µg, i.m. or subcut., b.i.d. photoperiod is the most common and predictable technique Deslorelin (GnRH agonist) Ovuplant 2.1 mg, subcut. implant used to induce follicular development early in the year. Deslorelin (GnRH agonist) Compounded 125 µg, i.m., b.i.d. However, light therapy does not work in all situations. Improper Domperidone Equidone 1.1 mg/kg bwt, per os, s.i.d. or inappropriate use of phototherapy may limit efficacy, and Equine FSH eFSH 6.25–12.5 mg, i.m., b.i.d. GnRH (native) LHRH a) 2–50 µg/h, subcut., not all mares respond to light therapy by ovulating early in the pulsatile or continuous season. In addition, many mares are not maintained under infusion lights in the winter months and yet owners still want them bred b) 50–500 µg, i.m., b.i.d. to early in the season. As a consequence, various therapeutic t.i.d. strategies have been investigated over the years to stimulate Goserelin (GnRH agonist) Zoladex One-third to one-half of a 3.6 mg implant, subcut., follicular development in anoestrous mares and advance the once date of the first ovulation of the year (Table 1). HCG Chorulon 2500 units, i.v., once Progesterone Generic or 150 mg, i.m., s.i.d. Gonadotropin releasing hormone therapy Compounded Sulpiride Compounded [-] sulpiride 0.5 mg/kg bwt, i.m., s.i.d. or b.i.d. Administration of gonadotropin releasing hormone (GnRH) or [±] sulpiride 1.0 mg/kg bwt, its analogues has been used in multiple studies to determine i.m., s.i.d. or b.i.d. the efficacy of inducing ovulation in seasonally anoestrous mares. Native GnRH has been reported to be effective when administered 2–3 times daily by injection (Evans and Irvine Administration of native GnRH (Evans and Irvine 1977; 1977; Fitzgerald et al. 1987; Minoia and Mastronardi 1987), in Johnson 1986a, 1987; Johnson and Becker 1988; Ainsworth hourly pulses using externally mounted infusion or peristaltic and Hyland 1991; McCue et al. 1991; Hyland et al. 1996) or a pumps (Johnson 1986a, 1987; Johnson and Becker 1988; GnRH agonist (McCue et al. 1991; Chen et al. 1993; Mumford McCue et al. 1991), or by constant infusion using et al. 1994; Nickerson et al. 1998) to anoestrous mares causes subcutaneously implanted osmotic minipumps (Hyland et al. an increase in blood levels of LH and, when measured, FSH. 1987; Ainsworth and Hyland 1991). Agonists of GnRH have The increase in gonadotropin response was often dependent been administered by twice daily boluses (Fitzgerald et al. on the dose of GnRH used (Johnson 1986a, 1987; Hyland 1987; Ginther and Bergfelt 1990; Harrison et al. 1990; McCue et al. 1987). Turner and Irvine (1991) and Allen et al. (1987) et al. 1991, 1992), constant release long-term implants (Allen noted an LH response but not an FSH response after et al. 1987; Harrison et al. 1990; Turner and Irvine 1991; Chen administration of native GnRH and a GnRH agonist implant, et al. 1993; Fitzgerald et al. 1993; Mumford et al. 1994), respectively, to anoestrous mares. or repeated administration of short-term implants (McKinnon Response to GnRH administration in anoestrous mares is et al. 1996; Nickerson et al. 1998). often, but not always, related to follicle size at onset of treatment or depth of anoestrus (deep anoestrus vs. transition). Typically, mares in transition with follicles *Author to whom correspondence should be addressed. 20–25 mm in diameter or greater are more likely to respond 216 EQUINE VETERINARY EDUCATION / AE / MAY 2007 than mares with follicles <15 mm at the onset of treatment. TABLE 3: Effect of a GnRH implant (Goserelin) on induction of Treatment endpoints that may be correlated with follicle size ovulation in anoestrous mares (modified from Mumford et al. 1994) at onset of treatment or depth of anoestrus are ovulation rates and number of treatment days to ovulation (Hyland Interval to ovulation et al. 1987; Ginther and Bergfelt 1990; Ainsworth and Treatment group (n) No. of ovulations (%) (days ± s.e.) Hyland 1991; McCue et al. 1991; Mumford et al. 1994; a McKinnon et al. 1996; Nickerson et al. 1998). McCue et al. 0 (control) 20 0 (0) – 0.9 mg 20 0a (0) – (1991) noted that administration of native GnRH via hourly 1.8 mg 20 2ab (10) 22.0 ± 3.0a pulses resulted in a greater ovulatory response than twice 3.6 mg 20 7b (35) 16.6 ± 1.4ab daily administration of a GnRH agonist to mares in deep 5.4 mg 20 6b (30) 13.0 ± 0.7b anoestrus. Administration of a long-term implant containing a potent GnRH agonist (goserelin) was associated with a low ovulation rate when administered to mares in late January Mares are more likely to continue to cycle after a GnRH- (Chen et al. 1993), a moderate ovulation rate when induced ovulation if treatment is initiated later in the spring. administered to mares in February (Fitzgerald et al. 1993; In several studies, all anoestrous mares continued to cycle Mumford et al. 1994), and a high ovulation rate when after a GnRH-induced ovulation (Minoia and Mastronardi administered to anoestrous mares between February and May 1987; Ainsworth and Hyland 1991; Turner and Irvine 1991). (Allen et al. 1987) in the Northern hemisphere. The difference The rate of multiple ovulations may be higher in GnRH in response rates during the different calendar months is treated anoestrous mares than mares spontaneously ovulating presumably related to depth of anoestrus on the date of during the physiological breeding season (Johnson 1987; treatment. Goserelin is available commercially for use in Johnson and Becker 1988; Ginther and Bergfelt 1990). The human medicine as an implant containing 3.6 or 10.8 mg of number of follicles ovulated has been correlated to the dose the GnRH agonist (Zoladex)1, but it may be prohibitively of GnRH administered (Johnson 1987; Johnson and Becker expensive for routine use in mares. 1988) and to the follicle size at onset of treatment (Ginther Several reports have indicated that hCG can be used and Bergfelt 1990). successfully to induce ovulation in anoestrous mares in which The corpus luteum that forms after a GnRH-induced development of the dominant follicle had been stimulated by ovulation in an anoestrous mare is similar to one formed GnRH (Ginther and Bergfelt 1990; McCue et al. 1992; following spontaneous ovulation in a cycling mare during the Fitzgerald et al. 1993). physiological breeding season in most instances (Johnson Increasing GnRH dose and/or treatment frequency tends to 1986a, 1987; Allen et al. 1987; Ainsworth and Hyland 1991; increase follicular development, percentage of mares that Chen et al. 1993; Mumford et al. 1994). However, occasional ovulate, and/or number of ovulations (Tables 2 and 3) (Allen et examples of failure of normal corpus luteum formation or al. 1987; Johnson and Becker 1988; Ainsworth and Hyland function after a GnRH induced ovulation have been reported 1991; Turner and Irvine 1991; Mumford et al. 1994). In contrast, (Evans and Irvine 1977; Hyland et al. 1987; Turner and Irvine some studies have reported no differences in interval to 1991; Nickerson et al. 1998). ovulation for anoestrous mares treated with different dosages Ovulations induced with GnRH in anoestrous mares are of native GnRH administered via an infusion pump (Johnson generally considered to be fertile (Allen et al. 1987; Fitzgerald 1986a, 1987). Similarly, Fitzgerald et al. (1993) did not observe et al. 1987; Minoia and Mastronardi 1987; Ainsworth and a dose-response relationship between amount of a long-term Hyland 1991; McCue et al. 1992). GnRH agonist implant and percentage of mares that ovulated. Down-regulation of the pituitary as noted following Anoestrous mares induced to ovulate with GnRH may, on administration of a single short-term GnRH agonist implant to some occasions, return to anoestrus after the conclusion of cycling mares for induction of ovulation (Farquhar et al. 2001; therapy (Johnson 1986a; Ginther and Bergfelt 1990; McCue McCue et al. 2002), does not usually occur with use of native et al. 1992; Mumford et al. 1994; McKinnon et al. 1996). This GnRH or multiple daily boluses of GnRH agonists in anoestrous may be most common if treatment is initiated early in the mares. However, down-regulation may occur following year when mares are in deep anoestrus at onset of treatment. administration of long-term implants or repeated use of short- term implants (McKinnon et al. 1996; Nickerson et al. 1998). TABLE 2: Effect of native GnRH delivered via an infusion pump on induction of ovulation in anoestrous mares (modified from EPE and eFSH Therapy Johnson and Becker 1988) Douglas et al. (1974) first reported the successful induction of Interval to ovulation Treatment group (n) No. of ovulations (days ± s.e.) ovulation in seasonally anoestrous mares with exogenous hormones. An extract prepared from equine pituitaries (EPE) 0 (control) 12 0 >60 was administered to pony mares with small inactive ovaries 2 µg/h 9 1.3 ± 0.2a 11.4 ± 1.0a containing follicles ≤10 mm in diameter.