Tutorial Article Management of the Transition Period: Hormone Therapy P

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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. In that study, 87% of b a 20 µg/h 10 2.9 ± 0.5 11.4 ± 0.5 mares treated with EPE ovulated and 58% of those mares 100 µg/h 4 3.5 ± 0.9b 11.5 ± 1.6a ovulated more than one follicle. EQUINE VETERINARY EDUCATION / AE / MAY 2007 217

TABLE 4: Effect of equine follicle stimulating hormone (eFSH) when administered only once daily (P.M. McCue, unpublished on induction of ovulation in transitional mares (modified from data). Thirty transitional mares (follicles >20 mm in diameter) Niswender et al. 2001) were administered (n = 10 per group) either saline placebo, Interval to 6.25 or 12.5 mg eFSH once daily for a maximum of 10 days. Treatment No. of mares Ovulation rate ovulation Human chorionic gonadotropin (2500 units) was administered group (n) ovulating (%) (No. ± s.e.) (days ± s.e.) when a follicle reached 35 mm in diameter. Ovulation rates were 20, 50 and 60% following saline, low-dose eFSH and Control 10 0 (0) – 39.5 ± 17.2 eFSH 10 8 (80%) 2.5 ± 1.7 7.6 ± 2.4 high-dose FSH treatment, respectively. One mare treated with 12.5 mg eFSH had a prolonged interval to the next ovulation (56 days), while the remaining mares had an interovulatory Lapin and Ginther (1977) administered EPE to 11 pony interval of normal duration. It was concluded that twice daily mares in deep seasonal anoestrus (follicles ≤10 mm in treatment with eFSH as used the previous season was more diameter). All mares treated with EPE ovulated while none of advantageous in stimulating follicular development in the control mares receiving saline vehicle ovulated during the transitional mares than a once daily protocol. 14 day observation period. There was no difference in the number of ovulations for mares given EPE alone (1.6 ± 0.4 Ovulation-inducing agents ovulations) and EPE followed by hCG (1.8 ± 0.3 ovulations). A subsequent study by Woods and Ginther (1982) showed Human chorionic gonadotropin (hCG) is a glycoprotein that the efficacy of EPE in inducing ovulation in anoestrous hormone with inherent luteinising hormone (LH) type activity. mares increased progressively as the diameter of the largest Administration of hCG (Chorulon)3, has been reported to be follicle at the onset of treatment increased. Transitional mares effective in inducing ovulation in late transitional mares that with small follicles (20–25 mm) at the onset of EPE treatment were expressing behavioural oestrus and had a large (>40 mm) experienced a lower ovulation rate (2 of 7 mares treated, follicle present (Colbern et al. 1987; Carnevale et al. 1989). 28.6%) and a longer interval to ovulation (28.4 ± 5.3 days) as Deslorelin acetate is a potent agonist of gonadotropin compared to transitional mares with larger follicles (30–35 mm), releasing hormone. Farquhar et al. (2000) reported the in which all mares ovulated an average of 9.1 ± 1.0 days after efficacy of an implant containing 2.1 mg deslorelin onset of treatment. Overall, 8 of 18 anoestrous mares (44%) (Ovuplant)4, on ovulation rate relative to mare age and induced to ovulate had multiple ovulations. It was also noted season. There was no statistical difference between the that 6 of 11 treated mares that ovulated and did not become ovulation rates of transitional (72.2%) and cycling (89.5%) pregnant returned to an anovulatory condition after the mares administered deslorelin in March and April. cessation of treatment. If an ovulation-inducing agent is not administered when a Coy et al. (1999) compared ovulation rates following EPE large dominant follicle is present in a transitional mare, the administration to mares in deep winter anoestrus (follicles follicle may regress without ovulation, a new follicular wave <15 mm in diameter) and transition (diameter of the largest would eventually develop and the ultimate result may be a follicle >25 mm in diameter). Human chorionic gonadotropin longer transition period. was administered when a follicle ≥35 mm was detected. A higher percentage of mares in transition (8 of 9, 89%) Progesterone and progestin therapy ovulated in response to EPE administration than mares in deep anoestrus (2 of 9, 22.2%). Four of the 8 transitional Numerous studies, primarily in the late 1970s and early 1980s, mares had multiple ovulations. The average interval from have evaluated the effect of administration of natural onset of treatment to ovulation for the 8 transitional mares progesterone or synthetic progestins (i.e. Regumate)3, on was 11.8 ± 5.0 days. management of the anovulatory season (for reviews, see A commercially available purified equine FSH product Ginther 1992 and Squires 1993). Conflicting reports certainly (eFSH)2 has also been used in transitional mares to stimulate exist as to the efficacy of progesterone in advancing the first follicular development and advance the first ovulation of the ovulation of the year. However, a majority of controlled year (Niswender et al. 2004). Ten mares in spring transition research studies indicate that progesterone therapy: 1) will not with follicles >25 mm in diameter were administered 12.5 mg consistently advance the first ovulation when administered to of eFSH i.m. twice daily. Ten additional transitional mares mares in deep seasonal anoestrus or early transition (Squires served as untreated controls. Mares were administered hCG et al. 1979; Allen et al. 1980; Turner et al. 1981; Alexander (2500 units) when one or more follicles reached 35 mm in and Irvine 1991); 2) may synchronise the return to oestrus and diameter. Administration of eFSH followed by hCG resulted in advance the first ovulation in late transitional mares (Squires ovulation in 80% of mares treated (Table 4). The interval from et al. 1979; Allen et al. 1980); and 3) is effective in suppressing onset of treatment to ovulation was 7.6 ± 2.4 days. None of the prolonged and often irregular periods of oestrus in the control mares ovulated multiple follicles at the first transitional mares (Turner et al. 1981). spontaneous ovulation of the year. Progesterone has been reported to be effective in Equine FSH administration was not as effective in inducing synchronising the first ovulation of the year when follicular development and ovulation in transitional mares administered to mares after being maintained under a 218 EQUINE VETERINARY EDUCATION / AE / MAY 2007

stimulatory artificial photoperiod for 2 months (Palmer 1979; TABLE 5: Effect of dopamine antagonists on interval to Squires et al. 1979; Taylor et al. 1982). However, some authors ovulation in anoestrous mares (modified from Brendemuehl and Cross 2000; Besognet et al. 1997) have indicated that progesterone therapy was not effective at advancing the first ovulation of the year irrespective of the size Treatment Treatment Date of Mean number of of the largest follicle or stage of anoestrus at the onset of group (n) start date ovulation treatment days treatment (Turner et al. 1981; Alexander and Irvine 1991). Vaginal inserts containing progesterone, such as PRID5 and Domperidone 8 14th January 20th Feb ± 8.2 37 Control 8 – 9th May ± 13.6 – CIDR-B6, and progesterone-impregnated vaginal sponges have been used in anoestrous mares in an attempt to stimulate Sulpiride 9 5th February 18th March ± 7.9 41.3 follicular development and advance the first ovulation of the Control 9 – 20th April ± 6.8 – year. Thompson et al. (1984) reported an immediate surge of FSH in 4 of 8 mares following intravaginal insertion of a polyurethane sponge that did not contain any hormones. Four 28 days and then declined. The date of first ovulation of the of 8 treated mares also exhibited behavioural oestrus. None of year was hastened in mares administered rpPRL (6th February the control mares exhibited an increase in FSH or showed signs ± 3 days) relative to control mares (14th March ± 6 days). It of heat. The authors theorised that the FSH surges were due was noted that antibodies to rpPRL were high in all treated to neural impulses stimulated by the genital manipulation. mares by Day 28. Newcombe and Wilson (1997) noted that administration Nequin et al. (1993) and Thompson et al. (1997) both of CIDR-B6 vaginal inserts containing 1.9 g of natural suggested that the effect of exogenous prolactin may be at progesterone (P4) to anoestrous mares resulted in an increase the level of the ovary and not due to enhancement of pituitary in follicular diameter during the treatment period. A majority gonadotropin secretion. (87%) of treated mares ovulated within 10 days following insert removal and administration of hCG. Pregnancy rate for Dopamine antagonist therapy mares bred during the oestrus that followed removal of the insert was reported to be 88.9 %. Foglia et al. (1999) reported Pituitary production of prolactin is primarily regulated through that a significant increase in follicular diameter occurred in inhibition by the neurotransmitter dopamine (Cross et al. 13 transitional mares during treatment with a CIDR-B6 vaginal 1995). Administration of dopamine agonists results in insert. Follicular diameter increased from 26.5 ± 2.6 mm prior suppression of serum prolactin levels, while treatment with to the onset of therapy to 39.0 ± 8.0 mm at the end of the dopamine antagonists causes an increase in circulating 12 day treatment period. Follicular diameter of control mares prolactin concentrations. Several dopamine agonists and only changed from 26.4 ± 1.9 mm to 28.8 ± 5.6 mm during antagonists have been administered to mares for research and the same period. Ten of the 13 treated mares were therapeutic purposes. The 2 most commonly used dopamine administered a GnRH agonist (Ovuplant)4 one day after insert antagonists are domperidone and sulpiride. Sulpiride has been removal and 8 mares subsequently ovulated. reported to cross the blood-brain barrier, while domperidone apparently does not (Olin et al. 1991). Prolactin therapy Nequin et al. (1993) treated 6 seasonally anoestrous mares with the dopamine D2 receptor blocker fluphenazine Concentration of prolactin in peripheral blood has been decanoate once daily for 21 days beginning in January. It was reported to be directly correlated with changes in reported that fluphenazine treatment increased endogenous photoperiod, with prolactin levels being low in the winter and plasma prolactin levels and accelerated follicular growth in high in the summer (Johnson 1986b; Thompson et al. 1986). anoestrous mares but did not hasten the date of the first In 1993, Nequin and coworkers noted that plasma prolactin ovulation of the season as compared with untreated controls. levels were highly correlated with follicular diameter during In a series of studies, daily administration of sulpiride has the spring transition period. been documented to stimulate follicular development and Nequin et al. (1993) treated 5 anoestrous mares with one advance the day of the first ovulation of the season when dose of ovine prolactin and 4 control mares received a saline administered to anoestrous mares at a dose of 200 mg/mare placebo in January. Rapid follicular growth was noted in 3 of of [-] sulpiride once daily (Besognet et al. 1997) (Table 5) or the 5 mares within 3 days of prolactin treatment, while none of 1.0 mg/kg bwt of [±] sulpiride once daily (Besognet et al. the control mares exhibited significant follicular development. 1996). Sulpiride administration results in increased plasma Thompson et al. (1997) reported the effects of repeated prolactin concentrations. Pronounced shedding of the winter daily administration of recombinant porcine prolactin (rpPRL) hair coat in anoestrous mares secondary to the increased to anoestrous pony mares. Eight seasonally anoestrous mares prolactin caused by sulpiride treatment has been reported were given 4 mg of rpPRL subcutaneously once daily, while (Besognet et al. 1997). The luteal phase following ovulations 8 other pony mares received daily doses of a placebo in sulpiride-treated anoestrous mares are of normal length and beginning on 15th January. Blood prolactin levels were progesterone profile (Besognet et al. 1997) and the fertility of immediately increased following onset of treatment. Hair ovulations following sulpiride treatment is apparently normal shedding in treated mares began within 14 days, peaked at (Besognet et al. 1996). Besognet et al. (1996) reported that EQUINE VETERINARY EDUCATION / AE / MAY 2007 219

one of 4 anoestrous mares stimulated to ovulate with sulpiride administered to anoestrous mares housed indoors under a that did not become pregnant after being bred returned to stimulatory artificial photoperiod. anoestrus following a luteal phase of normal duration. Dopamine antagonist treatment (sulpiride or Daels et al. (2000) reported that administration of domperidone) is not universally successful in stimulating [-] sulpiride at a dose of 0.5 mg/kg bwt twice daily to seasonally follicular development in anoestrous mares. Success rate is anoestrous mares decreased the interval to first ovulation, but likely to be higher in transitional mares and mares maintained had no effect on FSH secretion parameters. It was suggested indoors under a stimulatory artificial photoperiod. The most that environmental parameters, such as environmental current proposed mechanism (Duchamp and Daels 2002) by temperature (i.e. indoor housing) and stimulatory photoperiod, which dopamine antagonists may stimulate follicular may influence the effect of dopamine antagonist treatment development is as follows: (Daels 2000; Daels et al. 2000). 1. Dopamine antagonist treatment results in increased Duchamp and Daels (2002) evaluated the effect of plasma prolactin levels. sulpiride treatment in 22 matched pairs of anoestrous mares 2. Prolactin acts directly on the ovary to stimulate expression that had similar reproductive histories, dates of entry into of gonadotropin receptors. anoestrus, body condition scores and bodyweights. All mares 3. Pituitary gonadotropin (FSH and LH) secretion is not were subjected to a 14.5 h light:9.5 h dark light regimen altered by dopamine antagonist therapy, but treated mares beginning on 10th January. Mares were administered are more sensitive to endogenous gonadotropins due to [±] sulpiride (1 mg/kg bwt, b.i.d.) for a maximum of 21 days increased numbers of gonadotropin receptors. beginning on Day 14 of the artificial photoperiod. The sulpiride-treated mare ovulated before the untreated mare in Prostaglandin therapy 86% of the pairs. Treatment advanced the first ovulation by an average of 16.7 days. Administration of prostaglandins has been reported to result In contrast to the above mentioned studies, Donadeu and in stimulation of follicular development and ovulation in Thompson (2002) reported that administration of 1 mg/kg anoestrous mares with no functional corpus luteum (Lamond bwt sulpiride once daily to deep anoestrous mares (maximum et al. 1975; Howey et al. 1983). Lamond et al. (1975) follicle size ≤20 mm) from 14th January to 14th February administered a prostaglandin analogue to 30 mares that had increased plasma prolactin levels but did not stimulate progesterone levels <1.0 ng/ml at the time of treatment. follicular development nor advance the first ovulation of the Twenty of the mares were bred within 7 days after treatment year. Mares in that study were not maintained under an and 15 of the 20 were subsequently diagnosed as pregnant. It artificial photoperiod. was not clear from the report if any or all of the 30 mares were Brendemuehl and Cross (1996, 2000) reported that experiencing a prolonged period of anoestrus (acyclicity) at the administration of domperidone (1.1 mg/kg bwt) to seasonally time of treatment or if in fact some were ‘silent heat’ mares. anoestrous mares maintained under natural photoperiod A later study in Australia reported that the synthetic beginning 15th January stimulated follicular development prostaglandin alfaprostol was administered to 26 anoestrous within 14 days of the onset of treatment and advanced the mares with baseline progesterone levels (Howey et al. 1983). day of the first ovulation of the season (20th February Twenty-one mares subsequently came into heat and were ± 8.2 days and 9th May ± 13.6 days for domperidone-treated mated, 19 ovulated and 15 became pregnant. Again, little to and control mares, respectively) (Table 5). All mares no information was presented as to the duration of anoestrus administered domperidone ovulated during treatment and prior to alfaprostol treatment. the mean interval from onset of treatment to ovulation was Peterson (1985) attempted to determine whether alfaprostol 27 days. Six of the 8 mares treated with domperidone administration to anoestrous mares would stimulate LH release continued to cycle after the first ovulation, while 2 mares had or follicular development. As in the previous prostaglandin prolonged intervals until the second ovulation (i.e. reverted to studies, the reproductive status of the mares at the onset of anoestrus). Progesterone concentrations during the luteal treatment was vague, the number of horses treated was small phase of the 6 mares that continued to cycle were of normal and the observation interval was brief. Consequently, this study duration, while levels in the other 2 mares were <1.0 ng/ml by shed little light on the effect of prostaglandins on reproductive Day 7 post ovulation. Domperidone treatment resulted in a performance of anoestrous mares. significant elevation in plasma prolactin concentrations, but In an attempt to determine if prostaglandins could elicit a had no effect on FSH or LH secretion. The investigators release of GnRH, LH or FSH, a study was conducted in which suggested that either domperidone or prolactin may have a the intercavernous sinus (ICS) was cannulated in 4 anoestrous direct effect on the ovary. or transitional mares (Jöchle et al. 1987). Blood samples were Domperidone was reported to be ineffective in stimulating collected prior to and after administration of the synthetic follicular development and ovulation when administered at a prostaglandin analogue luprostiol. An increase in gonadotropin dose of either 1.1 or 2.2 mg/kg bwt once daily for a maximum levels were detected in 7 of 8 mares within 5–10 min after of 60 days to mares housed outdoors under ambient light treatment. Interestingly, it was noted that an increase in LH and conditions (McCue et al. 1999). In addition, no effect was FSH was detected in ICS blood several minutes before an noted in a subsequent study when domperidone was increase in GnRH was detected in ICS blood. 220 EQUINE VETERINARY EDUCATION / AE / MAY 2007

In the same paper Jöchle et al. (1987) reported the results to induce oestrus and ovulation in seasonally anoestrous of a field study in which 192 mares that had not started to Thoroughbred mares. Equine vet. J. 12, 141-145. cycle yet during the breeding season were administered one or Besognet, B., Hansen, B.S. and Daels, P.F. (1996) Dopaminergic 2 doses of prostaglandins (alfaprostol, cloprostenol or regulation of gonadotrophin secretion in seasonally anoestrous mares. J. Reprod. Fert. 108, 55-61. dinoprost). It was noted that 35.3% came into oestrus and Besognet, B., Hansen, B.S. and Daels, P.F. (1997) Induction of 67.7% ovulated within 10 days of prostaglandin treatment. reproductive function in anestrous mares using a dopamine The evidence from Jöchle et al. (1987) is strong that antagonist. Theriogenol. 47, 467-480. exogenous prostaglandins can cause release of GnRH from the Brendemuehl, J.P. and Cross, D.L. (1996) Effects of the dopamine hypothalamus and gonadotropins from the pituitary. antagonist domperidone on follicles, time to ovulation and luteal Additional well defined and controlled studies are clearly function in seasonally anestrus mares. In: Proceedings of the needed to determine if prostaglandin products currently Society for Theriogenology, Kansas City. p 304. available (dinoprost and cloprostenol) have any significant Brendemuehl, J.P. and Cross, D.L. (2000) Influence of the dopamine antagonist domperidone on the vernal transition in seasonally effect on inducing follicular development in deep anoestrous anoestrous mares. J. Reprod. Fert., Suppl. 56, 185-193. or transitional mares. Carnevale, E.M., Squires, E.L., McKinnon, A.O. and Harrison, L.A. (1989) Effect of human chorionic gonadotropin on time to Summary ovulation and luteal function in transitional mares. J. equine vet. Sci. 9, 27-29. Multiple management and therapeutic modalities have been, Chen, F.J., Day, W., Evans, G., Evans, J.W. and Peterson, K.D. (1993) and will continue to be, combined in attempts to stimulate Follicular, estrus, gonadotropin and ovulation responses in follicular development and advance the first ovulation of the anestrous mares treated with a GnRH analogue (CH 690030). J. equine vet. Sci. 13, 636-642. year in seasonally anoestrous mares. The use of a stimulatory Colbern, G.T., Squires, E.L. and Voss, J.L. (1987) Use of altrenogest artificial photoperiod in conjunction with GnRH agonists, and human chorionic gonadotropin to induce normal ovarian progestins, dopamine antagonists and/or hCG is currently cyclicity in transitional mares. J. equine vet. Sci. 7, 69-72. common in equine practice. Administration of GnRH agonists Coy, R.E., McCue, P.M., Bruemmer, J.E. and Squires, E.L. (1999) and eFSH appear to hold the most potential for inducing Follicular response of mares in deep or transitional anestrus to follicle development and ovulation in a relatively short time equine pituitary extract. In: Proceedings of the Equine Nutrition frame (i.e. <2 weeks). Dopamine antagonists may not be and Physiology Symposium, Raleigh. 16, 65-68. effective under all management conditions and the duration Cross, D.L., Redmond, L.M. and Strickland, J.R. (1995) Equine fescue toxicosis: signs and solutions. J. anim. Sci. 73, 899-908. of treatment may be prolonged (i.e. >4 weeks). Progesterone therapy is effective at suppressing oestrus and synchronising Daels, P.F. (2000) Seasonal anestrus in mares: physiology, diagnosis and treatment. In: Proceedings of the Society for Theriogenology, ovulation when administered to mares late in transition. Hastings, Nebraska. pp 189-196. Initiation of any treatment to mares in deep winter Daels, P.F., Fatone, S., Hansen, B.S. and Concannon, P.W. 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