How to Reduce Drug Costs and Side Effects when Using Prostaglandins to Short-Cycle Mares

Administering 25 μg of cloprostenol IM on day 6 after ovulation will short-cycle a mare, virtually eliminate unwanted side effects, and reduce drug costs by 1000 - 2000%.

1. Introduction

Prostaglandin is widely administered throughout the equine industry to manipulate ovulatory cycle length in mares by inducing luteolysis. Compounded examples are available; however, two labeled prostaglandin products are primarily used in the United States: dinoprost tromethamine (PGF2α) [a] and cloprostenol [b]. The natural PGF2α is labeled for use in horses but causes considerable side effects when administered. Owners often report that their mares develop a considerable sweat, and some also become quite colicky. On the other hand, cloprostenol, a prostaglandin analogue, is not labeled for horses but is commonly believed to cause fewer and less severe side effects.

A standard labeled dose of PGF2α for mares is 1 mg/100 lb body weight. This is loosely interpreted as a 2-ml (10 mg) dose for a standard-sized mare (~1000 lb). Although not labeled for horses, cloprostenol has been used clinically in mares for a number of years. The labeled dose for cattle is 500 μg (2 ml), and 1- to 2-ml doses are commonly administered in mares.

A recent study conducted at Auburn University compared prostaglandin products, doses, and administration sites. The ancillary results unexpectedly indicated that smaller doses of PGF2α than labeled for and smaller doses of cloprostenol than commonly administered consistently shorten the interovulatory interval (IOI) in mares [1]. Results also dispel the common belief that the prostaglandin analogue cloprostenol causes fewer side effects than natural PGF2α when administered at standard doses. Additionally, reducing the dose of each agent minimizes side effects and still shortens IOI. Reduced drug costs are another added benefit of lowering the dose of prostaglandin administered.

Among veterinarians and horse breeders, the authors have encountered considerable interest about the use of microdoses of prostaglandin for short-cycling mares. We will present our current recommendation for short-cycling mares using reduced doses of prostaglandin and the parsed results from our study to justify our recommendation.

2. Method of Shortening IOI

Our current recommendation for short-cycling mares to reduce drug costs and side effects is to administer 0.05 - 0.1 of a standard 250- to 500-μg dose of cloprostenol. Mares are treated with a microdose of cloprostenol (25 μg [0.1 ml] IM) on day 6 after ovulation. The dose is drawn into a tuberculin syringe to make measuring and administering the small volume easier.

3. Results

Treating mares with a microdose of PGF2α or cloprostenol on day 6 after ovulation results in a shortened cycle. Circulating progesterone concentrations in mares treated with a microdose of PGF2α seem to remain higher over the first 96 h after administration than in mares treated with a microdose of cloprostenol or a standard dose of either prostaglandin; however, IOI is similar among doses and prostaglandins administered. Systemic responses (side effects) are reduced in mares receiving a microdose of either prostaglandin compared with those receiving a standard dose.

Seventeen mares were treated in 57 estrous cycles. Treatments were administered IM and included 10 mg PGF2α (PGF), 0.5 mg PGF2α (micro-PGF), 500 μg cloprostenol (CLO), 25 μg cloprostenol (micro-CLO), and 2 ml sterile water (control). Treatments were randomized within each mare and among her available estrous cycles during the breeding season. Mean IOIs were 22.0 days (control; range, 18 - 26 days), 15.2 days (PGF; range, 13 - 18 days), 16.6 days (micro-PGF; range, 12 - 21 days), 15.1 days (CLO; range, 12 - 18 days), and 14.3 days (micro-CLO; range, 10 - 21 days). The mean IOIs for all prostaglandin-treatment groups were significantly (p < 0.01) shorter than for the control group.

Individually, all mares treated with PGF, CLO, or micro-CLO seemed to have a shortened IOI. One micro-CLO mare had a 21-day IOI; however, her circulating progesterone concentration at 96 h after treatment was 0.0 ng/ml, and her control cycle had a 25-day IOI. The same mare also had a 21-day IOI when treated with micro-PGF. Only one mare did not have a shortened IOI in any of the prostaglandin-treatment groups. She was treated with micro-PGF and had a circulating progesterone concentration of 10.9 ng/ml at 96 h after treatment.

Mean circulating progesterone concentrations did not differ at the time of treatment among any of the groups (p = 0.44). However, mean circulating progesterone concentrations for all prostaglandin-treatment groups were lower than observed in the control group at all other sampling times after treatment (p < 0.001). Mean circulating progesterone concentrations remained higher in the micro-PGF group for 96 h after treatment than in any other prostaglandin group (p < 0.05). At 96 h after treatment, circulating progesterone concentrations were <1 ng/ml in 13 of 13 mares in the PGF group, 2 of 10 mares in the micro-PGF group, 12 of 12 mares in the CLO group, and 9 of 9 mares in the micro-CLO group.

Systemic response was measured in 10 mares for each treatment. Mean heart rate, respiratory rate, rectal temperature, and sweat score were not different among treatment groups at administration (P = 0.45, 0.86, 0.91, and 0.45, respectively). Mean heart and respiratory rates increased over control levels in the PGF and CLO groups after treatment (p < 0.05), whereas mean rates in the microdose groups were not different than the controls throughout the observation period (p > 0.05). The highest mean heart rates observed were 56 and 66 beats/min in the PGF and CLO groups, respectively. The highest mean respiratory rates were 48 and 44 breaths/min in the PGF and CLO groups, respectively. Heart and respiratory rates returned to control levels by 60 min after treatment.

Mean rectal temperatures declined below control levels (p < 0.001) by 30 min after treatment in the PGF and CLO groups, reaching a low of 35.7°C for the PGF group and 35.5°C for the CLO group by 90 min. Temperatures had not recovered to control levels by the end of the observation period at 240 min (p < 0.001). Mean rectal temperatures in the microdose groups never differed from control levels (p > 0.05).

Moderate sweating was observed in 9 of 10 and 10 of 10 mares in the PGF- and CLO-treatment groups, respectively. Mares in the PGF and CLO groups sweated more than the control or microdose groups (p < 0.001). The CLO group had a higher mean sweat score than the PGF group (p < 0.05) 45 - 90 min after treatment, and by 240 min, no sweat was evident on any mare.

Specific data were not recorded for other systemic responses to treatment, although some observations are worth noting. Nearly every mare defecated multiple times during a 240-min observation period. Some of the mares treated with a conventional dose of prostaglandin passed fecal material that became progressively less formed during the observation period. Because accurate data were not recorded for these variables, it was not possible to analyze for differences among treatment groups.

4. Discussion

We are unaware of any published studies that have investigated the luteolytic affect of a microdose of cloprostenol. Our results indicate that 25 μg of cloprostenol administered IM on day 6 after ovulation is highly effective at reducing circulating progesterone levels, shortening IOI, and reducing unwanted side effects. There is evidence suggesting the corpus luteum becomes more sensitive to prostaglandin with age, because smaller doses than tested in this study have been consistently used in clinical practice to lyse older copra lutea [c]. Therefore, we feel confident suggesting that 25 μg of cloprostenol can also be expected to effect luteolysis on days subsequent to day 6 of diestrus. The minimum effective dose of cloprostenol required for luteolysis has not been established. It is understandable that this work has not been done, because cloprostenol is not labeled for use in horses.

Of interest, circulating progesterone concentrations did not fall as fast or as low in the micro-PGF group as the other prostaglandin-treatment groups. However, this did not seem to matter, because the micro-PGF group of mares ovulated at an interval that was statistically the same as the other prostaglandin groups. Our findings in mares treated with a micro-PGF dose contradicted the results reported by two international research groups [2,3]. In their studies, a single microdose of PGF2α (0.5 mg in one study and 1.25 mg in another study) administered IM did not shorten the IOI [2,3]. Interestingly, progesterone levels in their studies declined in a way similar to that observed in our microdose group [2,3]. In contrast, our mares had a shortened IOI that was not observed in their treatment groups. One of the studies reported that administering two 0.5-mg doses of PGF 24 h apart reduced circulating progesterone concentrations in a fashion similar to that observed in our other treatment groups [2]. They also observed a shortened IOI with the two-dose protocol [2].

Signs of sweating and changes in rectal temperature observed in our PGF group were similar to previously reported findings [4]. In contrast, we detected significant increases in heart and respiratory rates over control levels. However, it was unexpected that the prostaglandin analogue, cloprostenol, caused similar or more severe systemic changes than did the natural PGF2α,  - PubMed - dinoprost tromethamine. It is commonly believed that prostaglandin analogues induce fewer and less frequent adverse effects than natural PGF2α. Our observations may be attributable to using the labeled dose for cattle.

Our results indicate that a single micro-CLO dose is equally effective at short-cycling mares as a standard PGF or CLO dose, yet it virtually eliminates unwanted side effects and reduces drug costs by 1000 - 2000%. Although a micro-PGF dose resulted in similar shortening of the IOI, the delayed decline in circulating progesterone concentrations prevents us from recommending it as a routine method for short-cycling mares. A two-dose micro-PGF protocol has been described; however, it requires treatment on consecutive days. A second treatment does not seem to be necessary when using a microdose of cloprostenol. Therefore, we currently recommend administering a single 25-μg dose of cloprostenol IM on day 6 or later after ovulation to short-cycle mares and reduce side effects and drug costs.

This project was supported by the Department of Large Animal Surgery and Medicine, the Office of Research and Graduate Studies, and the Department of Anatomy, Physiology, and Pharmacology at Auburn University. Portions of the results reported in this abstract were previously published [1].

Footnotes

1. Lutalyse, Pfizer Animal Health, New York, NY 10017.
2. Estrumate, Schering-Plough, Kenilworth, NJ 07033.
3. Newcombe J. Personal communication, January 11, 2001.