Original ResearchInhibitory Effects of Pergolide and Cabergoline Formulations on Daily Plasma Prolactin Concentrations in Geldings and on the Daily Prolactin Responses to a Small Dose of Sulpiride in Mares
Introduction
Pergolide is a dopamine receptor agonist that was removed from the US market for human use due to its association with heart valve dysfunction [1]. However, it has recently been approved for use in horses as a treatment for pituitary pars intermedia dysfunction (PPID) in horses [2].
Cabergoline is another dopamine receptor agonist that is highly active on dopaminergic type D2 receptors [3]. It was also commercially available for human use and went off patent in 2005 but has the same potential side effects as pergolide [1]. It may be a potential replacement for pergolide for use in horses due to its long-acting nature [4].
In the first phase of the current research [5], we demonstrated that either estrogen-primed geldings in spring or cyclic mares in summer provided a possible paradigm for the assessment of the efficacy and duration of activity of dopamine agonists for suppression of the prolactin responses to repetitive small doses of sulpiride. Prolactin secretion from the lactotropes of the anterior lobe of the adenohypophysis is controlled by tonic suppression by hypothalamic dopamine input in the same manner as α-melanocyte stimulating hormone (MSH) secretion from the melanotropes of the intermediate lobe [6], [7], [8]. Thus, we proposed that measuring drug effects on prolactin secretion could serve as an alternative to monitoring MSH concentrations, thereby providing researchers flexibility in their experimental approach.
Two experiments were conducted herein. The first experiment was designed to determine and compare the effects of the current drug of choice, pergolide, in two possible formulations (oral administration and intramuscular injection) to those of cabergoline (injected) on unstimulated daily plasma prolactin concentrations in geldings. Based on those results, the second experiment compared the efficacy of daily pergolide injections to a single injection of cabergoline for suppression of prolactin responses to small doses of sulpiride in mares.
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Materials and Methods
All procedures described herein were approved by the Institutional Animal Care and Use Committee of the LSU Agricultural Center. The mares and geldings used were of light horse breeds and were long-term residents of the LSU Agricultural Center horse farm in Baton Rouge, LA. They were routinely kept on native grass pasture most of the year and on winter ryegrass pasture when native grasses were dormant; grass hay was provided in transitional periods when grasses were insufficient to maintain
Experiment 1
Mean plasma prolactin concentrations in the four groups of geldings for the first 2 days after treatment are shown in Figure 1. The means for each treated group are plotted against the means for the vehicle-treated (control) geldings for clarity. There was an effect of treatment (P = .061) as well as a treatment × time interaction (P = .0062) in the ANOVA. Relative to controls, all treatments reduced (P < .05) prolactin concentrations, but the treatments varied as to the degree of reduction and
Discussion
Although a starting dose of pergolide of 0.5 to 1.0 mg/day orally is recommended for horses suspected of having PPID [2], [13], [14], a single dose of 2 mg was used in the present experiment as a typical dose that would be given after a gradual increase up to the effect. It is not uncommon for the dose to be ramped up to as high as 6 mg/day [2], [6]. This 2-mg dose, when administered orally, had a very short-lived effect on plasma prolactin concentrations in experiment 1. If the inhibitory
Acknowledgments
The authors thank A.F. Parlow and the National Institute of Diabetes and Digestive and Kidney Diseases, National Hormone and Pituitary Program, Harbor-University of California Los Angeles Medical Center, Torrance, CA, for reagents. Approved for publication by the Director of the Louisiana Agricultural Experiment Station as manuscript number 2012-230-7526.
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Cited by (7)
Dopaminergic and Antidopaminergic Effects on Heart Rate in Healthy Horses When Challenged With Brief 2-minute Exercise Bouts
2018, Journal of Equine Veterinary ScienceLong-term and Short-term Dopaminergic (Cabergoline) and Antidopaminergic (Sulpiride) Effects on Insulin Response to Glucose, Glucose Response to Insulin, or Both in Horses
2017, Journal of Equine Veterinary ScienceCitation Excerpt :Plasma prolactin concentrations were used in these experiments to confirm the dopaminergic and antidopaminergic activities of the cabergoline and sulpiride injections. We have reported on several occasions [4,8,16] that cabergoline is a potent dopaminergic agonist that suppresses prolactin secretion for at least 5 days, and we [7,8,20] and others [6,21] have reported the stimulatory, antidopaminergic activity of sulpiride in horses. In each experiment, the expected action of the selected agent on prolactin secretion was in fact observed.
Seasonal Assessment of Duration of Prolactin Suppression Following Cabergoline Treatment in Mares: Unstimulated Versus Sulpiride and Thyrotropin-Releasing Hormone-Stimulated Responses
2017, Journal of Equine Veterinary ScienceCitation Excerpt :In humans, cabergoline is used frequently in low doses to treat hyperprolactinemia [2,3] and does not appear to be associated with deleterious side effects, such as heart valve dysfunction reported for other dopamine receptor agonists such as pergolide and bromocriptine [4–7]. Hebert et al [8] and Arana Valencia et al [9] assessed the effects of cabergoline on plasma prolactin in mares and geldings as a potential replacement therapy for pergolide in the treatment of pituitary pars intermedia dysfunction (PPID) in horses. Both authors began cabergoline treatments during the fall and reported complete suppression of prolactin in the face of low-dose challenges with the dopamine antagonist sulpiride.
Effect of Repeated Cabergoline Treatment on the Vernal Transition and Hair Shedding of Mares (Year 1) and a Subsequent Comparison of the Effect of Starting Date on Prolactin Suppression (Year 2)
2016, Journal of Equine Veterinary ScienceCitation Excerpt :Additionally, Arana Valencia et al [13] administered a total of seven cabergoline injections 10 days apart and demonstrated no incidences of refractoriness to cabergoline in horses challenged with sulpiride (1 day before the next cabergoline injection) or side effects to the cabergoline compound. Based on those results, we hypothesized (experiment 1) that cabergoline in the same vehicle used in the experiments conducted by Hebert et al [12] and Arana Valencia et al [13] would suppress PRL in the long term and thus allow a better assessment of the need of circulating PRL in follicular growth and eventual ovulation in mares transitioning from winter anovulation to a breeding season state in the spring. Given the less-than-total suppression of PRL by cabergoline in late spring in experiment 1, experiment 2 was performed to test whether the lack of suppression was due to (1) a refractoriness of the mares to long-term cabergoline exposure or perhaps (2) some seasonal change in the mares made them less susceptible to cabergoline suppression.
Prolactin in the Horse: Historical Perspective, Actions and Reactions, and Its Role in Reproduction
2015, Journal of Equine Veterinary ScienceCitation Excerpt :In a study with similar results (no effect on first ovulation), Oberhaus et al [53] used a long-acting dopaminergic compound, cabergoline, in every-10-day injections in a slow-release vehicle to suppress prolactin concentrations in mares starting on February 4. Identical injections of cabergoline had been previously shown to suppress prolactin secretion and the prolactin response to low-dose sulpiride injections for at least 10 days [54,55]. For comparison, administration of 2 mg of pergolide, another dopaminergic compound commonly used to treat pituitary pars intermedia dysfunction in horses [56], reduced plasma prolactin concentrations in geldings for only 6 hours when given PO and only 24 hours when injected intramuscularly in a slow-release vehicle formulation [54].
Long-term treatment of insulin-insensitive mares with cabergoline: Effects on prolactin and melanocyte stimulating hormone responses to sulpiride and on indices of insulin sensitivity
2014, Journal of Equine Veterinary ScienceCitation Excerpt :Hebert et al [1] suggested that the dopaminergic effects of cabergoline observed for prolactin secretion would likely be similar for melanotrope hormonal output, primarily α-melanocyte stimulating hormone (MSH) and perhaps adrenocorticotropin in pituitary pars intermedia dysfunction (PPID), because of the similar physiologic control by dopamine (via the portal blood for lactotropes and via neural input for melanotropes [3,4]). Hebert et al [1] did not include plasma MSH concentrations in their report, thus we are providing those data herein as a prelude to the main experiment. Recently, we have reported that mares displaying hyperleptinemia, hyperinsulinemia, and a diminished response to injected insulin also have exaggerated MSH responses to sulpiride and thyrotropin releasing hormone [5], similar to, but not as great a magnitude of, horses displaying symptoms of PPID [6,7].