Treatment with Pergolide or Cyproheptadine of Pituitary Pars Intermedia Dysfunction (Equine Cushing's Disease)

Treatment with Pergolide or Cyproheptadine of Pituitary Pars Intermedia Dysfunction (Equine... Medical records of 27 horses (including 13 ponies) treated with pergolide or cyproheptadine for pituitary pars intermedia dysfunction were reviewed to determine the effect of treatment on plasma ACTH, insulin, and glucose concentrations and clinical signs. Prior to treatment, the most common clinical signs were laminitis, hirsutism, and abnormal body fat distribution. The median pergolide dose was 3.0 g/kg PO q24h (range, 1.7–5.5 g/kg). All horses treated with cyproheptadine were given 0.25 mg/kg PO q24h. After pergolide treatment, ACTH concentrations (n 20; median 30.4 pg/ml; range, 4.2–173) were significantly lower (P .01) than those in horses treated with cyproheptadine (n 7; median 141.0 pg/ml; range, 10–1,230). Among horses treated with pergolide, there was a correlation between ACTH concentration after treatment and the duration of treatment (P .001) and pergolide dose (P .04). Significantly (P .02) more owners of horses treated with pergolide (85%, 17/20) reported an improvement in clinical signs compared to owners of horses treated with cyproheptadine (28%, 2/7). Key words: ACTH; Hyperadrenocorticism; Pituitary adenoma; Pituitary dysfunction; Pituitary hyperplasia; Pituitary tumor. ituitary pars intermedia dysfunction (PPID), also known as equine Cushing’s disease, is probably the most common equine endocrinopathy, although definitive reports of the prevalence of this disease are lacking. Loss of dopaminergic inhibition of the pars intermedia results in increased proopiomelanocortin synthesis and increased plasma concentrations of adrenocorticotropic hormone (ACTH), melanocyte stimulating hormone, and beta-endorphin.1,2 Common clinical signs of hirsutism, muscle wasting, polyuria, and polydipsia are associated with PPID and are accompanied by high plasma ACTH concentrations.3 Pituitary pars intermedia dysfunction can be diagnosed by numerous methods.4 The overnight dexamethasone suppression test (DST) is the most sensitive and specific diagnostic method; however, because of the purported infrequent association between corticosteroid administration and laminitis and the frequent existence of laminitis in affected horses, some clinicians prefer to use other tests.5 Horses with advanced PPID have plasma ACTH concentrations above the reference range.2,3,6 The convenience and recent increase in the availability of plasma ACTH assays validated for the horse have made this diagnostic test more widely available and used.3,7,8 The reported sensitivity of plasma ACTH concentration in the diagnosis of PPID is from 84 to 100%.3,6,8 In addition to the use of ACTH in the diagnosis of PPID, it might be useful as an objective evaluation of treatment efficacy.7,9 Horses with PPID are frequently insulin resistant and have increased serum glucose and insulin concentrations.10 Although hyperglycemia has a reported diagnostic sensitivity of only 64%, it has been reported to be a useful guide From the Department of Clinical Studies—New Bolton Center (Donaldson, Morresey, Smith, Beech), and the Department of Animal Biology (LaMonte), School of Veterinary Medicine, University of Pennsylvania, Kennett Square, PA. Reprint requests: Mark T. Donaldson, VMD, DACVIM, New Bolton Center, School of Veterinary Medicine, University of Pennsylvania, 382 West Street Road, Kennett Square, PA 19348; e-mail: mtd@vet.upenn.edu. Submitted January 22, 2002; Revised April 29, 2002; Accepted July 23, 2002. Copyright 2002 by the American College of Veterinary Internal Medicine 0891-6640/02/1606-0017/$3.00/0 for evaluating response to treatment when present.11,12 A higher diagnostic sensitivity of 77% has been reported for resting insulin concentration, which is perhaps because of insulin resistance that can precede hyperglycemia.11 Measurement of cortisol concentrations and evaluation of cortisol diurnal rhythm are not reliable diagnostic tests.5,6 Good husbandry and an awareness of potential complications of PPID are essential in the management of this disease. Affected horses should receive regular dental and foot care, deworming, and good nutrition. Horses with hirsutism should be clipped to prevent heat stress and dermatologic problems associated with sweating.12 In the presence of metabolic derangements, laminitis, sole abscesses, infections, or a decreased ability to perform, horses with PPID should receive specific treatment.13 Pergolide and cyproheptadine are the 2 most commonly used treatments for PPID.4,7–9,14–16 Because pergolide is a long-acting dopaminergic agonist, there is a good rationale for its use; however, there are few reports of endocrine responses to treatment with this medication.2,7,8,14–16 Cyproheptadine, a serotonin antagonist, is widely used, and some horses have a decrease in ACTH concentrations and a clinical response to treatment.9,15 However, the rationale for use of cyproheptadine is less clear, and response to treatment with this medication is not consistent.3,7 The role of serotonin in the regulation of the equine pars intermedia has not been evaluated; however, in the limited number of horses studied, normal and affected horses have similar pars intermedia serotonin concentrations.1 The purpose of this study was to evaluate the response of horses with PPID to treatment with pergolide or cyproheptadine by evaluating clinical signs and plasma ACTH, insulin, and glucose concentrations before and after treatment. Based on our clinical experience and knowledge of equine pituitary physiology, we hypothesized that pergolide would be a more effective treatment than cyproheptadine. We also sought to evaluate the owners’ subjective evaluation of response to treatment. Materials and Methods Patient Selection The medical records of all horses that underwent diagnostic evaluation for PPID by the ambulatory service of the George D. Widener Equine Cushing’s Disease Table 1. Clinical signs in horses with pituitary pars intermedia dysfunction before and after treatment with pergolide or cyproheptadine. Pergolide Clinical Sign Laminitis Hirsutism Bulging supraorbital fat Abnormal fat distribution Hyperhidrosis Foot abscess Dermatophilosis Lethargy Polyuria/polydipsia Weight loss Exercise intolerance Infertility Before (n 16 11 6 7 5 5 1 5 2 3 2 1 (80%) (55%) (30%) (35%) (25%) (25%) (5%) (25%) (10%) (15%) (10%) (5%) 20) After (n 3 5 2 7 2 0 1 1 0 1 0 0 (15%) (25%) (10%) (35%) (10%) (0%) (5%) (5%) (0%) (5%) (0%) (0%) 20) P .001 NS NS NS NS NS NS NS NS NS NS NS Before (n 4 5 1 2 2 1 1 0 0 1 1 0 (57%) (71%) (14%) (29%) (29%) (14%) (14%) (0%) (0%) (14%) (14%) (0%) 7) Cyproheptadine After (n 4 4 0 3 2 1 1 0 0 1 1 0 (57%) (57%) (0%) (43%) (29%) (14%) (14%) (0%) (0%) (14%) (14%) (0%) 7) P NS NS NS NS NS NS NS NS NS NS NS NS Hospital or at the Hospital from June 1996 to November 2001 were reviewed. Criteria for inclusion in the study were a resting plasma concentration of ACTH 50 pg/mL and at least 1 clinical sign (laminitis, hirsutism, chronic infection, weight loss, or infertility) and evaluation before and after treatment with either pergolide or cyproheptadine. Data obtained from medical records included signalment, physical examination abnormalities, dose of pergolide or cyproheptadine given, duration of treatment, and the owner’s subjective evaluation of general response to treatment. Plasma concentrations of ACTH, insulin, and glucose before and after treatment were recorded. Results One hundred fifty-seven horses underwent diagnostic evaluation for PPID during the study period. Twenty-seven horses (including 13 ponies) met the criteria for inclusion in the study and were treated with pergolide (n 20) and cyproheptadine (n 7). The median age of the horses treated with pergolide was 19 years (range, 4–29 years). The group was comprised of 6 ponies of undetermined breed, 3 Quarter Horses, 3 Thoroughbreds, 3 Welsh ponies, 2 Morgans, 1 Appaloosa, 1 Connemara pony, and 1 Tennessee Walking Horse. There were 14 geldings and 6 mares. The median age of the horses treated with cyproheptadine was 20 years (range, 11–25 years). The group was comprised of 3 ponies of undetermined breed, 1 Thoroughbred, 1 Quarter Horse, 1 Connemara pony, and 1 crossbred horse. There were 4 geldings and 3 mares. Physical examination and historical abnormalities in both groups (Table 1) included laminitis (n 20), hirsutism (16), abnormal fat distribution (9), hyperhidrosis (7), prominent supraorbital fat pad (7), subsolar abscess (6), lethargy (5), weight loss (4), exercise intolerance (3), dermatophilosis (2), polyuria/polydipsia (2), and infertility (1). There was a significant decrease in the number of horses with laminitis after treatment with pergolide (P .001). The median pergolide dose was 3.0 g/kg (range, 1.7– 5.5 g/kg) PO q24h. The 7 horses treated with cyproheptadine were given 0.25 mg/kg PO q24h. The median duration of treatment with pergolide or cyproheptadine was 2.0 months (range, 1.0–10.0) and 2.5 months (range, 1.0– 11.5), respectively. There was no significant difference in age or duration of treatment between treatment groups. ACTH, insulin, and glucose concentrations after treatment were lower in the pergolide treatment group (P .01). Comparison of ACTH, insulin, and glucose concentrations before and after treatment revealed a significant (P .001) decrease in ACTH concentration after treatment with pergolide and no significant differences in insulin or glucose concentrations. There was no significant difference in ACTH, insulin, or glucose concentrations after treatment with cyproheptadine (Table 2). Biochemical Assays Blood samples for glucose measurement were collected in glass tubes containing sodium fluoride and potassium oxalate as a glycolytic inhibitor and were determined by the glucose oxidase method at the clinical laboratory of the George D. Widener Hospital. The reference range for glucose was 72–114 mg/dL. Blood was collected for ACTH and insulin concentrations in silicone-coated glass tubes containing potassium edetic acid (EDTA) and immediately refrigerated. Plasma was separated and placed in a polypropylene tube within 3 hours of collection. Plasma for ACTH and insulin assay was then stored at 20 C up to 72 hours before overnight shipment to the endocrinology laboratory at Cornell University (College of Veterinary Medicine, Ithaca, NY) for evaluation by chemiluminescent immunoassay (CIA) and radioimmunoassay (RIA), respectively.8,17 Most samples were shipped within 24 hours of collection. The reference range for ACTH was 9– 35 pg/ml. The reference range for insulin was 10–30 IU/ml. Statistical Analysis Nonparametric methods (Kruskal-Wallis ANOVA) were employed with Dunn’s multiple comparison posttest in the evaluation of biochemical parameters before and after treatment and for comparison of biochemical parameters between treatment groups. Age and duration of treatment in the pergolide and cyproheptadine groups were compared by the Mann-Whitney test. If more than 1 sample was collected on a single day for measurement of ACTH, insulin, or glucose, the mean value for those samples was used in data analysis. The frequency of physical examination abnormalities before and after treatment was evaluated by Fisher’s exact test. Comparison of the owners’ evaluation of response to treatment with pergolide or cyproheptadine was performed by Fisher’s exact test. The correlation between duration of treatment, dose of pergolide, and ACTH concentration after treatment was examined by the Spearman rank test. Statistical calculations were performed by commercially available software.a For all statistical tests, P .05 was considered significant. Donaldson et al Table 2. Median (range) biochemical parameters in horses with PPID before and after treatment with pergolide or cyproheptadine. Biochemical Variable (Reference Range) ACTH (8–35 pg/mL) Pergolide (n) Before After Cyproheptadine (n) Before After (20) 136* (50.7–353) 30.4* (4.2–173) (7) 146 (61.1–613) 141** (10.0–1,230) Insulin (10–30 IU/mL) (19) 59.5 (9.2–447) 58.9 (5.0–500) (7) 109 (11.5–247) 38.4 (3.6–381) .01. Glucose (72–114 mg/dL) (14) 109 (74–203) 92.0 (76–221) (7) 99.0 (81–134) 95.0 (74–112) Fig 1. Relationship between pergolide dose and ACTH concentration after treatment in horses treated for PPID. Spearman r .468, P .04. Significantly different at *P .001 and **P One data point was excluded from analysis of ACTH concentrations after treatment because it was greater than 3 standard deviations from the mean ACTH concentration. There was a correlation between pergolide dose and ACTH concentration after treatment (r .468, 95% CI, .766 to .002, P .04; Fig 1) and a correlation between duration of treatment with pergolide and ACTH concentration after treatment (r .726, 95% CI, .891 to .393, P .001; Fig 2). More owners of horses treated with pergolide (17/20, 85%) reported an improvement in clinical signs compared to horses treated with cyproheptadine (2/7, 28%) (P .02). Discussion The results of this study suggest that pergolide is more effective than cyproheptadine in the treatment of PPID. Comparison of ACTH concentrations after treatment revealed lower ACTH concentrations in the pergolide treatment group. Furthermore, ACTH concentration decreased markedly after pergolide treatment to within the normal range in most horses. Finally, a greater proportion of horses treated with pergolide had an owner-reported improvement in clinical signs. Previous studies have evaluated the effect of treatment with pergolide or cyproheptadine on pituitary function in horses with PPID. Peters et al14 reported treatment of 9 equids with a low dose of pergolide (1.7 g/kg PO q24h). Two of 9 (22%) horses had a normal dexamethasone suppression test after treatment, 5 had an improvement in the dexamethasone suppression test but were not normal, and 2 were unchanged.14 In a study of the effects of long-term treatment with pergolide, 6 horses were treated for 6 to 26 months with pergolide (1.8–2.8 g/kg PO q24h). Improvement was seen in the results of the dexamethasone suppression test in all 6 horses, but the number returning to normal was not reported.16 In a study conducted in Michigan, treatment with pergolide (2 g/kg PO q24h) for 6–12 months resulted in a normal dexamethasone suppression test in 7 of 20 (35%) horses. Treatment with cyproheptadine (1.2 mg/kg3/4 PO q24h) resulted in a normal dexamethasone suppression test in 1 of 7 (14%) horses. In a study of the effects of treatment with cyproheptadine on ACTH concentration and clinical signs, a clinical response was seen in 20 of 29 (69%) horses treated and ACTH concentrations decreased in 9 of 20 (45%) but increased in 8 of 20 (40%).9 Our study is consistent with previous reports of the treatment of PPID in which pergolide was a superior treatment. Furthermore, the higher median dose of pergolide used in this study (3.0 g/kg PO q24h) resulted in an improvement in ACTH concentration in all horses, and 12 of 20 (60%) horses had a normal ACTH concentration after treatment. Similarly, none of the horses treated with cyproheptadine in this study had normal ACTH concentrations after treatment. Previous studies have suggested that measurement of plasma ACTH concentration is a reliable test for PPID. We chose ACTH concentrations 50 pg/mL as criteria for inclusion in this study because this break point value was associated with the greatest sensitivity and specificity in previous studies.3,6 When evaluating the biochemical response to treatment, measuring ACTH concentration would appear to be an appropriate test in horses in which it is initially high. Among the biochemical parameters evaluated (ACTH, insulin, and glucose), only ACTH concentration revealed a statistically significant change after treatment. Among horses treated with pergolide, ACTH concentration Fig 2. Relationship between duration of treatment with pergolide and ACTH concentration after treatment in horses treated with PPID. Spearman r .726, P .001. Equine Cushing’s Disease was lower after treatment in all 20 horses, and it was in the normal range (9–35 pg/mL) in 12 horses. The lack of decline in serum insulin concentrations in both treatment groups could have been due to incomplete control of PPID or the presence of other factors that result in dysregulation of insulin secretion. Previous studies that evaluated serum insulin concentrations in response to treatment of PPID with pergolide also revealed a lack of improvement in serum insulin concentrations.15 Because large fluctuations in serum insulin concentration occur throughout the day in normal horses, and presumably in horses with PPID, the evaluation of single samples could be misleading.18 Previous studies have revealed an association among body condition, hyperinsulinemia, and impaired glucose tolerance in obese ponies.19 Therefore, it is possible that hyperinsulinemia might persist in spite of effective control of PPID in obese horses. However, we have observed thin horses treated with pergolide for PPID that remain hyperinsulinemic in spite of normal ACTH concentrations. Abnormal 11-beta-hydroxysteroid dehydrogenase (11 HSD) activity has been proposed as a cause of insulin resistance in people. Further study is needed to determine whether this syndrome occurs in horses.20 It is also possible but unlikely that the original diagnosis of PPID was incorrect. The specificity of ACTH concentration in the diagnosis of PPID has been reported to be from 78% with a cut-off of 35 pg/mL for the chemiluminescent immunoassay to 100% with a cut-off of 50 pg/mL for the radioimmunoassay.3,8 Because the specificity of the chemiluminescent immunoassay was lower, we chose to use 50 pg/mL as the inclusion criteria in this study to reduce the possibility of false positive results. Although true insulin-dependent diabetes mellitus in association with PPID is rare, this situation would confound interpretation of insulin and glucose concentrations in horses undergoing treatment for PPID.21,22 Pancreatic beta cell exhaustion should be suspected in horses with hyperglycemia and normal or only mildly high insulin concentrations. Previous studies have evaluated the dexamethasone suppression test in response to treatment.7,14 Although the dexamethasone suppression test has the advantage of testing the hypothalamic-pituitary-adrenal axis, it requires the administration of dexamethasone and collection of at least 2 blood samples on different days. Because of the anecdotal association between dexamethasone administration and laminitis, and thus the reluctance of some owners to use the test, we chose not to use the dexamethasone suppression test in the diagnosis or subsequent evaluation of equids with PPID and evidence of laminitis. Baseline endogenous ACTH concentration is a valuable diagnostic test for PPID in horses.3,6 There does not appear to be a prolonged increase in ACTH concentration due to isolation stress, other systemic illness, or exercise.3 The effect of pain, such as that associated with laminitis, on ACTH concentration has not been reported, but we have measured normal ACTH concentrations in horses with severe laminitis. Endogenous ACTH concentration is used in other species to diagnose pituitary dysfunction. Approximately 10–15% of dogs with pituitary-dependent hyperadrenocorticism have resting ACTH concentrations that overlap with those of normal dogs and therefore are considered nondiagnostic.23 A similar situation exists in horses. Because the sensitivity of ACTH concentrations in the diagnosis of PPID is less than 100%, not all horses with PPID will have high plasma concentrations of ACTH.3 Inherent in a retrospective study such as this is a bias in the selection of treatment type. We tried to identify potential differences that existed between the 2 treatment groups before treatment. With respect to clinical signs, treatment groups were similar before treatment (Table 1). There was no statistically significant difference in age, plasma ACTH concentration before treatment, insulin or glucose concentrations, or duration of treatment. Because owners were frequently informed of the clinical impression that pergolide is more effective than cyproheptadine, owners of more severely affected horses might have selected pergolide treatment. Therefore, there may be a bias against observing a favorable response in horses treated with pergolide. However, the likelihood of detecting a difference could be greater in more severely affected horses. Owners of horses treated with pergolide might have reported a more favorable response to treatment because of our clinical impression that it was more effective. Appropriate administration of the drug could have been more likely in the pergolide-treated group because of the severity of illness and cost of medication. A large dose range has been reported for treatment of PPID with pergolide from 1.7 to 12.5 g/kg PO q24h.4,14 Cyproheptadine is most frequently given at 0.25 mg/kg PO q12–24h.12 The efficacy of twice daily dosing or the use of higher doses of cyproheptadine was not evaluated in this study. The bioavailability and pharmacokinetics of both medications in horses is unknown. The lack of perceived drug effect could be due to inadequate blood and tissue concentrations. It is also possible that the apparent clinical effect of cyproheptadine is not related to the suppression of ACTH secretion. Footnotes InStat Macintosh v2.0, GraphPad Software, San Diego, CA http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Journal of Veterinary Internal Medicine Wiley

Treatment with Pergolide or Cyproheptadine of Pituitary Pars Intermedia Dysfunction (Equine Cushing's Disease)

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1939-1676
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Abstract

Medical records of 27 horses (including 13 ponies) treated with pergolide or cyproheptadine for pituitary pars intermedia dysfunction were reviewed to determine the effect of treatment on plasma ACTH, insulin, and glucose concentrations and clinical signs. Prior to treatment, the most common clinical signs were laminitis, hirsutism, and abnormal body fat distribution. The median pergolide dose was 3.0 g/kg PO q24h (range, 1.7–5.5 g/kg). All horses treated with cyproheptadine were given 0.25 mg/kg PO q24h. After pergolide treatment, ACTH concentrations (n 20; median 30.4 pg/ml; range, 4.2–173) were significantly lower (P .01) than those in horses treated with cyproheptadine (n 7; median 141.0 pg/ml; range, 10–1,230). Among horses treated with pergolide, there was a correlation between ACTH concentration after treatment and the duration of treatment (P .001) and pergolide dose (P .04). Significantly (P .02) more owners of horses treated with pergolide (85%, 17/20) reported an improvement in clinical signs compared to owners of horses treated with cyproheptadine (28%, 2/7). Key words: ACTH; Hyperadrenocorticism; Pituitary adenoma; Pituitary dysfunction; Pituitary hyperplasia; Pituitary tumor. ituitary pars intermedia dysfunction (PPID), also known as equine Cushing’s disease, is probably the most common equine endocrinopathy, although definitive reports of the prevalence of this disease are lacking. Loss of dopaminergic inhibition of the pars intermedia results in increased proopiomelanocortin synthesis and increased plasma concentrations of adrenocorticotropic hormone (ACTH), melanocyte stimulating hormone, and beta-endorphin.1,2 Common clinical signs of hirsutism, muscle wasting, polyuria, and polydipsia are associated with PPID and are accompanied by high plasma ACTH concentrations.3 Pituitary pars intermedia dysfunction can be diagnosed by numerous methods.4 The overnight dexamethasone suppression test (DST) is the most sensitive and specific diagnostic method; however, because of the purported infrequent association between corticosteroid administration and laminitis and the frequent existence of laminitis in affected horses, some clinicians prefer to use other tests.5 Horses with advanced PPID have plasma ACTH concentrations above the reference range.2,3,6 The convenience and recent increase in the availability of plasma ACTH assays validated for the horse have made this diagnostic test more widely available and used.3,7,8 The reported sensitivity of plasma ACTH concentration in the diagnosis of PPID is from 84 to 100%.3,6,8 In addition to the use of ACTH in the diagnosis of PPID, it might be useful as an objective evaluation of treatment efficacy.7,9 Horses with PPID are frequently insulin resistant and have increased serum glucose and insulin concentrations.10 Although hyperglycemia has a reported diagnostic sensitivity of only 64%, it has been reported to be a useful guide From the Department of Clinical Studies—New Bolton Center (Donaldson, Morresey, Smith, Beech), and the Department of Animal Biology (LaMonte), School of Veterinary Medicine, University of Pennsylvania, Kennett Square, PA. Reprint requests: Mark T. Donaldson, VMD, DACVIM, New Bolton Center, School of Veterinary Medicine, University of Pennsylvania, 382 West Street Road, Kennett Square, PA 19348; e-mail: mtd@vet.upenn.edu. Submitted January 22, 2002; Revised April 29, 2002; Accepted July 23, 2002. Copyright 2002 by the American College of Veterinary Internal Medicine 0891-6640/02/1606-0017/$3.00/0 for evaluating response to treatment when present.11,12 A higher diagnostic sensitivity of 77% has been reported for resting insulin concentration, which is perhaps because of insulin resistance that can precede hyperglycemia.11 Measurement of cortisol concentrations and evaluation of cortisol diurnal rhythm are not reliable diagnostic tests.5,6 Good husbandry and an awareness of potential complications of PPID are essential in the management of this disease. Affected horses should receive regular dental and foot care, deworming, and good nutrition. Horses with hirsutism should be clipped to prevent heat stress and dermatologic problems associated with sweating.12 In the presence of metabolic derangements, laminitis, sole abscesses, infections, or a decreased ability to perform, horses with PPID should receive specific treatment.13 Pergolide and cyproheptadine are the 2 most commonly used treatments for PPID.4,7–9,14–16 Because pergolide is a long-acting dopaminergic agonist, there is a good rationale for its use; however, there are few reports of endocrine responses to treatment with this medication.2,7,8,14–16 Cyproheptadine, a serotonin antagonist, is widely used, and some horses have a decrease in ACTH concentrations and a clinical response to treatment.9,15 However, the rationale for use of cyproheptadine is less clear, and response to treatment with this medication is not consistent.3,7 The role of serotonin in the regulation of the equine pars intermedia has not been evaluated; however, in the limited number of horses studied, normal and affected horses have similar pars intermedia serotonin concentrations.1 The purpose of this study was to evaluate the response of horses with PPID to treatment with pergolide or cyproheptadine by evaluating clinical signs and plasma ACTH, insulin, and glucose concentrations before and after treatment. Based on our clinical experience and knowledge of equine pituitary physiology, we hypothesized that pergolide would be a more effective treatment than cyproheptadine. We also sought to evaluate the owners’ subjective evaluation of response to treatment. Materials and Methods Patient Selection The medical records of all horses that underwent diagnostic evaluation for PPID by the ambulatory service of the George D. Widener Equine Cushing’s Disease Table 1. Clinical signs in horses with pituitary pars intermedia dysfunction before and after treatment with pergolide or cyproheptadine. Pergolide Clinical Sign Laminitis Hirsutism Bulging supraorbital fat Abnormal fat distribution Hyperhidrosis Foot abscess Dermatophilosis Lethargy Polyuria/polydipsia Weight loss Exercise intolerance Infertility Before (n 16 11 6 7 5 5 1 5 2 3 2 1 (80%) (55%) (30%) (35%) (25%) (25%) (5%) (25%) (10%) (15%) (10%) (5%) 20) After (n 3 5 2 7 2 0 1 1 0 1 0 0 (15%) (25%) (10%) (35%) (10%) (0%) (5%) (5%) (0%) (5%) (0%) (0%) 20) P .001 NS NS NS NS NS NS NS NS NS NS NS Before (n 4 5 1 2 2 1 1 0 0 1 1 0 (57%) (71%) (14%) (29%) (29%) (14%) (14%) (0%) (0%) (14%) (14%) (0%) 7) Cyproheptadine After (n 4 4 0 3 2 1 1 0 0 1 1 0 (57%) (57%) (0%) (43%) (29%) (14%) (14%) (0%) (0%) (14%) (14%) (0%) 7) P NS NS NS NS NS NS NS NS NS NS NS NS Hospital or at the Hospital from June 1996 to November 2001 were reviewed. Criteria for inclusion in the study were a resting plasma concentration of ACTH 50 pg/mL and at least 1 clinical sign (laminitis, hirsutism, chronic infection, weight loss, or infertility) and evaluation before and after treatment with either pergolide or cyproheptadine. Data obtained from medical records included signalment, physical examination abnormalities, dose of pergolide or cyproheptadine given, duration of treatment, and the owner’s subjective evaluation of general response to treatment. Plasma concentrations of ACTH, insulin, and glucose before and after treatment were recorded. Results One hundred fifty-seven horses underwent diagnostic evaluation for PPID during the study period. Twenty-seven horses (including 13 ponies) met the criteria for inclusion in the study and were treated with pergolide (n 20) and cyproheptadine (n 7). The median age of the horses treated with pergolide was 19 years (range, 4–29 years). The group was comprised of 6 ponies of undetermined breed, 3 Quarter Horses, 3 Thoroughbreds, 3 Welsh ponies, 2 Morgans, 1 Appaloosa, 1 Connemara pony, and 1 Tennessee Walking Horse. There were 14 geldings and 6 mares. The median age of the horses treated with cyproheptadine was 20 years (range, 11–25 years). The group was comprised of 3 ponies of undetermined breed, 1 Thoroughbred, 1 Quarter Horse, 1 Connemara pony, and 1 crossbred horse. There were 4 geldings and 3 mares. Physical examination and historical abnormalities in both groups (Table 1) included laminitis (n 20), hirsutism (16), abnormal fat distribution (9), hyperhidrosis (7), prominent supraorbital fat pad (7), subsolar abscess (6), lethargy (5), weight loss (4), exercise intolerance (3), dermatophilosis (2), polyuria/polydipsia (2), and infertility (1). There was a significant decrease in the number of horses with laminitis after treatment with pergolide (P .001). The median pergolide dose was 3.0 g/kg (range, 1.7– 5.5 g/kg) PO q24h. The 7 horses treated with cyproheptadine were given 0.25 mg/kg PO q24h. The median duration of treatment with pergolide or cyproheptadine was 2.0 months (range, 1.0–10.0) and 2.5 months (range, 1.0– 11.5), respectively. There was no significant difference in age or duration of treatment between treatment groups. ACTH, insulin, and glucose concentrations after treatment were lower in the pergolide treatment group (P .01). Comparison of ACTH, insulin, and glucose concentrations before and after treatment revealed a significant (P .001) decrease in ACTH concentration after treatment with pergolide and no significant differences in insulin or glucose concentrations. There was no significant difference in ACTH, insulin, or glucose concentrations after treatment with cyproheptadine (Table 2). Biochemical Assays Blood samples for glucose measurement were collected in glass tubes containing sodium fluoride and potassium oxalate as a glycolytic inhibitor and were determined by the glucose oxidase method at the clinical laboratory of the George D. Widener Hospital. The reference range for glucose was 72–114 mg/dL. Blood was collected for ACTH and insulin concentrations in silicone-coated glass tubes containing potassium edetic acid (EDTA) and immediately refrigerated. Plasma was separated and placed in a polypropylene tube within 3 hours of collection. Plasma for ACTH and insulin assay was then stored at 20 C up to 72 hours before overnight shipment to the endocrinology laboratory at Cornell University (College of Veterinary Medicine, Ithaca, NY) for evaluation by chemiluminescent immunoassay (CIA) and radioimmunoassay (RIA), respectively.8,17 Most samples were shipped within 24 hours of collection. The reference range for ACTH was 9– 35 pg/ml. The reference range for insulin was 10–30 IU/ml. Statistical Analysis Nonparametric methods (Kruskal-Wallis ANOVA) were employed with Dunn’s multiple comparison posttest in the evaluation of biochemical parameters before and after treatment and for comparison of biochemical parameters between treatment groups. Age and duration of treatment in the pergolide and cyproheptadine groups were compared by the Mann-Whitney test. If more than 1 sample was collected on a single day for measurement of ACTH, insulin, or glucose, the mean value for those samples was used in data analysis. The frequency of physical examination abnormalities before and after treatment was evaluated by Fisher’s exact test. Comparison of the owners’ evaluation of response to treatment with pergolide or cyproheptadine was performed by Fisher’s exact test. The correlation between duration of treatment, dose of pergolide, and ACTH concentration after treatment was examined by the Spearman rank test. Statistical calculations were performed by commercially available software.a For all statistical tests, P .05 was considered significant. Donaldson et al Table 2. Median (range) biochemical parameters in horses with PPID before and after treatment with pergolide or cyproheptadine. Biochemical Variable (Reference Range) ACTH (8–35 pg/mL) Pergolide (n) Before After Cyproheptadine (n) Before After (20) 136* (50.7–353) 30.4* (4.2–173) (7) 146 (61.1–613) 141** (10.0–1,230) Insulin (10–30 IU/mL) (19) 59.5 (9.2–447) 58.9 (5.0–500) (7) 109 (11.5–247) 38.4 (3.6–381) .01. Glucose (72–114 mg/dL) (14) 109 (74–203) 92.0 (76–221) (7) 99.0 (81–134) 95.0 (74–112) Fig 1. Relationship between pergolide dose and ACTH concentration after treatment in horses treated for PPID. Spearman r .468, P .04. Significantly different at *P .001 and **P One data point was excluded from analysis of ACTH concentrations after treatment because it was greater than 3 standard deviations from the mean ACTH concentration. There was a correlation between pergolide dose and ACTH concentration after treatment (r .468, 95% CI, .766 to .002, P .04; Fig 1) and a correlation between duration of treatment with pergolide and ACTH concentration after treatment (r .726, 95% CI, .891 to .393, P .001; Fig 2). More owners of horses treated with pergolide (17/20, 85%) reported an improvement in clinical signs compared to horses treated with cyproheptadine (2/7, 28%) (P .02). Discussion The results of this study suggest that pergolide is more effective than cyproheptadine in the treatment of PPID. Comparison of ACTH concentrations after treatment revealed lower ACTH concentrations in the pergolide treatment group. Furthermore, ACTH concentration decreased markedly after pergolide treatment to within the normal range in most horses. Finally, a greater proportion of horses treated with pergolide had an owner-reported improvement in clinical signs. Previous studies have evaluated the effect of treatment with pergolide or cyproheptadine on pituitary function in horses with PPID. Peters et al14 reported treatment of 9 equids with a low dose of pergolide (1.7 g/kg PO q24h). Two of 9 (22%) horses had a normal dexamethasone suppression test after treatment, 5 had an improvement in the dexamethasone suppression test but were not normal, and 2 were unchanged.14 In a study of the effects of long-term treatment with pergolide, 6 horses were treated for 6 to 26 months with pergolide (1.8–2.8 g/kg PO q24h). Improvement was seen in the results of the dexamethasone suppression test in all 6 horses, but the number returning to normal was not reported.16 In a study conducted in Michigan, treatment with pergolide (2 g/kg PO q24h) for 6–12 months resulted in a normal dexamethasone suppression test in 7 of 20 (35%) horses. Treatment with cyproheptadine (1.2 mg/kg3/4 PO q24h) resulted in a normal dexamethasone suppression test in 1 of 7 (14%) horses. In a study of the effects of treatment with cyproheptadine on ACTH concentration and clinical signs, a clinical response was seen in 20 of 29 (69%) horses treated and ACTH concentrations decreased in 9 of 20 (45%) but increased in 8 of 20 (40%).9 Our study is consistent with previous reports of the treatment of PPID in which pergolide was a superior treatment. Furthermore, the higher median dose of pergolide used in this study (3.0 g/kg PO q24h) resulted in an improvement in ACTH concentration in all horses, and 12 of 20 (60%) horses had a normal ACTH concentration after treatment. Similarly, none of the horses treated with cyproheptadine in this study had normal ACTH concentrations after treatment. Previous studies have suggested that measurement of plasma ACTH concentration is a reliable test for PPID. We chose ACTH concentrations 50 pg/mL as criteria for inclusion in this study because this break point value was associated with the greatest sensitivity and specificity in previous studies.3,6 When evaluating the biochemical response to treatment, measuring ACTH concentration would appear to be an appropriate test in horses in which it is initially high. Among the biochemical parameters evaluated (ACTH, insulin, and glucose), only ACTH concentration revealed a statistically significant change after treatment. Among horses treated with pergolide, ACTH concentration Fig 2. Relationship between duration of treatment with pergolide and ACTH concentration after treatment in horses treated with PPID. Spearman r .726, P .001. Equine Cushing’s Disease was lower after treatment in all 20 horses, and it was in the normal range (9–35 pg/mL) in 12 horses. The lack of decline in serum insulin concentrations in both treatment groups could have been due to incomplete control of PPID or the presence of other factors that result in dysregulation of insulin secretion. Previous studies that evaluated serum insulin concentrations in response to treatment of PPID with pergolide also revealed a lack of improvement in serum insulin concentrations.15 Because large fluctuations in serum insulin concentration occur throughout the day in normal horses, and presumably in horses with PPID, the evaluation of single samples could be misleading.18 Previous studies have revealed an association among body condition, hyperinsulinemia, and impaired glucose tolerance in obese ponies.19 Therefore, it is possible that hyperinsulinemia might persist in spite of effective control of PPID in obese horses. However, we have observed thin horses treated with pergolide for PPID that remain hyperinsulinemic in spite of normal ACTH concentrations. Abnormal 11-beta-hydroxysteroid dehydrogenase (11 HSD) activity has been proposed as a cause of insulin resistance in people. Further study is needed to determine whether this syndrome occurs in horses.20 It is also possible but unlikely that the original diagnosis of PPID was incorrect. The specificity of ACTH concentration in the diagnosis of PPID has been reported to be from 78% with a cut-off of 35 pg/mL for the chemiluminescent immunoassay to 100% with a cut-off of 50 pg/mL for the radioimmunoassay.3,8 Because the specificity of the chemiluminescent immunoassay was lower, we chose to use 50 pg/mL as the inclusion criteria in this study to reduce the possibility of false positive results. Although true insulin-dependent diabetes mellitus in association with PPID is rare, this situation would confound interpretation of insulin and glucose concentrations in horses undergoing treatment for PPID.21,22 Pancreatic beta cell exhaustion should be suspected in horses with hyperglycemia and normal or only mildly high insulin concentrations. Previous studies have evaluated the dexamethasone suppression test in response to treatment.7,14 Although the dexamethasone suppression test has the advantage of testing the hypothalamic-pituitary-adrenal axis, it requires the administration of dexamethasone and collection of at least 2 blood samples on different days. Because of the anecdotal association between dexamethasone administration and laminitis, and thus the reluctance of some owners to use the test, we chose not to use the dexamethasone suppression test in the diagnosis or subsequent evaluation of equids with PPID and evidence of laminitis. Baseline endogenous ACTH concentration is a valuable diagnostic test for PPID in horses.3,6 There does not appear to be a prolonged increase in ACTH concentration due to isolation stress, other systemic illness, or exercise.3 The effect of pain, such as that associated with laminitis, on ACTH concentration has not been reported, but we have measured normal ACTH concentrations in horses with severe laminitis. Endogenous ACTH concentration is used in other species to diagnose pituitary dysfunction. Approximately 10–15% of dogs with pituitary-dependent hyperadrenocorticism have resting ACTH concentrations that overlap with those of normal dogs and therefore are considered nondiagnostic.23 A similar situation exists in horses. Because the sensitivity of ACTH concentrations in the diagnosis of PPID is less than 100%, not all horses with PPID will have high plasma concentrations of ACTH.3 Inherent in a retrospective study such as this is a bias in the selection of treatment type. We tried to identify potential differences that existed between the 2 treatment groups before treatment. With respect to clinical signs, treatment groups were similar before treatment (Table 1). There was no statistically significant difference in age, plasma ACTH concentration before treatment, insulin or glucose concentrations, or duration of treatment. Because owners were frequently informed of the clinical impression that pergolide is more effective than cyproheptadine, owners of more severely affected horses might have selected pergolide treatment. Therefore, there may be a bias against observing a favorable response in horses treated with pergolide. However, the likelihood of detecting a difference could be greater in more severely affected horses. Owners of horses treated with pergolide might have reported a more favorable response to treatment because of our clinical impression that it was more effective. Appropriate administration of the drug could have been more likely in the pergolide-treated group because of the severity of illness and cost of medication. A large dose range has been reported for treatment of PPID with pergolide from 1.7 to 12.5 g/kg PO q24h.4,14 Cyproheptadine is most frequently given at 0.25 mg/kg PO q12–24h.12 The efficacy of twice daily dosing or the use of higher doses of cyproheptadine was not evaluated in this study. The bioavailability and pharmacokinetics of both medications in horses is unknown. The lack of perceived drug effect could be due to inadequate blood and tissue concentrations. It is also possible that the apparent clinical effect of cyproheptadine is not related to the suppression of ACTH secretion. Footnotes InStat Macintosh v2.0, GraphPad Software, San Diego, CA

Journal

Journal of Veterinary Internal MedicineWiley

Published: Nov 1, 2002

Keywords: ; ; ; ; ;

References

  • Laboratory diagnosis of equine pituitary pars intermedia adenoma
    Kolk, JH; Wensing, T.; Kalsbeek, HC

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