Diagnosis and Management of Equine Cushing’s Disease Harold C. Schott II, DVM, PhD, DACVIM Professor, Equine Internal Medicine Department of Large Animal Clinical Sciences D-202 Veterinary Medical Center Michigan State University, East Lansing, MI 48824-1314 (517)-353-9710 email@example.com Prevalence: Although the frequency of diagnosis and treatment of pituitary pars intermedia dysfunction (PPID) in horses has clearly increased over the past decade, there is no evidence that the prevalence of PPID is actually increasing. Increased recognition of the disease is likely a consequence of clients maintaining their horses to more advanced ages as well as improved health care (e.g., diet and dentistry) being provided to older horses. A recent survey of horse owners in Queensland, Australia revealed a prevalence of 15-20% of PPID in horses and ponies 15 years of age and older. There is no gender predilection and average age of affected horses is around 20 years. All breeds and types of equids can be affected with PPID but Morgan horses and ponies appear to be at greater risk. Pathophysiology: In humans and dogs, Cushing’s disease is most commonly attributed to a corticotroph adenoma in the pars distalis of the pituitary gland. These adenomas are thought to arise spontaneously. In contrast, Cushing’s disease in horses is almost exclusively attributed to hyperplasia or adenoma formation in the pars intermedia that appears to be due to loss of hypothalamic innervation. Abnormal pars intermedia tissue in horses contains markedly reduced amounts of dopamine, about 10% that of normal pars intermedia tissue, consistent with a specific loss of hypothalamic dopaminergic innervation. Recent evidence suggests that this loss of dopaminergic innervation is due to oxidant-induced injury to hypothalamic tissue. Thus, a risk factor for affected horses may be reduced anti-oxidant defense mechanisms in neural tissue. Further, insoluble aggregates of the neural protein α-synuclein have been found in dopaminergic nerve terminals of PPID-affected horses. These protein aggregates are also found in humans with Parkinson’s disease suggesting that the two neurodegenerative disorders may share a similar pathogenesis. However, the population of neurons affected in horses, as compared to humans, appears to be different leading to the difference in clinical signs observed in each species. Abnormal pars intermedia cells, exclusively melanotropes, produce excessive amounts of pro- opiomelanocortin (POMC) and a number of POMC-derived peptides including adrenocoticotropin (ACTH). Also unlike Cushing’s disease in humans and dogs, adrenocortical hyperplasia accompanying equine Cushing’s disease is relatively uncommon, occurring in ~20% of affected horses. These differences in location and pathophysiology between human, canine, and equine pituitary adenomas have lead several authors to suggest that the disease in horses should not be called equine Cushing’s disease; rather, pituitary pars intermedia dysfunction (PPID) has been advanced as a more appropriate descriptor. Clinical signs: The classic clinical sign of PPID in horses is hirsutism, a long and curly hair coat that fails to shed. In some affected horses, coat color changes have also been observed. The pathogenesis of hirsutism, which is characterized by arrest of hair follicles in telogen, remains unknown. Hyperhidrosis is also observed in up to two-thirds of horses with PIPD, most commonly over the neck and shoulders, and has been attributed to a thermoregulatory response to the long hair coat. Weight loss and lethargy, or poor performance, are also commonly observed in horses with PPID. In addition to true weight loss, protein catabolism due to increased cortisol activity leads to loss of muscle mass. This is most notable in advanced cases as a loss of epaxial and rump musculature. Despite weight loss, appetite in affected horses is normal or even increased (polyphagia). However, dental abnormalities, leading to painful mastication and quidding, may compromise feed intake and contribute to weight loss in some horses. Combined with, or often preceding, loss of muscle mass is deposition of fat along the crest of the neck, over the tail head, and in the sheath of male horses. Another area where abnormal fat deposition may occur is above and behind the eyes. Horses with PPID have also been described as overly docile and more tolerant of pain than normal horses. The latter signs have been attributed to increased plasma and cerebrospinal fluid concentrations of -endorphin that are 60- and more than 100-fold greater, respectively, in horses with PPID than in normal horses. Chronic, insidious-onset laminitis is perhaps the major clinical complication of PPID with more than 50% of horses affected in most reports. Although the condition is more amenable to management in ponies due to their lower body weight, chronic or recurrent pain with exacerbation of laminitis or associated foot abscesses is often the reason for euthanasia. Polydipsia and polyuria (PU/PD) develops in about one- third of horses with PPID. Equids with PPID tend to have delayed wound healing and are frequently affected with secondary infections. Commonly recognized infections include skin infections (e.g., refractory “scratches” and fistulous tracts), recurrent subsolar abscesses, conjunctivitis, sinusitis, gingivitis, alveolar periostitis, and bronchopneumonia. Other signs that have been reported in horses with PPID include persistent lactation and infertility. Central nervous system (CNS) dysfunction, including ataxia, blindness, dementia, and seizure-like activity, are occasionally observed in equids with PPID. A major complication of hypercortisolism in affected human patients is osteoporosis. Although occurrence of this complication has not been investigated in horses, it is interesting to note that euthanasia of horses with PPID has been reported due to development of pelvic, pedal bone, mandibular, and multiple rib fractures. Clinicopathologic findings: Abnormal laboratory data in horses with PPID may include mild anemia, an absolute or relative neutrophilia, and an absolute or relative lymphopenia. Although one or more of these abnormalities is usually found in a third or more of equids afflicted with PPID, the true prevalence is not well documented. As well as being increased in number, neutrophils in affected animals may appear hypersegmented. This finding reflects maturity of neutrophils and can be attributed to a longer half-life of circulating neutrophils because cortisol excess limits diapedesis from the vasculature. Eosinopenia is also recognized in human and canine patients with hyperadrenocorticism but is difficult to document in horses because equids typically have a low numbers of circulating eosinophils. The most common abnormality detected on serum biochemical evaluation is mild to moderate hyperglycemia, reported in 25-75% of cases, depending on the upper end of the reference range used. Additional abnormal biochemical findings may include elevations in liver enzyme activities, hypercholesterolemia, and hypertriglyceridemia. Diagnosis: Practically, the diagnosis of PPID is most commonly made by observation of hirsutism and other clinical signs in older equids. However, establishing a diagnosis of PPID in less severely affected horses can be challenging. As a result, a number of endocrinologic tests have been used to evaluate horses with suspected PPID. Plasma cortisol concentration and loss of diurnal cortisol rhythm. Although hyperadrenocorticism can be accompanied by an elevated plasma cortisol concentration, resting cortisol concentration does not routinely exceed the upper end of the reference range in horses with PPID. Thus, measurement of plasma cortisol concentration alone is not a valid diagnostic test. Because plasma cortisol concentration has a diurnal rhythm of secretion, with an increase in the morning hours, loss of the diurnal rhythm has been advanced as an accurate screening tool for evaluation of horses with suspected PPID. However, the effects of external stressors and disease on plasma cortisol concentration make loss of cortisol rhythmicity a poor screening tool for PPID. Dexamethasone suppression test: The overnight dexamethasone suppression test (DST) is considered by many equine clinicians to be the “gold standard” endocrinologic test to support of a diagnosis of PPID. However, this statement is not without controversy and there is concern, although poorly documented, that administration of dexamethasone may induce or exacerbate laminitis in PPID-affected equids. In its most simple form, the overnight DST consists of measuring cortisol in the late afternoon (typically 5 pm) followed by administration of dexamethasone (40 g/kg, IM = 20 mg to a 500 kg horse) and subsequently measuring plasma cortisol concentration 17 to 19 hours later (between 10 am and noon the following day). The major limitation of the overnight DST for ambulatory practitioners is that it requires two visits to the horse. However, considering the fact that the most important value is the cortisol concentration following dexamethasone administration, the overnight DST can be simplified by dispensing dexamethasone to the client for administration and limiting the test to one visit the following morning. When using this test, it is probably wise to consider dexamethasone as a “sledgehammer” in terms of feedback to the hypothalamic-pituitary axis. In other words, failure of dexamethasone to induce suppression of circulating endogenous cortisol concentration is strongly supportive of PPID. However, the overnight DST may be less effective in diagnosis of PPID in the earlier stages of the disease process. In this clinician’s opinion, this is not an important limitation of the test because in the earlier stages of PPID, when DST results may be normal (not supportive of PPID), it may be difficult to justify treatments other than body clipping to limit hirsutism. An important limitation of using the DST is that seasonal variation can affect results. In a recent study of horses and ponies without clinical signs of PPID, abnormal DST results were found in 10 of 39 equids in September. To further examine the effect of season on DST results, the author performed the overnight DST monthly for a year in a group of 18 aged horses (>19 years) without clinical signs of PPID. Seven of 18 horses had normal overnight DST results throughout the year while 11 horses had overnight DST results supportive of PPID from 1 to 9 months of the year. Test results from late July through late October (in the northern hemisphere) were most commonly affected by seasonal variation. Thus, the overnight DST is best performed from December through June and overnight DST results from July through November, if abnormal, should be interpreted with caution. Although the author prefers not to perform the test during these months, it warrants emphasis that normal overnight DST results during late summer to fall can be useful. A further observation in the author’s study that warrants mention is that no signs of laminitis were induced in this group of older horses during performance of 216 overnight DSTs. Thyrotropin stimulation test and combined dexamethasone suppression/thyrotropin stimulation test. Thyrotropin (TRH) is a releasing hormone for several pituitary hormones that has been shown to increase plasma cortisol concentration when administered to horses and ponies with PPID. In theory, the TRH stimulation test should be a more specific test for PPID because TRH receptors are found on melanotropes in the pars intermedia but not on corticotrophs in the pars distalis. Although the TRH stimulation test has not been as well validated as the overnight DST, it has also been advocated for use in horses with laminitis because of concerns about exacerbating foot pain following dexamethasone administration. When used, a 50% increase in cortisol concentration between 15 and 90 minutes after administration of TRH can be supportive of a diagnosis of PPID. Unfortunately, interpretation of the response is complicated by considerable variability of the initial cortisol concentration as well as the problem that up to 50% of normal horses may have a false-positive result with this test. Thus, although theoretically better, the TRH stimulation test has not been demonstrated to be either highly sensitive or specific and is no longer recommended as an endocrine test for diagnosis of PPID. In an attempt to overcome these problems with the TRH stimulation test, a combined DST/TRH stimulation test has been developed. Three hours prior to TRH administration, dexamethasone (40 g/kg, IM) is administered to suppress cortisol concentration to similar values in both PPID-affected and normal horses. Cortisol concentration is subsequently measured before and 30 minutes after TRH (1 mg, IV) administration and equids with PPID show an increase in comparison to a lack of change in normal animals. After 24 hours, plasma cortisol concentration remains suppressed in normal horses while it returns to the basal (pre-dexamethasone) concentration in PPID affected horses. Although this combined test appears to improve the accuracy of the TRH stimulation test, it is both more expensive for the client as well as less practical for the ambulatory clinician than the overnight DST. As a consequence, this combined test has not been widely used. Plasma ACTH concentration. Horses with PPID typically have excessive amounts of ACTH in abnormal pars intermedia tissue and increased amounts of ACTH are released into plasma. Thus, plasma ACTH concentration would seem a likely choice for a single sample test to support a diagnosis of PPID. In fact, increased plasma ACTH concentrations, with a maximum reported value exceeding 12,000 pg/ml, have been documented in several reports of PPID in equids. Further, ACTH concentrations exceeding 27 or 50 pg/ml (6 and 11 pmol/l) in ponies and horses, respectively, have been reported to have a high sensitivity for diagnosis of PIPD. Limitations of using plasma ACTH concentration as the only endocrinologic test to support a diagnosis of PPID are that sample handling can be problematic and that different laboratories may use different assays for measuring ACTH. Because ACTH can be adsorbed onto glass and can be degraded by proteolytic enzymes in both whole blood and plasma, collection of blood into plastic tubes, rapid separation from red cells, and freezing of plasma prior to shipment for analysis has been recommended. Practitioners interested in using ACTH concentration as a diagnostic aid should contact the testing laboratory prior to sample collection for sample handling recommendations and should only send samples to a laboratory using an assay that has been validated as specific for ACTH in equine plasma. As with the overnight DST, another limitation of using plasma ACTH concentration is seasonal variation in test results. In normal ponies and horses without signs of PPID, plasma ACTH concentrations measured in September were above the threshold for diagnosis of PPID. This finding complicates use of plasma ACTH concentration as the sole endocrinologic test for both diagnosis and monitoring response to treatment of PPID. Domperidone stimulation test. The most recent endocrinologic test developed for diagnosis of PPID is a provocative test utilizing administration of domperidone, a dopamine receptor antagonist. In theory, this drug should exacerbate the loss of dopaminergic inhibition in horses with PPID and thereby increase release of endogenous ACTH by pars intermedia melanotropes. To test this hypothesis, plasma ACTH concentration was determined in 33 horses with or without clinical signs of PPID prior to and 4 and 8 hours after oral administration of domperidone (3.3 mg/kg). After testing, horses were euthanized for histopathological examination of the pituitary glands. In this study, plasma ACTH concentration increased modestly (by about 50%) in horses without clinical signs of PPID or significant pars intermedia pathology while plasma ACTH concentration more than doubled in horses with clinical signs of PPID and more advanced pars intermedia histolopathologic abnormalities. Unfortunately, the domperidone challenge test was performed in the late summer and fall in some horses leading to seasonal variation as a possible confounding factor. Nevertheless, this novel test may offer promise of detection of PPID in the earlier stages of the disease and further investigation is warranted. Serum insulin concentration. Many equids with PPID, especially ponies, may have insulin insensitivity and the frequency of hyperinsulinemia appears to be greater than that of hyperglycemia. As a consequence, an elevated fasting serum insulin concentration could support a diagnosis of PPID. However, hyperinsulinemia can accompany other metabolic disorders including type II diabetes mellitus and the “equine metabolic syndrome”. Thus, use of serum insulin concentration alone as a supportive test for diagnosis of PIPD can be misleading because hyperinsulinemia is not specific to PPID. However, measurement of fasting insulin concentration may be of benefit in the initial evaluation of equids with suspected PPID because one case series found poorer survival in PPID-affected equids with hyperinsulinemia as compared to PPID equids with a normal insulin concentration. Management: Management of pituitary pars intermedia dysfunction (PPID) in equids consists of improved husbandry, including adequate nutrition and limiting competition for feed, body-clipping, dentistry, and appropriate treatment of concurrent medical problems. In addition, specific treatment with the dopamine agonist pergolide can improve quality of life and reverse many clinical signs of the disease in PPID-affected equids. Treatment with both pergolide and cyproheptadine, in the author’s experience, may also prove beneficial in more advanced cases. For patients with chronic laminitis, appropriate trimming or shoeing and judicious use of analgesic medications is also necessary. Although many nutritional supplements and nutraceuticals have been advocated for use in equids with PPID, none have established data to support their claimed benefits. Finally, due to the expense of lifelong medication, a decision of whether or not to treat affected horses with pergolide should be made on a case-by-case basis in consideration of the client’s goals for the patient. Husbandry and nutritional considerations. Management of equids with PPID initially involves attention to general health care along with a variety of management changes to improve the condition of older animals. In the earlier stages of PPID, when hirsutism may be the primary complaint, body-clipping to remove the long hair may be the only treatment required. Next, since many affected animals are aged, routine oral care and correction of dental abnormalities cannot be overemphasized. In addition, assessment of diet and incorporation of pelleted feeds designed specifically for older equids (e.g., senior diets) should be pursued. In the author’s experience, aged horses both with and without clinical signs of PPID can easily gain 50 or more pounds within 3-4 weeks of placing them on a Senior feed. Sweet feed and other concentrates high in soluble carbohydrate are best avoided (unless that is all that horse will eat), especially when patients are hyperinsulinemic, hyperglycemic, or both. Also, affected equids may need to be separated from the herd if they are not getting adequate access to feed. Unfortunately, because the abdomen may become somewhat pendulous, weight loss and muscle wasting in more severely affected animals may not be well recognized by owners. In these instances, measurement of body weight, or estimation with a weight tape or body condition score, are important parameters to monitor during treatment. Whether or not it is “safe” to allow PPID-affected equids to graze pasture as a forage source remains controversial. Pasture, especially lush spring and early summer pasture, should be considered similar to feeding concentrates high in soluble carbohydrates and many veterinarians recommend that PPID- affected equids NOT be turned out on pasture. In my opinion, it is important to assess the overall condition of the patient. If the horse or pony is considered overweight and has abnormal fat deposits, supportive of insulin resistance, pasture turn out would not be recommended. Instead, feeding grass hay at 1.5% of the body weight daily would be the preferred forage diet and animals that are overweight clearly do not need an additional “low starch” concentrate feed. However, if body condition is somewhat poor, strategic grazing for several hours per day can be a useful way to increase caloric intake and produce weight gain. Again, caution is advised and access to lush spring or early summer pasture should be avoided or at least limited to one or more shorter periods per day, especially if there is a history of laminitis. Hoof care and secondary infections. Since the major musculoskeletal complication of PPID is chronic laminitis, regular hoof care is essential to lessen the risk of flare-ups. It is important to emphasize to clients that starting medical treatment for PPID (i.e., pergolide) may not lead to complete resolution of the pain and intermittent hoof abscessation that accompanies chronic laminitis, due to the damage to the laminar bed that has previously been sustained. Further, intermittent use of non-steroidal anti- inflammatory drugs, primarily phenylbutazone, may be necessary. Although flare-ups of chronic laminitis remain a leading cause for a decision for euthanasia in PPID-affected equids, it also warrants emphasis that a combination of medical treatment for PPID along with regular hoof care can lead to substantial clinical improvement. Finally, because many PPID affected patients may have secondary infections (e.g., sinusitis, dermatitis, and bronchopneumonia), intermittent or long-term administration of antibiotics, typically a potentiated sulfonamide, may be necessary. Medications for treatment of PPID: Medications that have been used to treat equids with PPID include serotonin antagonists (cyproheptadine), dopamine agonists (pergolide mesylate), and, more recently, an inhibitor of adrenal steroidogenesis (trilostane). Cyproheptadine was one of the initial drugs used because serotonin had been shown to be a secretagogue of ACTH in isolated rat pars intermedia tissue. Early indications that cyproheptadine (0.25 mg/kg, q 12-24 h) results in clinical improvement and normalization of laboratory data within 1-2 months have been disputed as a similar response has been obtained with improved nutrition and management alone. The margin of safety of cyproheptadine appears to be high as several horses have received twice the recommended dose twice daily without untoward effects. Mild ataxia has been described in some horses treated with cyproheptadine but this author has not observed this. Because loss of dopaminergic innervation appears to be an important pathophysiologic mechanism for PPID, treatment with dopaminergic agonists represents a logical approach to therapy. Pergolide administered in both “high dose” (0.006-0.01 mg/kg, PO, q 24 hours [3-5 mg to a 500 kg horse]) and “low dose” (0.002 mg/kg, PO, q 24 hours [1 mg/day for a 500 kg. horse]) protocols have been reported to be an effective treatment. Adverse effects of pergolide include anorexia, diarrhea, and colic; however, the latter problems are more often associated with higher doses of the drug. Usually, only transient anorexia is recognized during the initial week of “low dose” pergolide treatment and can be overcome in time or by cutting the dose in half for 2-4 days. Trilostane (0.4-1.0 mg/kg q 24 hours in feed), a competitive inhibitor of 3-β-hydroxysteroid dehydrogenase, has been reported to be effective in reversing both clinical signs (primarily laminitis) and abnormal endocrinologic test results in a series of equine PIPD cases. However, horses and ponies in that study received additional management for laminitis and the “improvement” in endocrinologic test results was not overly convincing. In contrast, early attempts at treatment with the adrenocorticolytic agent o,p’-DDD were largely unsuccessful. Because adrenocortical hyperplasia has been recognized in, at most, 20% of horses with PPID, drugs targeting adrenal steroidogenesis would intuitively seem less likely to be successful. However, it is possible that concurrent use of pergolide and trilostane (currently not available in the United States) could produce a greater clinical response than use of pergolide alone. At present, it is the author’s opinion that the initial medical treatment for equids with PPID should be pergolide mesylate at a dose of 0.002 mg/kg, PO, q 24 hours. If no improvement is noted within 8-12 weeks (depending on season as hair coat changes will vary with the time of year that treatment is initiated), the daily dose can be increased by 0.002 mg/kg monthly up to a total dose of 0.006 mg/kg (3 mg/day for a 500 kg horse). If only a limited response is observed with 0.006 mg/kg of pergolide and endocrinologic test results remain abnormal, the author typically recommends addition of cyproheptadine (0.5 mg/kg, PO, q 12 hours) to pergolide therapy. It is important to recognize that the rate of clinical improvement is higher than that for normalization of hyperglycemia and endocrinologic test results. For example, in a treatment study performed by the author, 13 of 20 pergolide treated horses were reported to have improved clinically while only 7 of 20 had normalization of endocrinologic test results. Thus, it is prudent to measure blood glucose concentration and regularly perform follow-up endocrinologic testing when managing an equid with PPID. The author currently recommends performing an overnight DST (or measurement of plasma ACTH concentration) at least yearly in horses that appear to be stable and 6-8 weeks after a change in medication dose or addition of cyproheptadine). Finally, it is important to remember that, at present, treatment with either pergolide or cyproheptadine remains both empirical and off-label, as pharmacological studies of the drugs have not been performed in equids. Further, although pregnant mares have been treated with the drugs, safety of use during pregnancy has not been studied in equids. Pergolide mesylate is currently only available from a number of compounding pharmacies as the pharmaceutical grade tablets (Permax) were recently removed from the human market due to development of heart valve problems in a limited number of patients. A major advantage of the compounded products is lower cost; however, pergolide may not remain stable in an aqueous solution (suspension) for longer than 7 days. Thus, it is important to determine how the drug is prepared and dispensed by the compounding pharmacy before specific formulations can be recommended for use. As with many chronic diseases in the horse, specific nutrient supplementation and complementary or alternative therapies, including acupuncture, homeopathy, and herbal remedies, have been recommended and used in equids with PPID. Both magnesium and chromium supplementation have been advocated for supportive treatment of this condition. Magnesium supplementation (to achieve a dietary calcium:magnesium ratio of 2:1) has been recommended because magnesium deficiency appears to be a risk factor for insulin insensitivity and type 2 diabetes in humans and anecdotal reports suggest that supplementation may help horses with obesity-associated laminitis. Similarly, chromium supplementation is recommended to improve carbohydrate metabolism (specifically glucose uptake) and improve insulin sensitivity in type 2 diabetes. An herbal product made from chasteberry has also been advocated for treatment of PPID. However, the claim was supported with a series of case testimonials in which the diagnosis of PPID was poorly documented and a recent field study demonstrated that this herbal product was ineffective for treatment of PPID. Prognosis: Once present, PPID is a lifelong condition. Thus, the prognosis for correction of the disorder is poor. However, PPID can be effectively treated with a combination of management changes and medications. Thus, the prognosis for life is guarded to fair. There has been little longitudinal study of equids with PPID but in one report survival time from initial diagnosis to development of complications necessitating euthanasia ranged from 120 to 368 days in four untreated horses. Further, there are numerous anecdotal reports of horses being maintained for several years as long as response to medical treatment was good and close patient monitoring and follow-up was performed. The author has followed a handful of horses treated for PPID with pergolide for nearly a decade and has gained a clinical impression that the drug improves the quality of life but that does not necessarily equate to prolonging life. A recent case series also found that concurrent presence of hyperinsulinemia with PPID was a negative prognostic factor. This finding supports measurement of fasting insulin concentration in the initial evaluation and ongoing management of horses with PPID.
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