and treatment of Cushing’s disease in horses Harold C. Schott II, DVM, PhD, DACVIM
Department of Large Animal Clinical Sciences
D-202 Veterinary Medical Center
Michigan State University, East Lansing, MI 48824-1314
Overview: 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 solid 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 increased health care being provided to older horses. All breeds and types of equids can be affected with PPID but ponies appear to be at greater risk (Figure 1). There is no gender predilection. The mean age of affected horses is generally 18 to 23 years but cases have been reported from horses as young as 7.
Figure 1. Pituitary pars intermedia dysfunction (PPID) affects equids of all sizes and breeds although it may be more common in ponies (image courtesy of Dr. J. H. van der Kolk, Utrecht, Netherlands)
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. Abnormal pars intermedia cells 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 (Figure 2). 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 (Figure 3). The pathogenesis of hirsutism, which is characterized by arrest of hair follicles in telogen, remains unknown. It has been suggested that it may
Figure 2. Pathophysiology of pituitary pars intermedia (PPI) dysfunction in horses: loss of hypothalamic dopaminergic innervation, that normally inhibits PPI production of pro-opiomelanocortin (POMC), leads to unregulated, increased production of POMC and POMC-derived peptides including adrenocorticotropin (ACTH). Serotonin is another hypothalamic neurotransmitter that may also have an effect on increasing production of POMC in normal PPI tissue. βLPH = β-lipocortin; βEND = β-endorphin; αMSH = α-melanocyte stimulating hormone; CLIP = corticotropin-like intermediate lobe peptide.
be a consequence of chronic elevations in POMC peptides, specifically melanocyte stimulating hormone. 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. 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 (supraorbital area). 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.
Figure 3. Hirsutism with coat color change (left), supraorbital fat deposition
(middle), and unilateral nasal discharge due to sinusitis (right) are some
of the clinical findings in horses with PPID.
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. In general, PU/PD in horses with PPID is usually modest and is rarely of clinical significance. A potential complication in horses with PPID is silent urinary tract infection. 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 clinical signs that have been reported in horses with PPID include persistent lactation and infertility, probably a consequence of altered release of prolactin and gonadotrophic hormones. Signs of central nervous system (CNS) dysfunction, including ataxia, blindness, 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. A final, and often disastrous, musculoskeletal complication that may develop in horses with PIPD is breakdown of the suspensory apparatus. This condition has been observed more frequently in the hind limbs and often necessitates euthanasia because of the poor response of this condition to analgesics.
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. Although diagnosis by clinical examination is likely to be accurate in more advanced cases, establishing a diagnosis of PPID in less severely affected horses can be challenging. As a result, a number of endocrinologic tests have been used but not all of these diagnostic tests have been validated in horses in which the diagnosis was confirmed by subsequent necropsy examination.
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, substantial inter-individual variation and the effects of external stressors and disease on plasma cortisol concentration makes 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 variation among testing protocols can potentially lead to different results. Further, there is concern, although poorly documented, that administration of dexamethasone may exacerbate laminitis in 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 further 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 useful 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 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, with DST results that are not supportive of PPID, it may be difficult to justify treatments other than body clipping to limit hirsutism.
Thyrotropin stimulation test and combined dexamethasone suppression/thyroptropin 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 contrast, no increase in plasma cortisol concentration was observed in normal horses after TRH administration. Although the TRH stimulation test has not been as well validated as the overnight DST, it has been advocated for use in horses with laminitis because of concerns about exacerbating foot pain following dexamethasone administration. When used, a 30% increase in cortisol concentration between 15 and 90 minutes after administration of TRH is supportive of a diagnosis of PPID. However, interpretation of the response is complicated by considerable variability of the initial cortisol concentration. In an attempt to obviate the problem of variability of initial cortisol concentration with the TRH stimulation test, a combined DST/TRH stimulation test has been developed. Three hours prior to TRH administration, dexamethasone (40 g/kg) 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 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 has not really been demonstrated to be any more sensitive or specific for diagnosis of PPID. Further, 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. Recently, substantial seasonal variation in plasma ACTH concentration, with values lowest in February and highest in September, has been documented. The higher values in September, in normal ponies and horses without signs of PPID, were above the threshold for diagnosis of PPID. This recent finding complicates use of plasma ACTH concentration as the sole endocrinologic test for both diagnosis and monitoring response to treatment of PPID.
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 true diabetes mellitus and a recently described 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.
Urinary corticoid to creatinine ratio: Because collection of urine from equids is not as convenient as in other domestic species, measurement of urinary corticoids has not been studied in detail as a supportive test for horses with suspected PPID. In a recent report of seven equids with clinical and histologically confirmed PPID, a urinary corticoid:creatinine ratio greater than 20 x 10-6 had a sensitivity of 100% (range of 25-110 x 10-6 in PPID affected animals in comparison to a range of 4.7-16 x 10-6 in normal horses). Thus, this diagnostic test may have use in the evaluation of horses with PPID but further validation is needed.
Treatment: Treatment 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 and hyperhidrosis may be the primary complaints, body clipping to remove the long hair coat may be the only treatment required. Next, since many affected animals are aged, routine dental care and correction of dental abnormalities cannot be overemphasized. In addition, assessment of diet and incorporation of pelleted feeds designed specifically for older equids should be pursued. Sweet feed and other concentrates high in soluble carbohydrate are best avoided (unless that is all that they will eat), especially when patients are hyperinsulinemic. Also, affected equids may have to be separated from herd mates 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. Since the major musculoskeletal complication of PPID is chronic laminitis, regular hoof care is essential to lessen the risk of flare-ups. Because many PPID affected patients may also have secondary infections, long term administration of antibiotics, typically a potentiated sulfonamide, may often be necessary.
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. 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 observed in some horses treated with cyproheptadine.
Figure 4. Medications used for treatment of pituitary pars intermedia dysfunction (PPID) in horses: the dopaminergic agent pergolide is used to replace dopamine lost as a consequence of hypothalamic dopaminergic denervation; cyporheptadine is an antagonist of serotonin, a neurotransmitter that may potentiate secretion of pro-opiomelanocortin (POMC); and trilostane, a competitive inhibitor of 3-β-hydroxysteroid dehydrogenase, that may limit cortisol production by the adrenal gland. See Figure 2 legend for abbreviations.
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 by cutting the dose in half for 3-5 days. A pertinent, yet unanswered, question is whether or not pergolide and cyproheptadine have synergistic effects in the treatment of PPID. Anecdotal reports suggest that greater improvement may be observed when the medications are used concurrently.
Recently, trilostane (0.4-1.0 mg/kg q 24 hours in feed), a competitive inhibitor of 3-β-hydroxysteroid dehydrogenase, was demonstrated to be effective in reversing both clinical signs and abnormal endocrinological test results in a series of equine PIPD cases. 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. Further study is needed to assess potential synergistic effect of a multiple drug approach to treatment of horses with PPID.
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 4-8 weeks, the daily dose can be increased by 0.002 mg/kg monthly up to a total dose of 0.01 mg/kg. Alternately, if no or only a limited response is observed with 0.004-0.006 mg/kg of pergolide and endocrinologic test results remain abnormal, 0.25-0.5 mg/kg of cyproheptadine (or potentially trilostane when it becomes available) could be added to pergolide therapy. However, it is important to remember that the rate of clinical improvement is higher than that for normalization of hyperglycemia and endocrinologic test results. Thus, it is prudent to measure blood glucose concentration and perform follow-up endocrinologic testing (overnight DST or plasma ACTH concentration) regularly (about a month after a change in medication or dose or twice yearly in horses that appear to be stable) when managing an equid with PPID. 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 available as pharmaceutical grade tablets (Permax) or as a liquid suspension or dry granule form (as a top dressing for feed or formulated into a horse treat) available through a number of compounding pharmacies. The major advantage of one of the latter compounded products is lower cost. Recently, there has been concern that pergolide may not remain stable in an aqueous solution (suspension) for longer than 7 days and most compounding pharmacies now only dispense a 30 day supply of the suspension. One pharmacy that the author routinely uses recently tested stability of its pergolide suspension and found no degradation after 30 days (under ideal storage conditions).
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 and supplementation with chromium tripicolinate has been demonstrated to increase glucose uptake during a glucose tolerance test in normal yearlings.
Recently, a herbal product made from chasteberry (Hormonize) has been advocated on the internet 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. 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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