Equine Endocrinology Pituitary Pars Intermedia Dysfunction and Equine Metabolic Syndrome

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Gregory French
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Equine Endocrinology Pituitary Pars Intermedia Dysfunction and Equine Metabolic Syndrome Rosemary Bayless, DVM Equine Internal Medicine Resident, Colorado State University Veterinary Teaching

1 Equine Endocrinology Pituitary Pars Intermedia Dysfunction and Equine Metabolic Syndrome Rosemary Bayless, DVM Equine Internal Medicine Resident, Colorado State University Veterinary Teaching Hospital Presented at the 2017 Colorado Veterinary Medical Association Convention September 24, 2017 Pathophysiology Pituitary Pars Intermedia Dysfunction (PPID) Degeneration of dopaminergic paraventricular neurons in the hypothalamus (unknown cause, possibly local oxidative damage) leads to reduced production of dopamine. Dopamine plays an important role in inhibiting cell division in the pituitary pars intermedia and limiting production of proopiomelanocortin (POMC), so lack of dopaminergic inhibition leads to proliferation and hypertrophy of melanocytes and increased production of POMCrelated peptides. There are multiple POMC-related peptides that are thought to contribute to clinical features of PPID (Figure 1). The ACTH that is produced in abnormal amounts by the melanotropes does not appear to be as bioactive as the form normally released from the corticotropes in the pars distalis, so adrenal hyperplasia is uncommon and total serum cortisol is typically not increased in PPID cases. However, there is some evidence that the free (biologically active) fraction of cortisol may be higher in horses with PPID. Compression of adjacent structures by enlargement of the pars intermedia and subsequent impact on products from those areas may be responsible for other clinical signs. Figure 1: Proposed effects of increased POMC-related peptides from melanotrope hypertrophy/hyperplasia Although the term Equine Cushing s may be more familiar to many clients, it is important to remember that PPID in horses is not analogous to canine Cushing s disease. Some clinical signs are similar between PPID and canine hyperadrenocorticism, but the primary lesion (hypothalamic neurodegeneration in the horse versus pituitary gland typically pars distalis or adrenal gland tumors in the dog) differs, as do other clinical features of the diseases, the recommended diagnostic approach, and treatment options.

2 Equine Endocrinology: PPID and EMS Page 2 Equine Metabolic Syndrome (EMS) The pathogenesis of EMS is not as well understood as that of PPID. Criteria of EMS have been adapted from the human metabolic syndrome and include insulin dysregulation, generalized obesity or regional adiposity, and predisposition to laminitis. Other components that are sometimes present include dyslipidemia (e.g. hypertriglyceridemia), adipokine dysregulation (e.g. hyperleptinemia), and systemic inflammation. Clinical EMS is thought to result from a combination of genetic factors, explaining why certain breeds seem to be predisposed, and management/environmental aspects, such as diet and exercise. Insulin dysregulation encompasses both hyperinsulinemia (increased concentrations of insulin in systemic circulation) as well as reduced action of insulin at the target tissues ( insulin resistance ). Hyperinsulinemia may be a compensatory response to decreased insulin sensitivity, but there is also evidence that increased circulating insulin concentration can also contribute to insulin resistance, so it is unknown which is primary. Induction of iatrogenic hyperinsulinemia in healthy horses and ponies can result in laminitis (clinical signs and histopathological changes in lamellar tissue) within hours, so it appears that high insulin concentrations are sufficient to cause laminitis even in the absence of preexisting disease (insulin dysregulation). The specific mechanism(s) by which increased insulin concentration leads to laminitis is an area of continued study, but recent research has provided evidence of vascular endothelial dysfunction in in vitro and ex vivo models of hyperinsulinemia. There is also data showing that vascular tissues from horses with naturally-occurring endocrinopathic laminitis have different responses to stimulation when compared with samples from control horses. Incretins, such as glucose-dependent insulinotropic polypeptide (GIP, previously gastric inhibitory peptide) and glucagon-like peptide-1 (GLP-1), are hormones that are released from specialized cells in the gastrointestinal tract in response to dietary carbohydrates and act on pancreatic beta cells to increase insulin secretion. The contribution of incretins to insulin production varies between species, and the role of the enteroinsular axis in the development of hyperinsulinemia in horses is still under investigation. The effect of incretins highlights the utility of the oral sugar test in horses with clinical suspicion of insulin dysregulation, as diagnostics involving solely intravenous glucose administration do not assess the possible contribution of ingested sugars to the insulin response.

3 Equine Endocrinology: PPID and EMS Page 3 Clinical Presentation PPID Signalment Usually older (>15 years) EMS Typically middle-aged (5-15 years) Clinical signs No breed predisposition identified Hypertrichosis Delayed/incomplete shedding Polyuria/polydipsia Muscle wasting Pot-bellied appearance Laminitis Lethargy/change in attitude Recurrent infections/parasitism Infertility Abnormal sweating ± Regional adiposity Breed predisposition: ponies, Arabians, Morgans, Saddlebreds, Tennessee Walking Horses, Paso Finos, warmbloods Generalized obesity (BCS 7/9) Regional adiposity (increased fat deposition along crest of neck, behind shoulder, over ribs, adjacent to tailhead, around prepuce) Laminitis Normal haircoat PPID and EMS are not mutually exclusive, and horses affected by both conditions can show a combination of clinical signs

4 Equine Endocrinology: PPID and EMS Page 4 Diagnostics (contact individual laboratories to confirm sample type and handling instructions) Pituitary Pars Intermedia Dysfunction Sample type: EDTA for ACTH, red top tube for cortisol Resting/Basal ACTH screening for PPID in horses with obvious clinical signs Collect blood, refrigerate within 3 h, Consider seasonal variation: increased upper centrifuge and transfer plasma to plastic tube limit of reference range in August-October within 2-4 h, ± freeze Autumnal increase in ACTH occurs in most Measure ACTH horses but is magnified in horses with PPID, No fasting needed so testing in fall months can improve For initial diagnosis, time of day is not sensitivity/specificity important for blood collection Basal ACTH may be normal in early PPID For monitoring, collect samples at same time Severe stress, pain, concurrent illness may each day elevate ACTH false positive results Thyrotropin releasing hormone (TRH) stimulation test detecting early PPID; more sensitive than resting ACTH or ODST (November-July) Collect baseline sample ACTH >35 pg/ml at baseline PPID Inject 1 mg thyroid releasing hormone IV ACTH >110 pg/ml (10 minutes) PPID Collect blood sample 10 (or 30) minutes later Alternative: >65 pg/ml (30 minutes) PPID Refrigerate samples until centrifugation and Reference intervals for fall (August-October) removal of plasma within 2-4 hours and transition months (July and November) Measure ACTH in both samples are pending watch for updated EEG Fasting not required (no grain prior to test) guidelines; until new reference intervals are released, testing during August-October NOT recommended. Overnight dexamethasone suppression test (ODST) no longer recommended by Equine Endocrinology Group (2015), but still performed in practice Optional: collect baseline blood sample Inject 20 mg (0.04 mg/kg) dexamethasone IM Collect second blood sample h later Allow blood to clot, remove serum, refrigerate/freeze Measure cortisol in both samples (November-July) Cortisol <1 µg/dl negative (normal) Cortisol >10 µg/dl positive (PPID) Low sensitivity in early PPID NOT RECOMMENDED in August-October; Seasonal variation (increased in autumn), but no reference intervals have been established for fall months

5 Equine Endocrinology: PPID and EMS Page 5 Equine Metabolic Syndrome (also recommended for PPID cases to assess insulin regulation, but do not test for PPID & EMS on same day combining diagnostic protocols may alter results) Sample types: either EDTA or red top tube for insulin, glucose, or leptin Resting insulin (± glucose) screening test Collect blood sample Centrifuge, remove plasma/serum; freezing recommended for shipment Measure insulin and glucose FASTING NO LONGER RECOMMENDED; allow regular access to forage, do not feed grain within 4 hours of sample collection Oral sugar test assessment of postprandial insulin response Fast 3-8 hours Optional: collect baseline sample Administer 0.15 ml/kg light corn syrup orally via dose syringe Collect blood samples 60 and 90 minutes later Centrifuge, remove & freeze plasma/serum Measure insulin and glucose In-feed oral glucose test assessment of postprandial insulin response Fast overnight Administer 0.5 or 1.0 g/kg dextrose powder in non-glycemic feed Collect blood 2 hours later Measure insulin and glucose Insulin tolerance test measure of insulin sensitivity Do NOT fast Collect baseline blood sample Administer 0.1 IU/kg regular insulin IV Collect blood 30 minutes later Measure glucose Leptin involved in appetite and regulation of body condition Collect blood Keep sample refrigerated Insulin < 20 µu/ml normal Insulin µu/ml borderline Insulin >50 µu/ml insulin dysregulation Elevated glucose possible uncompensated IR or diabetes mellitus (rare) Insulin >45 µu/ml insulin dysregulation Criteria for insulin dysregulation: Insulin > 68 µu/ml (for 0.5 g/kg dextrose) Insulin > 85 µu/ml (for 1.0 g/kg dextrose) <50% decrease in glucose from baseline sample insulin resistance < 10 ng/ml normal ng/ml intermediate > 20 ng/ml high Intermediate/high leptin associated with obesity (including internal adiposity) Increased leptin EMS/insulin dysfunction Friesians/light draft breeds may have higher normal reference range

6 Equine Endocrinology: PPID and EMS Page 6 Treatment/Management Pituitary Pars Intermedia Dysfunction Treatment Pergolide (Prascend ): first line therapy Dopamine agonist Starting dose: mg/kg PO q24h If side effects (inappetence, lethargy, etc) occur, dose can be split in half & given q12h or can be decreased to mg/kg PO q24h If clinical signs/test results do not improve, dose can be increased by mg/kg on a monthly basis with monitoring (max 0.01 mg/kg) Cyproheptadine Serotonin antagonist; MOA for PPID unknown 0.25 mg/kg PO q12h or 0.5 mg/kg PO q24h Can be added to pergolide if insufficient response to pergolide alone Equine Metabolic Syndrome Treatment Levothyroxine Synthetic thyroid hormone 0.1 mg/kg PO q24h for 3-6 months; taper over 4 weeks once target weight is reached Short term use in overweight/obese horses to enhance weight loss Increases metabolic rate and improves insulin sensitivity not treating hypothyroidism Metformin Biguanide drug used to increase insulin sensitivity in human type II diabetes mg/kg PO q12h, prior to feeding Oral bioavailability in horses is questionable Monitoring/Management Monitoring Re-evaluate clinical signs and recheck ACTH 1 month after starting treatment Repeat testing 1 month after any treatment alterations are made Once PPID is controlled, re-measure ACTH at least twice per year (including once in August-October) Management Diet modifications based on body score and insulin sensitivity Management Management of overweight/obese horses 1.5% BW hay, monitor weight monthly; can decrease to minimum of 1.2% BW if not losing weight slow feeder can be used to decrease time between meals Ideally test hay and find source with 12% NSC. Can also soak hay in cold water for 1 h prior to feeding Do not feed grain use vitamin/mineral supplement or ration balancer if needed Restrict access to pasture/grazing Increase exercise if not laminitic Management of lean/appropriate BCS cases Low-carbohydrate diet, add fat source if needed for additional calories Similar exercise recommendations as above

7 Equine Endocrinology: PPID and EMS Page 7 Resources Tufts Equine Endocrinology Group. Equine Metabolic Syndrome ACVIM Consensus Statement. Endocrine Disease. Edited by RE Toribio. Veterinary Clinics of North America: Equine Practice. April Review articles: Durham AE, McGowan CM, Fey K, Tamzali Y, and van der Kolk JH Pituitary pars intermedia dysfunction: Diagnosis and treatment. Equine Vet Educ. 26(4): Frank N and Tadros EM Insulin dysregulation. Equine Vet J. 46: McFarlane D Pathophysiology and clinical features of pituitary pars intermedia dysfunction. Equine Vet Educ. 26 (11): Tadros EM and Frank N Endocrine disorders and laminitis. Equine Vet Educ. 25 (3): Testing laboratories: Animal Health Diagnostic Center, Cornell University. Diagnostic Center for Population and Animal Health, Michigan State University.

8/22/ year-old Arabian gelding. 14-year-old Arabian gelding. Cushing s: Easily recognizable. Endocrine disorder?

8/22/ year-old Arabian gelding. 14-year-old Arabian gelding. Cushing s: Easily recognizable. Endocrine disorder? Practical Equine Endocrinology Hambletonian Continuing Education Seminar East Rutherford, NJ Nicholas Frank, DVM, PhD, DACVIM Professor of Large Animal Internal Medicine Tufts Cummings School of Veterinary