Treatment of pituitary pars intermedia dysfunction (classical Cushing's disease) and metabolic syndrome (peripheral Cushing's syndrome) in horses

Pituitary pars intermedia dysfunction (PPID) or Cushing's disease is the most common endocrinopathy of horses. Although hirsutism in older horses is a pathognomic finding, the two most important complications are laminitis and type II diabetes. Laminitis is also the most important complication of another endocrinopathy of obese, middle-aged horses without hirsutism. For decades, hypothyroidism has been suspected to be the cause of the latter syndrome, and many horses have been treated with exogenous thyroid hormone. Recent studies have implicated tissue-specific alterations in cortisol metabolism, rather than pituitary dysfunction, as a key feature leading to the descriptor peripheral Cushing's syndrome. However, parallels between obesity-associated laminitis and obesity and type II diabetes in humans, termed the metabolic syndrome, have most recently led to the name equine metabolic syndrome (EMS) for this syndrome. Several studies have been performed in the author's laboratory to compare treatments for PPID and to delineate the role of the hypothalamic–pituitary–thyroid axis and type I 11-β-hydroxysteroid dehydrogenase activity (11-β-HSD) in EMS. In Study 1, endocrine test results [plasma adrenocorticotropin (ACTH) concentration, serum insulin concentration, and overnight low-dose dexamethasone suppression test (ODST)] and treatment responses (pergolide vs. cyproheptadine vs. no treatment) were compared in 56 horses with PPID. In Study 2, ODST results, thyrotropin-releasing hormone (TRH) stimulation test results, and subcutaneous adipocyte 11-β-HSD activity were compared between nine EMS-affected horses and seven control horses. Ongoing studies are focused on specific medical treatments for EMS as well as mechanisms of laminitis in both syndromes of altered cortisol metabolism. The results of Study 1 revealed that both plasma ACTH and serum insulin concentrations were unreliable single-sample diagnostic tests in comparison to ODST results. In 24 horses (14 on pergolide, six on cyproheptadine and four untreated) that were re-examined after 6–12 months of treatment, both clinical improvement and a return to normal ODST results were greatest (P < 0.05) for pergolide treatment. The results of Study 2 revealed no differences in TRH stimulation test results between EMS-affected horses and control horses. Similar to humans with metabolic syndrome, basal plasma cortisol concentrations were lower in EMS-affected horses than in controls. Although there was a tendency for greater 11-β-HSD activity in subcutaneous adipocytes of EMS-affected horses than control horses, substantial variability in both groups precluded demonstration of a statistical difference. The findings of Study 1 provide further support that the ODST should be considered the gold standard diagnostic test for PPID and also provide strong evidence that pergolide is a better treatment for PPID than cyproheptadine. The findings of Study 2 conclusively demonstrate that hypothyroidism is not the cause of obesity-associated laminitis and decreased basal cortisol concentrations in EMS-affected horses, and provide support that tissue-specific dysregulation of cortisol metabolism may be an important factor in development of EMS. Finally, variability in adipocyte 11-β-HSD activity in both EMS-affected and control horses suggests that, similar to human metabolic syndrome, genetic variability in 11-β-HSD activity is a likely risk factor for, but not the cause of, EMS. Funding: Animal Health Diagnostic Laboratory, Michigan State University, Michigan Veterinary Medical Association.