April 18, 2017

Update on Pituitary Pars Intermedia Dysfunction in Horses

PPID is the most common endocrine disease in horses and occurs most often in animals over 15 years of age.

By Amy I. Bentz, VMD, DACVIM
Many horses today live 30 years or longer because of improvements in nutrition and management practices in recent decades. As they age, however, these animals may develop Cushing’s disease, also known as pituitary pars intermedia dysfunction (PPID). PPID is the most common endocrine disease in horses1 and occurs most often in animals over 15 years of age. Some heavy breeds such as quarter horses are more predisposed to the disease than are lighter breeds such as thoroughbreds.

Clinical Signs and Pathophysiology 
Although clinical signs in affected horses may vary, some horses exhibit the classic appearance of PPID: a wavy, dull, long haircoat that does not shed out completely in the spring and a pot-bellied appearance due to muscle wasting along the dorsum. Other clinical signs may include patchy sweating, abnormal fat deposition, laminitis, polyuria/polydipsia, or a depressed appearance. Additional possible clinical signs include narcolepsy, spontaneous lactation in mares without foals, tachypnea, and immunosuppression that leads to parasitism.

Horses with PPID are more prone to concurrent diseases, such as recurrent uveitis, heaves (recurrent airway obstruction), and sinusitis. Horses can often be categorized as having early or advanced clinical signs based on the Equine Endocrinology Group’s recommended categories.2 It is often easier to diagnose PPID in horses with advanced signs; much more subtle clinical signs in the early stages of the disease make diagnosis more difficult. For example, horses with suspensory desmitis have also recently been diagnosed with PPID.3 Abnormalities noted on blood tests may include hyperglycemia (blood glucose level >180 mg/dL), increased liver enzymes, neutrophilia, lymphopenia, and anemia. Hyperinsulinemia has been noted in approximately one-third of horses with PPID.4

The pituitary gland is the focus of PPID. The hypothalamus, which is located above the pituitary, is the master endocrine gland of the brain and controls many other endocrine glands. It is located above the pituitary and has neurons with long axons that synapse on melanotropes in the pituitary pars intermedia. Dopamine secreted by these hypothalamic neurons normally inhibits the production of hormones by the pituitary pars intermedia. The melanotropes produce pro-opiomelanocortin, which is cleaved by pro-hormone convertases to produce substances such as adrenocorticotropic hormone (ACTH).

In PPID, however, dopaminergic neuronal degeneration in the hypothalamus affects the pituitary gland through the loss of inhibition by dopamine. This leads to hyperplasia of the pituitary gland and proliferation of melanotropes. The pituitary produces excessive hormones, including alpha melanocyte-stimulating hormone, ACTH, beta-endorphin, beta-lipotropin, and corticotropin-like intermediate peptide (CLIP). The increased secretion of ACTH and CLIP stimulates the adrenal glands and leads to hyperadrenocorticism, producing excessive cortisol.

Diagnosis
Diagnosis of PPID is based on the horse’s history, signalment, physical examination, and bloodwork. Tests typically include serial resting basal endocrine testing measurements of ACTH, insulin, and glucose as well as the dynamic thyrotropin-releasing hormone (TRH) stimulation test, which measures ACTH at specific time intervals after TRH stimulation. ACTH levels increase seasonally from mid-July to mid-November, so results should be interpreted in light of the time of year.5,6 The overnight dexamethasone suppression test had been used in the past but is no longer recommended.

In a prospective study published in the Journal of Veterinary Internal Medicine, 57 healthy horses were compared with 40 horses and ponies with PPID (n = 20) or equine metabolic syndrome (EMS) (n = 20).7 Serum was collected from the healthy horses, and archived serum was used from the horses with PPID and EMS. Samples were analyzed for insulin, total and free cortisol concentrations, and free cortisol fraction (FCF). Horses with PPID and horses with EMS that had hyperinsulinemia were combined into a hyperinsulinemia (insulin dysregulation) group.

Results demonstrated that the horses’ body condition significantly impacted free cortisol concentrations: Free cortisol concentrations were increased in overweight/obese controls compared with lean controls. The mean FCF was significantly higher in horses with PPID or insulin dysregulation as compared with controls; however, the total cortisol concentrations were similar. Because the total cortisol concentrations were similar across the three groups (PPID, EMS, and healthy control horses), the increased FCF result reflects decreased bound cortisol in the horses with endocrine disease.7

According to the study authors, “There might be decreased availability or binding affinity of CBG [cortisol-binding globulin], the primary plasma binding protein for cortisol, in these endocrine diseases. Both obesity and aging also appear to be associated with a chronic low-grade inflammatory state in both people and animals, characterized by increased expression or activity of adipose-derived pro-inflammatory mediators such as interleukin-6 (IL-6) and leptin. In sepsis and other systemic inflammatory states, inflammatory mediators such as IL-6 and neutrophil elastase, respectively, inhibit hepatic production of CBG and perpetuate the cleavage of high-binding affinity CBG into a low-affinity confirmation. Thus, both mechanisms could lead to increases in FCF.”7

Treatement and Management
The primary treatment for PPID is the Food and Drug Administration–approved dopamine agonist pergolide mesylate (Prascend). Most horses with PPID respond well to treatment at the initial recommended dose of 0.5 mg/day PO for a 250-kg pony and 1.0 mg/day PO for a 500-kg horse (about 2μg/kg). However, some horses require higher doses of pergolide, so periodic physical examinations and testing are useful to monitor the horse’s response to treatment.

Horses with PPID can fare well with careful management and optimal care. Feeding the horse judiciously to maintain an ideal body weight is crucial. The horse should have regular care such as periodic teeth examinations and foot trimming. Regular deworming, fecal egg count monitoring, and proper manure management (eg, weekly removal of manure from the pasture) will aid in parasite control. Horses with PPID often have poor thermoregulation and patchy sweating associated with hirsutism. These patients are more comfortable with regular body clipping to minimize hirsutism and using blankets in the winter as needed.

 
Dr. Bentz is a 1997 graduate of the University of Pennsylvania of Veterinary Medicine. She is co-founder of Academic Veterinary Solutions, serves as equine chair for the Pennsylvania Veterinary Medical Association's Scientific Program Committee, teaches at University of Pennsylvania and Manor College, and is a consultant for Veterinary Information Network.
References:
  1. Frank N, Andrews F, Durham A, et al. Advanced pituitary pars intermedia dysfunction. Equine Endocrinology Group website. http://sites.tufts.edu/equineendogroup/advanced-pituitary-pars-intermedia-dysfunction/. Accessed March 11, 2017.
  2. Frank N, Andrews F, Durham A, et al. Recommendations for the diagnosis and treatment of pituitary pars intermedia dysfunction (PPID). Equine Endocrinology Group website. https://sites.tufts.edu/equineendogroup/files/2015/12/2015-10-16_EEG-2015-recommendations.pdf. Revised August 2015. Accessed March 11, 2017.
  3. Grubbs ST, Kirschner KA, Baus MR, et al. Clinical signs associated with PPID in the equine athlete. Equine Endocrinology Summit Dorothy Havemeyer Foundation 2017. International Endocrine Symposium III. Coral Gables, FL, January 3-6, 2017. https://sites.tufts.edu/equineendogroup/files/2017/01/2017-Equine-Endocrinology-Summit-D-Russell-Havemeyer-Foundation.pdf. Accessed March 11, 2017.
  4. McFarlane D. Equine pituitary pars intermedia dysfunction. Vet Clin North Am Equine Pract. 2011;27:93–113.


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