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Basics ⬇

Outline

BASICS

Definition!!navigator!!

PPID or equine Cushing disease is the most commonly diagnosed endocrinopathy in horses. This slowly progressive disorder shows a characteristic clinical picture. It is associated with functional adenomas or adenomatous hyperplasia of the pars intermedia of the pituitary gland.

Pathophysiology!!navigator!!

  • The pars distalis and pars intermedia of the pituitary gland secrete the same precursor molecule, POMC, but they process it into different hormones
  • The corticotroph cells of the pars distalis cleave POMC into ACTH and β-endorphin-related peptides. In health, glucocorticoid levels are maintained by ACTH secretion from the corticotroph cells
  • The melanotroph cells of the pars intermedia cleave POMC mainly into melanocyte-stimulating hormone and β-endorphin-related peptides, with relatively small amounts of ACTH.
  • Control of the pars intermedia appears to be via tonic inhibition of melanotrophs by dopamine secreted from hypothalamic neurons. Horses with PPID show oxidant-induced injury and degeneration of dopaminergic neurons of the hypothalamus and, consequently, decreased inhibition of the melanotrophs. This results in hyperplasia of the melanotrophs, significantly increasing POMC-related peptide synthesis and secretion (including ACTH)

Systems Affected!!navigator!!

Skin/Exocrine

Clinical signs most often include hypertrichosis, delayed hair coat shedding pattern, and abnormal sweating (hyperhidrosis).

Endocrine/Metabolic

Polyuria/polydipsia—may be due to:

  • Excess cortisol can increase the glomerular filtration rate and antagonize the effect of ADH on water reabsorption by the renal tubules
  • Hyperglycemia can lead to an osmotic diuresis, although polyuria/polydipsia is also observed in euglycemic horses
  • Compression or destruction of the pars nervosa by enlargement of the pars intermedia can decrease ADH secretion

Musculoskeletal

Laminitis appears to be associated with hyperinsulinemia.

Behavioral

The more docile behavior of some patients may result from increased β-endorphins.

Genetics!!navigator!!

N/A

Incidence/Prevalence!!navigator!!

Reported prevalence of PPID in horses >15 years of age between 15% and 30%.

Signalment!!navigator!!

  • All breeds—may be more prevalent in ponies and Morgans
  • Old horses—mean age is approximately 20 years, rare in horses <10 years
  • No sex predilection

Signs!!navigator!!

Historical Findings

Affected horses may have various problems that do not necessarily appear directly related to PPID, e.g. lethargy, exercise intolerance, weight loss, recurrent laminitis, infertility, or chronic infections.

Physical Examination Findings

  • Muscle atrophy (often most prominent along the epaxial musculature) and associated weight loss is common. A pot-bellied appearance may be observed
  • Hypertrichosis is the most common sign in late disease. In earlier stages, this may be observed as retained hairs under the mandible, along the distal limbs, or across the trunk. In end-stage disease, generalized hypertrichosis characterized by a long, wavy hair coat may be observed
  • In some, shedding of the winter coat is delayed; in others, hair grows earlier during the fall months
  • Excessive sweating, primarily in horses with hypertrichosis
  • Polyuria and polydipsia—may not be noticed if the horse is on pasture
  • Less frequent signs—chronic laminitis, regional adiposity, chronic infections, delayed wound healing, infertility, lethargy, blindness, or seizures

Causes!!navigator!!

Loss of dopaminergic innervation, may be due to oxidative stress.

Risk Factors!!navigator!!

Increasing age.

Diagnosis ⬆ ⬇

Outline

DIAGNOSIS

Differential Diagnosis!!navigator!!

  • Hypertrichosis is pathognomonic, except in breeds with a long hair coat—Missouri Foxtrotter or Bashkin
  • EMS—regional adiposity (cresty neck, tail-head fat pad, shoulder fat pads) or general obesity and insulin dysregulation are characteristic. EMS can affect horses of any age, but appears most common in middle-aged horses. EMS and PPID can occur concurrently
  • Chronic weight loss—poor management, parasitism, poor dentition, other chronic systemic diseases, or neoplasia
  • Polyuria/polydipsia—chronic renal failure, diabetes insipidus, or diabetes mellitus (rare in horses)

CBC/Biochemistry/Urinalysis!!navigator!!

  • No consistent changes in laboratory values—hyperglycemia reported
  • Hyperlipidemia may be observed
  • Serum liver enzyme activity may be elevated
  • CBC may show a stress leukogram

Other Laboratory Tests!!navigator!!

Endocrinologic testing of the pituitary–adrenal axis most often confirms the diagnosis.

Resting Plasma ACTH Level

  • Measurement of plasma endogenous ACTH concentration recommended for fall testing. Normal values vary among laboratories. ACTH levels vary with time of the year and latitude. Increased ACTH production extends between July and November with a peak in September. The highest specificity and sensitivity of plasma ACTH for the diagnosis of PPID is in the fall
  • The sample requires special handling—blood must be collected in disodium EDTA tubes, centrifuged and refrigerated within 3 h, and shipped overnight on ice. If delivery is delayed, plasma should be separated and kept frozen until assayed. Values in stressed normal horses and those with early PPID can overlap

TRH Stimulation Test

The TRH stimulation test is currently recommended for the diagnosis of PPID outside the fall period. Stimulation of thyroid receptors leads to increase in plasma ACTH in healthy and PPID horses although the response is higher in PPID horses. The test consists in the collection of a plasma sample for ACTH, followed by the administration of 1 mg of TRH IV and collection of plasma for ACTH determination 10 and/or 30 min later. ACTH concentrations above the cutoff values of 110 pg/mL (10 min) and 65 pg/mL (30 min) are suggestive of PPID.

Glucose Tolerance Test, Insulin Levels, and Insulin Tolerance Test

PPID horses may also be insulin dysregulated. In these cases:

  • Basal insulin levels also may be persistently increased, with or without hyperglycemia
  • Normal horses challenged with glucose (0.5 g/kg IV as a 50% solution) show an immediate rise in plasma glucose concentration and return to baseline level in 1.5 h
  • Insulin dysregulated horses show a delayed return of plasma glucose concentration to baseline
  • When subjected to an exogenous insulin tolerance test (0.4 IU/kg IV), insulin dysregulated horses show no significant decline in blood glucose
  • When undergoing an oral sugar test (0.15 mL/kg of Karo Light syrup PO), insulin dysregulated horses will have an increased insulin concentration 60–90 min following syrup administration

Imaging!!navigator!!

CT and MRI have been used.

Other Diagnostic Procedures!!navigator!!

N/A

Pathologic Findings!!navigator!!

  • Necropsy reveals an enlarged pituitary gland (3–4-fold normal weight)
  • Tumors are composed of large columnar or polyhedral cells with hyperchromatic nuclei
  • No metastases. Multiple sites of infection may be present

Treatment ⬆ ⬇

Outline

TREATMENT

Appropriate Health Care!!navigator!!

Pay particular attention to regular deworming, vaccination, dental care, and foot trimming.

Nursing Care!!navigator!!

Body clipping and appropriate blanketing recommended for horses with heavy hair coat.

Activity!!navigator!!

No need to decrease activity unless infections or laminitis.

Diet!!navigator!!

Increase the energy content of the ration of horses showing signs of weight loss.

Client Education!!navigator!!

  • Remind owners about the importance of husbandry
  • Owners need to be vigilant for complications (secondary infections, laminitis, nonhealing wounds) to readily recognize signs of disease and seek veterinary help early

Surgical Considerations!!navigator!!

Bilateral adrenalectomy has not been successful in the long term.

Medications ⬆ ⬇

Outline

MEDICATIONS

Drug(s) of Choice!!navigator!!

  • Pergolide mesylate is the drug of choice for the treatment of PPID. Its activity on the dopaminergic (D2) receptors of the melanotrophs of the pars intermedia decreases the secretion of hormones. Starting dose is 0.002 mg/kg (1 mg for an average-sized horse) PO once a day. Some ponies can be successfully maintained on 0.25 mg/day. Clinical improvement should be noted within 4 weeks. If horses show no improvement at lower doses, the dose can be increased by 0.5–1 mg/day to a maximum of 0.01 mg/kg
  • Anorexia is the most common adverse effect with pergolide and may be managed by stopping treatment until appetite returns, and then starting at a lower dose or splitting the dose into a morning and evening treatment. Abnormal weight loss, colic, diarrhea, and lethargy have also been observed
  • A complete treatment plan should include symptomatic therapy such as NSAIDs for laminitis and/or antibiotics for focal bacterial infections

Contraindications!!navigator!!

N/A

Precautions!!navigator!!

  • Pergolide mesylate has not been evaluated in breeding, pregnant, or lactating mares and should be used with caution in these horses
  • Pergolide mesylate is on the list of prohibited substances in equine competitions overseen by the Fédération Equestre Internationale

Possible Interactions!!navigator!!

Unknown

Alternative Drugs!!navigator!!

  • Cyproheptadine is a serotonin antagonist that has also been used to treat horses with PPID
  • Information regarding the basic pharmacokinetic behavior and metabolism of cyproheptadine in horses is lacking
  • Reports of clinical efficacy vary
  • Initial recommended dose is 0.25 mg/kg PO every 12–24 h for 1 month
  • If no clinical response occurs, the dose can be increased to 0.3–0.5 mg/kg
  • Cases in which cyproheptadine is unsuccessful often respond to pergolide treatment

Follow-up ⬆ ⬇

Outline

FOLLOW-UP

Patient Monitoring!!navigator!!

  • The first clinical improvements are often attitude and activity level (first month); subsequently, improvements in skeletal muscle mass, haircoat, laminitis, and a decrease in water consumption may be observed
  • Reevaluation of endogenous ACTH levels (4–6 weeks after starting therapy)
  • If starting treatment in the fall, seasonal influence may make control of ACTH levels more challenging and a higher dose may be required

Prevention/Avoidance!!navigator!!

N/A

Possible Complications!!navigator!!

N/A

Expected Course and Prognosis!!navigator!!

Prognosis depends on the severity of clinical signs.

Miscellaneous ⬆ ⬇

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MISCELLANEOUS

Associated Conditions!!navigator!!

Some horses with PPID may have concurrent EMS.

Age-Related Factors!!navigator!!

N/A

Zoonotic Potential!!navigator!!

N/A

Synonyms!!navigator!!

  • Equine Cushing's disease
  • Hyperadrenocorticism
  • Pituitary adenoma
  • Pituitary-dependent hyperadrenocorticism

Abbreviations!!navigator!!

  • ACTH = adrenocorticotropic hormone
  • ADH = antidiuretic hormone
  • CT = computed tomography
  • EMS = equine metabolic syndrome
  • MRI = magnetic resonance imaging
  • NSAID = non-steroidal anti-inflammatory drug
  • POMC = proopiomelanocortin
  • PPID = pituitary pars intermedia dysfunction
  • TRH = thyroid-releasing hormone

Suggested Reading ⬆ ⬇

Durham AE. Endocrine diseases in aged horses.Vet Clin North Am Equine Pract 2016;32:301–315.

Author(s) ⬆

Authors: Michel Levy and Heidi Banse

Consulting Editors: Michel Levy and Heidi Banse