1. General Considerations

   1. Pituitary pars intermedia dysfunction (PPID) or Cushing’s disease is a common and slowly progressive endocrine disorder of aged horses and ponies. It affects 15% to 20% of animals 15 years of age or older. The risk for PPID increases by 20% for every year after 15 years of age.
   2. It is associated with a dysfunction and adenomatous hyperplasia and hypertrophy of melanotrope cells in the pars intermedia of the pituitary gland.
   3. Hypersecretion of ACTH results in bilateral adrenocortical hyperplasia that may be diffuse or nodular, or both.
   4. In horses with PPID, adenomatous hyperplasia and hypertrophy of melanotrope cells result in a marked increase in the synthesis of MSH and ß-endorphin (ß-END)-related peptides and comparatively small but increased amounts of ACTH. The MSH and ß-END-related peptides have shown to induce a six-fold increase in the steroidogenic properties of ACTH compared to ACTH alone. Therefore, a small increase in ACTH levels coupled with a large increase in potentiating peptides (MSH and ß-END) can contribute to the melanotrope-mediated glucocorticoid dysfunction in the adrenal cortex seen in horses with PPID.

2. Clinical Signs

   1. Older horses and ponies are predisposed – 15% to 20% of horses older than 15 years will likely develop PPID.
   2. It has been reported to occur twice as frequently in females than in males.
   3. Often, attention is first drawn to the disease when the horse exhibits a rapid regrowth of long hair after a normal shed or fails to shed a longer than normal winter coat.
   4. The hirsutism is characterized by a shaggy or wavy hair coat up to 10-12 cm in length. The mane and tail are unaffected (see photo below).
   5. The pathogenesis of hirsutism in horses with PPID is unknown. It has been postulated that increased production of androgens by the hyperplastic adrenal cortices may be the cause.
   6. The skin of affected animals may be scaly and greasy.
   7. Secondary superficial skin infections are common.
   8. Wound healing is delayed in horses with PPID.
   9. Polydipsia and polyuria are not consistent signs. Some horses drink over 80 litters of water a day.
   10. Other common clinical signs include muscle atrophy (“wasted topline”), weight loss, and lethargy.
   11. Skeletal muscle wasting often leads to a swayback appearance, pendulous abdomen, and flaccid musculature.
   12. Fat redistribution occurs and is more prominent around the orbit.
   13. Chronic infections in the form of abscess, sinusitis, pneumonia, and fistula are common.
   14. Occasionally, horses will develop neurologic signs, blindness, and thermoregulatory disorders, presumably associated with pressure in the hypothalamus and optic chiasm by an enlarging pituitary tumor.
   15. Major sequelae of adenoma in the pituitary pars intermedia are type-2 diabetes mellitus (peripheral insulin resistance) and laminitis. In one study, 28 of 40 horses with laminitis showed high serum ACTH concentration suggesting PPID-related laminitis (the season when the ACTH was measured was not reported). Moreover, a meta-analysis showed that 56% of 223 horses with PPID developed laminitis. The pathomechanism of PPID-associated laminitis is unknown but may involve endogenous growth hormone and insulin resistance. An Australian study showed an odds ratio of 4.65 times for developing laminitis in horses with PPID compared to control horses.

3. Diagnosis

   1. Differential diagnosis include parasitism, inadequate nutrition, poor dentition, chronic infections, chronic renal or liver disease, chronic arsenic poisoning, and pheochromocytoma.
   2. Retention of winter coat can be seen in horses with chronic illnesses and dietary deficiencies.
   3. Definitive diagnosis is based on the following:
      1. Characteristic history.
      2. Characteristic clinical signs.
      3. Clinicopathological abnormalities.
      4. Adrenal functional tests.
   4. Clinicopathological abnormalities include the following:
      1. Complete blood cell count may reveal neutrophilia, lymphopenia and eosinopenia.
      2. A mild nonregenerative anemia is common.
      3. Urinalysis usually reveals a low urine specific gravity (1.005 to 1.017).
      4. Water deprivation tests may result in a marked increase in urine specific gravity.
      5. Horses with hyperglycemia may also have glucosuria.
      6. Serum chemistry profile abnormalities may include mild to marked insulin-resistant hyperglycemia, hypercholesterolemia, and lipemia.
      7. Basal thyroid hormone levels are usually low. These spuriously low thyroid hormone levels are caused by glucocorticoids and do not usually indicate concurrent hypothyroidism.
      8. Complete blood cell count and serum chemistry profile results are nonspecific; therefore, they are not diagnostic but can support a presumptive clinical diagnosis. Moreover, they may be important to identify concurrent diseases.

1. 5. Adrenal functional tests:
      1. General considerations: It is important to understand that none of the currently available tests is very sensitive (i.e. can accurately detect early disease) or specific (e.g. they are highly influenced by season). ). Therefore, the best factor in the diagnostic equation is the patient’s clinical signs (e.g. an old horse with hirsutism and muscle wasting). A negative endocrine test during the fall season likely indicates the absence of PPID.
      2. The tests currently used to confirm a clinical suspicion of PPID include (i) overnight dexamethasone suppression test (ODST), (ii) plasma endogenous ACTH concentration, and (iii) plasma basal (i.e. endogenous) ACTH concentration after the thyrotropin-releasing hormone (TRH) stimulation test.
      3. Overnight dexamethasone suppression test (ODST):
         1. Under normal feedback conditions, glucocorticoids suppress the secreation of ACTH by the corticotropes in the pars distalis of the pituitary gland with no effect on melanotrope cells. Horses with pituitary dysfunction have hypertrophy and hyperplasia of melanotrope cells, which lack glucocorticoid receptors; therefore, are not inhibited by glucocorticoides. Thus, because of the excess ACTH secretion by the pituitary pars intermedia in PPID, cortisol secretion may be maintained in the face of exogenous glucocorticoids. This permits using the dexamethasone suppression test to differentiate normal horses from horses with PPID.
         2. The ODST has been shown to be a sensitive and specific test in the diagnosis of advanced PPID; however, its value to identify early cases is not known at this time. False negative results (i.e. suppression after dexamethasone injection) may occur mainly at the early disease stages and false positive results (i.e. no suppression in horses without PPID) may occur if the test is performed during the fall months. Therefore, avoid testing horses with clinical signs of PPID in the fall.
         3. Overnight Protocol:
            1. Inject intramuscularly 0.04 mg /kg of dexamethasone at 5 hour in the afternoon.
            2. Collect blood samples 18 to 20 hours later.
            3. Post-dexamethasone cortisol levels should be higher than 1.0 mg/dl in horses with PPID (i.e. no suppression).
            4. Centrifuge the samples prior to shipping to the laboratory.
         4. The dexamethasone can hypothetically induce laminitis or worsen a pre-existent laminitis but there is no strong evidence to support this hypothesis.
      4. Plasma endogenous ACTH concentrations:
         1. This is probably the most practical test currently available because it only requires one blood sample and some laboratories provide seasonal reference intervals, which allows performing the test at any time during the year.
         2. One study (Copas and Durham, 2012) showed that the plasma basal ACTH concentration in horses with PPID is much higher in August, September and October (i.e. autumn season) compared to normal horses.
         3. Another study (McGowan et al, 2013) showed that the plasma basal ACTH concentration has the highest sensitivity and specificity for the diagnosis of PPID when performed during the autumn using a seasonally adjusted reference interval.
         4. Plasma basal ACTH can be influenced by various factors such as, in vitro stability, timing of sampling, seasonality, pain and stress. The following is recommended to reduce the impact of these variables:
            1. In vitro stability: ACTH is subject to in vitro degradation. To prevent a spuriously low value, chill the sample as soon as possible and within 3 hours of collection. Frozen whole blood and gravity-separated plasma will have spuriously high ACTH concentrations; therefore, make sure the sample is properly chilled but not frozen.
            2. Timing of sampling: there is a slight variation in ACTH concentration during the day. If multiple samples are collected in different days, try to collect the sample at the same time each day.
            3. Seasonality: make sure to work with laboratories that have developed seasonal reference intervals for plasma ACTH concentrations.
            4. Pain and stress: severe pain, moderate to severe illness, strenuous exercise, and general anesthesia may increase plasma basal ACTH concentrations.
            5. Interpret the results carefully in the presence of these factors.
      5. Plasma basal ACTH concentration after the TRH stimulation test:
         1. In horses, TRH stimulates the release of pars intermedia-derived hormones and the excessive secretion of ACTH in the pars intermedia of horses with PPID can be used to diagnose the disease.
         2. Currently, the TRH stimulation test with the measurement of post-TRH ACTH concentration appears to have higher sensitivity compared to the ODST and plasma basal ACTH concentration tests. It may also be able to identify early disease.
         3. Protocol e interpretation of test results:
            1. Collect a blood sample and place it in an EDTA tube for plasma ACTH analysis. Handle the sample as described above for measurement of plasma basal ACTH.
            2. Inject 1 mg of TRH intravenously.
            3. Collect the post sample 10 minutes after TRH administration for plasma ACTH measurement.
            4. An ACTH value > 110 ng/L is suggestive of PPID.
            5. Avoid performing this test during autumn because the ACTH response is higher in horses at this time of the year. Because no seasonal reference intervals have been determined by most commercial laboratories, falsely positive results are possible during the autumn months.
            6. Possible side effects of intravenous TRH administration include transient muscle trembling, yawning, lip smacking, and coughing.
         4. The accuracy of this test in diagnosing early or late cases of equine PPID has not been evaluated in large numbers of horses.
         5. TRH is not approved for use in horses and can be costly in some geographic regions.
      6. Other tests:
         1. Hyperinsulinemia is well established as one of the few factors shown to cause laminitis in horses and ponies and insulin sensitivity is commonly decreased in horses and ponies with PPID. In addition, basal insulin concentration has been negatively correlated with prognosis in PPID cases.
         2. Measurement of serum insulin and glucose is highly recommended in horses or ponies with PPID as an indicator of laminitis risk and diabetes mellitus and for prognostic purposes.
         3. The insulin response to oral sugar challenge appears to be a more sensitive test than the measurement of basal insulin concentrations.

4. Treatment

   1. Pergolide mesylate (Prascend®, Boehringer Ingelheim)
      1. It is currently the treatment of choice for PPID and is licensed for use in horses in the USA.
      2. Pergolide is a dopaminergic agent (i.e. dopamine receptor agonist) and an ergot alkaloid.
      3. The required dose to control the disease may vary between cases because of differences in disease severity and bioavailability of the drug.
      4. Recommended treatment protocol and monitoring (refer to article by Durham et al, 2014 for additional details):
         1. Obtain baseline clinical and laboratory values including plasma ACTH, glucose and insulin concentrations or insulin response to oral sugar challenge. Foot radiographs, even if laminitis is not clinically evident, is also recommended.
         2. Encourage owners to monitor on a monthly basis appetite, hair coat quality, water intake, bed wetting when housed, body condition score, lameness, and general demeanor.
         3. Start pergolide at 0.002 mg/kg orally q 24h (to the nearest 0.5 mg total dose). It is available as a 1 mg tablet. A rough estimation is as follows: 0.5 mg/day for horses weighting 200-350 kg; 1.0 mg/day for horses at 350-600 kg; and 1.5 mg/day for horses weighting 601-850 kg.
         4. After 30 days of treatment at the full dose, re-evaluate clinical signs (including owners’ observations) and endocrine values. One or more clinical signs is expected to improve and/or the plasma basal ACTH to have normalized or reduced significantly (close to normal) for that time of the year (again, send samples to laboratories that have established seasonal reference intervals). Because plasma ACTH concentrations can be altered by many factors (see above) make sure to re-test at the same time of the day and under the same conditions as baseline values.
         5. If clinical signs or endocrine values have not improved, increase the pergolide dose by 0.001 mg/kg and re-evaluate monthly with increases in the pergolide dose of 0.001 mg/kg until improvement in clinical signs and laboratory tests are noted or a maximal dose of 0.010 mg/kg has been reached.
         6. If signs of reduced appetite or worsening lethargy are noted, reduce the dose by increments of 0.001 mg/kg and investigate for concurrent disease.
         7. The frequency of clinical and endocrine monitoring can be reduced to 2 to 4 times per year when the disease has been well controlled. Make sure to schedule at least one of the visits during autumn (August – October).
         8. Owners should call the veterinarian immediately if clinical signs worsen and/or new signs develop.
         9. Chronic diseases may not respond well initially but may eventually respond after 3-4 years of treatment.
         10. Side effects:
             1. The most common side effect is reduced appetite (16%-33% of cases) and it typically occurs during the first week of treatment and is generally transient. However, it can persist or recur.
             2. If inappetence occurs, the pergolide dose should be reduced or the drug should be temporarily stopped. Thereafter, a gradual dose increase should be instituted.
             3. To avoid anorexia, a recommendation is to start horses on half the dose given every other day for 2 days and then half the dose daily for 3 days.
   2. Oral cyproheptadine (Periactin®):
      1. The drug has anti-serotonin, antihistamine, and anti-acetylcholine activities and may prevent serotonin-induced ACTH release.
      2. It is generally given concurrently with pergolide and reserved for horses with advanced PPID on higher doses of pergolide. The recommended dose is 0.25 mg/kg orally every 12 h.

5. Prognosis

   1. The prognosis for equine PPID is guarded to poor.
   2. Many horses suffer a chronic course of progressive debilitation.
   3. Septicemia, pneumonia, and encephalitis are the usual causes of death.
   4. If an owner elects to keep a horse with PPID, a high plane of nutrition, adequate nursing care, and attempts to minimize infections are necessary.

References

Copas VE and Durham AE. Circannual variation in plasma adrenocorticotropic hormone concentrations in the UK in normal horses and ponies, and those with pituitary pars intermedia dysfunction. Equine Vet J 2012; 44:440-443.

Durham AE, McGowan CM, Fey K et al. Pituitary pars intermedia dysfunction: Diagnosis and treatment. Equine Vet Educ 2014; 26(4):216-223.

Kirkwood NC, Hughes KJ and Stewart AJ. Pituitary pars intermedia dysfunction (PPID) in horses. Vet Sci 2022; https://doi.org/10.3390/vetsci9100556.

McFarlane D. Equine pituitary pars intermedia dysfunction. Vet Clin Equine 2011; 93-113.

McGowan TW, Pinchbeck GP and McGowan CM. Evaluation of basal plasma a-melanocyte-stimulating hormone and adrenocorticotrophic hormone concentrations for the diagnosis of pituitary pars intermedia dysfunction from a population of aged horses. Equine Vet J 2013; 45:66-73.

McGowan CM, Frost R, Pfeiffer DU et al. Serum insulin concentrations in horses with equine Cushing’s syndrome: response to a cortisol inhibitor and prognostic value. Equine Vet J 2004; 36:295-298.

Secombe CJ, Bailey SR, de Laat MA et al. Equine pituitary pars intermedia dysfunction: current understanding and recommendations from the Australian and New Zealand equine endocrine group. Aust Vet J 2018; 96: 233-242.

Spelta CW. Equine pituitary pars intermedia dysfunction: current perspectives on diagnosis and management. Vet Med (Auckl) 2015; 20:293-300.