Diagnosis and Treatment of PPID

Diagnosis and Treatment of Pituitary Pars Intermedia Dysfunction (PPID)

Prepared by the PPID Working Group:

Nicholas Frank, DVM, PhD, DACVIM (Group Coordinator)

Frank Andrews, DVM, MS, DACVIM

Ben Buchanan, DVM, DACVIM, DACVECC

Andy Durham, BSc, BVSc, CertEP, DECEIM, MRCVS

Janice Kritchevsky, VMD, MS, DACVIM

Dianne McFarlane, DVM, PhD

Hal Schott, DVM, PhD, DACVIM

September 2011 Table 1 Clinical presentation of PPID

Early Advanced

Decreased athletic performance Lethargy Change in attitude/lethargy Generalized hypertrichosis Delayed hair coat shedding Loss of seasonal hair coat shedding Regional hypertrichosis Skeletal muscle atrophy Change in body conformation Rounded abdomen Regional adiposity Abnormal sweating (increased or decreased) Laminitis Polyuria/polydipsia Recurrent infections (eg, sole abscesses) Regional adiposity Absent reproductive cycle/infertility Laminitis Hyperglycemia Neurologic deficit/blindness Table 2 Resting adrenocorticotropin hormone (ACTH) concentration test

Procedure • Plastic tubes containing ethylenediaminetetraacetic acid (EDTA; purple top) recommended • Collect at any time of the day • Some clinicians collect 2 samples 15 min apart and submit both or pool equal amounts of plasma • Keep samples cool (ice packs or refrigerator) at all times • Centrifuge within 8 h • Ship via overnight mail with ice packs • Preservatives (eg, aprotinin) or freezing are not required • Samples can be frozen

Assays used Chemiluminescent assay • Reference intervals provided below are for this assay Radioimmunoassay • Lower values are often obtained with these assays • Use reference intervals provided by the testing laboratory

Interpretation Use reference intervals provided by the laboratory of results* November to July ≤29 pg/mL† Negative ≤35 pg/mL‡

Above reference interval Positive

August to October ≤47 pg/mL† Negative

Above reference interval Positive

* Note that resting ACTH concentrations are variable, so another sample should be submitted or an evocative test performed if the result falls close to the upper limit of reference interval (ie, equivocal). † Liphook Equine Hospital (www.liphookequinehosp.co.uk/). ‡ Cornell University Animal Health Diagnostic Laboratory (http://ahdc.vet.cornell.edu/). Table 3 Overnight DST

Procedure • A single cortisol measurement is adequate • Veterinarian administers 0.04 mg/kg dexamethasone (20 mg for 500-kg horse) via intramuscular injection at approximately 5 PM • Blood is collected into a tube without anticoagulant at noon (19 h) the next day • Some clinicians prefer to measure cortisol concentrations at 0 h (pre-injection) and 19 h, although a single cortisol measurement at 19 h is adequate in most cases • Allow blood to clot and then keep samples cool (ice packs or refrigerator) • Centrifuge any time during work day • Ship via overnight mail with ice packs • Samples can be frozen

Assays used Multiple assays available • Most diagnostic laboratories currently use the cortisol radioimmunoassay

Interpretation November to July of results <10 ng/mL (1.0 µg/dL; 27 nmol/L) Negative

>10 ng/mL Positive

August to October

<10 ng/mL Negative

>10 ng/mL Positive or false positive (cannot be interpreted) Table 4 Thyrotropin-releasing hormone (TRH) stimulation test

Procedure • Veterinarian administers 1.0 mg (total dose) TRH intravenously • Blood samples are collected in tubes containing EDTA at 0 min and 30 min relative to TRH administration • Submit plasma for measurement of ACTH

Assays used Chemiluminescent assay • Reference intervals listed below were established with this assay

Interpretation November to July of results <35 pg/mL* Negative

>35 pg/mL at 0 min or 30 min Positive

August to October

Reference values not available at this time

* Cornell University Animal Health Diagnostic Laboratory (http://ahdc.vet.cornell.edu/). Table 5 Diagnostic Testing for PPID

Supportive • Relative neutrophilia and lymphopenia • Hyperinsulinemia* Findings • Hyperglycemia • Hypertriglyceridemia

Tier 1 • Resting ACTH concentration(s) • Overnight DST

Tier 2 • TRH stimulation test with ACTH measured

Other available • Oral domperidone challenge test tests with lower • Combined dexamethasone suppression/TRH stimulation test with cortisol measured recommendation • Magnetic resonance imaging (MRI) specific for pars intermedia enlargement

Other potential • a -melanocyte-stimulating hormone concentrations tests that are not • Bioactive ACTH concentrations commercially • Pro-opiomelanocortin (POMC) concentrations available • b -endorphin concentrations • Corticotropin-like intermediate peptide (CLIP) concentrations

Not indicated for • ACTH stimulation test PPID diagnosis

Not useful • Resting cortisol concentration • Diurnal cortisol rhythm • TRH stimulation test with cortisol measured (without DST) • Urinary cortisol concentration • Salivary cortisol concentration

* Collect blood under short-term (6–8 h) fasting conditions. Measure insulin in the baseline (time = 0) blood sample when performing a DST because insulin concentrations may increase after dexamethasone administration. Table 6 Treatment of PPID and monitoring

Initial treatment plan • Pergolide is administered at an initial dosage of 2 µg/kg (0.5 mg for a 250-kg pony; 1.0 mg for a 500-kg horse) every 24 h orally. Recheck after 30 days

Initial response • Improved attitude (first 30 days) • Increased activity • Improvement in polyuria/polydipsia • Control of hyperglycemia

Long-term response • Improvement in hair coat abnormalities (1–12 months) • Increased skeletal muscle mass • Less pronounced rounding of the abdomen • Fewer/milder episodes of laminitis • Infections are less likely to develop

Timeline • Recheck plasma ACTH concentrations (2 samples collected 15 min apart preferred) and/or the overnight DST after 30 days* • A period of 2 months is required before conclusions should be drawn about changes in clinical signs

Treatment strategies Adequate laboratory response • If test results are negative at the 30-day recheck, the dosage is held constant and the patient is placed on an every 6-month recheck schedule, with 1 appointment occurring in the August–October season. This allows assessment of the patient during the seasonal increase in ACTH concentrations and ensures that treatment is adequate during this period. Inadequate laboratory response with good clinical response • If test results remain positive at 30 days, yet the patient is responding well clinically, the dosage can be held at the same level or increased, according to the veterinarian’s preference Inadequate laboratory response with poor clinical response • If test results remain positive at 30 days and the patient is not responding well clinically, increase the dosage by 1–2 µg/kg/day (0.5–1.0 mg/day for a 500-kg horse) and recheck after 30 days

Maximum dosages • The maximum dosage for pergolide is 10 µg/kg (5 mg for a 500-kg horse) daily. Cyproheptadine can be administered in combination (0.25 mg/kg orally every 12 h or 0.5 mg/kg every 24 h) with pergolide once the maximum dosage has been attained

* Plasma ACTH concentrations can be rechecked as early as 7 days after initiating treatment. Figure 1 Diagnosis and treatment reference chart

Horse with history and clinical signs consistent with PPID

Tier 1: Resting ACTH* Tier 1: Overnight DST* Single sample or 2 samples taken 2 samples (0 h and 19 h) 15 min apart and combined or 1 sample at 19 h

Positive Negative† Negative† Positive Use seasonally adjusted >10ng/mL reference intervals (1.0 µg/dL) at 19 h

Initiate treatment

November to July August to October Cannot be Initiate treatment interpreted Horse is not affected by PPID Diagnostic testing complete

Option 1: Perform another Tier 1 test Option 2: Perform Tier 2 test Resting ACTH concentration TRH stimulation test with Overnight DST ACTH measured*

Positive Negative†

Initiate treatment

* See Tables 1–4 inside. † If clinical signs persist or progress, retest 6 to 12 months later or perform a Tier 2 test.

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