Pituitary gland function in horses (Proceedings)

Anatomy: lies in the sella turcica at the base of the brain. It is connected to the hypothalamus by the pituitary stalk.

The gland is divisible into 2 distinct parts:

I. Anterior lobe (pars distalis, intermedia and tuberalis)

II. Posterior lobe ( pars nervosa, infundibular stalk)

Pituitary Gland

Pituitary Gland Function in horses

Physiology:

• Glucocorticoids from the adrenal cortex essential for regulation of carbohydrate and lipid metabolism.

• Secretion of glucocorticoids controlled by ACTH from the anterior pituitary.

• Release of ACTH mediated by exercise, stress, temperature, light and hypoglycemia*

• ACTH primarily formed in corticotropes of pars distalis from proopiomelanocortin (POMC).

• POMC is also a precursor of B-endorphin and A-melantropin.

• Pars intermedia composed of melanotropes and also contains POMC.

Anterior Lobe Dysfunction

Definition and Etiology:

• Functional adenomas of the pars intermedia have been recognized for years in older horses.

• "Equine Cushing's Disease" clinical similarities with human condition. [pituitary pars intermedia

• Dysfunction =PPID. Pars intermedia pituitary adenoma = PIPA.]

• Characterized by hypercorticism secondary to ACTH hypersecretion from a pituitary tumor

• Hyperplasia of pars intermedia associated with increased secretion of B-END, A-MSH and ACTH (to a lesser degree).

• Clinical signs due to excess glucocorticoids, destruction of pars nervosa, increased concentrations of POMC.

• Differences between Cushing's in horses and humans:

- anatomic location

- POMC post-translational processing.

Clinical Signs: result from complex metabolic aberrations.....

• average age = 19years

• no sex or breed predilection (Ponies ???)

• hirsutism and failure to shed seasonally

• lethargy

• muscle wasting

• PU/PD

• recurrent infections

• chronic laminitis

Clinical Pathology:

• normal to reduced white cell count with neutrophilia (stress), lymphopenia and eosinopenia

• mild anemia +/-

• hyperglycemia*

• Hyperlipemia

Pathophysiology:

• PU/PD- decreased ADH secretion due to destruction of pars nervosa

• muscle wasting- corticosteroid myopathy, disuse atrophy, aging

• recurrent infections- immune suppression due to hypercortisolism (defect in CMI?)

• laminitis- hypercortisolism and stimulation of adrenergic receptors

The variation in clinical signs as well as progression reflect differences in secretory activity and growth of the tumor.

The size of the tumor (determined at necropsy) does not always correlate with severity of clinical signs.

Diagnosis:

• tentative diagnosis based on clinical signs

• baseline plasma cortisol levels may be low, normal or elevated. Exercise, stress or hypoglycemia may also elevate.

• diurnal rhythm in cortisol concentrations lost in affected horses

Functional Diagnostic Testing:

The dexamethasone suppression test (DST) is

commonly used to evaluate pituitary function in horses.

In normal horses, administration of 0.04 mg/kg of

dexamethasone IM (approximately 20mg/450 kg horse).

DST Overnight Protocol

1. baseline- predex. cortisol sample between 4 &6pm

2. Administer dex. IM

3. Draw post-dex cortisol sample at noon the following

day (about 19 hours later)

Most normal horses will suppress cortisol levels to < 1ug/ml by 16 hours. Cushing's horses will have levels over 1ug/ml at 16 hours.

*Excellent screening test and easy to perform*

Standard DST

1. Take pre-dex cortisol sample at midnight

2. Administer dex IM

3. Draw post-dex cortisol samples at 8am, noon,

4pm, 8pm and midnight

This protocol is better in assessing degree of loss of function and monitoring functional changes.

TRH Response Test

1. Baseline cortisol sample drawn

2. Administer 1 mg TRH IV and take plasma cortisol samples at 15, 60 and 90 minutes

In Cushing's horses, plasma cortisol will increase 90% above baseline at 15 minutes while normal horses will increase only 17%.

Combined Dex suppression & Thyrotropin Releasing hormone stimulation test

Provides 2 checks to dx PIPA

1. Baseline plasma cortisol & IV dex .04 mg/kg

2. Sample #2 3 hrs later &IV TRH 1mg IV

3. Sample #3 taken 30 min. after TRH

4. Final draw 24 hrs post dex

• Both normal and PIPA horses have suppression of cortisol 3 hrs post dex.

• Horses w/ PIPA have 66-294% increase in cortisol conc. 30 min post TRH injection [normal horses do not] & cortisol near baseline 24 hrs post dex (escapes dex suppression) & normal horses remain suppressed

• Test can provide info on thyroid axis (sample 2&4 hrs post TRH for T3 & T4)

• test improves straight TRH test but is NO more sensitive or specific to dx PIPA

• more expensive & less practical for vet

• To obtain TRH- human pharmacy ($75-120/1 mg) or TRH salt from Sigma Aldrich Co. [ 800-521-8956 or www.sigma-aldrich.com] $45/ 50mg

Glucose Tolerance Test

• Following glucose challenge (0.5 g/kg IV), healthy horses show an immediate increase in plasma glucose concentration and return to baseline within 1.5 hrs.

• Cushing's horses demonstrate a lower rise in plasma glucose and a delayed return to baseline.

• Cushing's horses demonstrate an altered glucoregulatory mechanism and are often insulin resistant.

• *(not very practical diagnostic test)

Adrenocorticotropin concentration

• Plasma ACTH concentrations determined with commercial human RIA- ACTH assay.

• Mean plasma ACTH concentrations in healthy horses was 18.7 + 7 pg/ml while in Cushing's horses concentrations were 199.2 + 182.9 pg/ml. [ACTH > 55pg/ml may indicate PIPA]

• This study concluded that ACTH concentrations are valuable predictors of Cushing's horses.

Plasma ACTH concentrations

Advantages

• If high, dx made with single sample

Disadvantages

large daily variation

• large seasonal increase (in autumn)false positives

• false (-)'s other times of year + handling requirements

'Seasonal' issues

• Plasma [ACTH] in September were similar and significantly > than January & May results

• Dexamethasone suppression test results all w/in reference interval tested in January and w/in ref. interval (74%) of tested subjects in September

Anterior Lobe Dysfunction

Serum Insulin concentration;

• PIPA horses may have insulin insensitivity

• Measurement of fasting serum insulin with a cutoff of 57 µU/ml; normal horses= 27 - 53 µU/ml; PIPA horses= 35 - 260 µU/ml Mean= 105 + 20.2 µU/ml 92% sensitivity

• Measurement of serum insulin concentration is not an accurate single-sample endocrinologic test to support dx of PIPA.

The Bottom Line (diagnostically)

• ACTH stim test has NOT been consistently informative

• The MOST helpful tests are: dexamethasone suppression test, endogenous ACTH level and insulin determination and generally any combination of these 3 tests.

Treatment and Prognosis:

Supportive care, husbandry and feeding practices are central to the "treatment" of Cushing's horses. If

diagnosed early, various drugs can be administered. Pharmacologic intervention based on neurotransmitter

regulation. Three classes of drugs are available:

1. selective adreno-corticolytic agents (o,p-DDD)

2. dopamine agonists (pergolide, bromocriptine)

3. serotonin antagonists (cyproheptadine)

• Pergolide (Permax) 1 mg tablet, $3.06/tablet dosed at 5 mg/day. Current reports indicate that 1mg/day or every other day has been very successful.

• Cyproheptadine- 0.25mg/kg PO qd for 8 wks. If no improvement after 8 weeks drug should be discontinued.

• Bromocriptine (Parlodel) 2.5mg tablets $1.44/tab or 5mg capsule @$2.55/capsule. Administer 2 to 5 mg/day PO.

• Both bromocriptine and pergolide are ergot derivatives which may cause vasoconstriction (laminitis?)

• Careful evaluation of history and clinical examination of horses with signs suggestive of a pars intermedia tumor is critical.

• Definitive diagnosis of PIPA is a challenge to the clinician because there is no single unequivocal test.

• In human medicine, diagnosis of pituitary tumors involves a joint effort between the radiologist and endocrinologist.