Pars pituitary intermedia dysfunction (Proceedings)

Review Material

The Hypothalamus

The hypothalamus overlies the pituitary gland and serves as a translator between the central nervous system and the pituitary gland. The hypothalamus synthesizes releasing and inhibitory factors responsible for control of hormone release from the adenohypophysis and neurohypophysis. Equine Pars Pituitary Intermedia Dysfunction (Cushing's disease) may be a primary hypothalamic disorder- due to dopaminergic neurodegeneration.

The Pituitary Gland

The anterior lobe of the pituitary consists of three parts: pars distalis, pars intermedia, and pars tuberalis. The pars distalis and pars tuberalis are well vascularized and depend on vessels to carry the hypothalamic-releasing and inhibitory factors from the median eminence. The pars intermedia is poorly vascularized and secretion is controlled by neurotransmitter release from axons that extend directly from the hypothalamus to the pars intermedia.

The pars distalis is a pleocellular gland that contains 5 different cell types. The cell types include somatotrophs (growth hormone), lactotrophs (prolactin), gonadotrophs (FSH, LH), and thyrotrophs (TSH). Cortiotrophs produce pro-opiomelanocortin (POMC). Post-translational processing by the action of prohormone convertase I, converts the majority of POMC into ACTH.

The pars intermedia is a homogenous cell population (melanotrophs) and is responsible for synthesis and secretion of POMC as well. However, melanotropes contain active prohormone convertase I and II. The POMC in the pars intermedia is cleaved into alpha-MSH, Beta-endorphin, corticotrophin-like intermediate peptide (CLIP), and some ACTH (but to as much as in pars distalis). Secretory control of the pars intermedia appears to be primarily through tonic inhibition by dopamine with additional modulation by serotonin, beta-adrenergic and gamma-aminobutyric acid (GABA)-ergic inputs. Dopamine in the pars intermedia is released directly from nerve terminals. The neurons originate in the periventricular nucleus of the hypothalamus. Dopamine released from these nerve terminals interacts at the D2 receptors of the melanotropes to decrease POMC production.

The posterior lobe of the pituitary gland consists of the pars nervosa and infundibular stalk, which are composed of axons extending from nerve cell bodies in the hypothalamus and pituicytes which appear to perform a primarily supportive function for the axons. Oxytocin and ADH (vasopressin) are secreted from the axon terminals directly into the circulation.

Pars Pituitary Intermedia Dysfunction Ppid

(Equine Cushing's disease, Pituitary Adenoma)

This disease probably better described as PPID, as Cushing's disease in humans and dogs are not identical to the disease in horses. Hyperplasia or dysfunction of the pars intermedia results in excessive secretion proopiomelanocortin (POMC) by melanotropes. In contrast to horses, dogs –Cushing's disease is due either to an adrenal tumor or usually a tumor of the pars distalis.

POMC produced by the melanotrophs is a precursor for: 1) beta-endorphin; 2) alpha-MSH (melanocyte stimulating hormone), 3) CLIP (corticotrophin like peptide) and 4) ACTH (adrenocorticotropin). To note ACTH concentrations are increased in horses with PPID, but the beta-endorphin and alpha-MSH concentrations are much more proportionally increased.

What causes the hyperplasia/dysplasia of the pars intermedia? Dopamine normally has a tonic inhibitory control over the pars intermedia. Evidence that there is dopaminergic neurodegeneration in the hypothalamus due to local oxidative stress.

Clinical signs are due to 1) increased ACTH (and glucocorticoids); 2) physical destruction of the pars nervosa and 3) increased circulating concentrations of POMC-derived peptides.

Clinical Presentation - The average age is 19 years (7 to 40 years), and there is no gender or breed predilection (except ponies in general).

Hirsutism-most consistent finding long, curly coat, with thick guard hairs, failure to shed in spring, early development of winter haircoat. The only differential diagnosis for hirsutism in horses is breed standard (Bashker curly, Missouri Fox Trotter).

Chronic laminitis- often will result in need for euthanasia. Laminitis associated with cortisol- unknown why – may be related to ischemia, insulin resistance, or glucotoxicity.

Immunosuppression: (due to cortisol) - potential to result in euthanasia.

Polyuria and polydipsia why? 1) destruction of the pars nervosa (ADH) by the enlarged pars intermedia, 2) Cortisol blocking ADH at collecting tubule 3) hyperglycemia→glucosuria→osmotic diuresis, 4) cortisol directly increases GFR.

Hyperhidrosis - suspect beta-adrenergic stimulation via beta-endorphin

Excessive cortisol associated with - muscle wasting, hyperlipemia, insulin resistance, abnormal fat deposits, pendulous abdomen.

Diagnostic findings:

Complete blood count – Stress leukogram-normal to high PMNs, normal to low lymphocytes, mild anemia.

Serum chemistry profile – hyperglycemia (150 to 350) is common, hyperlipemia may occur, mild elevations in liver enzymes.

Urinalysis – glucosuria (renal threshold is approximately 150 mg/dl).

Diagnosis: many and confusing

Classical clinical signs: an old pony with 3 inches of hair – probably doesn't require further conformation.

Dexamethasone suppression test – most reliable. Based on feed-back inhibition of POMC from corticotrophs in response to exogenous cortisol administration. Horses with PPID fail to suppress. Take baseline cortisol, and give 40 ug/kg dexamethasone at 5 PM, take second sample 19-20 hours later (12 PM)- normal horses suppress < 1 ug/ml. Disadvantage - administration of exogenous CCS in laminitic patient.

Plasma ACTH concentration – can be done (Michigan or Cornell) Normal ACTH concentrations less than 50 pg/ml; and 27 pg/ml in ponies. Must separate plasma from blood within three hours of taking sample.

Combined Dex suppression/TRH stimulation: combination of 2 tests; start dex suppression; 3 hours post dex administer TRH; Cortisol samples taken at T=0, T=3 hours; T=3.5 hr; T=24 hours; diagnosis of PPID if plasma cortisol > 1 ug/dl at 24 hours or if 66% increase in plasma cortisol 30 minutes after TRH stimulation.

Domperidone stimulation: recent reports of administration of domperidone (a dopamine antagonist) that resulted in significant increases in endogenous ACTH. ACTH measures at 8 AM; 2.5 mg/kg domperidone given orally. Second ACTH concentration at 4 hours. (2.9 + 0.68 times baseline at 4 hours)

Measurement of POMC Peptides (Beta-endorphin and alpha MSH) have been reported- but not commercially available at this time.

**Note: Recent studies document that there are many more false positives in the fall specifically in Sept. - and season likely affects pituitary function! Be careful interpreting these tests in the fall.

Treatment of Pituitary Adenoma:

Supportive care - fastidious attention to deworming (daily dewormer), dental care, nutritional support (senior diet), wound management, comfortable environment (dry, warm), hoof care. Management is more important to long-term prognosis than medical therapy.

Pergolide - dopaminergic agonist - improvement in clinical signs (haircoat, weight gain, and increased activity), lower ACTH concentrations reported. Recommended starting doses vary- 0.5 to 1.0 mg orally once a day.

Cyproheptidine (0.25 to 0.5 mg/kg, SID to BID) antiserotonergic activity. No objective data to support that this drug is efficacious.

Adrenocorticolytic drug (op-DDD) - fails to have any functional or morphologic effect on the adrenal glands of normal horses or horses with pituitary adenoma.

Alternative therapies:

Magnesium, cinnamon: may improve insulin sensitivity

Chromium: improves insulin sensitivity

Hormonize/Evitex (herbal product from chaseberry) - expensive, no supportive data.