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Pars pituitary intermedia dysfunction (Proceedings)

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Apr 01, 2008

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.