One of the most critical signs is chronic, insidious laminitis. Though the relationship of Cushing's and laminitis is not
well understood, according to Philip Johnson, BVSc, MS, MRCVS, Dipl. ACVIM, Dipl. ECEIM, University of Missouri at Columbia
veterinary school, excess cortisol may increase the risk of laminitis through several mechanisms: reducing blood supply to
the lamellar tissue; weakening hoof lamellar attachments; impairing ongoing hoof lamellar restitution; and reducing glucose
delivery to the hoof cells. "These are some plausible mechanisms that might contribute to the risk of laminitis associated
with glucocorticoids, but the scientific evidence for which — if any — is truly significant, is lacking," Johnson says.
Oxidant damage to the dopaminergic neurons and secondary hyperplasia and adenoma formation of the pituitary pars intermedia
results in increased production of POMC, and, in turn, increased production of adrenocorticotropin (ACTH), along with beta-endorphin,
alpha-melanoctye stimulating hormone (MSH) and corticotrophin-like intermediate lobe peptide (CLIP) — all POMC- derived peptides
(up to 40-fold increase in plasma of PPID horses).
Excess ACTH leads to excess cortisol production by the equine adrenals. Pituitary damage and excessive cortisol is the common
thread to Cushing's in each species, except for dogs with primary adrenal gland disease.
Cortisol normally helps maintain blood pressure and cardiovascular function, regulates the immune system's response to infection
and inflammation and balances the effects of insulin in regard to glucose and also in the regulation of fat and protein metabolism.
Cortisol regulates nerve tissue function, muscle tone and connective tissue repair. Its primary function is to help the animal
respond to stress. In one way or another, almost all cells throughout the body are responsive to cortisol.
While Cushing's in dogs and people is really attributable directly to excess cortisol, the condition in horses is distinctly
different, in that excess cortisol is not always very significant, but the production and release of excessive quantities
of pars intermedia-derived POMC peptides is inescapably significant and represents an equine-specific difference.
Cortisol exerts its effect on the functioning of the cell by entering the cell and interacting with a receptor in the cell's
nucleus. The cell's function is altered depending on the extent to which cortisol is or is not acting to control the transcription
of specific proteins at the genetic level.
It is not possible to define optimal in this context. The active concentration of cortisol within the cell is defined by both
the circulating plasma concentration and the extent to which the intracellular (cytoplasmic) concentration of cortisol is
changed by a cell-specific enzyme.
This "steroid-converting enzyme," 11-beta hydroxysteroid dehydrogenase (HSD), is capable of either increasing or reducing
the cytoplasmic concentration of active cortisol in different cells.
According to Johnson, this enzyme regulates the extent to which glucocorticoid receptors are activated by cortisol. The enzyme,
a product of the cell, either will "allow" cortisol to activate the nuclear transcription process or not. Depending on its
isoenzyme type, it can destroy cortisol before it gets close to its receptor, or it can produce more cortisol (from its inactive
cousin, cortisone), increasing the local effectiveness of glucocorticoids.
"The old-fashioned idea that the activity of cortisol in a given tissue is simply a function of its circulating concentration
is thus no longer applicable," says Johnson.
"Under normal circumstances," he says, "the concentration of cortisol within the cell is adjusted by HSD within the cell itself.
This ensures that the requirements of the cell at any given time are met. It has been suggested that Cushing's syndrome may
sometimes be attributed to abnormal HSD activity within the cells."
Specifically, within the abdomen in people and in laboratory rodents, excess fat tissue contains increased HSD that contributes
to the medical problems attributable to abdominal obesity. Human researchers have likened this phenomenon to a tissue-specific
Cushing's disorder, known as "Omental Cushing's."