One of the most common endocrine disorders of dogs is hyperadrenocorticism (HAC). Clinical disease results from excess secretion
of hormone from the adrenal cortex. Canine Cushing's Syndrome (CCS), refers to a collection of clinical signs and chemical
abnormalities that stem from chronic exposure to excessive concentrations of glucocorticoids. Under the general category of
naturally occurring HAC are pituitary dependent hyperadrenocorticism (PDH) and adrenal dependent hyperadrenocorticism (ADH).
Regardless of the underlying cause of the HAC, there is an elevation of systemic adrenocortical hormones. The clinical signs
most frequently seen in a Cushing's patient are: polydipsia, polyuria, alopecia, pendulous abdomen, hepatomegaly, polyphagia,
muscle weakness, anestrus, muscle atrophy, comedones, panting, hyperpigmentation, testicular atrophy, calcinosis cutis, and
facial nerve paralysis. Laboratory abnormalities associated with CCS include: mature leukocytosis, neutrophilia, lymphopenia,
eosinopenia, increased alkaline phosphatase, alanine transferase, cholesterol, fasting blood glucose, abnormal bile acids,
lipemia, and a urine specific gravity (USG) < 1.015 (Table 2). Diagnosis of CCS is generally made based on clinical signs,
laboratory abnormalities, and results of one, or a combination of screening tests: adrenocorticotropic hormone (ACTH) stimulation
test, low dose dexamethasone (LDDS) test, urine cortisol:creatinine ratio.
Patients sometimes present with the constellation of clinical signs compatible with CCS, without concurrent elevation of plasma
cortisol levels. Instead, plasma levels of cortisol precursors or androgens are elevated. "Atypical Cushing's" has been used
to describe the syndrome in these patients. It been hypothesized that these 'atypical' cases may involve a relative deficiency
in some of the enzymes critical to the synthesis of cortisol. 21-β hydroxylase and 11-β hydroxylase have been investigated
as enzymes that are deficient in the synthesis pathway. It has been suggested that without the requisite enzymes the steroid
synthesis pathway is blocked, resulting in abnormal increases in plasma concentrations of active cortisol precursors or sex
hormones. This has been seen in dogs with adrenal dysfunction, PDH, and non-cortisol secreting adrenal tumors (ATs). In these
cases, neither ACTH stimulation, measuring cortisol, nor low dose dexamethasone tests will be diagnostic for CCS. Thus, a
patient can present with clinical signs strongly suggestive of CCS, but without supportive diagnostic results on routine endocrine
screening tests. These patients can be diagnosed using the extended adrenal panel. The results of these panels must be interpreted
with caution. To make the diagnosis of atypical cushing's disease, there must be a significant increase of at least 2 precursor/sex
hormones along with appropriate patient clinical signs.
A similar syndrome of excess adrenorcortical hormone secretion that does not involve cortisol has been described: Alopecia
X. Many of these patients are seen by dermatologists for evaluation of alopecia. It should be noted that while Atypical CCS
and Alopecia X are poorly understood and may share similar clinical signs of hair loss, they are not the same syndrome. The
clinical signs of the latter are predominantly limited to changes in hair coat; the clinical signs of the former are far more
similar to PDH or AT. The relationship of steroid hormones and Alopecia X as well as the treatment of this condition with
trilostane, melatonin, and mitotane has been examined. However, to our knowledge, no detailed examination of treatment efficacy
in atypical CCS has been made.
Trilostane is a hormonally inactive steroid competitive inhibitor 3β-hyydroxysteroid dehydrogenase. This enzyme mediates the
conversion of pregnenolone, 17-hydroxypregnenolone, dehydroepiandrosterone, and androstenediol. Trilostane has been reported
to be effective in the treatment of Alopecia X and CCS. Historically mitotane has been used to treat HAC, specifically PDH.
Mitotane selectively and progressively destroys the adrenal cortex. This can be partial or complete, depending upon the treatment
protocol selected. There are clear advantages to mitotane, including reported efficacy >80% in dogs with PDH. However, there
are disadvantages that must be considered, including potential for development of adrenocortical insufficiency, relatively
high relapse frequency, and drug intolerance. Melatonin alters gonadotropin release and sex hormone concentrations. While
melatonin does impact the circadian and seasonal reproductive cycles, it does not appear to impact the glucocorticoids.