Steroids that may be involved with atypical Cushing's disease are androstenedione, estradiol, 17-hydroxyprogesterone, progesterone
and aldosterone. Other steroids that are not measured commonly may be involved as well, such as corticosterone and deoxycortisone.
Estradiol is unique because treatment of excess estradiol can be difficult. The hormone can be secreted by tissues other than
the gonads or adrenal glands and secretion is independent of ACTH stimulation or dexamethasone suppression testing, as currently
For dogs with atypical Cushing's disease (PDH cause), expect the presence of hepatomegaly, hepatopathy and bilateral adrenomegaly,
along with increased endogenous ACTH levels and the usual clinical signs, blood-work results and often hair-coat problems.
For dogs with atypical Cushing's disease (ADH cause), expect the presence of hepatomegaly, hepatopathy and unilateral adrenomegaly
(and maybe atrophy of contralateral adrenal glands) along with decreased endogenous ACTH level and the usual clinical signs,
blood-work results and often hair-coat problems.
For primary hyperaldosteronism conditions, due to primary adrenal tumor or bilateral adrenal hyperplasia, expect hypertension
in association with hypernatremia and muscular weakness (cervical ventroflexion, hind-limb weakness) due to hypokalemia. Retinal
hemorrhage and blindness and renal disease can occur in cats. For hyperadrenocorticoid cases that also have low aldosterone
levels, this pattern can be indicative of a primary adrenal tumor, and ultrasound study is indicated to confirm a tumor's
presence or absence.
Treatment implications for primary adrenal tumors
Adrenal steroid profiles reveal that adrenal tumors in dogs, cats and ferrets have a variety of secretory patterns, with
serum cortisol levels often being normal. In ferrets, mice, rats, guinea pigs and hamsters, sex steroid-producing adrenocortical
tumors occur following gonadectomy, in association with the significant increase in serum gonadotropin levels that develop.
The elevated luteinizing-hormone (LH) level that occurs following gonadectomy leads to neoplastic transformation and expression
of LH hormone receptors on sex steroid-producing adrenocortical cells in ferrets and rodents. In spayed female dogs, plasma
gonadotropin levels post-gonadectomy rise to levels 10 times what they were pre-gonadectomy, providing evidence of the strong
and continuous LH stimulus that possibly plays a role in adrenocortical tumor development.
Surgical removal of adrenal tumors usually is indicated, but age and health considerations impact this decision. If surgery
is not an option, then mitotane is usually the next consideration. Adrenal profiles are indicated to determine the functionality
of adrenal tumors in light of the multiple hormone secretion patterns that are seen.
Mitotane. Adrenal hormone profiles reveal that most intermediate hormones are decreased by mitotane the same as for cortisol, but that
estradiol may remain unaffected. In cases that continue to have elevated estradiol levels, varying clinical signs of Cushing's
disease will be present.
Trilostane. Enzyme inhibition by trilostane occurs for 3-beta hydroxysteroid dehydrogenase, but also for 11-beta hydroxylase. Thus, 11-deoxycortisol
levels build up in dogs treated with trilostane. It is apparent that other intermediate steroid levels increase (androstenedione,
17-hydroxyprogesterone, estradiol and progesterone) in dogs treated with trilostane, which could be due to the 11-beta hydroxylase
inhibition, and possibly 21-hydroxylase enzyme inhibition.
The reason only 11-deoxycortisol levels are increased may be due to the length of trilostane exposure (three to seven weeks)
as compared to dogs that are exposed to trilostane for extended periods. Trilostane reportedly offers effective control of
Cushing's syndrome, but the long-term effects of the elevated intermediate steroids remain ill-defined. Some dogs do have
return of clinical signs of Cushing's syndrome while on trilostane. Because trilostane seems to predispose dogs to increased
adrenal toxicity with mitotane, an acute switch from trilostane to mitotane treatment should not be done.
Aromatase enzyme inhibitors (anastrozole, exemestane, melatonin). The aromatase enzyme occurs in gonadal and adrenal tissues (and other tissues such
as fat and skin cells), and converts androstenedione to testosterone or estrone, both of which are then converted to estradiol.
Neither estrone nor testosterone have been observed to be increased in dogs with adrenal disease, but estradiol frequently
is increased and causes many of the clinical signs associated with Cushing's disease. Aromatase enzyme-inhibiting drugs will
decrease estradiol levels, but currently are infrequently used in animals due to cost considerations.
Anti-gonadotropin drugs (melatonin, leuprolide acetate, deslorelin acetate, androgens). Adrenal tissues in different species (e.g., ferrets and rodents)
are known to have luteinizing-hormone (LH) receptors present. In ferret studies, anti-gonadotropin drugs are effective in
lowering sex-steroid levels. Sex-steroid levels also are decreased in dogs with adrenal disease that are treated with melatonin,
but it is not known whether LH receptors are present in canine adrenal tissues. Androgenic drugs have anti-gonadotropin effects
via negative feedback effects on the hypothalamo-pituitary tissues.