Steroid Profiles in the Diagnosis of Canine Adrenal Disorders.
Jack W. Oliver, Proceedings 25th ACVIM Forum, Pp. 471-473, Seattle, WA. 2007.
See the Treatment Section. Discussed topics include “Primary Adrenal Tumors”, “Mitotane”, “Trilostane”, “Aromatase Enzyme Inhibitors”, “Anti-Gonadotropin Drugs”, “Melatonin” and Phytoestrogens (“Lignans”).
Treatment Option Considerations
Atypical Cushing's revised July 2011
Estradiol Increase (Hyperestrinism)
Estradiol typically causes increased liver involvement (hepatomegaly, steroid hepatopathy, increased ALP and ALT) and PU/PD. Other signs that are seen with true Cushing’s disease can also be present, such as haircoat problems, dilute urine, muscle weakness, hypertension and pot-bellied appearance. Melatonin and lignans may be the best treatment approach at this time. Give them together, and allow 4 months for a good treatment response to occur. Monitor improvement in clinical signs, reduction in ALP and ALT levels or re-run a baseline estradiol level, or our adrenal steroid profile, to see what effects the treatment is having on hormone levels.
See also the “Treatment Section” of Steroid Profiles in the Diagnosis of Canine Adrenal Disorders. Jack W. Oliver, Proceedings 25th ACVIM Forum, Pp. 471-473, Seattle, WA. 2007.
Elevated aldosterone levels should be accompanied by hypernatremia and hypertension, and hypokalemia and muscle weakness. Aldosterone levels can be increased in cases of adrenal hyperplasia or primary adrenal tumor, but aldosterone can also be increased in cases where the renin-angiotensin system is increased (e.g., renal and cardiac problems). Also, low aldosterone level frequently indicates the presence of a primary adrenal tumor, so that ultrasound exam of the adrenals is indicated in this situation.
Primary Adrenal Tumors
Primary adrenal tumors have a variety of hormonal secretory patterns, including many that have normal cortisol levels. Steroid hormone panels are the best way to establish whether or not a primary adrenal tumor is functional.
Ketoconazole; Combination of Melatonin, Lignan, and low-dose ketoconazole
In cases of Atypical Cushing’s disease, with increased intermediate adrenal steroid levels, and elevated estradiol levels, consider using ketoconazole at a conservative dose (see article by Lien and Huang, "Use of ketoconazole to treat dogs with pituitary - dependent hyperadrenocorticism: 48 cases (1994-2007)", JAVMA, 233:1896-1901, 2008) plus melatonin and lignan. KETOCONAZOLE inhibits the 17-alpha-hydroxylase enzyme early in the adrenal pathway (steroid intermediate levels decrease), and the 11-beta-hydroxylase enzyme late in the adrenal pathway (serum cortisol level decreases). MELATONIN has anti-gonadotropic activity (effective for ferret adrenal disease), and it inhibits aromatase enzyme (decreases androstenedione and testosterone conversion into estradiol) and 21-hydroxylase enzyme (effectively lowers cortisol level). LIGNAN inhibits the 3-beta hydroxysteroid dehyrogenase enzyme early in the adrenal pathway (cortisol and intermediate adrenal steroid levels decrease), along with the aromatase enzyme (estradiol level decreases). Because of these multiple sites of enzyme inhibition with KETOCONAZOLE, MELATONIN and LIGNAN, the dose of ketoconazole needed can be reduced, with less chance of liver toxicity occurring. Consider using a conservative oral dose of ketoconazole (6 - 12 mg/kg, BID), plus melatonin and lignan (see treatment option Considerations above for dose of melatonin and lignan). Monitor treatment effectiveness by improvement in clinical signs, biochemistries or by repeat of our adrenal steroid profile.
A melatonin implant eliminates the need to give a melatonin pill twice each day. To monitor clinical effectiveness, look for improvement in clinical signs, or run our steroid hormone profile at some point. If the melatonin implant is used, it produces melatonin blood levels for 4 months, so a repeat adrenal profile at that point would be good. Veterinarians have observed very good haircoat re-growth in many instances, in dogs with alopecia.
Lysodren; Combination of Melatonin, Lignan and Maintenance Lysodren
Lysodren is a traditional treatment for Cushing’s disease. Predictable effects on hormone levels occur, and as noted on our Treatment Option Sheet, Lysodren effectively and reliably reduces cortisol levels, but also those of androstenedione, progesterone and 17-hydroxyprogesterone. Effect on estradiol is variable, and probably related to the fact that estradiol is produced in various tissues (the adrenals, but also fat and hair follicle cells). In Atypical Cushing’s disease, where cortisol levels are normal but intermediate and/or sex steroids are increased, treatment is often begun with melatonin and lignan (see Treatment Option Considerations above). But, if clinical response over time is less than desired, some then add a maintenance dose of Lysodren to the melatonin/lignan treatment. If additional response seems needed, then adjustment can be made in the dose of Lysodren, or in Lysodren treatment frequency. Serum cortisol levels are monitored, as would be done with traditional Lysodren treatment, to prevent cortisol levels from reaching a critically low level (Addisonian level). Treatment effectiveness is monitoried by improvement in clinical signs, biochemistries or repeat of our adrenal steroid profile. When cortisol levels are suppressed to the 3-5ug/dL range on post-ACTH stim, then intermediate steroid levels are usually also suppressed to normal range (again, with the possible exception of estradiol).