Congenital adrenal hyperplasia-like syndrome/ Hyperestrinism/ "Atypical Cushing's"

[acushdogsmom]

We have several members whose dogs have been diagnosed as having congenital adrenal hyperplasia-like syndrome, and we've had many other people asking about "Atypical Cushing's" recently, so I am posting the following for anyone who might be looking for information.

If a dog continues to exhibit Cushing's symptoms, yet tests negative for Cushing's on the usual tests (ACTH stimulation test and Low Dose dexamethasone suppression test) your Vet or Internal Medicine Specialist Vet may feel that it is a good idea to test for "Atypical Cushing's", congenital adrenal hyperplasia-like syndrome or hyperestrinism. An "adrenal panel" blood test can be sent to the University of Tennessee for analysis.

Although not actually Cushing's, dogs with these conditions often have many of the same clinical symptoms as Cushing's dogs do, and the treatment is also usually similar.

A Vet can contact Dr. Jack Oliver at the University of Tennessee for more information.

Dr. Oliver's Contact information can be found here:

http://www.vet.utk.edu/faculty/oliver.shtml

Here is some information about this "Cushing's-like syndrome" in the form of a Research Abstract of the presentation that was given by Dr. Jack Oliver recently at a meeting of the Society for Comparative Endocrinology in May/June 2005:

http://www.compendo.org/SCEAbstracts05.rtf

HYPERESTRINISM IN DOGS
Jack W. Oliver, D.V.M., Ph.D.
Director, Clinical Endocrinology Service
The University of Tennessee

The Clinical Endocrinology Service at the University of Tennessee utilizes steroid hormone profiling in the diagnosis of adrenal disease. Many of the cases received have had preliminary diagnostic workups with either ACTH stimulation or low dose dexamethasone suppression testing that has been negative, but signs of Cushing's disease persist. Many of these atypical Cushing's-like cases will have abnormal levels of adrenal intermediate steroids and sex hormones. Included in the atypical cases are a considerable number of dogs that have hyperestrinism (elevated estradiol levels), with and without increased levels of other steroids. The dogs with hyperestrinism typically present with some or all of the following clinical signs: “Cushingoid” appearance, presence of chronically elevated levels (usually extremely elevated) of serum alkaline phosphatase, hepatomegaly, steroid hepatopathy on biopsy, PU/PD, dilute urine, panting, haircoat problems and skin biopsies that indicate presence of an endocrinopathy. The talk will focus on case presentations that associate clinical signs presented by dogs with primary hyperestrinism (elevated serum estradiol levels), including the association of high estradiol with increased alkaline phosphatase, and the fact that sex steroids can cause elevated cortisol/creatinine ratios. Treatment concerns will be addressed, such as mitotane and trilostane resistance. Other potential treatments for hyperestrinism will be discussed.

Also see:
http://www.vet.utk.edu/diagnostic/en...articles.shtml

Steroid Profiles in the Diagnosis of Canine Adrenal Disorders.
Jack W. Oliver, Proceedings 25th ACVIM Forum, Pp. 471-473, Seattle, WA. 2007.
http://www.vet.utk.edu/diagnostic/en...is%20of%20.doc

Diagnostic Laboratory Insight with Regard to Adrenal Disease.
Jack W. Oliver, Proceedings 20th ACVIM Forum, Pp. 541-543, Dallas, TX. 2002.
http://www.vet.utk.edu/diagnostic/en...tg,%202002.doc

Client Information Adrenal Steroid Profiles in the Diagnosis of Adrenal Disease.
http://www.vet.utk.edu/diagnostic/en...gs,%202006.doc

And a document from UTenn Endocrinology Lab which explains how the tests that they do should be performed:
http://www.vet.utk.edu/diagnostic/en...ts_info_07.pdf

(see #3 on the above document link for the explanation of the UTenn Lab adrenal function tests, and specifically, #3g for an explanation of the ACTH stimulation test plus a full adrenal "panel", which includes cortisol and other adrenal hormones)

[acushdogsmom]

http://www.vet.utk.edu/diagnostic/en...lient_info.pdf

CLIENT INFORMATION
ADRENAL STEROID PROFILES IN THE DIAGNOSIS OF ADRENAL DISEASE
Dr. Jack W. Oliver, D.V.M., Ph.D.
Clinical Endocrinology Service (865-974-5638; FAX 865-974-5640; http://www.vet.utk.edu )
College of Veterinary Medicine The University of Tennessee

The Clinical Diagnostic Service at the University of Tennessee provides adrenal steroid profile testing. The adrenal hormone profiles are determined in dogs, cats, ferrets and other species that are suspected of having adrenal disease. The profiles provide a more complete evaluation of adrenal function by assessing hormone levels that arise from different parts of the hormone synthesis pathways. Most tests of adrenal function in animals involve the measurement of the hormone cortisol to determine whether or not the adrenal glands are functioning in a normal fashion. Excessive production for
adrenocorticotropic hormone (ACTH) from the pituitary gland results in bilateral enlargement of the adrenals, with excess release of cortisol. Excess release of ACTH from the pituitary is the usual disorder that results in adrenal disease of animals. However, perhaps 20% of adrenal disease is caused by a primary tumor of one of the adrenal glands that spontaneously secretes excess cortisol into the bloodstream.

For ferrets, adrenal disease is due to primary adrenal tumors, and hormones other than cortisol are involved. Whether or not an animal (other than ferrets) has adrenal disease is usually determined by stimulating the adrenal glands with synthetic ACTH (ACTH stimulation test), or by suppressing the release of ACTH from the pituitary gland (low dose dexamethasone suppression test). Using the stimulation test, one is looking for excessive release of cortisol from the adrenal glands; and using the suppression test, one is looking at whether or not cortisol levels can be completely suppressed for a prolonged period of time. However, in some individuals, these usual tests of adrenal function give normal results even though the animal has very suggestive clinical signs of adrenal disease. In these latter cases, adrenal steroid profile testing is very helpful to determine if hormones other than cortisol are involved, and causing problems for the animal. Steroid profiles for ferrets will determine whether or not a suspected adrenal tumor is present.

Congenital adrenal hyperplasia is a syndrome that occurs in humans where inherited defects of adrenal hormone synthesis occur, with steroids other than cortisol being secreted in excess. Congenital hyperplasia-like syndrome can occur in animals due to inherited defects of hormone synthesis, tumor presence in the adrenal glands that affects the enzymes involved with adrenal hormone synthesis, or other factors that are ill defined at present. In these atypical cases of adrenal disease, the adrenal steroid profiles are very effective in assessing the status of the adrenal glands. This is because different levels of adrenal hormone synthesis are being examined, and not just the end product of the synthetic pathway (cortisol).

Clinical signs are similar in animals that have increased levels of cortisol or the adrenal intermediate hormones. These signs include frequent and excessive urination, temperament changes, thin skin, hair loss, changes in tests of liver function, and frequently, concurrent diabetes. In ferrets, where adrenal tumors are associated with high serum levels of the hormones 17-hydroxyprogesterone, androstenedione and estradiol, clinical signs include the occurrence of hair loss, swollen vulvas, return to male sexual behavior and enlarged prostate glands that cause difficult urination.

The congenital hyperplasia-like syndrome that occurs in animals, where adrenal intermediate hormones are elevated, certainly occurs in both intact and neutered individuals. However, the majority of dogs submitted to the University of Tennessee Clinical Endocrinology Service have been spayed or neutered. This eliminates difficulty with interpretation of results due to presence of similar secretory tissues (adrenals/gonads). Ferrets are nearly always spayed or neutered at a very young age to prevent problems with estrogen toxicity, and odor associated with accessory sex glands. A basal serum sample is all that's needed for ferret assays. For dogs and cats, it is most meaningful to perform an ACTH stimulation test so that comparisons of both basal and stimulated hormone concentrations can be made. Treatment options should be discussed with a veterinarian.

From: J.W. Oliver, Proc. ACVIM Forum, Dallas, TX, 2002.

[acushdogsmom]

If you are in the UK or Europe, and if your Vet cannot contact the University of Tennessee, maybe your Vet could try to contact Dr. Ian Ramsey, BVSc PhD DSAM DipECVIM, MRCVS (Senior Lecturer in Small Animal Medicine, Faculty of Veterinary Medicine, University of Glasgow, Bearsden, Glasgow, United Kingdom). Since Dr. Ramsey also seems to have presented a Research Study (about Trilostane) at that same Society for Comparative Endocrinology conference where Dr. Oliver was a Speaker (see post above), he may be familiar with "Atypical Cushing's" too.

Dr. Ramsey is the Exceutive Secretary of the ECVIM (European College of Veterinary Internal Medicine) and his contact information can be found here:

http://www.ecvim-ca.org

[acushdogsmom]

http://www.melatek.net/images/Treatm...d_Aug_2006.doc

Steroid Profiles for Diagnosis of Atypical Cushing’s Disease: Test Results/Treatment.
Clinical Endocrinology Service (Phone-865-974-5638; Fax-865-974-7147; Web-www.vet.utk.edu)
College of Veterinary Medicine, The University of Tennessee

Where positive test results of increased adrenal activity are present, consider the need for:
1) Ultrasound. To rule out the chance of a primary adrenal tumor (AT) being present.
2) Melatonin. Often used as a first treatment, especially if alopecia is present, since it is cheap, has few side effects and is available in health food stores or via nutrient suppliers on the Internet. Typically, a total dose of 3 to 6 mg is given q12h. Use regular melatonin rather than rapid release or extended release products. Expect positive results within 2 to 3 months. The mode of action of melatonin is vague at this time, but it does have anti-gonadotropic activity. (See Plumb’s Formulary, 5th Edition, and Kirk’s CVT XIII, pg. 546, for melatonin information). Monitor treatment effectiveness via improvement in clinical signs or serum biochemistries (e.g., alk. phos).
3) Melatonin Implants. Now available for dogs from the Melatek Company (1-877-635-2835). Sizes are 8, 12 and 18 mg for <25, 25-50 and >50 lb dogs, respectively. Effects last 4-6 months.
NOTE: Melatonin and flaxseed oil with lignans can be used together when estradiol is increased.
4) LysodrenTM. Lysodren is very effective in lowering cortisol, androstenedione, progesterone or 17-hydroxyprogesterone levels. NOTE: Estradiol is not always suppressed by LysodrenTM, so determining a baseline estradiol level 1-2 months post-Lysodren will determine efficacy.
5) Flaxseed oil with lignans (FSO). The lignans in FSO have phytoestrogenic activity, and may compete with estradiol for tissue estrogen receptors with less biological effect. Sources for animals include health food stores or Internet sites such as www.barleans.com. Give SID; one teaspoonful per 25 lbs on food; or, one FSO capsule (1000 mg) with lignans; or, consider one Barlean’s BrevailTM capsule.
6) Ketoconazole or Anipryl. By the usual protocol for treatment of adrenal disease.
7) Androgen treatment. For estrogen/androgen imbalance or low androgen levels. (E.g.,
methyltestosterone or anabolic steroids {expensive} such as OxandrinTM). Androgen treatment may have positive effect in reducing estradiol level via negative feedback effect, and may also have replacement value. Monitor liver function when androgen treatment is used.
8) Trilostane. Available in the UK and Europe, but not approved in the U.S. The drug can be used in the U.S. with FDA approval (see Plumb’s Formulary, 5th Ed., pg 778 & 886). Note: trilostane always increases 17-hydroxyprogesterone, and frequently increases estradiol and androstenedione as well. LysodrenTM may be preferred for Atypical Cushing’s cases. FURTHER NOTE. Care should be used in switching from trilostane to LysodrenTM. Allow adequate time for either drug’s effects on adrenal tissues to subside before making a change in treatment. (E.g., one month off drug; return of clinical signs of Cushing’s; or post-ACTH stim cortisol levels within normal range).
9) Specific hyperestrinism treatment. ArimidexTM and AromasinTM have particular indication for treatment of hyperestrinism in dogs, but kinetic studies are lacking – consult PDR for effects.
10) Ovarian Remnant or Retained Testicle. Ultrasound or exploratory surgery.
11) For clarification, phone or e-mail Dr. Jack Oliver (865-974-5729; joliver@utk.edu) or Dr. Kellie Fecteau (865-974-5833; kfecteau@utk.edu).

In summary, atypical forms of adrenocortical disease (ACD) occur in dogs and cats (i.e., normal or subnormal cortisol response to the usual adrenal function tests). For dogs, it is common to have elevation of progesterone and 17-hydroxyprogesterone (17-OHP). Increase in androstenedione and estradiol occur frequently, but less so than for progesterone and 17-OHP. Testosterone is increased only rarely. Several patterns of hormone increase occur, so running the complete steroid panel will be the most advantageous, in terms of diagnosis of suspected ACD. Also, it is most meaningful to perform an ACTH stimulation test so that comparisons of basal vs. stimulated hormone concentrations can be made. Usually the stimulated values give the most meaningful information. For cats, infrequent samples are received for testing, but two recent case reports implicate progesterone as being increased along with adrenal androgens and testosterone. From: J.W. Oliver, Proc. ACVIM Forum, pp. 541-543, Dallas, TX, 2002.

Thanks to Brandi for the link.

[acushdogsmom]

Newer tests shed light on causes, treatment of adrenal disorders
By:Johnny Hoskins, DVM, PhD, Dipl. ACVIM
DVM Newsmagazine, Jan 1, 2008

http://veterinarynews.dvm360.com/dvm....jsp?id=485128

Page 1 of article:
http://www.dvmnews.com/dvm/article/a...ID=1&sk=&date=

Page 2 of article:
http://www.dvmnews.com/dvm/article/a...date=&pageID=2

Page 3 of article:
http://www.dvmnews.com/dvm/article/a...date=&pageID=3