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

[k9cushings]

We have had several members whose dogs have been diagnosed as having congenital adrenal hyperplasia-like syndrome, and we have many other people asking about "Atypical Cushing's", so this is for anyone who might be looking for information on those conditions.

If a dog continues to exhibit Cushing's symptoms, yet tests negative or borderline 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 may also be similar.

Here is the Research Abstract of a presentation that was given by Dr. Jack Oliver at a meeting of the Society for Comparative Endocrinology in May/June 2005:


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.


Steroid Profiles in the Diagnosis of Canine Adrenal Disorders.
Jack W. Oliver, Proceedings 25th ACVIM Forum, Pp. 471-473, Seattle, WA. 2007.
https://vetmed.tennessee.edu/wp-content/uploads/sites/4/Steroids_Profiles_in_the_Diagnosis.pdf

Diagnostic Laboratory Insight with Regard to Adrenal Disease.
Jack W. Oliver, Proceedings 20th ACVIM Forum, Pp. 541-543, Dallas, TX. 2002.
See attached image

Client Information Adrenal Steroid Profiles in the Diagnosis of Adrenal Disease.
https://vetmed.tennessee.edu/wp-content/uploads/sites/4/Endo_Client_Info.pdf

A document from UTenn Endocrinology Lab which explains how the tests that they do should be performed:
https://vetmed.tennessee.edu/wp-content/uploads/sites/4/Submission-Guidelines-and-Test-Protocols-V3.pdf

(Under “Adrenal Function,” see section F for an explanation of the ACTH stimulation test plus a full adrenal "panel", which includes cortisol and other adrenal hormones)

Treatment Option Considerations (revised 1-27-16):
https://vetmed.tennessee.edu/wp-content/uploads/sites/4/Treatment-Considerations.pdf

Lignans (phytonutrients) Information:
https://vetmed.tennessee.edu/wp-content/uploads/sites/4/LIGNANS-INFORMATION.pdf

[k9cushings]

https://vetmed.tennessee.edu/wp-content/uploads/sites/4/Endo_Client_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.

[k9cushings]

Congenital adrenal hyperplasia-like syndrome
Kirk’s Current Veterinary Therapy XII: Small Animal Practice
Author: John D. Bonagura
Published: July 1995

Thanks to Bonnie and Crissy Ann for this document.

[k9cushings]

Hormone replacement skin products affect users’ pets, confound veterinarians
June 10, 2010
By: Edie Lau
For The VIN News Service


The spreading popularity of topical hormone treatments in people — especially but not exclusively menopausal women — is having unintended medical consequences for the users’ pets.

Spayed dogs and young female puppies are showing up in veterinary exam rooms with markedly swollen vulvas as if they are in heat. Male dogs present with enlarged mammary glands and abnormally small penises. Animals of both genders experience fur loss.

The phenomenon frequently stumps veterinary practitioners; sometimes patients go undiagnosed for weeks or months because clinicians don’t recognize the connection. Medical doctors in the human realm likewise are unfamiliar with the situation, a Veterinary Information Network (VIN) News Service inquiry found.

The problem appears to stem from the use by pet owners of hormone replacement treatments in the form of lotions, gels or sprays that are applied to the arms — especially inner elbows and wrists — or legs. The users then handle and snuggle their animals, unwittingly transferring the drug to the pets.

Symptoms of hormonal imbalance also may occur in pets that ingest the medications, either by licking where product was applied or eating an improperly stored or discarded transdermal patch or similar item.

The issue was brought to the attention of the VIN News Service by a clinician who has seen three such cases in his Bradenton, Fla., practice in the past year. The news service subsequently found that the phenomenon has been reported anecdotally for at least five years on message boards of VIN, a professional organization and online community of veterinarians. But the cases have been described in isolation from one another, and no one has documented the incidents scientifically.


Full article can be read here:
http://news.vin.com/VINNews.aspx?articleId=15950

__________________________________________________ _____________________________________________

FDA alert:
Evamist Hormone Spray May Cause Illness in Pets
07/29/2010





The Center for Veterinary Medicine would like pet owners to know that Evamist (estradiol transdermal spray), a topical hormone replacement product, sprayed on the forearm to reduce hot flashes in women during menopause, has the potential to cause health problems in pets exposed to the product on the owner’s skin.


Since Evamist’s approval in 2007, FDA’s Center for Veterinary Medicine (CVM) received two reports of dogs experiencing mammary, or nipple, enlargement and vulvar, (external genital) swelling. In one case the dog experienced liver failure and vaginal prolapse and in the other case the dog had elevated estrogen levels.


In both cases, the owners had been applying Evamist spray to their forearms. Secondary exposure to the pets likely occurred when the dogs licked the owner’s arms, or while the dog was held by the owner. Small pets (dog, cat, pocket pet) may be especially sensitive to the estrogen in Evamist.


To help prevent estrogen exposure to a pet, FDA suggests that women using this product wear long sleeves to cover the application site and prevent pets from licking or touching the arm where Evamist was sprayed. Small pets may be especially sensitive to the estrogen in Evamist and may exhibit signs associated with excessive levels of estrogen. This would include signs such as swollen vulva and nipples, vaginal bleeding, and vaginal prolapse. If your pet's skin or fur is accidentally exposed to Evamist, it may help to bathe the animal with shampoo and water to remove any residual product.


If you are using Evamist and your pet shows any of these signs, or other illness, contact your local veterinarian.


Full FDA alert can be read here:
http://wayback.archive-it.org/7993/20170112031846/http:/www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProvi ders/ucm220185.htm
__________________________________________________ _______

Scrutiny of secondary topical hormone exposures deepens
September 9, 2010
By: Edie Lau
For The VIN News Service


The Veterinary Information Network (VIN) plans to survey tens of thousands of veterinarians around the world to gauge how widespread and significant are accidental exposures of pets to their owners’ topical hormone preparations.

The problem has been described intermittently in online discussion boards of VIN and elsewhere for years, but the phenomenon has received scant mention in the medical literature.

In the past three years, the U.S. Food and Drug Administration has garnered reports of at least eight children and four dogs inadvertently exposed to topical female hormone products. In July, the agency issued a safety announcement about the potential for accidental exposures in children and pets to Evamist, a spray-on estrogen treatment for hot flashes.

An investigation by the VIN News Service published in June found that a number of cases of accidental exposures in pets involve the use of hormone replacement therapies prepared by compounding pharmacies, as well. One of the canine exposures reported to the FDA was to a compounded product containing estradiol and progesterone. Yet the agency has not issued a caution about compounded hormone preparations.

However, David Miller, CEO and executive vice president of the International Academy of Compounding Pharmacists (IACP), said he would be willing to help alert pharmacists to the need to warn consumers of the risk of topical medication transfer.

“It is fantastic that this issue is being raised not only in the veterinary community but to patients in general,” Miller said. “We so often take for granted prescription medications and over-the-counter medications. We don’t realize we’re dealing with pretty potent and potentially dangerous substances.”

Dr. Paul Pion, president and co-founder of VIN, an online professional community, said the survey will be distributed to the nearly 28,000 practitioner members of VIN, the majority of whom are small-animal veterinarians.

Pion said that while the survey will not document with scientific precision the prevalence of accidental exposures in pets, it may give a first estimate of the problem. “It’s just the next step to try to figure out what we’ve stumbled upon,” he said.

Observers anticipate that as Baby Boomers age and turn to hormone therapies to combat the effects of aging, the potential for secondary exposures will rise.

“I think it’s going to become a bigger and bigger problem,” predicted Dr. Joni Freshman, a veterinary internal medicine specialist in Colorado and consultant to VIN and the laboratory of VCA Antech. Freshman saw her first case in a male German shepherd mix in Texas nearly 20 years ago. Now she comes across suspect cases two or three times a month in her role as a consultant.

Veterinary cases usually involve dogs that have been exposed to hormone creams, gels, lotions or sprays used by their owners, either by coming in contact with or by licking the owner’s treated skin. Although the owners generally are menopausal women, topical hormone therapies are used by men as well, and the same risk presumably applies.

Female dogs exposed to female hormone products typically present with swollen vulvas, nipples and/or mammary glands. Male dogs exposed to female hormones also may exhibit swollen mammary tissues as well as abnormally small or underdeveloped penises and/or testes and prostate problems. Exposed dogs of either gender may lose fur, as well.

Overexposure to estrogen may be toxic to dogs and cats, potentially causing bone marrow suppression leading to chronic anemia, and raising the risk of mammary cancer.

The phenomenon of accidental secondary exposures in pets was brought to the attention of the VIN News Service this spring by a clinician in Florida who had seen three such cases within a year. In the most compelling of those cases, Dr. Terry Clekis, owner of Braden River Animal Hospital in Florida, operated on a pug he had previously spayed, thinking he’d left behind remnants of ovarian tissue. It wasn’t until after the surgery that he realized the pug’s signs of apparent heat were caused by exposure to her owner’s compounded hormone replacement cream.

In its investigation, VIN News Service documented 22 cases of probable cutaneous hormone product exposure in dogs. Most, but not all, were puppies and small breeds.

After the story was posted on the Internet, several pet owners wrote to say that their dogs similarly were affected.

Among them was Carole Curtis, whose e-mail message from Australia suggests the problem is international in scope. Curtis, of Gold Coast, Queensland, wrote that about five months after she began using a compounded estrogen cream, her 10-year-old Shih Tzu-Chihuahua mix, Poppie, developed discoloration on the skin of her stomach, inner thighs and vulva. Then Poppie went bald on her underside, and her vulva began to swell.

Curtis said the dog was examined by two different veterinarians and underwent several blood tests that showed her liver, kidney and thyroid functions were normal, and that she was not diabetic. Her hormone levels were not measured. The symptoms had persisted for nearly a year when Curtis came across the VIN News article about accidental hormone exposures.

Like other loving dog owners, Curtis said she cuddled Poppie frequently without a notion that the dog might be affected by contact with the cream.

“It is such a nice moisturiser, I have used it on my face and neck and hands,” she wrote. “I am always smooching Poppie and carrying her around and kissing her as she is only 2.5 kilo (5.5 pounds) in weight.”

Once she recognized the possible link between Poppie’s symptoms and exposure to the cream, Curtis acted immediately. “I have now changed all my bed linen, washed all my clothes that Poppie may have come in contact with and will be using my cream on my tummy and applying it with gloves,” she wrote. “... I hope I have discontinued the use of cream in areas accessible to Poppie in time for her to fully recover.”

In what may be the only published scientific paper on the subject, Rebecca Schwarze and Dr. Walter Threlfall, a veterinary reproduction expert at The Ohio State University, described a single case of secondary hormone exposure involving an intact 4-month-old bichon frise. The case study appeared in the Journal of the American Veterinary Medical Association, Vol. 233, No. 2, July 15, 2008, under the title “Theriogenology Question of the Month.”

The case illustrates how blind pet owners may be to the possibility that their medications and behavior may be the source of a pet’s ills. This owner, five days after purchasing the pup, noticed that the pet repeatedly licked her vulva and had a bloody discharge. The vulva was swollen, as well.

Threlfall said in an interview that he asked upfront whether the dog was exposed to an outside source of estrogen. The owner said no. The veterinarian began a series of diagnostic tests, thinking perhaps the pup had follicular cysts. It wasn’t until the third or fourth visit that the owner asked, “Could it be the estrogen cream that I put on my arms? She likes to lick it.”

As a comparative theriogenologist, Threlfall said he has seen a variety of species with hyperestrinism. He routinely asks whether the animal may have had exogenous estrogen exposure, such as through an injected or implanted medication or something it ate (red clover, for example, contains isoflavones that mimic estrogen in the body).

“It’s tough to diagnose when people knowingly or not knowingly give you the wrong answer,” he said.

At the same time, the subject of a client’s own health history and habits is so delicate that Threlfall said he would hesitate to inquire aggressively, even after that experience. “I think that is getting a little personal,” he said. “I have to stay in my area. You have to walk a thin line. If the same (situation) came out today, I wouldn’t specifically pinpoint it. I probably would be a little more diligent in beating around the bush.”

Even pet owners who are medical professionals can be unaware. A primary-care physician whose dog developed nipple enlargement was oblivious to the cause until she heard about secondary-exposure risk via the North American Menopause Society (NAMS), which was alerted by the VIN News Service investigation.

The physician used the spray-on topical estrogen Evamist. Dr. Cynthia Stuenkel, president of NAMS, said the physician was stunned to make the connection between her hormone therapy and her pet’s condition. “Oh my god,” she realized, “I’m petting my dog and my dog is licking me.”

At the University of Tennessee College of Veterinary Medicine, Dr. Jack Oliver, a professor in the Department of Comparative Medicine, runs a clinical endocrinology diagnostic laboratory. He sees some 50 cases a week of dogs with hyperestrinism.

Most of those animals have adrenal gland disorders such as Cushing’s disease. With experience, Oliver has come to recognize distinctions between those dogs and the animals whose problem is likely exposure to exogenous sex hormones: Whereas the typical adrenal case will have an estradiol level of 85 pg/ml in the blood, dogs with outside exposures have much higher readings — well over 100 pg/ml, and usually on the order of 150 pg/ml or greater. Oliver said he has seen levels as high as 250 pg/ml.

In addition, the dogs often have an associated increase in levels of progesterone and 17-hydroxyprogesterone, which Oliver surmises is due to topical hormone products having both an estradiol and progesterone component.

Oliver said he began noticing cases of exogenous hormone exposure in dogs five to six years ago. The frequency has since increased. “In the last two or three years, we’ve seen ... maybe one or two a month,” he said.

Another of Oliver's observations is that hormone levels are confoundingly slow to abate after exposure ends. “The biological half-life of steroids is about an hour. You’d think they’d go away fairly quickly,” Oliver said. But in cases he’s seen for follow-up analysis, the levels remained high even after a few months. “In one dog, it took almost nine months for the clinical signs like nipple enlargement and swollen vulva to go away,” he said.

Oliver went on: “I always suggest the potential for hormone exposure when I see cases with high estradiol levels and especially in young dogs with new owners. But we’re just one lab. More veterinarians need to become aware of this potential toxicity with estradiol.”


See full article here:
http://news.vin.com/VINNews.aspx?articleId=16512

[lulusmom]

Atypical Cushing's Syndrome in Dogs: Arguments For and Against.
Ellen N. Behrend, VMD, Phd, Robert Kennis, DVM, MS
Source: Department of Clinical Sciences, College of Veterinary Medicine, Auburn University, Auburn, AL 36849, USA.

ABSTRACT
In the past 5 to 10 years, much interest has arisen in the syndrome of occult hyperadrenocorticism. Patients with occult hyperadrenocorticism purportedly have many clinical signs and routine laboratory abnormalities suggestive of the presence of typical hyperadrenocorticism, or Cushing's syndrome (ie, hypercortisolism either due to a pituitary or adrenal tumor). However, the standard diagnostic tests-corticotropin (ACTH) stimulation and low-dose dexamethasone suppression tests-are normal. A theory has arisen that the clinical signs of occult hyperadrenocorticism are due to excess adrenal secretion of sex hormones rather than cortisol. The authors believe that the role of sex hormones has not been proven. The article reviews the evidence both for and against the importance of sex hormones in creating occult hyperadrenocorticism.
Link to abstract
https://pubmed.ncbi.nlm.nih.gov/20219489/

______________________________________________

Atypical Cushing's Disease: Is It Really Atypical?
Rhett Nichols, DVM, ACVIM (Internal Medicine)

SUMMARY


The major question is the following - is atypical Cushing’s disease a distinctly different disorder than classic Cushing’s disease? Interestingly, only 14 cases of atypical Cushing’s have been reported in the veterinary literature and the majority of cases are ATs (1,16,17,18). Published and unpublished data would indicate that it is not uncommon for ATs to be associated with excessive sex steroid production and normal screening tests. In other words, many ATs often fit the description of ACD, but this description can be considered “normal” for an adrenocortical tumor, especially an adrenal carcinoma. Of even more interest is the expression of 21-hydroxylase is normal in ATs, and, therefore, a deficiency of 21-hydroxylase is not the cause of excessive steroid production (11).

Summary impact point: Some ATs fit the description of ACD, but this presentation is not uncommon for ATs.

Primary bilateral adrenal hyperplasia caused by aberrant expression of receptors in the adrenal cortex is a relatively new form of Cushing’s disease reported in the dog which fits the definition of ACD. The primary example is food-induced Cushing’s disease. These cases present with obvious signs of HAC, negative screening tests, suppressed endogenous ACTH concentrations, and symmetrically enlarged adrenal glands.

A theory for non-suppressed ACTH cases (ACTH-dependent ACD) is the cut-off levels for the current endocrine screening tests are simply too high, especially in mild cases. In other words, some or possibly many cases of classic Cushing’s disease are misdiagnosed as ACD. And lastly, the possibility that ACD is a congenital adrenal hyperplasia-like syndrome is unclear at this time. To prove or disprove this theory, adrenal glands from dogs with ACD, preferably not treated with mitotane or trilostane, would have to be tested for deficiencies of the various enzymes involved in the cortisol biosynthetic pathways.

And finally, and maybe most important, no matter what the underlying cause of ACD, medical therapy with trilostane or mitotane is efficacious in most cases.

FULL PDF
http://sewvma.org/files/march_2015_meeting/atypical_cushings.pdf