Adrenal-Dependent Atypical Hyperadrenocorticism in a Labrador Retriever
This rare case of adrenal-dependent AHAC provides evidence that trilostane therapy may effectively manage associated clinical signs if surgical intervention is not pursued.
Spontaneous canine hyperadrenocorticism (HAC), also referred to as Cushing’s syndrome, is one of the most frequently diagnosed endocrinopathies in small animal practice. The syndrome reflects prolonged exposure to excessive amounts of glucocorticoids. Dogs with HAC generally exhibit polyuria, polydipsia, polyphagia, a pot-bellied appearance, and decreased fur coat quality. A clinical suspicion of HAC is supported by laboratory findings associated with hypercortisolemia, such as increased alkaline phosphatase (ALP) activity, hypercholesterolemia, thrombocytosis, and proteinuria.1,2
The 2021 Case Report Challenge, brought to you by Dechra Veterinary Products: A panel of judges will choose 5 finalists whose case reports will be published in Today’s Veterinary Practice during 2021. TVP’s Facebook followers will then select the grand prize winner from among the 5 finalists; the winner gets a trip to VMX 2022, including registration, hotel, and airfare.
Estimated prevalence of HAC is 0.2%.3 For most patients, the underlying disorder is a pituitary tumor releasing inappropriate amounts of adrenocorticotropic hormone (ACTH); this disorder is referred to as pituitary-dependent HAC and is associated with bilateral adrenomegaly. Other patients have adrenal-dependent HAC, in which an adrenal cortical tumor autonomously produces glucocorticoids.4 Most patients exhibiting signs of spontaneous HAC have excessive cortisol levels, and the terms “HAC” and “hypercortisolemia” are used interchangeably. Therefore, standard diagnostic tests for HAC (e.g., low-dose dexamethasone suppression test, ACTH stimulation test, and urine cortisol:creatinine ratio) rely on measurement of cortisol.2
Infrequently reported are dogs that display a cushingoid phenotype but secrete cortisol at either normal or subnormal levels. For some of these individuals, increased concentrations of various cortisol precursors (e.g., 17-hydroxyprogesterone and androstenedione) have been reported and it is hypothesized that these steroids interact with glucocorticoid receptors and cause the clinical signs traditionally associated with hypercortisolemia.5-8 The term “atypical HAC” (AHAC) describes this syndrome and is best defined by cushingoid signs in the absence of documented hypercortisolemia. Because increased concentrations of various cortisol precursors in dogs with both hypercortisolemia and nonadrenal disorders have been reported, the actual pathogenesis of AHAC remains unclear.9 Previous reports have described AHAC associated with an adrenal tumor and clinical signs that resolved after adrenalectomy.10 Also reported is clinical improvement in dogs with AHAC after medical therapy with either trilostane or mitotane.5,8,11
The recommended treatment for HAC is based primarily on the underlying cause. For pituitary-dependent HAC, the primary treatment is medical management with either trilostane or mitotane.12,13 Trilostane inhibits an enzyme needed for the synthesis of cortisol; it is licensed for the treatment of both forms of HAC in dogs and is generally well tolerated. Mitotane induces irreversible adrenal necrosis; it is not approved for use in dogs, and the dose must be carefully titrated. For dogs with adrenal-dependent HAC and no metastatic disease, adrenalectomy is considered the treatment of choice and may be curative. Removal of the affected gland also prevents complications such as rupture or vascular invasion with thrombosis.14 However, for dogs that are poor surgical candidates or that have other considerations that preclude adrenalectomy, medical therapy may be prescribed. Therapeutic recommendations for cases of AHAC mirror those for typical HAC in that adrenalectomy is the treatment of choice for functional adrenal neoplasms and medical management is used for pituitary-dependent disease.
This case report describes the case of a Labrador retriever with adrenal-dependent AHAC that was clinically well-managed with trilostane.
The patient was a 9-year-old, castrated male Labrador retriever. For several months before the dog’s presentation to the Texas A&M University Veterinary Medical Teaching Hospital (TAMU VMTH) in late April 2020, the client noted that the dog seemed restless, characterized by pacing at night and persistent panting. Initially, this behavior was presumed to be a manifestation of discomfort secondary to osteoarthritis, but various analgesic treatments (tramadol, nonsteroidal anti-inflammatory drugs, gabapentin) did not alleviate the clinical signs. The client also reported that the dog was polydipsic and had recently started waking her up in the middle of the night to urinate. After having been groomed 12 months earlier, the patient’s fur failed to adequately grow back, and recently, patches of alopecia started to appear over his body.
Multiple urinalyses performed within 18 months of presentation revealed hyposthenuria, with specific gravities ranging from 1.005 to 1.006, but no proteinuria. Mild hypokalemia was also identified, with values ranging from 3 to 3.1 mmol/L (reference range [RR] 3.5 to 5.8 mmol/L). No elevations in ALP activity were observed and the platelet count was within the reference range. Months before presentation, levothyroxine therapy was initiated due to a subnormal serum thyroid concentration (0.9 µg/dL; RR 1 to 4), but this therapy was discontinued approximately 1 month later because of a perceived worsening of the patient’s clinical state and a substantially elevated post-pill total thyroid level (5.9 µg/dL). Thoracic radiographs raised concern for either a dilated aorta or a potential heart-base mass; 2 days later, the patient was referred to the TAMU VMTH Cardiology Service.
At presentation to TAMU VMTH, the patient had a pendulous, distended abdomen and multiple patches of alopecia (dorsal tail base, dorsal cervical and scapular regions). The general coat quality was poor (FIGURE 1). The patient was considered to be overweight; body condition score (BCS) was 7/9. Persistent panting without stridor and mild muscle wasting on the hindlimbs were noted.
Noninvasive blood pressure measurement (Doppler) identified severe systemic hypertension (220 to 250 mm Hg systolic), and a fundic examination identified punctate retinal hemorrhages bilaterally consistent with a hypertensive retinopathy. No other abnormalities were noted.
Diagnostic Tests and Results
Repeated thoracic radiographs showed widening of the cranial mediastinum and an enlarged aortic arch, considered secondary to systemic hypertension (FIGURE 2). Echocardiographic findings were also consistent with systemic hypertension, identifying trace aortic insufficiency and aortic dilation. Abdominal ultrasonography identified a markedly enlarged and globoid left adrenal gland (39 × 51 mm) with evidence of invasion of the adjacent caudal vena cava (FIGURE 3). The right adrenal gland was an appropriate shape with a caudal pole width of 5.5 mm. In light of this dog’s systemic hypertension, differential diagnoses for the adrenal tumor included a cortical tumor secreting cortisol plus/minus aldosterone or a pheochromocytoma. Because the history and physical examination findings were most suggestive of abnormal adrenal cortical function, this possibility was prioritized.
An ACTH stimulation test using cosyntropin at a dose of 1 µg/kg IV was performed. Baseline and 1-hour post-ACTH serum samples were submitted for the measurement of cortisol, androstenedione, estradiol, progesterone, 17-hydroxyprogesterone, and testosterone (University of Tennessee College of Veterinary Medicine, vetmed.tennessee.edu/vmc/dls/endocrinology). Serum aldosterone was also measured at 1 hour after ACTH administration (Michigan State Veterinary Diagnostic Laboratory, cvm.msu.edu/vdl) (TABLE 1). The cortisol response to ACTH stimulation was blunted; the baseline value was 3.1 µg/dL (RR <1 to 5.6) and the post-ACTH value was 4.3 µg/dL (RR 7.1 to 5.1). The baseline and poststimulation androstenedione concentrations were markedly elevated; the baseline was more than 10 times the upper limit of the reference range (4.4 ng/mL [RR 0.05 to 0.36]), and the poststimulation value was too high to measure (>10 ng/mL [RR 0.24 to 2.9]).
Testing for a pheochromocytoma with a urine metanephrine:creatinine ratio (UMCR) was not performed at this time. Although this test may reliably identify dogs with a pheochromocytoma, many dogs with HAC are reported to have an increased UMCR. This test is therefore less discriminatory in dogs with Cushing’s syndrome and results should be interpreted with caution.15
To address the patient’s hypertension while awaiting results of the adrenal function tests, amlodipine besylate was prescribed at 0.2 mg/kg PO q12h. Unilateral adrenalectomy was discussed with the client, who declined out of concern for risk and cost. After review of the hormone test results, trilostane (Vetoryl; Dechra, dechra-us.com) was prescribed at 1.2 mg/kg PO q12h.
Blood pressure rechecked 12 hours after amlodipine administration showed significant reduction in systolic pressure. However, within a week of starting this medication and before starting trilostane, severe peripheral edema, a rare side effect of amlodipine in dogs,16 developed and was managed with a 50% reduction in dose. This reduction led to resolution of the edema and adequate control of the hypertension (average systolic blood pressure 145 mm Hg) within 3 weeks. The positive response to amlodipine made a pheochromocytoma unlikely, so UMCR testing was not performed for this patient.
After approximately 1 month of trilostane therapy, the client reported significant improvement in the dog’s status, with less pacing and panting at night and decreased polyuria and polydipsia. After 4 months of trilostane therapy, recheck serum chemistry documented a persistent mild hypokalemia (3.1 mmol/L [RR 3.5 to 5.8]), but potassium supplementation was withheld due to potential alterations in potassium handling secondary to trilostane administration. ACTH stimulation tests are routinely used to monitor dogs receiving trilostane therapy, although target post-ACTH cortisol concentrations are controversial.13,17 Because this dog’s cortisol secretion was subnormal at the time of diagnosis, the decision was made to not measure either baseline or post-ACTH cortisol again, as long as the dog was clinically well. An ACTH stimulation test would certainly be indicated if the dog were to show any signs of hypocortisolemia.
Over the next 5 months, the client appreciated an improvement in coat quality and growth of new hair in the alopecic areas (FIGURE 4). In addition, the pot-bellied appearance resolved and the dog’s muscle mass improved. The client has not noticed any signs associated with hypoadrenocorticism (lethargy, vomiting, diarrhea, or inappetence). At 13 months after initial diagnosis, the dog is reportedly still doing well at home and receiving the same dose of trilostane.
For most patients with HAC, the cushingoid signs are secondary to hypercortisolism, although numerous reports have documented concurrent increases in cortisol precursor concentrations. However, several case reports describe patients with cushingoid signs, such as the patient reported here, in which cortisol secretion is within normal limits or is suppressed and steroid precursor concentrations are elevated.5,6,8,18,19 For this patient, extended adrenal function testing was recommended due to the presence of an adrenal mass and the normal ALP activity.20 The persistent hypokalemia remains unexplained but may reflect an interaction between androstenedione (or other unmeasured steroid precursors) and either mineralocorticoid receptors or endogenous mineralocorticoid activity.21,22
Trilostane is a 3β-hydroxysteroid dehydrogenase inhibitor (FIGURE 5) and one of the most commonly used medical therapies for dogs with pituitary-dependent HAC.23 In addition, trilostane has been shown to be effective in dogs with hypercortisolemia resulting from functional adrenal tumors.24 Of note, androstenedione concentrations are apparently unaffected by trilostane administration.25 In humans, this drug is known to modulate the interaction of estrogen with its receptor and is used for this purpose in women with tamoxifen-resistant breast cancer.26 In rats, trilostane administration has been shown to down-regulate mRNA for glucocorticoid receptors.27 Decreased receptor function or expression in target organs could mitigate the effects of steroid hormones even if serum concentrations remain unaffected, but no current evidence supports this hypothesis for dogs.
This rare case of adrenal-dependent AHAC provides evidence that trilostane therapy may effectively manage associated clinical signs and improve quality of life if surgical intervention is not pursued. However, the clinical response cannot be predicted, and clients must be warned about the risks of iatrogenic hypoadrenocorticism.
Dr. Cook has received honoraria from Dechra Veterinary Products for past projects.
1. Ruckstuhl NS, Nett CS, Reusch CE. Results of clinical examinations, laboratory tests, and ultrasonography in dogs with pituitary-dependent hyperadrenocorticism treated with trilostane. Am J Vet Res. 2002;63(4):506–512.
2. Behrend EN, Kooistra HS, Nelson R, et al. Diagnosis of spontaneous canine hyperadrenocorticism: 2012 ACVIM consensus statement (small animal). J Vet Intern Med. 2013;27(6):1292–1304.
3. Carotenuto G, Malerba E, Dolfini C, et al. Cushing’s syndrome—an epidemiological study based on a canine population of 21,281 dogs. Open Vet J. 2019;9(1):27–32.
4. Hoffman JM, Lourenco BN, Promislow DEL, Creevy KE. Canine hyperadrenocorticism associations with signalment, selected comorbidities and mortality within North American veterinary teaching hospitals. J Small Anim Pract. 2018;59(11):681–690.
5. Gomes Pöppl Á, Quishpe Contreras L. Canine atypical hyperadrenocorticism associated with hypothyroidism. Revista MVZ Córdoba. 2019;24(2):7262–7267.
6. Frank LA, Henry GA, Whittemore JC, et al. Serum cortisol concentrations in dogs with pituitary-dependent hyperadrenocorticism and atypical hyperadrenocorticism. J Vet Intern Med.
7. Norman EJ, Thompson H, Mooney CT. Dynamic adrenal function testing in eight dogs with hyperadrenocorticism associated with adrenocortical neoplasia. Vet Rec. 1999;144(20):551–554.
8. Benitah N, Feldman EC, Kass PH, Nelson RW. Evaluation of serum 17-hydroxyprogesterone concentration after administration of ACTH in dogs with hyperadrenocorticism. JAVMA. 2005;227(7):1095–1101.
9. Behrend EN, Kennis R. Atypical Cushing’s syndrome in dogs: arguments for and against. Vet Clin North Am Small Anim Pract.
10. Syme HM, Scott-Moncrieff JC, Treadwell NG, et al. Hyperadrenocorticism associated with excessive sex hormone production by an adrenocortical tumor in two dogs. JAVMA. 2001;219(12):1725–1728, 1707–1708.
11. Ristic JME, Ramsey IK, Heath FM, et al. The use of 17-hydroxyprogesterone in the diagnosis of canine hyperadrenocorticism. J Vet Intern Med. 2002;16(4):433–439.
12. Kintzer PP, Peterson ME. Mitotane (o,p’-DDD) treatment of 200 dogs with pituitary-dependent hyperadrenocorticism. J Vet Intern Med. 1991;5(3):182–190.
13. Arenas Bermejo C, Perez Alenza D, Garcia San Jose P, et al. Laboratory assessment of trilostane treatment in dogs with pituitary-dependent hyperadrenocorticism. J Vet Intern Med. 2020;34(4):1413–1422.
14. van Sluijs FJ, Sjollema BE, Voorhout G, et al. Results of adrenalectomy in 36 dogs with hyperadrenocorticism caused by adreno-cortical tumour. Vet Q. 1995;17(3):113–116.
15. Kook PH, Boretti FS, Hersberger M, et al. Urinary catecholamine and metanephrine to creatinine ratios in healthy dogs at home and in a hospital environment and in 2 dogs with pheochromocytoma. J Vet Intern Med. 2007;21(3):388–393.
16. Creevy KE, Scuderi MA, Ellis AE. Generalised peripheral oedema associated with amlodipine therapy in two dogs. J Small Anim Pract. 2013;54(11):601–604.
17. Boretti FS, Holzthum J, Reusch CE, Sieber-Ruckstuhl NS. Lack of association between clinical signs and laboratory parameters in dogs with hyperadrenocorticism before and during trilostane treatment. Schweiz Arch Tierheilkd. 2016;158(9):631–638.
18. Monroe WE, Panciera DL, Zimmerman KL. Concentrations of noncortisol adrenal steroids in response to ACTH in dogs with adrenal-dependent hyperadrenocorticism, pituitary-dependent hyperadrenocorticism, and nonadrenal illness. J Vet Intern Med. 2012;26(4):945–952.
19. Hill KE, Scott-Moncrieff JC, Koshko MA, et al. Secretion of sex hormones in dogs with adrenal dysfunction. JAVMA.
20. Reusch CE, Feldman EC. Canine hyperadrenocorticism due to adrenocortical neoplasia. Pretreatment evaluation of 41 dogs. J Vet Intern Med. 1991;5(1):3–10.
21. Sekihara H. 19-Hydroxyandrostenedione: evidence for a new class of sodium-retaining and hypertensinogenic steroids. Endocrinology. 1983;113(3):1141–1148.
22. Torpy DJ, Mullen N, Ilias I, Nieman LK. Association of hypertension and hypokalemia with Cushing’s syndrome caused by ectopic ACTH secretion: a series of 58 cases. Ann N Y Acad Sci. 2002;970:134–144.
23. Lemetayer J, Blois S. Update on the use of trilostane in dogs. Can Vet J. 2018;59(4):397–407.
24. Arenas C, Melian C, Perez-Alenza MD. Long-term survival of dogs with adrenal-dependent hyperadrenocorticism: a comparison between mitotane and twice daily trilostane treatment. J Vet Intern Med. 2014;28(2):473–480.
25. Sieber-Ruckstuhl NS, Boretti FS, Wenger M, et al. Cortisol, aldosterone, cortisol precursor, androgen and endogenous ACTH concentrations in dogs with pituitary-dependant hyperadrenocorticism treated with trilostane. Domest Anim Endocrinol. 2006;31(1):63–75.
26. Puddefoot JR, Barker S, Vinson GP. Trilostane in advanced breast cancer. Expert Opin Pharmacother. 2006;7(17):2413–2419.
27. Malouitre SD, Barker S, Puddefoot JR, et al. Regulation of hepatic steroid receptors and enzymes by the 3beta-hydroxysteroid dehydrogenase inhibitor trilostane. J Steroid Biochem Mol Biol. 2006;101(2-3):97–105.