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Plasma cortisol response to exogenous ACTH in 22 dogs with hyperadrenocorticism caused by adrenocortical neoplasia
Mark E. Peterson, DVM; Steven R. Gilbertson, DVM; William D. Drucker, MD
SUMMARY
The plasma cortisol response to exogenous ACTH (ACTH stimulation test) was evaluated in 22 dogs with hyperadrenocorticism caused by adrenocortical neoplasia. The mean basal cortisol concentration (6.3 µg/dl) was high, but 7 dogs had basal cortisol concentrations that were within normal range.
Administration of exogenous ACTH increased the plasma cortisol concentrations in each dog. Normal post-ACTH cortisol concentrations were found in 9 (41%) of the 22 dogs; 13 (59%) had an exaggerated increase in cortisol concentrations after ACTH ad- ministration. In 9 of 13 dogs with carcinoma and in 4 of 9 with adenoma, the cortisol response was exagger- ated. The mean post-ACTH cortisol concentration in the dogs with carcinoma was approximately 4 times that of the dogs with adenoma; the 7 dogs with the highest concentrations had carcinoma.
Repeat studies were performed in 6 dogs 2 to 8 weeks after initial testing. In 5 of the 6 dogs, repeat testing yielded data of similar diagnostic signifi- cance. One dog, however, had an abnormally high post-ACTH cortisol concentration at initial evalua- tion, but had only a minimal response to ACTH administration, with a normal post-ACTH cortisol concentration, at time of retesting.
Although ACTH stimulation testing is useful in diagnosing hyperadrenocorticism, it can not reliably separate dogs with hyperfunctional adrenocortical tumors from clinically normal dogs or from dogs with pituitary-dependent hyperadrenocorticism (bilat- eral adrenocortical hyperplasia).
HYPERADRENOCORTICISM (Cushing’s syndrome) is a well-recognized endocrine disorder in the dog.1-4 Canine hyperadrenocorticism is most frequently associated with bilateral adrenocortical hyperplasia but is caused by adrenocortical adenoma or car- cinoma in 15% to 20% of reported cases.1-4 An ACTH stimulation test is useful in diagnosing canine hyper-
adrenocorticism.1,3-6 Most dogs with pituitary-de- pendent hyperadrenocorticism (bilateral adrenal hy- perplasia) have normal to high basal plasma cortisol concentrations, and have an exaggerated response to the administration of exogenous ACTH.1,3-7 It has been suggested that ACTH stimulation testing can also be used to differentiate canine pituitary-depend- ent hyperadrenocorticism from hyperfunctional adrenal tumor, based on the assumption that adrenal neoplasms will have little or no response to ex- ogenous ACTH.1,4,6,8 However, other investigators have shown that adrenal tumors may respond to exogenous ACTH, and that ACTH stimulation test- ing is not reliable in differentiating the causes of canine hyperadrenocorticism.9-11,a
In the present report, the plasma cortisol re- sponse to ACTH stimulation was evaluated in 22 dogs with hyperadrenocorticism caused by functional adrenocortical neoplasia.
Materials and Methods
From January 1978 to December 1980, 22 dogs with hyperadrenocorticism resulting from adrenal tumor were examined at The Animal Medical Center. The dogs ranged in age from 6 to 14 years (mean ±SD=11.2+2.1 years). Fifteen (68%) of the dogs were female and 7 were male (Table 1). The tentative diagnosis of hyperadrenocorticism was based on history, results of physical examination, and results of routine hematologic and biochemical tests. Ab- dominal radiography revealed unilateral radiopaque den- sities in the region of an adrenal gland in 9 (41%) of the 22 dogs. The diagnosis of hyperadrenocorticism caused by adrenal tumor was made when the administration of a high dose of dexamethasone (1 mg/kg of body weight, IM) failed significantly (P>0.05; Student’s t test) to decrease plasma cortisol concentrations below base-line valuesb; unilateral adrenocortical tumors were subsequently confirmed by laparotomy in 12 dogs and at necropsy in 10. Of the 22 adrenocortical neoplasms, 9 were adenomas and 13 were carcinomas (Table 1). Eleven of the 13 dogs with adrenocor- tical carcinoma had metastasis, whereas the remaining 2 dogs (No. 11 and 12) had poorly differentiated carcinomas; dog 12 also had extension of the tumor into the vena cava. In all dogs, the contralateral adrenal gland was atrophied.
An ACTH stimulation test was performed by collecting heparinized blood samples before and 2 hours after IM injection of 20 units of ACTH gel.º The plasma was frozen until assayed for cortisol by competitive protein binding or radioimmunoassay.12 In 26 control dogs, base-line cortisol concentrations determined by competitive protein binding
From The Animal Medical Center, 510 E 62nd St, New York, NY 10021 (Peterson, Gilbertson), and The Medical College of Wisconsin, St Joseph’s Hospital, 5000 W Chambers St, Milwaukee, WI 53210 (Drucker).
Supported in part by National Research Service Award 1 F32 AMO 6261 (Peterson).
“Lubberink AAME: Diagnosis and treatment of canine Cushing’s syndrome, PhD thesis. State University of Utrecht, Utrecht, 1977.
Peterson ME, Drucker WD: Biochemical characterization and treatment of canine Cushing’s syndrome (abstr). Scientific Proceedings, Am Coll Vet Int Med, 124, 1980. “Acthar, Armour Pharmaceutical Co, Phoenix, Ariz.
JAVMA, Vol 180, No. 5
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| Dog No. | Age (yr) | Breed | Sex | Histopathologic diagnosis | ACTH stimulation test (µg of cortisol/dl of plasma)* | |
|---|---|---|---|---|---|---|
| 0 hr | 2 hr | |||||
| 1 | 11 | German Short- haired Pointer | F | Adenomat | 5.3 | 14.7 |
| 2 | 13 | Wire Fox Terrier | M | Adenoma | 2.2 | 9.2 |
| 3 | 13 | Poodle | F | Adenoma | 9.9 | 16.0 |
| 4 | 11 | Boxer | F | Adenoma | 2.3 | 16.2 |
| 5 | 8 | Wire Fox Terrier | M | Adenoma | 4.1 | 20.5 |
| 6 | 13 | Poodle | M | Adenoma | 3.5 | 6.6 |
| 7 | 14 | Poodle | F/S | Adenoma | 4.3 | 7.4 |
| 4.8¢ | 12.8# | |||||
| 8 | 11 | Shih Tzu | F/S | Adenoma | 6.5 | 26.8 |
| 9 | 9 | German Shepherd Dog | F | Adenoma | 3.6 | 8.8 |
| 10 | 12 | Mixed-breed dog | F | Carcinoma | 5.6 | 39.9 |
| 11 | 14 | Mixed-breed dog | F | Carcinoma | 24.5 | 135.6 |
| 12 | 14 | Puli | M | Carcinoma | 7.6 | 195.2 |
| 13 | 11 | Poodle | F | Carcinoma | 2.9 | 8.9 |
| 14 | 12 | Poodle | F | Carcinoma | 4.7 | 93.6 |
| 15 | 11. | Poodle | F | Carcinoma | 8.1 | 17.7 |
| 16 | 9 | Viszla | M | Carcinoma | 5.3 | 40.8 |
| 17 | 11 | German Short- | F/S | Carcinoma | 11.7 | 40.8 |
| haired Pointer | 12.5$ | 14.5 | ||||
| 18 | 11 | Old English | F/S | Carcinoma | 1.7 | 6.0 |
| Sheepdog | 8.9 | 13.6 | ||||
| 19 | 6 | Samoyed | M | Carcinoma | 4.9 | 7.3 |
| 4.9$ | 6.7# | |||||
| 20 | 13 | Poodle | F | Carcinoma | 2.4 | 76.8 |
| 21 | 10 | Schnauzer | M | Carcinoma | 9.9 | 29.8 |
| 8.3 | 16.1# | |||||
| 22 | 9 | Mixed-breed dog | F/S | Carcinoma | 6.9 | 14.6 |
| 5.1¢ | 8.1¢ | |||||
*Plasma cortisol concentration determined, using competitive protein binding in dogs 1 to 5 and 10 to 16 and radioimmunoassay in dogs 6 to 9 and 17 to 22. +The tumors were unilateral (13 right, 9 left). Repeated 2 to 8 weeks after initial testing.
ranged from 0.9 to 3.8 µg/dl (mean±SD=2.1±0.8 µg/dl); a range of 0.5 to 4.1 µg/dl (mean±SD=1.6±1.0 µg/dl) was found in 21 control dogs, using radioimmunoassay. The normal post-ACTH cortisol concentrations in the same animals ranged from 4.6 to 13.9 µg/dl (mean ± SD=9.6±2.6 ug/dl), using competitive protein binding, and 4.6 to 14.8 pg/dl (mean±SD=8.5±2.4 µg/dl) using radioim- munoassay. There was no significant difference (P>0.05) in cortisol concentrations determined by competitive protein binding or radioimmunoassay techniques. Using either competitive protein binding or radioimmunoassay tech- niques, a post-ACTH cortisol concentration >15.0 µg/dl was considered an abnormal response.
Results
Table 1 gives ACTH stimulation test results in 22 dogs with unilateral cortisol-producing adrenocorti- cal tumors. In the 22 dogs, the basal cortisol concen- trations ranged from 1.7 to 24.5 µg/dl (mean ±SD= 6.3 ±4.9 µg/dl). Significant differences were not noted between the mean resting cortisol concentra- tions measured by radioimmunoassay and those determined by competitive protein binding (P>0.05). Although the mean cortisol concentration was high, 7 of the dogs had plasma cortisol concentrations that were within normal range. The mean resting cortisol concentration of the dogs with adenoma (4.6 µg/dl) was lower than in those with carcinoma (7.4 µg/dl).
Administration of exogenous ACTH gel resulted in a rise in plasma cortisol concentration in all 22 dogs with adrenocortical tumor, with a mean post- ACTH cortisol concentration of 37.9 µg/dl. The re- sponse to ACTH stimulation was normal in 9 (41%) of the 22 dogs; of these 9, 5 also had normal base-line
cortisol concentrations. Thirteen (59%) of the 22 dogs had an exaggerated increase in plasma cortisol concentrations after ACTH administration-9 (69%) of 13 dogs with carcinoma and 4 (44%) of the 9 with adenoma had an exaggerated response. The mean post-ACTH cortisol concentration in dogs with adre- nocortical carcinoma was 54.4 g/dl; in dogs with adrenocortical adenoma, the mean concentration was 14.0 µg/dl. All 7 dogs with post-ACTH cortisol concentrations greater than 30 µg/dl had adrenocor- tical carcinoma.
In 6 dogs, repeat ACTH stimulation tests were performed 2 to 8 weeks after initial evaluation (Table 1). In 5 of the 6 dogs, basal cortisol concentrations were similar at both testing times. Dog 18, however, had a normal basal cortisol concentration at the time of first testing, but an abnormally high concentration when reevaluated 5 weeks later. Although fluctua- tions occurred, dogs 7, 18, 19, and 22 had normal post-ACTH cortisol concentrations at both testing times; dog 21 had an exaggerated response to ex- ogenous ACTH both times. Dog 17 had an abnor- mally high post-ACTH cortisol concentration at time of initial testing, but had only a minimal response when retested 3 weeks later.
Discussion
In the normal adrenal gland, endogenous ACTH is essential for maintenance of adrenocortical struc- ture and function. Adrenocortical neoplasms that cause hyperadrenocorticism are thought to secrete cortisol independent of endogenous ACTH control. In fact, endogenous production and secretion of pitui- tary ACTH are suppressed by the excessive secretion of cortisol from the hyperfunctioning adrenal tumor; low to undetectable concentrations of plasma ACTH have been reported in both man and the dog with hyperadrenocorticism caused by adrenal tumor.5,10,13 Inadequate circulating concentrations of ACTH re- sult in atrophy of the remaining normal adrenocorti- cal tissue; with unilateral adrenocortical tumors, atrophy of the contralateral adrenal gland occurs. Thus, it might be expected that adrenocortical tu- mors causing hyperadrenocorticism would increase basal concentrations of cortisol and have little to no response to exogenous ACTH, since such neoplasms do not require endogenous ACTH for growth and steroid production.
Although an increased mean basal cortisol con- centration was found in the 22 dogs in this study, approximately one third had basal cortisol concen- trations within normal range. This is in agreement with findings in other studies wherein it was demon- strated that single basal cortisol determinations usually have no diagnostic significance because of considerable overlap with normal range; a normal basal cortisol concentration does not exclude hyper- adrenocorticism.1,7,11 Further, similar basal cortisol concentrations have been found in dogs with adre- nocortical hyperplasia and neoplasia, and can not be used to differentiate these causes of canine hyper- adrenocorticism.7,11
Theoretically, although dogs with adrenocortical
March 1, 1982
tumors could have minimal or no rise in cortisol concentrations following exogenous ACTH adminis- tration, all dogs of this report responded to ACTH stimulation-41% of the dogs had a normal response, whereas 59% had an exaggerated increase. The prevalence and magnitude of the responses were greater in the dogs with carcinoma: of the dogs with adenoma, 44% had an exaggerated response, whereas 69% of the dogs with carcinoma hyperre- sponded. Furthermore, the mean response of the dogs with carcinoma was approximately 4 times greater than that of the dogs with adenoma. The 7 dogs with the highest post-ACTH cortisol concentrations had adrenocortical carcinoma.
In the 6 dogs in which repeat ACTH stimulation tests were performed, fluctuation in cortisol response was found in 5 of the 6; only 1 dog (No. 19) had equivalent results. Even though test results fluctu- ated in 5 dogs, data of similar diagnostic significance were obtained from both stimulation tests in 4 of the 5; 3 dogs had normal responses, whereas 1 had abnormally high post-ACTH cortisol concentrations at both testing times. In 1 dog (No. 17) basal cortisol concentrations were high at both testing periods, but the cortisol response to ACTH administration dif- fered markedly at repeat testing. An abnormally high post-ACTH cortisol concentration was found during initial testing, whereas only minimal re- sponse was found on retesting 3 weeks later. There- fore, a “classical” response to ACTH stimulation, ie, high basal cortisol concentrations with little to no response to ACTH administration, was found only once in 28 ACTH stimulation tests performed in these 22 dogs with functional adrenocortical neo- plasms. In another study, 4 of 5 dogs with functional adrenocortical tumors had markedly dissimilar cor- tisol responses when repeated ACTH stimulation tests were performed.1º Although such large fluctua- tions in basal and post-ACTH cortisol concentrations were not found in the majority of dogs in this report in which ACTH stimulation tests were repeated, it is apparent that basal and/or post-ACTH cortisol con- centrations may vary in some dogs with functional adrenocortical tumors in which repeat testing is performed.
The mechanism responsible for the ability of canine adrenocortical neoplasms to increase cortisol secretion following administration of exogenous ACTH is not known. Despite the fact that these tumors are independent of endogenous ACTH con- trol, they appear to retain their cell surface ACTH receptors and the adenyl cyclase-cyclic adenosine monophosphate pathways responsible for stimulat-
ing adrenocortical steroid production. The con- tralateral adrenal cortex might have been responsi- ble for the increased secretion of cortisol in the dogs of this report, but this is unlikely inasmuch as there was adrenocortical atrophy in all dogs.
Although ACTH stimulation testing is valuable in diagnosing canine hyperadrenocorticism, normal ACTH responses are found in many dogs with hyperadrenocorticism resulting from adrenocortical tumor. Therefore, if hyperadrenocorticism is sus- pected, the diagnosis should not be excluded on the basis of normal response to ACTH stimulation. In addition, inasmuch as over half of the dogs with functional adrenocortical neoplasms have an exag- gerated cortisol response to ACTH administration, neither can the ACTH stimulation test reliably differentiate pituitary-dependent hyperadrenocorti- cism from functional adrenocortical tumor. Other means to evaluate pituitary-adrenocortical function, such as dexamethasone-suppression testing or mea- surement of endogenous plasma ACTH concentra- tions, must be used in canine hyperadrenocorticism to make this differentiation.
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