Dynamic adrenal function testing in eight dogs with hyperadrenocorticism associated with adrenocortical neoplasia
E. J. NORMAN, H. THOMPSON, C. T. MOONEY
The results of adrenocorticotropin (ACTH) stimulation and low-dose dexamethasone suppression tests (LDDST) were evaluated retrospectively in eight dogs with clinical signs of hyperadrenocorticism arising from functional adrenocortical tumours, and compared with the results from 12 dogs with confirmed pituitary- dependent hyperadrenocorticism (PDH). The post-ACTH cortisol concentration in the dogs with adrenocortical tumours ranged from 61 to 345-6 nmol/litre (median 251-5 nmol/litre) and they were within the reference range (150 to 450 nmol/litre) in five and unexpectedly low (<150 nmol/litre) in three dogs. Both the basal and post-ACTH cortisol concentrations were significantly lower in the dogs with adrenocortical neoplasia than in the dogs with PDH. Eight hours after the LDDST, only two of six dogs with adrenocortical tumours had a cortisol concentration above 30 nmol/litre, and the median resting, three, and eight-hour cortisol concentrations were 31-5, 23-0, and 22-7 nmol/litre respectively. There was no significant cortisol suppression during the LDDST, although interpretation was complicated by the low cortisol concentrations, but two dogs showed a pattern of apparent suppression. Two dogs with adrenal tumours showed a diagnostically significant increase in 17-OH-progesterone concentration in response to ACTH although their cortisol concentrations did not increase greatly. These results differ from previous reports of the response of functional adrenal tumours to dynamic endocrine tests.
Veterinary Record (1999) 144, 551-554
E. J. Norman, BVSc, MACVSc, MRCVS, C. T. Mooney, MVB, MPhil, PhD, DipECVIM-CA, MRCVS, Division of Small Animal Clinical Studies, H. Thompson, BVMS, PhD, MRCVS, Department of Veterinary Pathology, University of Glasgow Veterinary School, Bearsden Road, Glasgow G61 1QH
Dr Mooney’s present address is Department of Small Animal Clinical Studies, Faculty of Veterinary Medicine, University College Dublin, Dublin 4, Ireland
SPONTANEOUS hyperadrenocorticism is a common endocrine disorder of dogs, but functional adrenocortical tumours account for only 15 to 20 per cent of the cases (Feldman and Nelson 1996). The clinical and routine clini- copathological abnormalities of dogs with adrenocortical tumours are indistinguishable from those of dogs with pitu- itary-dependent hyperadrenocorticism (PDH), unless there are signs relating to an enlarging abdominal or intracranial mass (Reusch and Feldman 1991). The adrenocorticotropin (ACTH) stimulation test and the low-dose dexamethasone suppression test (LDDST) are widely accepted for the diagno- sis of hyperadrenocorticism. Published results suggest that approximately 60 per cent of dogs with adrenocortical tumours are positive for hyperadrenocorticism by the ACTH stimulation test while the remainder give a normal response. In contrast 100 per cent of dogs with adrenocortical tumours are positive by the LDDST (Reusch and Feldman 1991). Furthermore, dogs with PDH cannot be differentiated from dogs with adrenocortical tumours on the basis of the corti- sol response to ACTH (Reusch and Feldman 1991). However, evidence of suppression in the LDDST supports a diagnosis of PDH. Recently, the authors’ clinical impression has been that dogs with adrenocortical tumours rarely give the classical results suggested in the literature. A retrospective study was therefore undertaken to examine the usefulness of these two endocrine tests for confirming a diagnosis of hyperadreno- corticism and the site of the lesion in dogs with adrenocorti- cal tumours.
MATERIALS AND METHODS
The records of the University of Glasgow Small Animal Hospital were examined for canine adrenocortical tumours diagnosed between 1988 and 1997. The criteria for inclusion in the study were the presence of clinical features consistent with hyperadrenocorticism (Feldman and Nelson 1996) in the absence of exogenous glucocorticoid therapy and histo- logical evidence of atrophy of unaffected adrenal tissue. All the histological slides were examined by one author and the tumours were classified as carcinomas if there was evidence of metastasis or invasion of the capsule or adjacent blood ves-
sels. This group consisted of two German shepherd dogs, one labrador, one boxer, one poodle, one Bedlington terrier, one fox terrier and one crossbreed. Their mean (sd) bodyweight was 26-7 (15.6) kg with a range of 9.3 to 53 kg. Only three weighed less than 20 kg. The dogs ranged in age from eight to 11 years and there were five males and three females.
For comparison a group of 12 consecutive cases with PDH diagnosed between 1994 and 1996 were used. Inclusion in this group was dependent on the presence of clinical features con- sistent with hyperadrenocorticism and either: a) postmortem finding of pituitary neoplasia or hyperplasia with adrenal hyperplasia or typical mitotane adrenolysis; or b) successful response to mitotane treatment typical of PDH, characterised by post-ACTH cortisol concentrations below 50 nmol/litre after cumulative mitotane induction doses of less than 530 mg/kg and maintenance doses of less than 53 mg/kg per week (Kintzer and Peterson 1991, Feldman and others 1992, Kintzer and Peterson 1994, Feldman and Nelson 1996). The results of the ACTH stimulation test were indicative of hyper- adrenocorticism in six cases, and the LDDST was positive in five cases; in the remaining case the results of the ACTH stimula- tion test were equivocal. In most cases the results of the LDDST, and occasionally the high-dose dexamethasone suppression test (HDDST), or the assay of endogenous ACTH supported a diagnosis of PDH.
The ACTH stimulation tests and LDDST were performed on separate days, and other procedures were avoided until they were completed. For the ACTH stimulation tests, heparinised blood samples were collected before, and 60 or 90 minutes after the intramuscular administration of 250 µg of tetracos- actrin (Synacthen; Ciba). For the LDDST heparinised blood samples were collected before, and three or four and eight hours after the intravenous administration of 0-01 to 0-015 mg/kg of dexamethasone alcohol (Azium; Schering-Plough). Samples for cortisol determination were centrifuged and plasma was stored at -20℃ until assayed. Cortisol concen- trations were measured by means of a commercial magnetic separation radioimmunoassay kit (Magic Cortisol; Ciba Corning Diagnostics) validated for use in the dog. Post-ACTH cortisol concentrations greater than 600 nmol/litre and eight- hour LDDST results above 30 nmol/litre were consistent with a diagnosis of hyperadrenocorticism. The criteria used for
suppression in the LDDST were either: a) a cortisol concentra- tion of less than 30 nmol/litre; b) less than 50 per cent of the basal concentration after three or four hours; and/or c) a cor- tisol concentration below 50 per cent of the basal concentra- tion after eight hours.
For the ACTH assays (ACTH IRMA; Nichols Institute) blood was collected into cooled plastic tubes containing EDTA and the plasma immediately separated in a refrigerated centrifuge. The plasma was stored frozen until it was delivered in com- mercial packs to SCL Bioscience Services for assay. Concentrations above 45 pg/ml were considered to indicate PDH and concentrations of less than 10 pg/ml were considered to indicate an adrenocortical tumour. The concentration of 17-OH-progesterone was analysed by using a commercial radioimmunoassay kit (17-OH-P Coat-a-Count; DPC) at the same laboratory. A 17-OH-progesterone concentration greater than 6-0 nmol/litre one hour after the administration of ACTH was considered abnormal (reference range less than 3.0 nmol/litre, increasing to no more than 4-0 nmol/litre).
All the results are reported as mean (sd) or median [semi- interquartile range (SIR)]. The data were analysed statistically by using Minitab for Windows software (release 10-2, 1994). Because of the small sample sizes and the skewed nature of the data a Mann Whitney U test was used for all unpaired comparisons. For paired data, Wilcoxon and Friedman tests were used as appropriate. A P value <0-05 was considered sig- nificant.
RESULTS
Eight dogs met the inclusion criteria for adrenocortical tumours. They all had obvious clinical signs of hyperadreno- corticism (Fig 1). Six were diagnosed by biopsy (dogs 1, 2, 4, 5, 6 and 8) and two by postmortem examination (dogs 3 and 7). Three had adenomas (dogs 2, 4 and 7) and five had carci- nomas (dogs 1, 3, 5, 6 and 8). All the tumours were unilateral, and six involved the left adrenal gland. Dogs 2 and 8 were adrenalectomised successfully and their clinical signs resolved for follow-up periods of between five and 12 months. In dogs 1, 5 and 6 the clinical signs recurred five to 16 months after
| TABLE 1: Results of endocrine testing of eight dogs with functional adrenocortical neoplasms | ||||||
|---|---|---|---|---|---|---|
| Dog | ACTH stimulation test cortisol (nmol/litre) | 0 hr | LDDST cortisol (nmol/litre) | Tumour type | ||
| 0 hr | 1 hr | 3 hr | 8 hr | |||
| 1 | 54.0 | 61.0 | 27.0 | 25-0 | 23 | Carcinoma |
| 2 | 44-7 | 345-6 | 33-0 | 13-0 | 5.0 | Adenoma |
| 3 | 27-0 | 91.0 | Carcinoma | |||
| 4 | 244 | 337 | 191 | 152 | 117 | Adenoma |
| 5 | 25.0 | 92-0 | 24-0 | 18-9 | 22-4 | Carcinoma |
| 6 | 162 | 294 | 121 | 161 | 128 | Carcinoma |
| 7 | 124 | 209 | Adenoma | |||
| 8 | 40-0 | 305 | 30-0 | 21.0 | 8-0 | Carcinoma |
| Mean | 90-1 | 216-8 | 71-0 | 65-2 | 50-6 | |
| Median | 49.3 | 251-5 | 31.5 | 23-0 | 22-7 | |
| SIR | 61-2 | 118-9 | 56-15 | 68-4 | 56-3 | |
adrenalectomy. Dog 4 was lost to follow-up after adrenalec- tomy, and dog 7 was treated with ketoconazole and mitotane for four months, before it was euthanased because of chronic pyelonephritis. Dog 3 was euthanased one month after it was first examined because of acute cerebral haemorrhage, before it had received any treatment.
Twelve cases met the inclusion criteria for PDH. Two dogs were necropsied and the remaining 10 responded adequately to treatment with mitotane. Their post-ACTH cortisol con- centrations were less than 50 nmol/litre after a mean mitotane induction dose of 48.3 (4.6) mg/kg per day given for a mean of 6-3 (2.6) days. Before the treatment began the results of the LDDST supported a diagnosis of PDH in eight of the dogs and the results of the HDDST supported it in one of them. The remaining dog had a circulating ACTH concentration of 373 pg/ml which similarly supported a diagnosis of PDH.
An ACTH stimulation test was applied to all the dogs with adrenocortical tumours (Table 1). The median basal cortisol concentration was significantly lower (P<0.05) than the post- ACTH concentration, but this was below 600 nmol/litre in all cases. Five stimulation test results were within the reference range (post-ACTH cortisol 150 to 450 nmol/litre) and three were lower than expected (post-ACTH cortisol below 150 nmol/litre). Before treatment with mitotane, the median basal cortisol concentration in the dogs with PDH was 164-5 (63-5) nmol/litre which was significantly higher (P<0.05) than in the dogs with adrenocortical tumours. Their median post- ACTH cortisol concentration was 605 (215-3) nmol/litre which was also significantly higher (P<0-001) than that of the dogs with adrenocortical tumours.
A LDDST was applied to six of the dogs with adrenocorti- cal tumours (Table 1). There was no significant difference between the resting, three-hour and eight-hour cortisol con- centrations. However, only two had an eight-hour post-dex- amethasone concentration of above 30 nmol/litre, consistent with hyperadrenocorticism. The concentration of cortisol in the eight-hour sample was suppressed by less than 50 per cent of the baseline value in four cases. Four of the cases met at least one of the criteria for suppression with the LDDST and one case met all three criteria.
Both ACTH stimulation testing and a LDDST were applied to six of the dogs with adrenocortical tumours. Two of them were positive for hyperadrenocorticism on the basis of pub- lished criteria with at least one test, and four were negative with both.
The concentration of endogenous ACTH in dog 8 was 44 pg/ml, and was non-diagnostic. In dogs 1 and 8 the concen- trations of 17-OH-progesterone post-ACTH administration were 22.0 and 19-6 nmol/litre, above the reference range, and they had basal concentrations of 5-4 and less than 1.0 nmol/litre) respectively.
DISCUSSION
The selection criteria for the dogs with adrenal tumours dif- fered from those in other studies, which have included abnor- mal results of an ACTH stimulation test or LDDST (Reusch and Feldman 1991), an abnormal ratio of cortisol to creatinine in urine (Feldman 1983a, Feldman and others 1996), an abnormally low endogenous ACTH concentration (Feldman and others 1996) or an abnormal result in an HDDST (Peterson and others 1982). However, the criteria were designed to pro- vide a high degree of certainty of the diagnosis, while not excluding dogs with unusual endocrine test results, so that the frequency of these results could be studied. In combination with the presence of consistent clinical findings the use of his- tological criteria is in keeping with other studies of adreno- cortical tumours (Feldman 1981, 1983b). The majority of the dogs with adrenocortical tumours weighed over 20 kg, as in other reports (Reusch and Feldman 1991). The breeds and ages of the dogs were also similar.
Not all the dogs with a diagnosis of PDH had been exam- ined postmortem or had undergone other discriminatory diagnostic testing to use these criteria alone to select them. Hence the selection criteria included sensitivity to mitotane therapy. The induction doses and periods were similar to those reported by Feldman and others (1992) who found mean post-ACTH cortisol concentrations of 88 (94) nmol/litre after seven days treatment with mitotane at a mean dose of 47.5 (9.7) mg/kg per day in 13 dogs with PDH. Thus only dogs which were very sensitive to the adrenolytic actions of mitotane were included in the present study. This supports a diagnosis of PDH because the mean post-ACTH cortisol con- centration of 13 dogs with adrenocortical tumours was 502 (386) nmol/litre after similar doses of mitotane for a similar period (Feldman and others 1992). There is no significant correlation between induction times and pretreatment cor- tisol concentrations (either basal or post-ACTH) in dogs with PDH (Kintzer and Peterson 1991) and, therefore, the selection of mitotane-sensitive cases is unlikely to have biased the results in favour of specific pretreatment endocrine test results.
The absence of an exaggerated response to the adminis- tration of ACTH in any of the eight dogs with adrenocortical tumours differs from earlier findings in which 13 of 22 dogs (Peterson and others 1982) and 26 of 41 dogs (Reusch and Feldman 1991) with adrenocortical tumours had abnormally high post-ACTH cortisol concentrations. In three of the eight dogs the response to ACTH was lower than would be expected in a normal dog (less than 150 nmol/litre) and this response was maintained in one dog that was retested. None of the 22 dogs studied by Peterson and others (1982) and only one of the 41 dogs studied by Reusch and Feldman (1991) had such a low post-ACTH cortisol concentration (118 nmol/litre). Feldman (1983b) reported that seven dogs with adrenocor- tical tumours had lower post-ACTH cortisol concentrations than 57 dogs with PDH, although this difference was not sig- nificant. In a more recent study no significant difference was found in the post-ACTH cortisol concentrations of dogs with adrenal tumours or PDH (Reusch and Feldman 1991). In con- trast, in this study the dogs with adrenal tumours had signif- icantly lower basal cortisol concentrations and lower post-ACTH cortisol concentrations than the dogs with PDH.
The adrenal tumours in the eight dogs demonstrated a capacity to respond to ACTH as evidenced by the significant increase in their post-ACTH cortisol concentrations. Adrenal neoplasms retain their ACTH receptors and the intracellular pathways integral to an ACTH response despite their autonomous function (Feldman and Nelson 1996). In the uncommon cases of adrenal tumours that fail to respond to ACTH (Feldman and Nelson 1996) it has been postulated that there is a defect in the ACTH receptors. However, if that were
the case, there would be no increase in cortisol precursors. It has been suggested that 17-OH-progesterone might be used as a marker for alopecia associated with a sex hormone imbal- ance (Schmeitzel and Lothrop 1990). The activity of 17-a- hydroxylase, which is responsible for the production of 17-OH-progesterone by the adrenal gland, is strongly stim- ulated by ACTH. The further metabolism of 17-OH-proges- terone by 21-hydroxylase and 11-ß-hydroxylase results in the production of 11-deoxycortisol and cortisol respectively. There was an exaggerated 17-OH-progesterone response to ACTH stimulation in two of the dogs which had adrenal car- cinomas, one of which had a subnormal cortisol response. This result suggests that the adrenal gland may retain the abil- ity to respond to ACTH but that its cortisol pathway may not be intact. In human beings, adrenal carcinomas are particu- larly likely to produce large amounts of intermediates in the biosynthesis of cortisol, and a partial or complete deficiency of 11-ß-hydroxylase is common (Bondy 1985). It is possible that this was the case in these dogs.
Only two of six dogs with adrenal tumours had an eight- hour cortisol concentration above 30 nmol/litre after a low dose of dexamethasone, whereas in previous studies all dogs with adrenocortical tumours have had concentrations greater than 30 nmol/litre (Feldman 1983b, Reusch and Feldman 1991). To the authors’ knowledge, only one other study of a necropsy-confirmed case of an adrenal tumour has observed such a low cortisol concentration after eight hours (Van Liew and others 1997). However, the criteria used to determine whether this neoplasm was functional are not clear, and the dog did not have the common clinical signs of hyperadreno- corticism. In four of the dogs in the present study the eight- hour cortisol concentration was above 50 per cent of the basal value. Feldman (1983b) concluded that the evaluation of the percentage change was not helpful in distinguishing dogs with or without hyperadrenocorticism, because fewer dogs with hyperadrenocorticism were positive by this criterion (42 of 64) than if an absolute value (>39 nmol/litre) was used as the criterion (59 of 64). However, when the dogs with adreno- cortical tumours are considered alone the difference is not as pronounced; five of six had an eight-hour cortisol concen- tration above 50 per cent of the basal concentration whereas all of them had an eight-hour cortisol concentration greater than 39 nmol/litre (Feldman 1983b). In another study, all 28 dogs with adrenocortical tumours satisfied both criteria (Reusch and Feldman 1991). Thus, the value of evaluating percentage changes may have been underestimated for dogs with adrenocortical neoplasia.
In the LDDST, the basal, three-hour and eight-hour corti- sol concentrations were not significantly different in this study, indicating that, as expected, there was an overall failure of dexamethasone to have a suppressive effect. The interpre- tation of the cortisol concentrations in many of the dogs was complicated by the low values and resulted in many of them fulfilling at least one criterion for suppression. However, in two cases a definite pattern of sustained suppression was observed, as occurs in a normal dog or in up to 5 per cent of dogs with PDH (Peterson 1984), but is considered to be extremely unusual in dogs with adrenal tumours (Feldman and Nelson 1996). It has been suggested that the apparent suppression is a result of unusual fluctuations in cortisol con- centration in which a transient nadir coincides with the tim- ing of the blood sample (Feldman and Nelson 1996). However, in one of the dogs the LDDST was repeated, and the pattern of suppression was also repeated. The other dog had an ACTH concentration within the reference range, although it was lower than would have been expected in a dog with PDH, and it is therefore possible that the administration of dexamethasone to this dog was able to suppress cortisol pro- duction by the adrenal gland by reducing the ACTH concen- tration further. However, it is not unusual for dogs with
adrenal tumours to have ACTH concentrations that fluctuate into the reference range (Reusch and Feldman 1991) and fur- ther work is necessary to characterise the response to dex- amethasone in cases with apparent suppression. Dexamethasone is metabolised rapidly by 75 per cent of dogs with hyperadrenocorticism (Lothrop and Oliver 1984) and its rapid metabolism had been proposed as an explanation for the escape from dexamethasone suppression in dogs with PDH. In the present study, none of the dogs with adrenal tumours exhibited escape from suppression with the LDDST. Although the reasons for the differences between dogs with adrenal tumours and dogs with PDH are not clear the results of this study reinforce the reliability of this finding in indi- cating the presence of PDH.
The responses of the eight dogs with functional adreno- cortical tumours to the ACTH stimulation test and the LDDST were different from those normally expected for such dogs. This group of dogs may represent a previously undiagnosed type, or they may have been excluded from previous reports in which positive endocrine test findings were used as selec- tion criteria. The study has shown that dogs with adrenal tumours may have unexpectedly low circulating cortisol con- centrations and may be negative for hyperadrenocorticism by either ACTH stimulation testing or the LDDST or both. As a result, these cases are difficult to diagnose without the use of other diagnostic tests such as radiography or ultrasonogra- phy. The evaluation of the 17-OH-progesterone response to ACTH administration may aid in the diagnosis of hypera- drenocorticism in dogs with adrenal tumours, but further work is needed to assess its usefulness.
ACKNOWLEDGEMENTS
The authors would like to acknowledge Helen Evans of SCL Bioscience who kindly arranged the 17-OH-progesterone measurements. Thanks are also due to Professor Andrew Nash, Jacques Penderis and Richard Dixon of the University of Glasgow who originally examined some of the clinical cases, and Professor Stuart Reid for his help with the statisti- cal analyses.
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ABSTRACTS
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