Hyperadrenocorticism associated with adrenocortical tumor or nodular hyperplasia of the adrenal gland in ferrets: 50 cases (1987-1991)
Karen L. Rosenthal, DVM; Mark E. Peterson, DVM; Katherine E. Quesenberry, DVM; Elizabeth V. Hillyer, DVM; Neal L. Beeber, DVM; Scott D. Moroff, VMD; Clinton D. Lothrop, Jr., DVM, PhD
Summary: Adrenocortical adenoma, nodular hyper- plasia, or carcinoma was diagnosed in 50 ferrets. Thirty-five (70%) ferrets were female and 15 (30%) were male. The mean age at which clinical signs were first noticed was 3.4 years (range, 1 to 7 years). Clin- ical signs included large vulva (n = 31; 89% of females), alopecia (n = 43; 86%), pruritus (n = 20; 40%), and increased consumption of water and increased urine output (n = 4; 8%). A mass was pal- pated at the cranial pole of the kidney during physical examination of 17 (34%) ferrets. Ultrasonography, performed on 39 of 50 ferrets, revealed a unilateral adrenal gland mass in 19 (49%). Four ferrets were anemic, and 2 ferrets were thrombocytopenia. Baseline plasma concentrations of cortisol and corticosterone were within or below the reference range in all 17 fer- rets tested, whereas baseline plasma estradiol concen- trations were high in 4 of the 11 ferrets (36%) tested. After adrenocorticotropic hormone (ACTH) adminis- tration, only 1 ferret had a slightly exaggerated response on the basis of plasma cortisol concentra- tions, and all 17 had normal responses on the basis of plasma corticosterone concentrations. There was little or no increase in plasma estradiol concentrations af- ter ACTH administration. Of the 50 ferrets, 39 were treated by adrenalectomy. Unilateral adrenalectomy was performed in 34 ferrets in which 1 adrenal gland was large, whereas subtotal bilateral adrenalectomy was performed in 5 ferrets with bilateral adrenal dis- ease. Five ferrets died in the immediate postoperative period, and follow-up information was available for the remaining 34, 1 to 34 months after surgery. A de- crease in vulvar size was generally noticed by 2 days after surgery, and complete hair regrowth was noticed by 2 months.
From the Departments of Medicine (Rosenthal, Quesen- berry, Hillyer, Peterson) and Pathology (Moroff), The Animal Medical Center, New York, NY 10021; Rutherford Animal Hos- pital, Rutherford, NJ 07070 (Beeber); and College of Veterinary Medicine, University of Tennessee, Knoxville, TN 37916 (Lo- throp). Dr. Lothrop’s present address is Scott-Ritchey Research Center, College of Veterinary Medicine, Auburn University, AL 36849.
The authors thank Elizabeth M. Bailey and Emily Smathers for technical assistance.
Supported by a grant from the Morris Animal Foundation.
Because clinical signs resolved after adrenalec- tomy, it was likely that the adrenocortical tumors and nodular hyperplasias of the adrenal gland were hyperfunctional. However, these ferrets did not have excessively high circulating concentrations of cortisol. At present, we recommended that diagnosis of adreno- cortical disease in ferrets be made on the basis of characteristic clinical signs, results of abdominal ul- trasonography, and finding large adrenal glands dur- ing surgery. Results of ACTH stimulation tests, with de- termination of plasma cortisol or corticosterone concentrations, were of no value in the diagnosis.
H yperadrenocorticism has been reported in 3 pet ferrets (Mustela putorius furo).1-3 One ferret was male, had an adrenocortical carcinoma, and a high baseline cortisol concentration.1 The other 2 ferrets were female, and clinical signs re- solved after surgical removal of an adenoma of the left adrenal gland.2,3 Although hyperadrenocorti- cism (ie, cortisol excess) was suspected in all 3 fer- rets on the basis of clinical signs, predominantly truncal alopecia, and pathologic lesions in the adrenals, it was not confirmed by use of pituitary- adrenal function tests.1-6
The purpose of the study reported here was to describe clinical, laboratory, radiographic, ultra- sonographic, surgical, and histologic findings, and long-term follow up in 50 ferrets with hypera- drenocorticism.
Criteria for Selection of Patients
Records of ferrets examined at The Animal Medical Center or the Rutherford Animal Hospital between 1987 and 1991 because of truncal alope- cia or an enlarged vulva were reviewed. Only fer- rets with pathologic changes in the adrenal glands, as confirmed by examination of biopsy or necropsy specimens, were included in this study. Fifty ferrets met the criteria for inclusion.
Tests and Procedures
A complete physical examination had been performed on, and samples for a CBC and serum
biochemical analysis had been obtained from each ferret. Radiography of the whole body and abdom- inal ultrasonography had been performed on 16 and 39 of the ferrets, respectively. An adrenocor- ticotropic hormone (ACTH) stimulation test had been performed on 17 ferrets by collecting blood for determination of plasma cortisol, corticoster- one, and estradiol concentrations before and 1 and 2 hours after administration of cosyntropin (1.0 µg/kg, IV).
Of the 50 ferrets, 39 were treated by adrena- lectomy by use of ventral midline celiotomy.ª Lac- tated Ringer’s solution (20 ml/kg of body weight/d, IV) and ampicillin (20 mg/kg, Iv, q 8 h) were administered to all ferrets during the perioperative period. Prednisolone succinate (20 mg/kg, Iv) was administered during surgery to 22 ferrets, whereas corticosteroid supplementation was not given to the other 17 ferrets that underwent surgery. In 4 of the 39 ferrets, ketoconazole (15 mg/kg, PO, q 12 h) administration for 1 to 4 months before surgery did not result in the resolution of clinical signs.
Of the remaining 11 ferrets, 6 were euthana- tized at their owner’s request, and 5 died before treatment could be initiated. A complete necropsy was performed on each of these 11 ferrets.
Assays
Plasma cortisol and corticosterone concentra- tions were measured by use of a radioimmunoas- say, validated for use in ferrets as described.6 Plasma estradiol concentrations were measured by use of a radioimmunoassay, by modification of a reported method.7 Assays of serial dilutions of pooled ferret plasma containing high concentra- tions of estradiol resulted in a curve that was par- allel to the standard curve. The sensitivity of the estradiol assay was 5 pmol/L. The intra-assay co- efficient of variation for the assay was 14.4% (n = 5), and the interassay coefficient of variation was 11.2% (n = 5).
Reference values for plasma cortisol, cortico- sterone, and estradiol concentrations were deter- mined by testing 8 adult, clinically normal ferrets (4 males, 4 females), as reported.º
Data Analysis
All results are given as mean ± SD. Baseline hormone concentrations were compared with post-ACTH concentrations by use of analysis of variance for repeated measures. Single-factor anal- ysis of variance and the Scheffé F-test were used to compare baseline and post-ACTH concentrations of cortisol, corticosterone, and estradiol to concen- trations in normal ferrets. For all statistical analy- ses, a P value of ≤0.05 was considered significant.8
Results
Of the 50 ferrets, 35 (70%) were female and 15
ªMullen H. Surgical treatment of ferrets (abstr), in Proceed- ings. 27th Annu Meet Am Coll Vet Surg, 1992.
(30%) were male. Only 1 ferret, a female, was sex- ually intact. The mean age at which clinical signs were first noticed by the owner was 3.4 ± 1.4 years (range, 1 to 7 years).
Of the 35 female ferrets, 31 (89%) had an en- larged vulva and 23 (66%) had a mucoid vulvar discharge. Forty-three (86%) of the 50 ferrets had alopecia. The alopecia generally was reported to have begun on the tail and then progressed to the flanks, dorsum, and the remainder of the trunk. Most owners stated that the alopecia had begun in the spring and initially involved only the tail and tailbase. In 15 ferrets (7 males and 8 females), the first episode of alopecia lasted only a few months. The alopecia resolved without treatment, but re- curred the next spring. After recurrence, it had a wider distribution and did not resolve. Twenty (40%) of the 50 ferrets had generalized pruritus, 19 of which also had alopecia. A mass was palpated at the cranial pole of the kidney during initial phys- ical examination of 17 (34%) of the 50 ferrets. Owners of 4 ferrets (8%) reported that their ferrets were drinking more water and producing more urine than usual.
Four ferrets were anemic (PCV = 14 to 28%; normal > 45%), and 2 of these also were throm- bocytopenic (platelet count < 25,000 cells/pl; normal > 300,000 cells/pl). Two ferrets had high aspartate transaminase activity (178 and 289 IU/L; normal < 100 IU/L), and 10 had hypoglycemia (glucose < 60 mg/dl). All 10 ferrets with hypogly- cemia were subsequently found by histologic ex- amination of biopsy samples to have concurrent insulin-secreting tumors of the pancreas.
Adrenal masses or evidence of adrenal miner- alization was not seen on radiographs of any of the ferrets. Ultrasonography revealed a unilateral ad- renal gland mass in 19 of 39 ferrets (49%).
Baseline plasma concentrations of cortisol and corticosterone were within or below the reference ranges in all 17 ferrets tested (Table 1). On the ba- sis of plasma cortisol concentrations, 1 ferret had a slightly exaggerated response to ACTH adminis- tration (plasma cortisol concentration 60 minutes after ACTH administration > 350 nmol/L), and 16 ferrets had normal responses (plasma cortisol con- centrations 60 and 120 minutes after ACTH admin- istration < 350 nmol/L). On the basis of plasma corticosterone concentrations, all 17 ferrets had normal responses to ACTH administration (plasma corticosterone concentrations 60 and 120 minutes after ACTH administration < 100 mmol/L).
Mean plasma concentration of estradiol in fer- rets with adrenocortical disease was significantly higher than mean plasma concentration in clini- cally normal ferrets (Table 1), and 4 of the 11 fer- rets (36%) tested had high baseline values. In con- trast to cortisol and corticosterone concentrations, however, there was little to no detectable increase in plasma estradiol concentrations after ACTH administration in either the clinically normal fer-
| Plasma hormone concentration | |||
|---|---|---|---|
| Hormone | Baseline | Time after ACTH administration | |
| 60 min | 120 min | ||
| Plasma cortisol (nmol/L) | |||
| Before surgery | 29.6 ± 19.7 | 191.9 ± 56.8 | 155.1 ± 141.0 |
| (n = 17) | (5 to 72) | (105 to 500) | (41 to 276) |
| After surgery | 17.9 ± 20.9 | 122.6 ± 63.1*+ | 104.7 ± 67.8 |
| (n = 12) | (5 to 59) | (20 to 220) | (25 to 220) |
| Clinically normal | |||
| ferrets | 50.8 ± 20.2 | 211.4 ± 63.5 | 98.4 ± 25.8 |
| (n = 8) | (27 to 84) | (143 to 308) | (68 to 139) |
| Plasma corticosterone (nmol/L) | |||
| Before surgery | 4.6 ± 3.2 | 43.6 ± 21.3 | 39.2 ± 28.0 |
| (n = 6) | (1.4 to 9.8) | (12.6 to 72) | (6.4 to 75) |
| After surgery | 3.3 ± 2.1 | 27.8 ± 18.3 | 19.2 ± 10.9 |
| (n = 4) | (1.7 to 61) | (10.4 to 49.6) | (3.6 to 28.6) |
| Clinically normal | |||
| ferrets | 6.3 ± 6.8 | 58.4 ± 20.3 | 39.4 ± 28.9 |
| (n = 8) | (1.7 to 17.9) | (29.5 to 83.7) | (4.6 to 72.3) |
| Plasma estradiol (pmol/L) | |||
| Before surgery | 183 ± 112* | 212 ± 137* | 198 ± 105* |
| (n = 11) | (39 to 338) | (39 to 502) | (39 to 346) |
| After surgery | 120 ± 70.9 | 114 ± 56 | 138 ± 51 |
| (n = 4) | (51 to 208) | (51 to 178) | (101 to 211) |
| Clinically normal | |||
| ferrets | 85.9 ± 73.7 | 85.4 ± 72.4 | 84.9 ± 76.4 |
| (n = 8) | (37 to 240) | (37 to 234) | (37 to 227) |
*P < 0.05 as compared with mean concentration in clinically normal ferrets. tP < 0.05 as compared with mean concentration before surgery. To convert cortisol (nmol/L) to µg/dl, divide given values by 27.6. To con- vert corticosterone (nmol/L) to ng/ml, divide given values by 2.9. To convert estradiol (nmol/L) to pg/ml, divide given values by 3.67.
Results are expressed as mean ± SD. Numbers in parenthesis indicate range.
rets or in ferrets with adrenocortical disease (Table 1).
Thirty-nine ferrets underwent exploratory ce- liotomy via a ventral midline approach. Unilateral adrenalectomy was performed in 34 ferrets in which, during surgery, 1 adrenal gland appeared to be obviously large and the contralateral adrenal gland appeared to be of normal size. Of these, left adrenalectomy was performed in 27 (79%), and right adrenalectomy in 7 (21%). In 5 ferrets, both adrenal glands appeared to be larger than normal; therefore, subtotal bilateral adrenalectomy was performed, with complete resection of the large adrenal gland and subtotal resection (approximate- ly half) of the other adrenal gland.
In 12 ferrets, ACTH stimulation tests were per- formed 1 to 3 days after surgery. After ACTH ad- ministration, the plasma cortisol concentrations (measured in all 12 ferrets) and plasma cortico- sterone concentrations (measured in 4 ferrets) were lower than plasma concentrations before surgery (Table 1). Signs of severe adrenocortical insufficiency, however, did not develop in any of these ferrets. Of the 4 ferrets in which plasma es- tradiol concentrations were determined before and after surgery, values were high in 2 ferrets (both fe- male) before surgery, but were within the reference range after adrenalectomy.
Five of the 39 ferrets died in the immediate postoperative period. One ferret died 1 day after surgery because of intestinal torsion, and 4 died 2
days after surgery with clinical signs consistent with cardiac disease (eg, dyspnea, pleural effusion, and cardiac murmur). Dilutative cardiomyopathy was confirmed in the ferret that was necropsied. The remaining 34 ferrets were evaluated 1 to 34 months after surgery (mean, 9.7 ± 7.2 months). Of these, 30 were alive, 2 were euthanatized because of complications associated with insulino- mas, and 2 died of unknown causes.
In all but 1 of the ferrets treated by adrenalec- tomy, a decrease in vulvar size was noticed by 2 days after surgery. In the remaining ferret, which had bilateral adrenocortical nodular hyperplasia and was treated by a subtotal bilateral adrenalec- tomy, resolution of vulvar swelling was noticed 2 months after surgery. In the 34 ferrets evaluated more than 1 month after surgery, complete or par- tial hair regrowth was noticed by all owners. Own- ers also reported that pruritus subsided once the hair coat started to regrow. Clinical signs did not recur in any of the ferrets during the follow-up pe- riod.
Eleven of the 50 ferrets were not treated. Of these ferrets, 6 were euthanatized because of an insulin-secreting tumor of the pancreas (n = 3), bladder tumor (n = 1), pancytopenia (n = 1), or because the owner was unwilling to treat their fer- rets (n = 1). The remaining 5 ferrets died of unknown causes before treatment could be insti- tuted.
Overall, of the 50 ferrets, 32 (64%) had disease of the left adrenal gland, 10 (20%) had disease of the right adrenal gland, and 8 (16%) had bilateral adrenal disease. In 3 ferrets with bilateral disease in which necropsy was performed, the pituitary glands appeared grossly normal. The histologic di- agnosisb was adrenocortical adenoma in 32 (64%), nodular adrenocortical hyperplasia in 13 (26%), and adrenocortical adenocarcinoma in 5 (10%). In the 5 ferrets with adenocarcinoma, however, gross or microscopic evidence of metastasis was not seen.
Discussion
In human beings, dogs, and cats, adrenocorti- cal tumors and nodular hyperplasia of the adrenal gland can be associated with excessive corticoste- roid production, ie, glucocorticoids, mineralocor- ticoids, or sex steroids.9-14 Technically, hyper- adrenocorticism is a condition characterized by excessive production of any adrenal steroid hor- mone; however, the term generally is used to de- fine the condition associated with high circulating concentrations of cortisol. In human beings and dogs, the condition associated with cortisol excess is commonly referred to by the eponyms Cushing’s disease or Cushing’s syndrome.9,10,12,14 Adreno- cortical disease in ferrets also has been termed
bMoroff SD, Sckerman MR, Hawkins KL, et al. Proliferative lesions of the adrenal cortex in ferrets (abstr), in Proceedings. 43rd Annu Meet Am Coll Vet Pathol, 1992.
Cushing’s syndrome, 1-3 but this probably is incor- rect, because high circulating concentrations of cortisol, a characteristic finding in human beings and dogs with Cushing’s syndrome, have not been consistently found in ferrets of previous reports or the present report.
Atrophy of the contralateral adrenal gland and adrenal insufficiency after adrenalectomy also are characteristic findings in dogs and human beings with functional cortisol-secreting tumors of the adrenal cortex.9,14 Ferrets in this study that had a unilateral adrenal adenoma or carcinoma, did not have apparent atrophy of the contralateral adrenal gland, and their plasma cortisol concentrations did not decrease into the hypoadrenocortical range af- ter surgery. Therefore, it is unlikely that the tumors in these ferrets were secreting excessive amounts of cortisol. However, a cause-and-effect relationship between the pathologic changes (ie, adrenocortical adenoma, nodular hyperplasia, or carcinoma) and the clinical signs was apparent, inasmuch as the signs resolved after surgical removal of the abnor- mal adrenal gland(s). In the broadest sense of the word, then, these ferrets do have hyperadrenocor- ticism, but it does not appear that excessive production of cortisol is responsible for the syn- drome.
In rabbits and rats, the predominate glucocor- ticoid secreted by the adrenal cortex is corticoster- one rather than cortisol.15 It has been reported that in normal ferrets, administration of ACTH stimulates the secretion of cortisol and corticosterone6; how- ever, cortisol appears to be the predominate circu- lating glucocorticoid in ferrets,6,15 as in dogs and cats.16 In the present study, we have shown that secretion of corticosterone was normal in ferrets with adrenocortical disease, and, therefore, corti- costerone excess does not appear to be responsi- ble for the clinical signs.
In some respects, the clinical signs in the fer- rets of this report with adrenocortical disease resemble those that commonly develop in intact female ferrets with persistent or prolonged es- trus.17-19 Because female ferrets are seasonally polyestrous and are induced ovulators, they have signs of estrus in the spring, and most remain in estrus throughout the summer unless bred.2º Dur- ing estrus, plasma estrogen concentrations in- crease, resulting in vulvar enlargement and, in some ferrets, hair loss.20 Persistent hyperestrogen- emia also has been implicated as the cause of bone marrow depression that develops in up to a third of female ferrets that are not bred. 17-19
Inasmuch as adrenocortical disease in ferrets appears to be feminizing (as evidenced by vulvar enlargement), it is possible that estrogenic sub- stances are being secreted by the adrenal cortex. In support of this, high plasma concentrations of es- tradiol were found in 4 of 11 ferrets tested in this study. In clinically normal ferrets, because estra- diol is not normally produced by the adrenal cor-
tex, administration of ACTH did not stimulate secretion of estradiol. The high baseline estradiol concentrations in some ferrets may have been a result of direct secretion of estradiol by the tumor or of conversion of excess adrenal androgen into estradiol by peripheral tissues.14 Bone marrow de- pression also developed in 4 of the ferrets of this study (unfortunately, plasma estradiol concentra- tions were not measured in these 4 ferrets); how- ever, the prevalence of this complication was lower in the ferrets of this study than has been reported in sexually intact female ferrets during persistent estrus.17-19 We believe that estradiol excess may play a role in the pathogenesis of adrenocortical disease in ferrets, but estradiol is probably not se- creted in excessive amounts in all ferrets. In addi- tion, it is likely that other adrenal androgens also are secreted in excessive concentrations.
The underlying cause of the pathologic changes in these ferrets’ adrenal glands is unknown, but it is tempting to speculate that premature neutering plays a role. In support of this, studies in some strains of mice have shown that gonadectomy at an early age can lead to adrenocortical nodular hy- perplasia or to tumors of 1 or both adrenal glands that hypersecrete estrogens or androgens.21-23 Ova- ries and adrenal glands develop in close anatomic relation to one another during embryologic devel- opment; both arise in intimate association in the urogenital ridge.24 Small nests of gonadal cells may be carried with the adrenal glands during migra- tion. With appropriate stimulation (ie, gonadec- tomy with resultant unopposed pituitary gonadot- ropin activity), these undifferentiated gonadal cells in the adrenal capsule may be transformed into cells that are functionally similar to cells of gonadal tissue. Like mice that are gonadectomized during the first few days of life, most, if not all, commer- cially-raised ferrets in the United States are ovari- ohysterectomiaed or castrated before they are 6 weeks old. Therefore, it is possible that adrenocor- tical hyperplasia and tumors may develop in ferrets as a result of metaplasia of undifferentiated gonadal cells in the adrenal capsule.
At present, we recommend that adrenocortical disease in ferrets be diagnosed on the basis of characteristic clinical signs and finding, during surgery, that one or both adrenal glands are large. In this study, adrenal masses could not be seen on radiographs, but were seen during abdominal ultrasonography in about half of the ferrets in which it was performed. However, results of ACTH stimulation tests with determination of plasma cortisol or corticosterone concentrations were of no value in the diagnosis of adrenocortical disease. Finding higher than normal plasma estrogen or adrenal androgen concentrations may be diagnos- tic, but the role that estrogens and androgens play in this disease is unknown.
In the ferrets of this report, adrenalectomy was an effective means of treatment. Treatment with
ketoconazole, the antifungal imidazole derivative shown to block steroid production in dogs and hu- man beings,25 was not effective. Treatment with the adrenocorticolytic agent mitotane (o,p’-DDD) could possibly be effective in ferrets,26 but none of the ferrets in this report were treated with this drug. It should be remembered, however, that although mitotane generally works well in dogs, the drug is of limited effectiveness in human beings and cats. 10,12,27 Therefore, one must not assume that mitotane would be effective or nontoxic in ferrets.
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