Department of Veterinary Clinical Sciences, College of Veterinary Medicine, Oklahoma State University, Stillwater, OK, USA
Session #1006
Abstract
Endocrinology is the science that studies the influence of hormones on the body. The endocrine system has a major role on the normal function of the body. Many diseases can affect the endocrine system, from neoplastic processes to abnormal responses to physiological stimuli. Although endocrine disorders are well described in humans and small animals, there is limited information on exotic mammals. This presentation will focus on disease processes affecting the endocrine glands and/or systems that are relevant in exotic mammals. During this presentation, we will further review endocrine physiology, diagnostic tests for the assessment of the endocrine tissue, and treatment options for specific conditions.
Introduction
Endocrinology is the science that studies the influence of hormones on body function.1 Endocrine glands are specialized tissues/cells that synthesize, store, and release their hormonal secretions directly into the blood.2 The primary function of the endocrine system is to maintain normal metabolic function through internal and external environmental variation; a balance is achieved through the secretion of different hormones, some antagonistic, others synergistic.3 Endocrine disorders appear to be involved in ∼10 to 20% of canine and approximately 5% of feline disease processes.4 In exotic animals there is relatively little information, but it is a growing field.
Diseases of the Pituitary Gland
Diabetes Insipidus (DI)
DI occurs due to failure to produce or secrete, or lack of renal effects of antidiuretic hormone. DI is further categorized as primary (neurogenic or central), nephrogenic, dipsogenic, or gestational.
Spontaneous DI in exotic small mammal species commonly kept as pets (rats and rabbits) can occur.5-7 Diagnostic tests like those described for small animals are also adequate for exotic mammals. The use of the water deprivation test for diagnosing psychogenic polydipsia was reported in a laboratory New Zealand white rabbit (Oryctolagus cuniculus).8 A clinical case of partial DI has been reported in a 6-year-old rabbit.9 The water intake was approximately 6x higher (760 ml/day) than normal and the urine production was 1.5x higher (530 ml/day). The urine specific gravity was low (1.001).9 The animal was treated with a synthetic intranasal vasopressin which led to improvement.9 Although DI has not been reported in gerbils (Meriones unguiculatus), it is important to note that this species may become polydipsic (without DI) if food is restricted.10
Neoplasia
Pituitary neoplasms have been reported in multiple species of small exotic mammals (e.g., rabbits, ferrets), but the most prevalent species is the rat.11-13 Older female rats are most commonly diagnosed with pituitary neoplasms, and as a consequence, it has been suggested that estrogen may play a role in the disease.14 Concomitant pituitary gland tumors were identified in rats with mammary gland fibroadenoma (21/28) and other mammary gland tumors (10/17).15
Reports of pituitary adenomas in pet rats and treatment of clinical cases are rare. A 2-year-old intact male albino pet rat was presented with a 3-week history of hypodipsia, suspected blindness, and behavioral changes.16 The rat was subsequently treated with cabergoline (0.6 mg/kg PO q 72 h).16 Clinical signs recurred at 8.5 months, and a pituitary adenoma was diagnosed on necropsy.16 In a laboratory setting, pituitary tumors were induced by administering 17b-estradiol for 6 weeks and subsequently treated with cabergoline and/or chloroquine.17 Cabergoline alone caused the pituitary tumors to decrease by 55% while cabergoline and chloroquine treatment decreased it by 69%.17
Diseases of the Thyroid Gland
Clinical Assessment
The most common initial assessment of thyroid function is circulating serum thyroid hormones. Total thyroxine (TT4) test has been shown to have poor sensitivity and specificity for thyroid disease.18 In human medicine, TT4 is not commonly used because the measurement of TT4 and total triiodothyronine (TT3) is unreliable since other nonthyroidal diseases can influence these values. This condition is commonly called euthyroid sick syndrome or nonthyroidal illness syndrome.19 Euthyroid sick syndrome refers to changes in serum TSH, serum thyroid hormones, and tissue thyroid hormone levels that occur in patients with various nonthyroidal conditions; however, it is not a primary thyroid disease.20 In cases of mild illness, only TT3 decreases; however, in severe cases, both TT3 and TT4 decrease.21
Because of the unreliability of the total thyroid hormone measurement, this method has been largely abandoned in human medicine. Measurement of the free hormones, when measured by reliable methods, is more adequate. Furthermore, in cases of euthyroid sick syndrome or nonthyroidal illness syndrome, decreases in free thyroxine (fT4) and free triiodothyronine (fT3) are usually modest when compared to decreases in TT3 and TT4.22 Nonetheless, free thyroid values can also be influenced by other nonthyroidal factors.23
Serum TSH measurement in humans is the single most reliable test to diagnose all common forms of hypothyroidism and hyperthyroidism.24 Unfortunately, this diagnostic test is not validated for non-traditional species.
Another thyroid function diagnostic test, mainly for hypothyroidism, is dynamic testing. Dynamic testing implies administering a certain hormone and determining the physiologic response. Among exotic species, limited studies assessing dynamic thyroidal testing have been published. TRH and TSH stimulation testing have been reported in multiple mammalian species (e.g., rats, mice, ferrets, guinea pigs).25-27
Diagnostic imaging (e.g., nuclear medicine) has long been used for the diagnosis of thyroid dysfunction, specifically cases of hyperthyroidism. Taking advantage of the physiologic iodine/iodide cycle, an isotope with high affinity to the thyroid gland is administered, and uptake by the thyroid gland is either quantified or compared with another organ. Normal ratios have been formulated for small animals and, when elevated, may be indicative of a hyperfunctioning thyroid gland, supporting a possible hyperthyroid diagnosis. Reference intervals of thyroid scintigraphy for exotic species have not been well established, although rabbits have been reported in a non-peer review format.28,29 Other imaging modalities used for thyroid diagnostic testing (e.g., ultrasonography, CT, and MRI) are mainly used for the diagnosis of neoplasia. Furthermore, these tests generally do not provide information regarding functionality.
Thyroid Dysfunction
Guinea Pigs
Guinea pigs (Cavia porcellus) are commonly diagnosed with hyperthyroidism. In addition to clinical reports, thyroid neoplasias have been reported as some of the most common neoplasias (3.6%) detected in guinea pigs by one laboratory service.30 Age and gender predisposition have not been determined, but some authors suggest there may be a female bias and a higher predisposition for animals older than 3 years.31 However, in a recent retrospective study of hyperthyroidism in a German population of guinea pigs, females were approximately 50% of the cases and the median age was 5 years old.32 In the same study, most animals were medically managed using thiamazole or carbimazole, while some were treated with surgical removal of the thyroid.32 Clinical improvement was noted in approximately 50% of the animals in which follow up was available.32 Specifically, veterinarians reported clinical improvement in 13/27 of the medically managed animals in which follow up was available and moderate improvement to complete recovery in 3/6 surgically managed animals.32 Several publications have reported normal thyroid reference intervals for guinea pigs, with specific intervals per sex, age, and environment.33-37 Conversely, hypothyroidism is rarely diagnosed in small mammal species. There is only one limited report of hypothyroidism in a guinea pig, and the case description is nonspecific.31
Rabbits
Although rabbits are one of the most commonly kept exotic small mammal pets and have long been used in medical research, naturally occurring and induced thyroid dysfunction are rarely reported.38-41 Although rabbit clinical thyroid disorders have not been published, the author is aware of several highly suspected cases of thyroid dysfunction. Thyroid dysfunction (e.g., euthyroid sick syndrome or nonthyroidal illness) was induced in rabbits that suffered skin wounds through experimental thermal.40,42,43 A recent publication reported euthyroid sick syndrome in pet rabbits.44 Unlike in dogs, TT4 and fT4 were equally decreased in diseased rabbits.44 Fractures and presumed obstructive ileus lead to more significant decreases in TT4, while urinary tract diseases had less impact on TT4 values.44 This study showed that TT4 and fT4 measurements alone should not be used to diagnose hypothyroidism in pet rabbits.44
Chinchillas
One case of concurrent diabetes mellitus and hyperthyroidism has been reported in a chinchilla (Chinchilla lanigera).45 Although correlation between the two conditions is considered unlikely, hyperthyroidism in cats can impair glucose tolerance, potentially leading to peripheral insulin resistance.45,46
Rats
Thyroid neoplasia, euthyroid sick syndrome or nonthyroidal illness, hypothyroidism, and hyperthyroidism have been reported in rats.47,48
Diseases Affecting the Endocrine Pancreas
Neoplasia
Insulinoma is an endocrinologically active insulin-secreting tumor of the pancreatic β cells. Hyperinsulinemia causes hypoglycemia by increased uptake of glucose by muscle tissue, fat, and the liver (all insulin target cells) and suppression of hepatic glycogenolysis and gluconeogenesis.49 Neoplastic hyperfunctioning islet cells continue to produce insulin due to lack of negative feedback.49
Rats
Both spontaneous and induced insulinomas have been reported in laboratory rats.50,51 In late stages of the disease, rats exhibited clinical signs of hypoglycemia, tachypnea, and partial limb paralysis.52 The prevalence of spontaneous islet cell adenoma in aged laboratory rats appears to be low, with pancreatic islet cell adenomas reported to represent 2 to 6% of all tumors.53-55
Guinea Pigs
There have been previous reports of insulinomas in guinea pigs.56 Insulinomas do not appear to be a common clinical problem in guinea pigs, with only a limited number of cases being diagnosed in vivo. In one case of insulinoma in a pet guinea pig, medical management (prednisolone, diazoxide, and frequent syringe feeding) was initially performed, but due to persistent hypoglycemia, an exploratory laparotomy was performed.57 Two pancreatic masses were located and removed, which were histologically diagnosed as insulinoma with osseous metaplasia.57 Four months later, clinical signs and hypoglycemia recurred, and medical management was attempted once again.57 Ultimately, the animal was euthanized.57
Rabbits
Insulinoma was diagnosed in one rabbit; a serendipitous diagnosis was obtained during a study assessing the usefulness of blood glucose measurement in pet rabbits.58
Diabetes Mellitus (DM)
Rodents
Some rodents, in particular members of the suborder Hystricomorpha, have some unique insulin characteristics and, therefore, unique physiology associated with DM. Spontaneous DM in guinea pigs has been reported in a laboratory colony and in a pet guinea pig.59,60 Degus may be one of the most common exotic small mammal species that develop spontaneous diabetes during obesity.61 In a retrospective study of degu diseases, DM was reported in 12/300, with a majority of animals (10/12) being 2 years old or older.62
Rabbits
Rabbits are used for diabetes research, and cases of spontaneous DM in New Zealand white rabbits have been reported.63 However, spontaneous DM in pet rabbits appears to be underreported.
Diseases of the Adrenal Gland
Hyperestrogenism
Rabbits
Hypertestosteronism associated with adrenal neoplasia and hyperplasia, leading to increased sexual and aggressive behavior, has been reported in older neutered rabbits.64 Normal rabbit adrenal glands secrete appreciable amounts of sex steroids.64 Several recent publications have described the occurrence of adrenal tumors in rabbits, in some cases with increased hormone production.64-67 The use of a deslorelin implant for the management of a rabbit with excessive sex hormone production has been reported.68 Macroscopic and ultrasonographic measurements of the adrenal glands of rabbits have been published.69,70
References
1. Norris DO. Vertebrate Endocrinology. 4th ed. San Diego, CA: Academic Press; 2007.
2. Capen C. Tumors of the endocrine glands. In: Meuten DJ, ed. Tumors in Domestic Animals. Ames, IA: Iowa State Press; 2008:607–696.
3. Marty MS, Carney EW, Rowlands JC. Endocrine disruption: historical perspectives and its impact on the future of toxicology testing. Toxicol Sci. 2011;120:S93–108.
4. Engelking L, Rebar AH. Metabolic and Endocrine Physiology. Jackson, WY: CRC Press; 2012.
5. Cheng K, Friesen H, Martin J. Neurophysin in rats with hereditary hypothalamic diabetes insipidus (Brattleboro strain). Endocrinology. 1972;90:1055–1063.
6. Kalimo H, Rinne U. Ultrastructural studies on the hypothalamic neurosecretory neurons of the rat. II. The hypothalamo-neurohypophysial system in rats with hereditary hypothalamic diabetes insipidus. Z Zellforsch Mikrosk Anat. 1972;134:205–225.
7. Boorman GA, Bree MM. Diabetes insipidus syndrome in a rabbit. J Am Vet Med Assoc. 1969;155:1218–1220.
8. Potter MP, Borkowski GL. Apparent psychogenic polydipsia and secondary polyuria in laboratory-housed New Zealand white rabbits. J Am Assoc Lab Anim Sci. 1998;37:87–89.
9. Onuma M, Kondo H, Ishikawa M, et al. Partial central diabetes inspidus in a rabbit. Nippon Juishikai Zasshi. 2009;62:717–719.
10. Kutscher CL, Stillman RD, Weiss IP. Food-deprivation polydipsia in gerbils (Meriones unguiculatus). Phys Behav. 1968;3:667–671.
11. Lipman NS, Zhao ZB, Andrutis KA, et al. Prolactin-secreting pituitary adenomas with mammary dysplasia in New Zealand white rabbits. Lab Anim Sci. 1994;44:114–120.
12. Sikoski P, Trybus J, Cline JM, et al. Cystic mammary adenocarcinoma associated with a prolactin-secreting pituitary adenoma in a New Zealand white rabbit (Oryctolagus cuniculus). Comp Med. 2008;58:297–300.
13. Schoemaker NJ, van der Hage MH, Flik G, et al. Morphology of the pituitary gland in ferrets (Mustela putorius furo) with hyperadrenocorticism. Comparative Study. J Comp Pathol. 2004;130:255–265.
14. Richardson V. Diseases of Small Domestic Rodents. 2nd ed. Oxford, UK; Malden, MA: Blackwell Publishing; 2003.
15. Vergneau-Grosset C, Keel MK, Goldsmith D, et al. Description of the prevalence, histologic characteristics, concomitant abnormalities, and outcomes of mammary gland tumors in companion rats (Rattus norvegicus): 100 cases (1990–2015). J Am Vet Med Assoc. 2016;249:1170–1179.
16. Mayer J, Sato A, Kiupel M, et al. Extralabel use of cabergoline in the treatment of a pituitary adenoma in a rat. J Am Vet Med Assoc. 2011;239:656–660.
17. Lin SJ, Wu ZR, Cao L, et al. Pituitary tumor suppression by combination of cabergoline and chloroquine. J Clin Endocrinol Metab. 2017;102:3692–3703.
18. Haarburger D. Thyroid disease: thyroid function tests and interpretation. Contin Med Ed. 2012;30:241–243.
19. Chopra IJ. Euthyroid sick syndrome: is it a misnomer? J Clin Endocrinol Metab. 1997;82:329–334.
20. McDermott MT. Endocrine Secrets. Philadelphia, PA: Elsevier Health Sciences; 2013.
21. De Groot LJ. Dangerous dogmas in medicine: the nonthyroidal illness syndrome. J Clin Endocrinol Metab. 1999;84:151–164.
22. Warner MH, Beckett GJ. Mechanisms behind the non-thyroidal illness syndrome: an update. J Endocrinol. 2009;205:1–13.
23. Midgley J, Moon CR, Wilkins TA. Validity of analog free thyroxin immunoassays. Part II. Clin Chem. 1987;33:2145–2152.
24. Ladenson PW, Singer PA, Ain KB, et al. American Thyroid Association guidelines for detection of thyroid dysfunction. Arch Intern Med. 2000;160:1573–1575.
25. Heard D, Collins B, Chen D, et al. Thyroid and adrenal function tests in adult male ferrets. Am J Vet Res. 1990;51:32–35.
26. Colzani RM, Alex S, Fang S-L, et al. The effect of recombinant human thyrotropin (rhTSH) on thyroid function in mice and rats. Thyroid. 1998;8:797–801.
27. Mayer J, Wagner R, Mitchell MA, et al. Use of recombinant human thyroid-stimulating hormone for evaluation of thyroid function in guinea pigs (Cavia porcellus). J Am Vet Med Assoc. 2013;242:346–349.
28. Harms C, Hoskinson J, Bruyette D, et al. Development of an experimental model of hypothyroidism in cockatiels (Nymphicus hollandicus). Am J Vet Res. 1994;55:399–404.
29. Brandão J, Ellison M, Beaufrère H, et al. Quantitative 99m technetium pertechnetate thyroid scintigraphy in euthyroid New Zealand rabbits (Oryctolagus cuniculus). In: Proceedings from the American College of Veterinary Radiology Annual Scientific Conference. 2014.
30. Gibbons PM, Garner MM, Kiupel M. Morphological and immunohistochemical characterization of spontaneous thyroid gland neoplasms in guinea pigs (Cavia porcellus). Vet Pathol. 2013;50:334–342.
31. Mayer J, Wagner R, Taeymans O. Advanced diagnostic approaches and current management of thyroid pathologies in guinea pigs. Vet Clin North Am Exot Anim Pract. 2010;13:509–523.
32. Girod-Rüffer C, Müller E, Marschang R, et al. Retrospective study on hyperthyroidism in guinea pigs in veterinary practices in Germany. J Exot Pet Med. 2019;29:87–97.
33. Fredholm D, Cagle L, Johnston M. Evaluation of precision and establishment of reference ranges for plasma thyroxine using a point-of-care analyzer in healthy guinea pigs (Cavia porcellus). J Exot Pet Med. 2012;21:87–93.
34. Müller K, Müller E, Klein R, et al. Serum thyroxine concentrations in clinically healthy pet guinea pigs (Cavia porcellus). Vet Clin Pathol. 2009;38:507–510.
35. Castro MI, Alex S, Young RA, et al. Total and free serum thyroid hormone concentrations in fetal and adult pregnant and nonpregnant guinea pigs. Endocrinology. 1986;118:533–537.
36. Anderson R, Nixon D, Akasha M. Total and free thyroxine and triiodothyronine in blood serum of mammals. Comp Biochem Physiol A Comp Physiol. 1988;89:401–404.
37. Quimby F. The Clinical Chemistry of Laboratory Animals. 2nd ed. ed. Philadelphia, PA: Taylor & Francis; 1999.
38. Kilicarslan H, Bagcivan I, Yildirim MK, et al. Effect of hypothyroidism on the NO/cGMP pathway of corpus cavernosum in rabbits. J Sex Med. 2006;3:830–837.
39. Kowalczyk E, Urbanowicz J, Kopff M, et al. Elements of oxidation/reduction balance in experimental hypothyroidism. Endokrynologia Polska. 2011;62:220–223.
40. Mebis L, Debaveye Y, Ellger B, et al. Changes in the central component of the hypothalamus-pituitary-thyroid axis in a rabbit model of prolonged critical illness. Crit Care. 2009;13:1–10.
41. Mustafa S, Al-Bader M, Elgazzar A, et al. Effect of hyperthermia on the function of thyroid gland. Eur J Appl Physiol. 2008;103:285–288.
42. Mebis L, Eerdekens A, Güiza F, et al. Contribution of nutritional deficit to the pathogenesis of the nonthyroidal illness syndrome in critical illness: a rabbit model study. Endocrinology. 2012;153:973–984.
43. Weekers F, Van Herck E, Coopmans W, et al. A novel in vivo rabbit model of hypercatabolic critical illness reveals a biphasic neuroendocrine stress response. Endocrinology. 2002;143:764–774.
44. Thöle M, Brezina T, Fehr M, et al. Presumptive nonthyroidal illness syndrome in pet rabbits (Oryctolagus cuniculus). J Exot Pet Med. 2019;31:100–103.
45. Fritsche R, Simova-Curd S, Clauss M, et al. Hyperthyroidism in connection with suspected diabetes mellitus in a chinchilla (Chinchilla laniger). Vet Rec. 2008;163:454–456.
46. Hoenig M, Ferguson D. Impairment of glucose tolerance in hyperthyroid cats. J Endocrinol. 1989;121:249–251.
47. Thorson L. Thyroid diseases in rodent species. Vet Clin North Am Exot Anim Pract. 2014;17:51–67.
48. Bray GA, York DA. Thyroid function of genetically obese rats. Endocrinology. 1971;88:1095–1099.
49. Lester NV, Newell SM, Hill RC, et al. Scintigraphic diagnosis of insulinoma in a dog. Vet Radiol Ultrasound. 1999;40:174–178.
50. Inoue C, Shiga K, Takasawa S, et al. Evolutionary conservation of the insulinoma gene rig and its possible function. Proc Natl Acad Sci. 1987;84:6659–6662.
51. Flatt P, Tan K, Bailey C, et al. Effects of transplantation and resection of a radiation-induced rat insulinoma on glucose homeostasis and the endocrine pancreas. Brit J Cancer. 1987;54:685–692.
52. Grant C. Gastrointestinal endocrine tumours. Insulinoma. Baillieres Clin Gastroenterol. 1996;10:645–671.
53. Walsh KM, Poteracki J. Spontaneous neoplasms in control Wistar rats. Fundam Appl Toxicol. 1994;22:65–72.
54. Bomhard E, Karbe E, Loeser E. Spontaneous tumors of 2000 Wistar TNO/W. 70 rats in two-year carcinogenicity studies. J Environ Pathol Toxicol Oncol. 1986;7:35–52.
55. Bomhard E. Frequency of spontaneous tumors in Wistar rats in 30-months studies. Exp Toxicol Pathol. 1992;44:381–392.
56. Hess LR, Ravich ML, Reavill DR. Diagnosis and treatment of an insulinoma in a guinea pig (Cavia porcellus). J Am Vet Med Assoc. 2013;242:522–526.
57. Agúndez MG, Velasco CI. Case report of a guinea pig (Cavia porcellus) with a surgically treated insulinoma. J Exot Pet Med. 2020;33:50–53.
58. Harcourt-Brown FM, Harcourt-Brown SF. Clinical value of blood glucose measurement in pet rabbits. Vet Rec. 2012;170:674–678.
59. Vannevel J. Diabetes mellitus in a 3-year-old, intact, female guinea pig. Can Vet J. 1998;39:503.
60. Belis JA, Curley RM, Lang M. Bladder dysfunction in the spontaneously diabetic male Abyssinian-Hartley guinea pig. Pharmacology. 1996;53:66–70.
61. Spear G, Caple M, Sutherland L. The pancreas in the degu. Exp Mol Pathol. 1984;40:295–310.
62. Jekl V, Hauptman K, Knotek Z. Diseases in pet degus: a retrospective study in 300 animals. J Small Anim Pract. 2011;52:107–112.
63. Roth S, Conaway H. Animal model of human disease. Spontaneous diabetes mellitus in the New Zealand white rabbit. Am J Pathol. 1982;109:359.
64. Lennox A, Chitty J. Adrenal neoplasia and hyperplasia as a cause of hypertestosteronism in two rabbits. J Exot Pet Med. 2006;15:56–58.
65. Rose JB, Vergneau-Grosset C, Steffey MA, et al. Adrenalectomy and nephrectomy in a rabbit (Oryctolagus cuniculus) with adrenocortical carcinoma and renal and ureteral transitional cell carcinoma. J Exot Pet Med. 2016;25:332–341.
66. Varga M. Hypersexuality in a castrated rabbit (Oryctolagus cuniculus). UK Vet Comp Anim. 2011;16:48–50.
67. Baine K, Newkirk K, Fecteau K, et al. Elevated testosterone and progestin concentrations in a spayed female rabbit with an adrenal cortical adenoma. Case Rep Vet Med. 2014;2014:239410.
68. Wright T, Eshar D, Rooney T, et al. Use of a deslorelin implant for management of hyperandrogenism associated with excessive sex hormone production in a female spayed pet rabbit (Oryctolagus cuniculus). J Exot Pet Med. 2022;40:12–15.
69. Stamatova-Yovcheva K, Dimitrov R, Dilek ÖG, et al. Some macrometric anatomical parameters of the adrenal glands in the New Zealand white rabbit. Vet J Mehmet Akif Ersoy Univ. 2021;6:64–67.
70. Banzato T, Bellini L, Contiero B, et al. Abdominal ultrasound features and reference values in 21 healthy rabbits. Vet Rec. 2015;176:101–108.