Department of Veterinary Clinical Sciences, College of Veterinary Medicine, Oklahoma State University, Stillwater, OK, USA
Session #1007
Abstract
Endocrine disorders are not well investigated in most non-traditional species. This may be because of low clinical significance in some species but also a consequence of the lack of established diagnostic tests. One notable exception is the domestic ferret (Mustela putorius furo). Ferrets commonly develop endocrinopathies, often secondary to the development of tumors in specific tissues. Insulinoma and adrenal gland disease are two of the most common conditions in ferrets; however, other conditions affecting the endocrine system have been reported. This presentation will cover endocrinopathies in ferrets.
Introduction
Although endocrine disorders are not well investigated in most non-traditional species, the domestic ferret (Mustela putorius furo) is a well-known species that develops several endocrinopathies. The two most common are adrenal gland disease and insulinoma. Both of these conditions are very prevalent and affect a significant number of typically older ferrets. Other less common endocrine conditions include diabetes mellitus and hypothyroidism. Although the reason for this predisposition to develop endocrinopathies is not clear, limited genetic background and some physiological or anatomical characteristics may predispose it.
Adrenal Gland
The adrenal gland is composed of two distinct parts: the cortex and the medulla. The cortex is composed of the zonae glomerulosa, fasciculata, and reticularis.1 Several hormones are produced by the cortex which include cortisol, corticosterone, aldosterone, and androgens. The medulla produces epinephrine and norepinephrine.1,2
The function of the adrenal gland is controlled by the hypothalamus-pituitary-adrenal axis (HPA-axis). The hypothalamus produces corticotrophin-releasing hormone (CRH) which stimulates the pituitary to produce adrenocorticotropic hormone (ACTH), which leads to stimulation of the adrenal itself. The negative feedback of the HPA-axis is caused by the glucocorticoids.3 In physiological situations in most species, ACTH is secreted pulsatile manner but can increase its production secondary to stress.
The ferret adrenal gland anatomy differs from many other mammals. In addition to the three traditional cortex layers, two other less prominent layers are also present; the zonae intermedia and juxtamedullaris.4 Although the functions are not completely understood, these layers may play a role in the development of adrenal gland disease in ferrets.5,6
The increased production of adrenal cortex hormones (i.e., hyperadrenocorticism) can be caused by hypertrophy and/or neoplasia. Several diseases can develop in mammals such as hyperaldosteronism or Conn’s syndrome (increased production of mineralocorticoids by the zona glomerulosa), hypercortisolism or Cushing’s syndrome (increased production of glucocorticoids by the zona fasciculata), or hyperandrogenism (increased production of androgens by the zona reticularis).
Hyperandrogenism, also commonly known as ferret adrenal gland disease, is the most common form of hyperadrenocorticism in pet ferrets. As previously stated, the distinct anatomy and physiology of the ferret adrenal gland may predispose this species to develop this disease; neuter at any age appears to influence its development.7,8
The most common clinical signs of hyperandrogenism in ferrets may include alopecia, increased sexual aggression, pruritus, vulvar swelling in females, and prostatomegaly and stranguria in males. Although the clinical signs may be suggestive of adrenal gland disease, additional confirmatory tests are necessary. Ultrasound is commonly used as it provides immediate results and the morphology of the gland appears to strongly correlate with the disease. On ultrasound, a rounded appearance of the gland, increased size at the cranial or caudal pole, heterogeneous structure, increased echogenicity, or signs of mineralization are strongly suggestive of adrenal gland disease.9 Other alternatives to diagnose this condition or further support the clinical diagnosis include measurement of circulating hormonal levels; estradiol, androstenedione, and 17a-hydroxyprogesterone. Elevation of these values in a neutered animal is supportive of adrenal disease; however, other conditions (e.g., ovarian remnant) may influence these results.10
Although surgical treatment has been described, currently, the most common treatment for this condition relies on gonadotropin-releasing hormone (GnRH) agonists (e.g., deslorelin, leuprolide), which cause down-regulation of GnRH receptors in the adenohypophysis. When surgical adrenalectomy was compared to medical management deslorelin implants, the medical management had longer periods free of clinical signs (16.5 mo, n=35) than surgical cases (13.6 mo, n=54).11
Pancreas
The pancreas is comprised of two sections, the endocrine and the exocrine pancreas. Disorders affecting the endocrine pancreas are the most relevant in ferrets. The endocrine pancreas contains the islets of Langerhans.1 The islets of Langerhans are composed of several cell types including glucagon secreting alpha cells, insulin secreting beta cells, somatostatin secreting delta cells, pancreatic polypeptide cells, and ghrelin producing epsilon cells.12-14 Many of the hormones produced by these cells are involved in glucose homeostasis, and diseases affecting it, such as insulinoma or diabetes mellitus, can cause glucose imbalances.13
Insulinomas
Insulinomas are functional beta cell tumors that secrete insulin indiscriminately and/or without normal physiological control, which typically leads to hypoglycemia.15,16 Insulinomas have been reported as the most common neoplasm in ferrets; approximately 25% of all neoplasms.10 Insulinomas in ferrets tend to be benign and nonmetastatic, although local metastases have been reported.17 It is suggested that ferrets may be predisposed to insulinomas because of an inappropriate diet, but there is no scientific evidence to support this theory.17
Clinical signs of insulinoma in a ferret are a consequence of the low circulating glucose levels. The most reported clinical signs include pawing at the mouth and/or nausea, “stargazing,” weakness most commonly affecting the hindlimbs, progressive weight loss, depression, lethargy, seizures and/or tremors, and coma. Many of the early signs may not be noted by the owners due to the slow progression of the clinical signs.
Although hypoglycemia is commonly found in ferrets with insulinoma, the diagnosis of hypoglycemia alone is not pathognomonic of insulinoma. Clinicians should consider other conditions that can result in hypoglycemia (e.g., sepsis, neoplasia, lab delay in assay based on shipment, anorexia) before making a clinical diagnosis of insulinoma. Additionally, the method used to measure glucose needs to be considered when evaluating the results. Handheld glucometers for humans or small animals have been shown to not be reliable in ferrets.18,19 Among the tested handheld glucometers, the AlphaTRAK 2 (Zoetis, Inc., Kalamazoo, MI) on a canine setting has been shown to have the greatest agreement.19 Nevertheless, glycemia should be confirmed with a laboratorial unit. Alternatively, a benchtop point-of-care chemistry analyzer using the hexokinase method (e.g., VetScan VS2 Chemistry Analyzer, Zoetis) for measurement of blood glucose concentration is recommended for rapid onsite results.20
Overall, glucose levels above 100 mg/dL are considered normal, while values below 70 mg/dL prior to any treatment are suggestive of hypoglycemia. Glucose values between 80 to 90 mg/dL are borderline low and should be monitored. Although not commonly performed and challenging to interpret, in cases of insulinoma, the glucose levels should be low and the insulin levels should be high. Normal insulin levels have been reported in ferrets.21 Measurement of fructosamine, a glycated protein used to assess glucose concentrations over the previous 1–3 weeks, has been diagnostically useful for dogs.22,23 However, in ferrets, no significant differences between the healthy and hypoglycemic ferrets were noted.24 Therefore, fructosamine concentration and fructosamine-albumin ratio do not appear useful to assess insulinoma-associated chronic hypoglycemia in ferrets.24 Diagnostic imaging such as ultrasound and computed tomography may be useful. Due to the small size of the neoplasia, nodules may not be identified. Nonetheless, these methodologies may allow for the evaluation of other diseases such as adrenal gland disease and lymphoma, and therefore be of value prior to exploring treatment options.
Treatment options include surgical or medical management. Surgical treatment includes nodulectomy and/or partial pancreatectomy. Surgical treatments have been compared to medical management (prednisolone and/or diazoxide) in one study.25 The longest mean disease-free period was achieved with the partial pancreatectomy (365 days; range 0–690) followed by nodulectomy (234 days; range 0–546).25 Medical management had fairly poor results with a mean disease-free period of 22 days (range 0–62) and mean survival time of 186 days (range 36–273).25 Although partial pancreatectomy has the best results, it is also the most invasive procedure and involves removal of 25 to 50% of the pancreas. Lastly, recurrence of insulinoma is possible and some cases may later develop diabetes mellitus.
Medical management can be performed using glucocorticoids (prednisolone or prednisone) or diazoxide. Glucocorticoids control the glucose levels by increasing hepatic gluconeogenesis, decreasing glucose uptake by peripheral tissues, and inhibiting insulin binding to its receptors. Diazoxide inhibits pancreatic insulin secretion by decreasing the intracellular release of ionized calcium, which subsequently prevents release of insulin from insulin granules, as well as by hepatic gluconeogenesis and glycogenolysis, and it decreases cellular glucose uptake.10 It is important to note that the inappropriate use of medical therapy in animals that do not have an insulinoma can lead to other conditions such as diabetes mellitus. In a case report of diabetes mellitus, the animal was treated with methylprednisolone acetate (unknown dosage, subcutaneous administrations) every 30 days for 2 years.26 Ultimately, this animal was diagnosed with diabetes mellitus.26
Diabetes Mellitus
Diabetes mellitus is the result of insulin deficiency (absolute or relative) and is the most common disease associated with the endocrine pancreas in dogs and cats. Type I diabetes is associated with the lack of insulin secretion while type II is associated with the lack of receptor response to insulin (insulin resistance).27 Both cases lead to decreased tissue utilization of glucose, accelerated hepatic glycogenolysis and gluconeogenesis, and accumulation of glucose in the circulation.
In ferrets, the most common cause of diabetes is iatrogenic, associated with surgical removal of an insulinoma. In these cases, the hyperglycemia may be transient, and insulin and glucose levels may normalize over time. The temporary low insulin levels may be caused by atrophy of the remaining insulin-secreting tissue that, due to the presence of the neoplastic nodule, was downregulated, or due to the removal of too much pancreatic tissue leaving the animal without sufficient pancreas to produce the necessary insulin. In the latter, treatment may be necessary as the animal does not have the physical capacity to produce sufficient amounts of insulin. Reports of spontaneous DM in the ferret are comparatively rare.28,29
Thyroid Gland
Hypothyroidism, low circulating thyroid hormones, has been reported in ferrets. In a case series of seven ferrets, typical clinical signs of hypothyroidism were reported; obesity, lethargy, inactivity, and excessive sleeping. The total thyroxine (TT4) were low and the animals had limited response on a thyroid-stimulating hormone (TSH) stimulation test.30 Another publication described a TSH stimulation test using a recombinant human TSH.31 Although not peer-reviewed, a hyperthyroid ferret was diagnosed using scintigraphic and treated with I131.32
References
1. Engelking L, Rebar A. Metabolic and Endocrine Physiology. CRC Press; 2012.
2. Hartman F, Brownell K. The hormone of the adrenal cortex. Exp Biol Med. 1930;27:938–939.
3. Behrend E. Canine hyperadrenocorticism. In: Feldman E, Nelson R, Reusch C, et al., eds. Canine and Feline Endocrinology. St Louis, MO: Elsevier; 2015:377–380.
4. Bielinska M, Parviainen H, Kiiveri S, et al. Review paper: origin and molecular pathology of adrenocortical neoplasms. Vet Pathol. 2009;46:194–210.
5. Miller C, Marini R, Fox J. Diseases of the endocrine system. In: Fox J, Marini R, eds. Biology and Diseases of the Ferret. 3rd ed. Ames, IA: Wiley-Blackwell; 2014:377–400.
6. Holmes RL. The adrenal glands of the ferret, Mustela putorius. J Anat. 1961;95:325–336.
7. Vinke C, van Deijk R, Houx B, et al. The effects of surgical and chemical castration on intermale aggression, sexual behaviour and play behaviour in the male ferret (Mustela putorius furo). Appl Anim Behav Sci. 2008;115:104–121.
8. Shoemaker NJ, Schuurmans M, Moorman H, et al. Correlation between age at neutering and age at onset of hyperadrenocorticism in ferrets. J Am Vet Med Assoc. 2000;216:195–197.
9. Kuijten AM, Schoemaker NJ, Voorhout G. Ultrasonographic visualization of the adrenal glands of healthy ferrets and ferrets with hyperadrenocorticism. J Am Anim Hosp Assoc. 2007;43:78–84.
10. Chen S. Advanced diagnostic approaches and current medical management of insulinomas and adrenocortical disease in ferrets (Mustela putorius furo). Vet Clin North Am Exot Anim Pract. 2010;13:439–452.
11. Lennox AM, Wagner R. Comparison of 4.7 mg deslorelin implants and surgery for the treatment of adrenocortical disease in ferrets. J Exotic Pet Med. 2012;21:332–335.
12. Elayat AA, el-Naggar MM, Tahir M. An immunocytochemical and morphometric study of the rat pancreatic islets. J Anat. 1995;186(Pt 3):629–637.
13. Andralojc KM, Mercalli A, Nowak KW, et al. Ghrelin-producing epsilon cells in the developing and adult human pancreas. Diabetologia. 2009;52:486–493.
14. Wierup N, Svensson H, Mulder H, et al. The ghrelin cell: a novel developmentally regulated islet cell in the human pancreas. Reg Peptides. 2002;107:63–69.
15. Lester NV, Newell SM, Hill RC, et al. Scintigraphic diagnosis of insulinoma in a dog. Vet Radiol Ultrasound. 1999;40:174–178.
16. Goutal CM, Brugmann BL, Ryan KA. Insulinoma in dogs: a review. J Am Anim Hosp Assoc. 2012;48:151–163.
17. Vinke CM, Schoemaker NJ. The welfare of ferrets (Mustela putorius furo T): a review on the housing and management of pet ferrets. Appl Anim Behav Sci. 2012;139:155–168.
18. Summa NM, Eshar D, Lee-Chow B, et al. Comparison of a human portable glucometer and an automated chemistry analyzer for measurement of blood glucose concentration in pet ferrets (Mustela putorius furo). Can Vet J. 2014;55:865.
19. Petritz OA, Antinoff N, Chen S, et al. Evaluation of portable blood glucose meters for measurement of blood glucose concentration in ferrets (Mustela putorius furo). J Am Vet Med Assoc. 2013;242:350–354.
20. Proulx M-P, Vergneau-Grosset C, Hébert J, et al. Comparison of a handheld point-of-care analyzer with a benchtop point-of-care chemistry analyzer for measurement of blood glucose concentration in client-owned ferrets (Mustela putorius furo). J Exot Pet Med. 2022.
21. Mann F, Stockham S, Freeman M, et al. Reference intervals for insulin concentrations and insulin: glucose ratios in the serum of ferrets. Scientifur. 1995;19:289–289.
22. Mellanby RJ, Herrtage ME. Insulinoma in a normoglycaemic dog with low serum fructosamine. J Small Anim Pract. 2002;43:506–508.
23. Thoresen SI, Aleksandersen M, Lønaas L, et al. Pancreatic insulin-secreting carcinoma in a dog: fructosamine for determining persistent hypoglycaemia. J Small Anim Pract. 1995;36:282–286.
24. Duhamelle A, Vlaemynck F, Loeuillet E, et al. Clinical value of fructosamine measurements and fructosamine-albumin ratio in hypoglycemic ferrets (Mustela putorius furo). J Exot Pet Med. 2018;27:103–107.
25. Weiss C, Williams B, Scott M. Insulinoma in the ferret: clinical findings and treatment comparison of 66 cases. J Am Anim Hosp Assoc. 1998;34:471–475.
26. 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.
27. Nelson R. Canine diabetes mellitus. In: Feldman E, Nelson R, Reusch C, et al., eds. Canine and Feline Endocrinology. St Louis, MO: Elsevier; 2015:213–217.
28. Benoit-Biancamano M-O, Morin M, Langlois I. Histopathologic lesions of diabetes mellitus in a domestic ferret. Can Vet J. 2005;46:895.
29. Boari A, Papa V, Di Silverio F, et al. Type 1 diabetes mellitus and hyperadrenocorticism in a ferret. Vet Res Commun. 2010;34:107–110.
30. Wagner R. Hypothyroidism in ferrets. In: Proceedings from the Assoc Exotic MamVet Conference. Oakland, CA; 2012:29–31.
31. Mayer J, Wagner R, Mitchell MA, et al. Use of recombinant human thyroid-stimulating hormone for thyrotropin stimulation testing in euthyroid ferrets. J Am Vet Med Assoc. 2013;243:1432–1435.
32. Vandermeulen E, Peremans K. Scintigraphic diagnosis and 131I treatment of hyperthyroidism in a ferret (Mustela putorius furo). In: Proceedings from the EVDI Annual Conference. 2013.