Exotis ISSN 2398-2985

Ferrets

Hyperadrenocorticism / hyperandrogenism

Contributor(s): Cathy Johnson-Delaney, Sarah Pellett

Introduction

  • The most common form of adrenal disease in ferrets is hyperadrenocorticism, which is characterized by a hyperfunction of the adrenal cortex.
  • The adrenal cortex is built up out of three layers; in principle, distinct syndromes may arise from hyperfunctioning of each of these layers:
    • Hyperaldosteronism or Conn’s syndrome, ie increased production of mineralocorticoids by the zona glomerulosa.
    • Hypercortisolism or Cushing’s syndrome, ie increased production of glucocorticoids by the zona fasciculata.
    • Hyperandrogenism, ie increased production of androgens by the zona reticularis.
  • In pet ferrets, hyperandrogenism is the most common form of hyperadrenocorticism, resulting in increased plasma concentrations of androstenedione, 17-hydroxyprogesterone and oestradiol.
  • In rare instances, hypercortisolism and hyperaldosteronism may also be seen.
  • A unilateral enlargement of the adrenal gland (without atrophy of the contralateral adrenal gland) appears to be most common (present in approximately 85% of ferrets). Bilateral enlargement may be found in the remainder of cases.
  • Adrenal tumors have been histologically classified as (nodular) hyperplasia, adenoma and adenocarcinoma. The histological diagnosis, however, does not provide any prognostic information, nor does it infer information about the functionality of the tumor.
  • Cause: neutering, housing ferrets indoors and genetic background.
  • Signs: symmetrical alopecia, pruritus.
  • Diagnosis: clinical signs, hormone analysis, urinalysis, radiography, ultrasonography, CT, preputial cytology.
  • Treatment: surgical removal of adrenal gland(s), cryosurgery, injection with alcohol, GnRH agonists.
  • Prognosis: fair.

Pathogenesis

Etiology

  • Different etiologies have been suggested for the high incidence of hyperadrenocorticism in ferrets; these include (early) neutering of ferrets, housing ferrets indoors and genetic background.
  • Pituitary adenomas have been detected in ferrets with adrenal tumors, however these tumors did not seem to secrete any of the pituitary hormones, thereby characterizing them as clinically non-functional gonadotrope tumors. Thus, in contrast to dogs with Cushing’s disease, pituitary tumors do not seem to be associated with hyperadrenocorticism in ferrets.

Pathophysiology

  • An exact incidence is not known, but it has been reported that up to 95% of ferrets presented for postmortem examination suffered from adrenal pathology.

(Early) neutering

  •  In the last two decades, a growing amount of evidence has been gathered supporting the hypothesis that the high incidence of hyperadrenocorticism in pet ferrets is the result of neutering. This evidence has shown that neutering results in increased concentrations of gonadotrophins (due to the loss of negative feedback from the gonads), which stimulate the LH receptors that are present in the adrenal cortex, eventually leading to the development of an adrenocortical neoplasm.
  • The prevalence of the disease appears similar in the Netherlands and the USA, where ferrets are neutered at a different age.
  • Based on these findings a significant correlation has been found between the age at neutering and the age at onset of hyperandrogenism. In addition, they indicate that age of neutering may be of less importance for the development of adrenocortical tumors than neutering itself.
  • Although less common, adrenal disease may also occur in intact ferrets. In these ferrets, diagnosing the disease may be more difficult as the clinical signs with which the ferrets present are difficult to differentiate from the normal hormonally driven physiological changes that occur in healthy intact ferrets.

Housing ferrets indoors

  • In line with the hypothesis that increased gonadotrophin levels induced by neutering pose an increased risk for developing adrenal gland tumors, indoor housing may also pose as a risk factor for developing increased gonadotrophins and subsequent hyperadrenocorticism.
  • Ferrets that are kept indoors will generally be exposed to more hours of light per day than ferrets that are housed outdoors. As a result, melatonin will be suppressed for longer periods of time, which – as a result of loss of inhibitory action of melatonin; subsequently results in elevated gonadotrophin plasma concentrations and increased risk of developing adrenal gland disease in both neutered and intact ferrets.

Genetic background

  • As ferrets have a high incidence of both insulinomas and adrenal gland tumors, it has been hypothesized that the hereditary changes causing multiple endocrine neoplasms in humans (MEN1, MEN2a and MEN2b), could also play a role in the etiology of the formation of adrenal tumors in ferrets.
  • Since many of the ferrets in the USA come from the same breeding facility, thereby sharing a similar genetic background, it is possible that in the USA the limited genetic variation of ferrets poses an explanation for the high incidence of the disease.
  • Thus far, however, no proof for a genetic predisposition has been found. In addition, ferrets in the Netherlands supposedly have a different genetic background from the ferrets in the USA. It therefore remains questionable if a genetic predisposition indeed is involved.
  • Pituitary adenomas have been detected in ferrets with adrenal tumors. However, these tumors did not seem to secrete any of the pituitary hormones, thereby characterizing them as clinically non-functional gonadotrope tumors. Thus, in contrast to dogs with Cushing’s disease, pituitary tumors do not seem to be associated with hyperadrenocorticism in ferrets.

Timecourse

  • In a recent study, 80% of 125 surgically neutered ferrets developed adrenal cortical disease over a period of 8 years.

Epidemiology

  • An exact incidence is not known, but it has been reported that up to 95% of ferrets presented for post mortem examination suffered from adrenal pathology.
  • In a recent study, 80% of 125 surgically neutered ferrets developed adrenal cortical disease over a period of 8 years.

Diagnosis

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Treatment

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Prevention

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Outcomes

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Further Reading

Publications

Refereed papers

  • Recent references from PubMed and VetMedResource.
  • Van Zeeland Y R A, Pabon M, Roest J & Schoemaker N J (2014) Use of a GnRH agonist implant as alternative for surgical neutering in pet ferrets. Vet Rec 175 (3), 66 PubMed.
  • Miller L A, Fagerstone K A, Wagner R A & Finkler M (2013) Use of a GnRH vaccine, GonaConTM, for prevention and treatment ofadrenocortical disease (ACD) in domestic ferrets. Vaccine 31 (41), 4619-4623 PubMed.
  • Lennox A M & Wagner R A (2012) Comparison of 4.7-mg deslorelin implants and surgery for the treatment of adrenocortical disease in ferrets. J Exotic Pet Med 21 (4), 332-335 VetMedResource.
  • Chen S (2010) Advanced diagnostic approaches and current medical management of insulinomas and adrenocortical disease in ferrets (Mustela putorius furo). Vet Clin North Am Exotic Anim Pract 13 (3), 439-452 PubMed.
  • Wagner R A, Finkler M R, Fecteau K A & Trigg T E (2009) The treatment of adrenal cortical disease in ferrets with 4.7-mg deslorelin acetate implants. J Exotic Pet Med 18 (2), 146-152 VetMedResource.
  • Schoemaker N J, Kuijten A M & Galac S (2008) Luteinizing hormone-dependent Cushing’s syndrome in a pet ferret (Mustela putorius furo). Domest Anim Endocrinol 34 (3), 278-283 PubMed.
  • Kuijten A M, Schoemaker N J & Voorhout G (2007) Ultrasonographic visualization of the adrenal glands of healthy ferrets and ferrets with hyperadrenocorticism. J Am Anim Hosp Assoc 43 (2), 78-84 PubMed.
  • Ramer J C, Benson K G, Morrisey J K, O'Brien R T & Paul-Murphy J (2006) Effects of melatonin administration on the clinical course of adrenocortical disease in domestic ferrets. J Am Vet Med Assoc 229 (11), 1743-1748 PubMed.
  • Wagner R A, Piché C A, Jöchle W & Oliver JW (2005) Clinical and endocrine responses to treatment with deslorelin acetate implants in ferrets with adrenocortical disease. Am J Vet Res 66 (5), 910-914 PubMed.
  • Schoemaker N J, Wolfswinkel J et al (2004) Urinary glucocorticoid excretion in the diagnosis of hyperadrenocorticism in ferrets. Domest Anim Endocrinol 27 (1), 13-24 PubMed.
  • Schoemaker N J, van der Hage M H, Flik G, Lumeij J T & Rijnberk A (2004) Morphology of the pituitary gland in ferrets (Mustela putorius furo) with hyperadrenocorticism. J Comp Pathol 130 (4), 255-265 PubMed.
  • Schoemaker N J, Teerds K J et al (2002) The role of luteinizing hormone in the pathogenesis of hyperadrenocorticism in neutered ferrets. Mol Cell Endocrinol 197 (1), 117-125 PubMed.
  • Wagner R A, Bailey E M, Schneider J F & Oliver J W (2001) Leuprolide acetate treatment of adrenocortical disease in ferrets. J Am Vet Med Assoc 218 (8), 1272-1274 PubMed.
  • Schoemaker N J, Schuurmans M, Moorman H & Lumeij J T (2000) Correlation between age at neutering and age at onset of hyperadrenocorticism in ferrets. J Am Vet Med Assoc 216 (2), 195-197 PubMed.
  • Neuwirth L, Collins B, Calderwood-Mays, M & Tran T (1997) Adrenal ultrasonography correlated with histopathology in ferrets. Vet Radiol Ultrasound 38 (1), 69-74 PubMed.
  • Rosenthal K L (1997) Adrenal gland disease in ferrets. Vet Clin North Am Small Anim Pract 27 (2), 401-418 PubMed.
  • Weiss C A & Scott M V (1997) Clinical aspects and surgical treatment of hyperadrenocorticism in the domestic ferret: 94 cases (1994–1996). J Am Anim Hosp Assoc 33 (6), 487-493 VetMedResource.
  • O’Brien R T, Paul-Murphy J & Dubielzig R R (1996) Ultrasonography of adrenal glands in normal ferrets. Vet Radiol Ultrasound 37 (6), 445 VetMedResource.
  • Rosenthal K L, Peterson M E et al (1993) Hyperadrenocorticism associated with adrenocortical tumour or nodular hyperplasia of the adrenal gland in ferrets: 50 cases (1987-1991). J Am Vet Med Assoc 203 (2), 271-275 PubMed.
  • Rosenthal K L, Peterson M E, Quesenberry K E & Lothrop C D (1993) Evaluation of plasma cortisol and corticosterone responses to synthetic adrenocorticotropic hormone administration in ferrets. Am J Ve Res 54 (1), 29-31 PubMed.

Other sources of information

  • Schoemaker N J & van Zeeland Y R A (2017) Disorders of the Endocrine System. In: Johnson-Delaney C A. CRC Press, USA. pp 191-218.
  • Miller C M, Marini R P & Fox J G (2014) Diseases of the Endocrine System. In: Biology and Diseases of the Ferret. 3rd edn. Eds: Fox J G & Marini R P. Wiley Blackwell, Ames, USA. pp 377-400.
  • Rosenthal K L & Wyre N R (2012) Endocrine Diseases. In: Ferrets, Rabbits and Rodents: Clinical Medicine and Surgery. 3rd edn Eds: Quesenberry K E & Carpenter J E. Elsevier, St. Louis, USA. pp 86-102.


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