Pituitary tumours are among the most common forms of intracranial tumours in humans. Despite this, traditional models of pituitary disease have predominantly relied upon induced tumorigenesis in rodents or fish. These models can be genetically tractable, and have helped our understanding of candidate gene involvement in the development of pituitary tumours. However, a combination of their tightly controlled husbandry conditions and the lack of genetic diversity in their backgrounds has led to increasing interest in uncovering spontaneous models of disease – and the animal kingdom has not disappointed.

SPONTANEOUS TUMOURS IN OTHER ANIMALS

The spontaneous development of pituitary tumours has been identified in numerous animal species, including birds, cats, dogs, horses and monkeys. In some of these species, pituitary tumours are predominantly identified at necropsy. However, in others, active pituitary disease presents through a broad range of clinical signs that strongly phenocopy symptoms of human patients with pituitary tumours, such as poorly controlled type 2 diabetes mellitus, polydipsia, polyuria, hunger, seizures and impaired cognitive function.

The most common functional pituitary neuroendocrine tumours (PitNETS) treated by veterinarians are somatotrophinomas (over-secreting growth hormone) and corticotrophinomas (over-secreting adrenocorticotrophin (ACTH)). These animal models of acromegaly (hypersomatotrophism) and Cushing’s disease (hyperadrenocorticism) present in some companion animals more commonly that others. Cats develop acromegaly far more frequently than dogs, whereas pituitary-dependent Cushing’s disease is the most common cause of cortisol excess in the dog population. These tumour types share similar features to those affecting humans, such as typically presenting as a local pituitary disease, and being challenging to medically manage. It turns out that our ‘best friends’ can help us understand even more about ourselves.

CANINE PITUITARY STUDIES

Dogs have provided some of the fundamental data that describe the link between the pituitary gland and metabolism. In the early 20th century, Bernardo Houssay and colleagues used hypophysectomy (surgical removal of the pituitary gland) to reveal the influence of the pituitary on the function of peripheral endocrine organs (such as the adrenal, thyroid and pancreas). These studies ultimately led to a Nobel Prize in Physiology or Medicine in 1947.

Pathological descriptions of pituitary lesions in dogs were made throughout the 20th century, and included cases of pituitary dwarfism as well as functional pituitary tumours. Pituitary disease is relatively common in dogs, with pituitary abnormalities being present in approximately 26% of dogs at the time of death (including cysts, neoplasias, carcinomas and hypophysitis),¹ and ACTH-secreting pituitary tumours are the most common form of clinically relevant pituitary disease in dogs. So what, if anything, can they teach us?

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Figure. Left: miniature schnauzer with an ACTH-secreting pituitary tumour. Note the poor coat condition due to too much cortisol. Middle and right: recovery post-hypophysectomy. ©Joe Fenn

INSIGHTS INTO GENETICS

Certain dog breeds are predisposed to Cushing’s disease (e.g. bichon frisé, border terrier, miniature schnauzer),² and strong genetic susceptibility has been identified in breed lines, such as in a family of Dandie Dinmont terriers described in Journal of Endocrinology.³ As our understanding of the canine genome improves, we can take advantage of these spontaneous models of pituitary disease to better inform treatment plans, and also look at the aetiology of tumour susceptibility.

Indeed, recent whole exome sequencing studies have taken a comparative approach to identify novel candidate genes involved in Cushing’s disease in humans and dogs, such as the transcriptional coactivator, MAMLD1.⁴ Furthermore, dogs with pituitary-dependent Cushing’s were instrumental in confirming the role of the transcription factor Tpit in corticotroph development,⁵ as well as uncovering the importance of Pax7 in mediating Tpit-induced differentiation of corticotrophs and melanotrophs.⁶ In common with human patients with Cushing’s disease, canine corticotroph tumours express PTTG1, and the expression level is negatively associated with disease-free interval.⁷ Most recently, canine pituitary organoid cultures have been established from patients with Cushing’s disease that provide a dynamic, 3D model system to perform techniques such as gene therapy and drug screenings, to enhance our understanding of corticotroph tumours.⁸

DIFFERENT CLINICAL APPROACHES

In many ways, the clinical manifestations of canine pituitary disease faithfully reproduce these endocrine disorders in the human population, and the major objective in treating these clinical signs is the reduction of cortisol. Here, treatment paradigms for dogs and humans with Cushing’s disease differ – canine patients are medically treated to reduce adrenal production of cortisol, with drugs such as trilostane, mitotane and ketoconazole. Working via different mechanisms, these compounds commonly reduce cortisol production, but do not deal with the pituitary tumour which can progress in size over time.

The most effective treatment of Cushing’s disease in dogs is neurosurgery. At present, very few centres around the world (e.g. the Royal Veterinary College in London, UK, and centres in Utrecht in The Netherlands and Washington State in the USA) have surgeons and medical teams capable of performing hypophysectomy, and of managing the dogs post-operatively. This is quite remarkable, considering a similar surgical approach was first used over 100 years ago to demonstrate the role of the pituitary in canine metabolic function. We hope that, in due course, hypophysectomy will become a more accessible procedure for companion animals with pituitary disease, as long term survival rates for these surgically treated Cushing’s patients can be up to five years.

In the UK alone, there are over 13 million dogs living with their accompanying humans, experiencing the same environmental exposures, and having lifestyles that often mimic our own (well, almost). Dogs undergoing hypophysectomy are typically treatment-naïve for pituitary-targeted management of their condition prior to surgery, so there is an opportunity for us to understand the cause of these tumours without interference from previous medical intervention. As we strive to better understand the debilitating effects of PitNETs in the human population, we would do well to look at companion animals to help us out. After all, there has never been a more relevant time to focus on a One Health approach to tackle globally relevant diseases.

CHRISTOPHER J SCUDDER
Senior Lecturer in Small Animal Internal Medicine, Royal Veterinary College, London

ROBERT C FOWKES
Professor of Comparative Endocrinology and Chair of Small Animal Clinical Sciences, Michigan State University College of Veterinary Medicine, East Lansing, MI, USA

REFERENCES

1. Polledo L et al. 2018 Veterinary Pathology 55 880–888.
2. Schofield I et al. 2021 Journal of Small Animal Practice 63 265–274.
3. Scholten-Sloof BE et al. 1992 Journal of Endocrinology 135 535–542.
4. Wang A et al. 2021 BMC Endocrine Disorders 21 185.
5. Hanson JM et al. 2007 Domestic Animal Endocrinology 34 217–222.
6. Budry L et al. 2012 Genes & Development 23 2299–2310.
7. Vastenhout N et al. 2018 Veterinary Journal 240 19–21.
8. Sanders K et al. 2021 Journal of the Endocrine Society 5 (Suppl 1) A533.