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Home / Equine Research Bank / Int J Mol Sci / Cushing’s Disease in the Animal Kingdom: Translational...
International journal of molecular sciences2025; 26(17); 8626; doi: 10.3390/ijms26178626

Cushing’s Disease in the Animal Kingdom: Translational Insights for Human Medicine.

Abstract: Cushing's disease (CD) is a rare neuroendocrine disorder caused by ACTH-secreting pituitary adenomas, presenting significant diagnostic and therapeutic challenges. Given the evolutionary conservation of the hypothalamic-pituitary-adrenal axis, this review explores the translational value of spontaneous CD forms in dogs, horses, cats, small mammals, and rats, as well as of experimental models in mice, rats, and zebrafish. Dogs are the most studied, showing strong molecular and clinical similarities with human CD, making them valuable for preclinical drug and diagnostic research. While equine and feline CD are less characterized, they may provide insights into dopaminergic therapies and glucocorticoid resistance. Nevertheless, practical and ethical challenges limit the experimental use of companion animals. In preclinical research, mouse models are widely used to study hypercortisolism and test therapeutic agents via transgenic and xenograft strategies. Conversely, few studies are available on a zebrafish transgenic model for CD, displaying pituitary corticotroph expansion and partial resistance to glucocorticoid-negative feedback at the larval stage, while adults exhibit hypercortisolism resembling the human phenotype. Future transplantable systems in zebrafish may overcome several limitations observed in mice, supporting CD research. Collectively, these animal models, each offering unique advantages and limitations, provide a diverse toolkit for advancing CD research and improving human clinical outcomes.
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Publication Date: 2025-09-04 PubMed ID: 40943544PubMed Central: PMC12429187DOI: 10.3390/ijms26178626Google Scholar: Lookup
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Summary

This research summary has been generated with artificial intelligence and may contain errors and omissions. Refer to the original study to confirm details provided. Submit correction.

Cushing’s disease (CD) research benefits from studying various animal models that naturally or experimentally mimic the human condition, offering insights into disease mechanisms and potential treatments. This review highlights the comparative value of spontaneous and induced CD models across several species to enhance understanding and therapeutic development for human CD.

Overview of Cushing’s Disease and Its Challenges

  • Cushing’s disease (CD) is a rare neuroendocrine disorder caused by pituitary adenomas secreting excess ACTH.
  • The disease presents significant challenges in diagnosis and treatment in humans due to its complex nature.
  • The hypothalamic-pituitary-adrenal (HPA) axis, which regulates cortisol levels, is evolutionarily conserved across species, making animal models relevant for translational research.

Spontaneous Animal Models of Cushing’s Disease

  • Dogs:
    • Most extensively studied spontaneous model for CD.
    • Exhibit molecular and clinical features closely resembling human CD.
    • Highly valuable for preclinical testing of diagnostic tools and drugs.
  • Horses (Equine CD):
    • Less well characterized than dogs but show potential to inform on dopaminergic therapies targeting pituitary function.
    • May provide insights into glucocorticoid resistance mechanisms relevant to human CD.
  • Cats and Small Mammals:
    • Data on spontaneous CD is limited.
    • Could contribute knowledge about disease variability and treatment response in different physiological contexts.
  • Practical and ethical considerations often limit the use of companion animals like dogs and cats in experimental settings.

Experimental Animal Models

  • Mouse models:
    • Widely used for preclinical research due to ease of genetic manipulation.
    • Transgenic and xenograft strategies allow detailed study of hypercortisolism (excess cortisol production) and therapeutic response.
  • Rat models:
    • Employed in some experimental contexts, though less commonly than mice.
  • Zebrafish models:
    • Emerging as an innovative tool due to transparency and rapid development.
    • Transgenic zebrafish show pituitary corticotroph cell expansion and partial resistance to glucocorticoid-negative feedback during larval stages.
    • Adult zebrafish display hypercortisolism phenotypes akin to human CD.
    • Potential for developing transplantable systems to overcome limitations seen in rodent models.

Translational Value and Future Directions

  • Each animal model offers unique advantages:
    • Dogs provide high clinical and molecular similarity to humans.
    • Mice and rats allow for controlled experimental manipulation and mechanistic studies.
    • Zebrafish offer genetic tractability and novel imaging opportunities.
  • Limitations exist, particularly ethical constraints in companion animals and certain physiological differences in species.
  • Combining insights from multiple species models can accelerate discovery of diagnostics and therapeutics for human CD.
  • Future developments such as transplantable zebrafish models could provide refined platforms overcoming some limitations of rodent studies.

Conclusion

  • Animal models of Cushing’s disease, spanning spontaneous forms in domestic animals to engineered experimental models, form a diverse and powerful toolkit.
  • They facilitate in-depth understanding of CD pathophysiology and evaluation of novel treatments.
  • These translational insights hold promise for improving clinical outcomes in human patients suffering from this complex disorder.

Cite This Article

APA
Massardi E, Gaudenzi G, Carra S, Oldani M, Rybinska I, Persani L, Vitale G. (2025). Cushing’s Disease in the Animal Kingdom: Translational Insights for Human Medicine. Int J Mol Sci, 26(17), 8626. https://doi.org/10.3390/ijms26178626

Publication

International journal of molecular sciences
ISSN: 1422-0067
NlmUniqueID: 101092791
Country: Switzerland
Language: English
Volume: 26
Issue: 17
PII: 8626

Researcher Affiliations

Massardi, Elena
  • Department of Medical Biotechnology and Translational Medicine, University of Milan, 20129 Milan, Italy.
Gaudenzi, Germano
  • Laboratory of Geriatric and Oncologic Neuroendocrinology Research, IRCCS, Istituto Auxologico Italiano, Cusano Milanino, 20095 Milan, Italy.
Carra, Silvia
  • Laboratory of Endocrine and Metabolic Research, IRCCS, Istituto Auxologico Italiano, Cusano Milanino, 20095 Milan, Italy.
Oldani, Monica
  • Laboratory of Geriatric and Oncologic Neuroendocrinology Research, IRCCS, Istituto Auxologico Italiano, Cusano Milanino, 20095 Milan, Italy.
Rybinska, Ilona
  • Department of Medical Biotechnology and Translational Medicine, University of Milan, 20129 Milan, Italy.
Persani, Luca
  • Department of Medical Biotechnology and Translational Medicine, University of Milan, 20129 Milan, Italy.
  • Laboratory of Endocrine and Metabolic Research, IRCCS, Istituto Auxologico Italiano, Cusano Milanino, 20095 Milan, Italy.
Vitale, Giovanni
  • Department of Medical Biotechnology and Translational Medicine, University of Milan, 20129 Milan, Italy.
  • Laboratory of Geriatric and Oncologic Neuroendocrinology Research, IRCCS, Istituto Auxologico Italiano, Cusano Milanino, 20095 Milan, Italy.

MeSH Terms

  • Animals
  • Humans
  • Pituitary ACTH Hypersecretion / metabolism
  • Pituitary ACTH Hypersecretion / pathology
  • Pituitary ACTH Hypersecretion / diagnosis
  • Pituitary ACTH Hypersecretion / etiology
  • Disease Models, Animal
  • Translational Research, Biomedical
  • Dogs
  • Mice
  • Zebrafish
  • Rats
  • Cats
  • Horses

Grant Funding

  • European Union - Next Generation EU, Mission 4 Component 1, CUP G53D23005000006. / Ministero dell'università e della ricerca

Conflict of Interest Statement

The authors declare no conflicts of interest.

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