Endocrinology2018; 159(11); 3791-3800; doi: 10.1210/en.2018-00726

Dysregulation of Cortisol Metabolism in Equine Pituitary Pars Intermedia Dysfunction.

Abstract: Equine Cushing disease [pituitary pars intermedia dysfunction (PPID)] is a common condition of older horses, but its pathophysiology is complex and poorly understood. In contrast to pituitary-dependent hyperadrenocorticism in other species, PPID is characterized by elevated plasma ACTH but not elevated plasma cortisol. In this study, we address this paradox and the hypothesis that PPID is a syndrome of ACTH excess in which there is dysregulation of peripheral glucocorticoid metabolism and binding. In 14 horses with PPID compared with 15 healthy controls, we show that in plasma, cortisol levels and cortisol binding to corticosteroid binding globulin were not different; in urine, glucocorticoid and androgen metabolites were increased up to fourfold; in liver, 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) expression was reduced; in perirenal adipose tissue, 11β-HSD1 and carbonyl reductase 1 expression was increased; and tissue cortisol levels were not measurably different. The combination of normal plasma cortisol with markedly enhanced urinary cortisol metabolite excretion and dysregulated tissue-specific steroid-metabolizing enzymes suggests that cortisol clearance is increased in horses with PPID. We infer that the ACTH excess may be compensatory and pituitary pathology and autonomous secretion may be a secondary rather than primary pathology. It is possible that successful therapy in PPID may be targeted either at lowering ACTH or, paradoxically, at reducing cortisol clearance.
Publication Date: 2018-10-06 PubMed ID: 30289445PubMed Central: PMC6202856DOI: 10.1210/en.2018-00726Google Scholar: Lookup
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  • Journal Article
  • Research Support
  • Non-U.S. Gov't

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.

This research investigates the dysregulation of cortisol metabolism in equine Cushing disease (pituitary pars intermedia dysfunction – PPID), which is a common condition in older horses. Interestingly, the disease is characterized by elevated plasma ACTH but not elevated plasma cortisol. This study offers evidence that cortisol clearance is increased in horses with PPID, suggesting it might be possible to treat PPID by reducing either ACTH or cortisol clearance.

Understanding Pituitary Pars Intermedia Dysfunction (PPID)

  • PPID, also known as equine Cushing disease, is a common condition in older horses. It involves the pituitary gland, which is responsible for releasing hormones like ACTH (adrenocorticotropic hormone).
  • Unlike other forms of hyperadrenocorticism, where cortisol (a stress hormone) levels are high, horses with PPID have elevated plasma ACTH levels but not elevated plasma cortisol levels. This breaks from the typical pattern and suggests a different underlying pathophysiology for PPID.

Methods and Findings of the Study

  • The study compared 14 horses with PPID to 15 healthy horses. It measured several variables related to cortisol metabolism and ACTH levels in different body fluids and tissues.
  • Despite the elevated ACTH in horses with PPID, plasma cortisol levels and cortisol binding to corticosteroid binding globulin were not different in comparison to healthy horses. This suggests that ACTH’s usual role in elevating cortisol levels may be disrupted in horses with PPID.
  • Researchers noted a fourfold increase in glucocorticoid and androgen metabolites in the urine of horses with PPID and found a reduced expression of an enzyme (11β-HSD1) in the liver.
  • The expression of 11β-HSD1 and carbonyl reductase 1 was found to be increased in perirenal adipose tissue of PPID-affected horses, indicating abnormal tissue-specific steroid metabolism. However, tissue cortisol levels remained the same.

Implications of the Findings

  • The observed evidence points towards increased cortisol clearance in horses with PPID, which could help explain the simultaneous finding of high ACTH levels and normal cortisol levels.
  • The researchers propose that the excess ACTH may be a compensatory response, trying to stimulate more cortisol production in the face of increased cortisol clearance.
  • This finding shifts the perspective on the pituitary pathology in PPID, suggesting it might be a secondary rather than primary pathology.
  • In terms of treatment strategies, the researchers suggest that successful therapy may be achieved by aiming to lower ACTH or, paradoxically, reducing cortisol clearance.

Cite This Article

APA
Morgan RA, Keen JA, Homer N, Nixon M, McKinnon-Garvin AM, Moses-Williams JA, Davis SR, Hadoke PWF, Walker BR. (2018). Dysregulation of Cortisol Metabolism in Equine Pituitary Pars Intermedia Dysfunction. Endocrinology, 159(11), 3791-3800. https://doi.org/10.1210/en.2018-00726

Publication

ISSN: 1945-7170
NlmUniqueID: 0375040
Country: United States
Language: English
Volume: 159
Issue: 11
Pages: 3791-3800

Researcher Affiliations

Morgan, Ruth A
  • University/British Heart Foundation Centre for Cardiovascular Science, The Queen's Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom.
  • Royal (Dick) School of Veterinary Studies, University of Edinburgh, Easter Bush Campus, Midlothian, United Kingdom.
Keen, John A
  • Royal (Dick) School of Veterinary Studies, University of Edinburgh, Easter Bush Campus, Midlothian, United Kingdom.
Homer, Natalie
  • University/British Heart Foundation Centre for Cardiovascular Science, The Queen's Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom.
Nixon, Mark
  • University/British Heart Foundation Centre for Cardiovascular Science, The Queen's Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom.
McKinnon-Garvin, Anna M
  • Royal (Dick) School of Veterinary Studies, University of Edinburgh, Easter Bush Campus, Midlothian, United Kingdom.
Moses-Williams, Jodie A
  • Royal (Dick) School of Veterinary Studies, University of Edinburgh, Easter Bush Campus, Midlothian, United Kingdom.
Davis, Sarah R
  • Royal (Dick) School of Veterinary Studies, University of Edinburgh, Easter Bush Campus, Midlothian, United Kingdom.
Hadoke, Patrick W F
  • University/British Heart Foundation Centre for Cardiovascular Science, The Queen's Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom.
Walker, Brian R
  • University/British Heart Foundation Centre for Cardiovascular Science, The Queen's Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom.
  • Institute of Genetic Medicine, Newcastle University, International Centre for Life, Newcastle upon Tyne, United Kingdom.

MeSH Terms

  • 11-beta-Hydroxysteroid Dehydrogenase Type 1 / metabolism
  • Adipose Tissue / metabolism
  • Adrenocorticotropic Hormone / metabolism
  • Androgens / metabolism
  • Androgens / urine
  • Animals
  • Carbonyl Reductase (NADPH) / metabolism
  • Case-Control Studies
  • Glucocorticoids / metabolism
  • Glucocorticoids / urine
  • Horse Diseases / metabolism
  • Horses
  • Hydrocortisone / metabolism
  • Hydrocortisone / urine
  • Liver / metabolism
  • Pituitary ACTH Hypersecretion / metabolism
  • Pituitary ACTH Hypersecretion / veterinary
  • Pituitary Gland, Intermediate / metabolism
  • Transcortin / metabolism

Grant Funding

  • 206587/Z/17/Z / Wellcome Trust
  • ISSF2 / Wellcome Trust
  • R42126/82976 / Biotechnology and Biological Sciences Research Council
  • Wellcome Trust
  • FS/18/20/33449 / British Heart Foundation
  • RG/11/4/28734 / British Heart Foundation

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