Cushing’s syndrome: a new approach to assess the individual impact of cortisol excess

Cushing’s syndrome is a condition characterised by an excess of cortisol and can be caused by chronic corticosteroid treatment (exogenous Cushing’s syndrome) or by tumours, generally benign, that produce cortisol (endogenous Cushing’s syndrome). Endogenous Cushing’s syndrome is a rare condition whose causes may be dependent on the adrenocorticotropic hormone (ACTH) – commonly a pituitary adenoma (Cushing’s disease) – or independent of ACTH – usually a benign adrenal adenoma. Overall, the annual incidence of endogenous Cushing’s syndrome varies between 1.8 and 8 cases per million inhabitants. Exogenous Cushing’s syndrome, on the other hand, is much more frequent, as corticosteroids are drugs commonly used for a wide range of diseases. Regardless of the cause of Cushing’s syndrome, chronic exposure to excess cortisol leads to the development of numerous complications, including high blood pressure, weight gain, diabetes mellitus, metabolic syndrome, immune system alterations, osteoporosis, and neurocognitive disorders. These comorbidities are associated with impaired quality of life and increased mortality.

The diagnosis and follow-up of patients is based on hormonal tests assessing the level of excess cortisol in blood and urine and on dynamic tests aimed at identifying the origin (pituitary or adrenal) of the excess cortisol. However, none of the available instruments have proven to be fully accurate due to the varying pattern of cortisol secretion and the limitations of enzyme immunoassays used in laboratories for cortisol determination. Furthermore, the clinical effects of chronic exposure to excess cortisol depend not only on the intensity and duration of the excess, but also on peripheral metabolism and individual sensitivity, which are not estimated by laboratory hormone tests. As a result, there is frequent evidence in clinical practice of high variability among patients with Cushing’s syndrome in terms of the development of complications (patients with the same level of cortisol excess are exposed to different complications with varying degrees of severity). Therefore, the management of these patients remains challenging as it is difficult to identify the patients most at risk.

To date, there are no instruments available in clinical practice that can correctly assess the individual effects of excess cortisol. A study conducted by Dr. Maria Francesca Birtolo – a 4th year Endocrinology resident at Humanitas University – during her research period in the ‘Genomic and signalling of endocrine tumours’ team at the Cochin Institut in Paris, and published in the leading scientific journal European Journal of Endocrinology in July 2024, explored the impact of excess cortisol on the transcriptome using blood samples from patients with hypercortisolism. This study demonstrated how new approaches, based on omics analysis, can predict the level of excess cortisol with excellent accuracy, overcoming the limitations of currently available laboratory tests. The use of the identified molecular markers can contribute to a precise risk profile characterisation of patients with hypercortisolism, improving their clinical management.