Explore how understanding of hypercortisolism has changed, and how today’s insights can shape diabetes and cardiometabolic care.

The following content is made possible due to educational grant support from Corcept Therapeutics. Content was developed independently by ADCES. 

Understanding the Full Spectrum of Hypercortisolism

Our understanding of hypercortisolism has evolved substantially since the initial report on Cushing syndrome nearly a century ago. The overt clinical case with moon facies, buffalo hump, and other distinctive features is actually a rare presentation, and just one facet of hypercortisolism. In the modern endocrinology perspective, hypercortisolism occurs on a spectrum that includes many more clinically less apparent signs, symptoms and conditions.

This section of the guide covers key points related to the evolution of our understanding of hypercortisolism, the relationship between elevated cortisol and diabetes, and the implications for cardiometabolic health.

Moving Beyond Traditional Definitions

In 1932, Dr. Harvey Cushing published a landmark report on pituitary adenomas that shaped what we think of today as the “classic” phenotype of Cushing syndrome, however, we now recognize hypercortisolism as a more diverse disease. 

While some people do present with classic Cushing syndrome features, many others will exhibit manifestations of hypercortisolism that may be easily overlooked in clinical practice. Patients may exhibit a broad spectrum of clinical features, from common, nonspecific symptoms (e.g., fatigue and depression) to metabolic comorbidities such as Type 2 diabetes (T2D) and hypertension.

Adopting a Broader Outlook on Hypercortisolism

By focusing too heavily on clinically overt features, we risk overlooking a much larger pool of people with hypercortisolism. While the “classic” Cushing syndrome presentation is quite rare, the clinically less apparent manifestations of hypercortisolism occur in 0.8% to 2.0% of adults in the general population, and are considerably more common in higher-risk groups. In people with well-managed T2D, the prevalence of hypercortisolism is as low as 2% to 3%. However, in people with T2D that is difficult to manage despite appropriate treatment, prevalence rates may be as high as 60%.

Key Causes of Hypercortisolism

As noted in the previous section, causes of persistently elevated cortisol can be endogenous (often via a hormone-secreting tumor) or exogenous (principally from exposure to glucocorticoid medications). However, hypercortisolism can be further classified according to whether it is dependent or independent of adrenocorticotropic hormone (ACTH), which activates adrenal glands to release cortisol.

Adrenal Causes of Hypercortisolism in T2D

For many patients with T2D and hypercortisolism, the underlying cause of elevated cortisol is often an adrenal source. Importantly, hypercortisolism caused by an adrenal source is associated with higher risk of cardiometabolic comorbidities. Some studies show an adrenal cause was identified in up to 88% of people with T2D and hypercortisolism. In a systematic review and meta-analysis including more than 100 people with T2D and endogenous hypercortisolism, imaging studies revealed adrenal tumors in 52% of cases. In an even larger data set, the CATALYST study of hypercortisolism in difficult-to-control T2D, adrenal imaging abnormalities were found in a substantial proportion of participants (nearly 35%, or 69 of 203 participants).

Impact of Hypercortisolism on Glycemic Outcomes and Metabolic Health

High levels of cortisol can have negative impacts on multiple organ systems and tissues, resulting in increased inflammation, elevated glucose and lipid levels, hypertension, among other consequences. Of note, glucose management can be negatively affected through multiple mechanisms. Endogenous hypercortisolism can contribute to increased insulin resistance, impairment of beta-cell function, and increased hepatic glucose output, all while inhibiting the insulin-stimulating effects of glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP).

Altogether, these negative impacts can make meeting glucose targets challenging, even with following treatment plans that would otherwise be effective. Even more importantly, however, the presence of hypercortisolism is linked to increased risk of cardiovascular disease and mortality among people with T2D.

Key Takeaways

• Hypercortisolism encompasses a spectrum, ranging from clinically overt, yet rare, cases to more common, clinically less apparent presentations associated with nonspecific symptoms and concerning metabolic complications.
• Clinically less apparent presentations of hypercortisolism are more prevalent among people with T2D that remains above target despite an appropriate treatment plan, particularly when other comorbidities are present.
• Hypercortisolism negatively impacts metabolic health by contributing to insulin resistance, impaired beta-cell function, and increased hepatic glucose output, and is linked to increased cardiovascular disease risk and mortality in people with T2D.
• In patients with T2D and endogenous hypercortisolism, the underlying cause is often an adrenal tumor, which is also associated with a higher risk of cardiometabolic comorbidities.
• Endogenous hypercortisolism should be considered as a possible underlying cause when diabetes remains difficult-to-manage despite the use of appropriate therapies.

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