By Samantha Pederson, PA-C
Hypercortisolemia has been traditionally conceptualized as Cushing Disease with classic buzz word features such as moon facies, “buffalo hump” (dorsal fat pad), striae, and hirsutism. However, leading endocrinologists are beginning to shift their suggestions on which patients may warrant work up for cortisol excess, and it doesn’t look like a textbook Cushing patient.
The etiology of hypercortisolism includes Cushing Disease (ACTH secreting pituitary tumor), ectopic ACTH secreting tumors (such as lung carcinoma), iatrogenic Cushing Syndrome (exogenous use of glucocorticoids), adrenocortical adenomas or carcinomas, and adrenal hyperplasia[1]. In these conditions, chronic excess of glucocorticoid exposure leads to disruption of a multitude of bodily functions and contributes to disease processes such as insulin resistance and type 2 diabetes, obesity, cardiovascular disease, hypertension, osteoporosis, and mental health disorders[2]. The effects of glucocorticoid exposure on GLP-1 production is particularly interesting. Studies have consistently shown that cortisol exposure leads to islet cell dysfunction and significant decrease in GLP-1 production[3], which is counterproductive and renders the clinical use of GLP-1 agonists such as semaglutide and tirzepatide (GLP-1/GIP) nearly ineffective.
GLP-1 agonists have been shown to achieve 15-20% weight loss in the majority of patients, so what happens when we run into the occasional patient who is a GLP-1 non-responder? As we titrate to the highest dose of these medications, but the patient cannot achieve weight loss or A1C control, do we chalk it up to noncompliance or could there be more to the story? Many leading endocrinologists are suggesting the latter. In a panel discussion held by Corcept Pharmaceuticals, endocrinologists recommend that the most challenging patients not achieving goals on multiple anti-diabetic treatments, especially those with comorbid hypertension, central obesity, osteoporosis, or depression, should be considered for further evaluation of hypercortisolism even in the absence of classic Cushing syndrome symptoms such as moon facies and dorsal fat pad[1]. They recommend attempting to work up an adrenal etiology of excess cortisol, which includes serum ACTH, DHEAs, overnight dexamethasone suppression test with cutoff of 1.8mcg/dL[2], and ultimately adrenal imaging[3]. Multiple case studies have shown improved A1C, weight loss (especially central adiposity), and blood pressure control once hypercortisolism is corrected, although the degree of improvement needs further study. More research needs to be done and guidelines have yet to be established, but as clinicians seeking to understand obesity medicine, this is a step in the right direction for some of our most challenging patients.
[1] Nieman, Lynnette, et al. “Causes and Pathophysiology of Cushing Syndrome.” Www.uptodate.com, Nov. 2022, www.uptodate.com/contents/causes-and-pathophysiology-of-cushing-syndrome?sectionName=Ectopic%20ACTH%20syndrome&search=hypercortisolism&topicRef=143&anchor=H9&source=see_link#H9. Accessed 17 Jan. 2024.
[2] Nieman, Lynnette, et al.“Epidemiology and Clinical Manifestations of Cushing Syndrome.” Www.uptodate.com, www.uptodate.com/contents/epidemiology-and-clinical-manifestations-of-cushing-syndrome?search=hypercortisolism&source=search_result&selectedTitle=3~150&usage_type=default&display_rank=3#H588675336. Accessed 17 Jan. 2024.
[3] Kappe, Camilla, et al. “Glucocorticoids Suppress GLP-1 Secretion: Possible Contribution to Their Diabetogenic Effects.” Clinical Science, vol. 129, no. 5, 11 June 2015, pp. 405–414, https://doi.org/10.1042/cs20140719. Accessed 27 Jan. 2020.
[4] Difficult-To-Control Diabetes: Is Cortisol at Play?” Www.mdedge.com, Oct. 2023, www.mdedge.com/endocrinology/article/264990/difficult-control-diabetes-cortisol-play. Accessed 17 Jan. 2024.
[5] Lacroix, André, and Hershel Raff. “Dexamethasone Suppression Tests.” Www.uptodate.com, Dec. 2023, www.uptodate.com/contents/dexamethasone-suppression-tests?search=dexamethasone%20suppression%20test&source=search_result&selectedTitle=1~29&usage_type=default&display_rank=1#H5. Accessed 17 Jan. 2024.
[6] Young, William F . “Evaluation and Management of the Adrenal Incidentaloma.” Www.uptodate.com, 2023, www.uptodate.com/contents/evaluation-and-management-of-the-adrenal-incidentaloma?search=adrenal%20adenoma&source=search_result&selectedTitle=1~54&usage_type=default&display_rank=1#H17. Accessed 17 Jan. 2024.