HPA-Axis Assessment Allows for Improved Corticosteroid Response Analysis

According to recent research, dual-dose cosyntropin testing effectively provides a practical framework for hypothalamic-pituitary-adrenal (HPA) axis safety assessment in a non-endocrine corticosteroid trial.¹

These data, presented at the Endocrine Society (ENDO) Annual Meeting 2026 in Chicago, Illinois, by Elena Christofides, MD, the chief executive officer of Endocrinology Associates, scientific and medical advisor for Sparrow Pharmaceuticals, and a clinical associate professor at the Ohio University Heritage College of Osteopathic Medicine, effectively provide clinicians with a way of monitoring HPA-axis safety and differentiating treatment-emergent suppression from adrenal dysfunction.¹

“The difficulty in this trial, like in any steroid trial in any non-endocrine condition, is the risk of adrenal suppression,” Christofides told HCPLive in an exclusive interview. “My job as the safety endocrinologist was to design a protocol to assess safety and avoid adrenal suppression during the course of the trial.”

The HPA axis is intrinsically associated with the body’s physical reaction to stress. Following a moment of severe stress, the axis – which includes the hypothalamus, pituitary gland, and adrenal glands – is activated to return the body to homeostasis. It releases a series of corticotropic hormones, leading to the synthesis and secretion of glucocorticoids, mineralocorticoids, and adrenal androgens.²

However, in trials involving corticosteroids outside of an endocrine specialty, baseline HPA-axis status is rarely considered relevant. This limits clinicians’ ability to determine the full effects of corticosteroids on the patients, as adrenal dysfunction and standard, treatment-emergent suppression may present similarly. To this end, Christofides and colleagues undertook the present study, titled CESSA.¹

CESSA was a randomized, double-blind, placebo-controlled study in adults with ulcerative colitis of the rectum. A total of 200 patients were randomly assigned to either next-generation hydrocortisone acetate (ngHCA) 90 mg once daily or twice daily, or to placebo. Patients were not permitted to use alternative corticosteroids.¹

The team initially used standard-dose 250 µg cosyntropin to filter out primary adrenal insufficiency. Follow-up safety visits utilized 1 µg cosyntropin at days 29, 39, and, if indicated, 53. Additionally, investigators conducted pharmacokinetic sampling for plasma corticosteroid levels on days 1, 15, and 28.¹

Of the 200 participants initially included and randomized, 25 were referred for targeted safety follow-up. Overall, 104 patients showed alterations to the HPA axis during the study; of these, 3 placebo recipients had persistent secondary adrenal suppression requiring endocrinology referral, which showed non-study corticosteroid exposure. All patients who were administered active study drug recovered HPA-axis function by the end of the safety period at day 53.¹

While the trial’s results ultimately included potential confounding for both safety and efficacy assessments, Christofides and colleagues determined that this study provided an effective framework to help address a significantly overlooked risk in patients assigned to receive corticosteroid treatment.¹

“We’re in need of more precise drug therapy metrics so that we can track that during a PK study,” Christofides said. “My preference would be if we could have some sort of continuous metabolic monitor where we’re measuring cortisol constantly, and we know what the patient’s endogenous cortisol rhythm is going into a trial – it would not be hard to then extrapolate whether their cortisol rhythm is expected based on the drug pharmacokinetics or not.”

Editors’ Note: Christofides reports disclosures with Ascendis, Eli Lilly, Novo Nordisk, Recordati, Corcept, Crinetics, and others.

References

1. Christofides E, Ensign M. Dual-dose Cosyntropin Stimulation Testing to Assess HPA-axis Safety and Identify Non-Study Corticosteroid Exposure in a Phase 3 Ulcerative Colitis Trial. Abstract presented at the Endocrine Society (ENDO) Annual Meeting 2026, Chicago, IL. June 13-15, 2026.

2. Joseph DN, Whirledge S. Stress and the HPA Axis: Balancing Homeostasis and Fertility. Int J Mol Sci. 2017;18(10):2224. Published 2017 Oct 24. doi:10.3390/ijms18102224