Evidence for Adverse Effects of High-Dose GC Treatment of Congenital Adrenal Hyperplasia Broadened, Deepened in New Literature Review

A new systematic literature review confirms the significantly deleterious effects of supraphysiologic doses of glucocorticoids (GC) in both children and adults living with congenital adrenal hyperplasia (CAH). The findings, presented by Neurocrine Biosciences at the 2025 International Society for Pharmacoeconomics and Outcomes Research (ISPOR) Annual Meeting, included decreased bone mineral density, increased insulin resistance and higher body mass index.1

The review is "the first to capture the impact of higher GC dose on the incidence and severity of all relevant adverse clinical outcomes in patients with CAH," according to a Neurocrine statement.

Of the 105 publications included, 65% (n=68) included individuals with CAH. Among all studies, 62% (n=65/105) reported statistically significant associations between GC dose and clinical outcomes, and 98% (n=64/65) of those linked higher GC doses with a range of adverse effects.

The review evaluated data from both pediatric and adult populations, with 55% (n=58) of the studies focused on adults. The reported on most frequently were bone health (43%; n=45), cardiometabolic complications (41%; n=43), and growth-related effects (24%; n=25). Of the 38% (n=40/105) of publications that did not find statistically significant associations, 9% (n=9) still noted trends suggesting adverse outcomes, while 28% (n=29) found no trend and 2% (n=2) observed trends toward improved outcomes.

CAH is a rare genetic condition resulting from a deficiency in the enzyme 21-hydroxylase, the reduced level a result of variants in the CYP21A2 gene. When severe, the deficiency is associated with failure of the adrenal glands to produce adequate cortisol and, in approximately three-quarters of cases, to produce physiologic levels of aldosterone. The body, however, is still able to produce androgens; thus the precursors that would support cortisol production instead result in overproduction of androgens--a condition that can result in salt wasting, extreme dehydration, and death.

Standard of care for individuals with CAH includes lifelong GC therapy to suppress adrenal androgen excess and replace deficient cortisol. The supraphysiologic GC doses typically required to achieve this balance, however, can lead to complications of steroid excess, such as weight gain, diabetes, cardiovascular disease, osteoporosis, mood disturbances, and reproductive health issues. In children, androgen excess is associated with abnormal bone growth and development, hirsutism and menstrual irregularities are often observed in women, and both men and women can be affected by fertility issues.

"CAH requires lifelong glucocorticoid therapy to manage adrenal androgen excess and cortisol deficiency, but high doses often lead to significant complications, including cardiometabolic, bone and growth issues," Eiry W Roberts, MD, Neurocrine Biosciences chief medical officer, said in the statement. "This review highlights the significant clinical burden of long-term, high-dose glucocorticoid use in CAH patients and the challenges clinicians face in optimizing treatment. The emergence of new therapeutic options offers hope for potentially reducing reliance on high-dose glucocorticoids, representing an important advancement in the management of CAH."

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