Erik Swain , 2025-04-18 14:44:00
April 18, 2025
3 min read
Click here to read the Cover Story, “After decades with only one option, new therapies emerge for congenial adrenal hyperplasia.”
Non-glucocorticoid therapies can decrease risk for complications from lifelong glucocorticoid treatment.
Yes, I do think we need non-glucocorticoid forms of therapy to treat 21-hydroxylase deficiency congenital adrenal hyperplasia.
The most common form of congenital adrenal hyperplasia (CAH) is a condition in which the deficiency of the 21-hydroxylase enzyme results in absent or very low cortisol production. CAH differs from adrenal insufficiency in that because of the 21-hydroxylase enzyme deficiency, cortisol precursors are shifted to a pathway of increased adrenal androgen production. Glucocorticoid replacement is given to prevent adrenal insufficiency and to suppress excess adrenal androgen production. If the decreased cortisol production can be uncoupled from the excess androgen production, then lower levels of glucocorticoid therapy can be used to treat CAH. There is negative feedback between the hypothalamic-pituitary-adrenal axis. The hypothalamus secretes corticotropin-releasing factor (CRF), which binds to the CRF-1 receptor. This leads to adrenocorticotropic hormone (ACTH) secretion, which stimulates the adrenal gland to produce cortisol. In individuals with CAH, because of insufficient cortisol production, there is increased CRF release leading to increased ACTH production and increased adrenal androgen production due to the 21-hydroxylase deficiency. If the CRF cannot bind to its receptor, then ACTH production is not increased and consequently adrenal androgen production is not increased. This would then allow for lower levels of glucocorticoids to be used to treat CAH since excess glucocorticoid is no longer necessary to suppress adrenal androgens.
Consequently, there would be decreased risk for complications, which can be quite significant because of the lifelong need for glucocorticoid replacement. Long term, there can be decreased bone mineral density and increased risk for metabolic syndrome with obesity, increased insulin resistance, higher lipid profiles and cardiovascular changes. There can be risk for diabetes and hypertension. Another complication of high-dose glucocorticoids, even short term, in children is suppression of growth. Also, current glucocorticoid therapy often results in higher adrenal androgen production, which can lead to advancement of bone age, earlier onset of puberty and, ultimately, shorter adult height. A medication that will suppress these untoward complications of excess adrenal androgen production without high-dose glucocorticoid use will allow for normal timing of puberty, height within genetic potential and decreased long-term complications.
Use of crinecerfont (Crenessity, Neurocrine Biosciences), a CRF-1 receptor antagonist recently approved by the FDA, in individuals with CAH can lead to a decrease in glucocorticoid requirements.
For more information:
Patricia Y. Fechner, MD, is medical director of Seattle Children’s Congenital Adrenal Hyperplasia Center and professor of pediatrics at the University of Washington School of Medicine.
Glucocorticoid therapy may be enough for some patients if the time of administration is optimized.
I can clearly see a certain patient population for which non-glucocorticoid therapies are a very exciting treatment, but I’m not entirely sure they are for everyone.
What is not very often discussed in the literature is that, even without changing glucocorticoid doses, you can optimize treatment by changing the time of administration. I think that is absolutely essential. It is something that we have done over the years, but not everyone is willing to do it. You have to get up early in the morning, 5 a.m., to give a dose to your child. Some people are willing to do this and can achieve excellent control. In my view, it’s not so much about the absolute dose, but around what time you are giving it.
There are many variables involved and I don’t want to oversimplify things, but in the international CAH registry, among the patients who are really well controlled, most of them, especially those younger than 18 years, take their glucocorticoids very early in the morning. And that can enable them to reduce dosage.
It’s a little like type 1 diabetes therapy. Some people will follow to the letter what you suggest to them. The other extreme is people who don’t take their medication. Then there are a lot of people in between who do as best as they can but probably not as much as you would like them to do. For CAH, like other chronic conditions, progression and control of the disease depends on adherence and frequency of doctor visits. I would be interested to see if people who won’t take glucocorticoids would want a treatment like a CRF-1 antagonist. For the people in between, if optimization of glucocorticoid regimen can’t be achieved, a CRF-1 agent could be very exciting to use to reduce glucocorticoid levels. The caveat is that we don’t know if metabolic complications as a result of not having glucocorticoids at the right time every day might still be an issue. That’s something the future will probably tell.
For more information:
Nils P. Krone, MD, FRCPCH, is professor of pediatric endocrinology and honorary consultant pediatric endocrinologist at the University of Sheffield School of Medicine and Population Health, Sheffield, U.K.
Sources/Disclosures
Collapse
Source:
Healio Interviews
Disclosures:
Fechner reports receiving research grants from Ascendis Pharma, Lumos Pharma, Neurocrine Biosciences, Pfizer and Spruce Biosciences and consulting and/or advising for Eaton Pharmaceuticals, Neurocrine Biosciences and Pfizer. Krone reports serving as an advisor and speaker for and receiving a research grant from Neurocrine Biosciences, as well as chairing a steering committee for an investigator-initiated trial sponsored by Neurocrine Biosciences.