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CRF and CRF1 Receptors

The potential of the CRF pathway in CAH management

Glucocorticoids were introduced as a treatment for CAH in the 1950s. Since then, the challenge when using GCs alone has been the same: replace cortisol deficiency and manage excess adrenal androgens, while avoiding the risks of high GC doses.1

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Length: 02:54

NARRATOR VO: Back in the 1950s, the introduction of corticosteroids (glucocorticoids and mineralocorticoids) was a game changer. For the first time, physicians had tools that could begin to offer patients with congenital adrenal hyperplasia (CAH) the possibility of a longer life. Corticosteroids compensate for cortisol and aldosterone deficiency in CAH. But controlling the overproduction of adrenal androgens remains a pressing challenge. Supraphysiologic doses of glucocorticoids (doses higher than needed to replace the missing cortisol) have been shown to lower levels of adrenocorticotropic hormone (ACTH) and androgens. But they do this indirectly, and can be associated with short- and long-term steroid-related risks. Despite, and maybe because of these risks, large retrospective studies show that about 2/3 of CAH patients have poorly controlled androgens. And today’s treatment paradigm requires constant trade-offs in the attempt to reduce androgens without exposing patients to the negative effects of high-dose steroids—just as it has for the past 70 years.

PATIENT VOICES: What the C@H?!

NARRATOR VO: While hydrocortisone and other glucocorticoids are the right tools for cortisol insufficiency, they are not ideal for managing androgen excess because of the potential collateral damage caused by the high doses most patients require. But cutting-edge research could reveal a solution—by looking deeper into the role of the hypothalamic-pituitary-adrenal (HPA) axis in regulating the body’s adaptive stress response. Corticotropin-releasing factor (CRF) has been identified as a primary regulator of the HPA axis including production of adrenal cortisol, aldosterone, and androgens. CRF is secreted by the hypothalamus and binds to CRF type 1 (CRF1) receptors in the pituitary gland, to promote ACTH release, which stimulates adrenal hormone production. When cortisol levels rise, CRF secretion is switched off, creating the negative feedback loop that allows the HPA axis to maintain homeostasis. But in patients with CAH, supraphysiologic doses of glucocorticoids are often needed to engage this negative feedback loop and suppress ACTH overproduction. The CRF pathway is being investigated as an opportunity for an independent mechanism to control androgen overproduction. Blocking CRF1 receptors or other receptors in the HPA axis could act directly to lower ACTH and androgen production—and allow the reduction of glucocorticoids to doses needed to replace cortisol—for potentially fewer high-dose steroid-related side effects and risks. Glucocorticoids changed the game of managing CAH, but for 70 years that has meant juggling with one hand tied behind our backs. We’ve waited long enough. It’s time to rethink CAH.

High GC doses indirectly manage adrenal androgens by lowering CRF release. This leads to2,3:

  • Reduced CRF1 receptor activation
  • Reduced ACTH release from the pituitary
  • Lower adrenal androgens
Graphic showing high GC doses indirectly lowering adrenal androgens by lowering CRF releaseGraphic showing high GC doses indirectly lowering adrenal androgens by lowering CRF release
Reducing ACTH and adrenal androgen overproduction more directly can enable lower GC doses and reduce the risk of GC-related comorbidities2,4

Antagonizing CRF1 receptors can1:

  • Reduce ACTH
  • Reduce adrenal androgens

Antagonizing ACTH receptors could also reduce adrenal androgens but does not reduce ACTH; this results in high levels of circulating ACTH.5,6

Graphic showing that CRF1 receptor antagonist could more directly reduce ACTH and adrenal androgensGraphic showing that CRF1 receptor antagonist could more directly reduce ACTH and adrenal androgens

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REFERENCES

  1. Mallappa A, Merke DP. Management challenges and therapeutic advances in congenital adrenal hyperplasia. Nat Rev Endocrinol. 2022;18(6):337-352. doi:10.1038/s41574-022-00655-w
  2. Claahsen-van der Grinten HL, Speiser PW, Ahmed SF, et al. Congenital adrenal hyperplasia—current insights in pathophysiology, diagnostics, and management. Endocr Rev . 2022;43(1):91-159. doi:10.1210/endrev/bnab016
  3. Turcu AF, Auchus RJ. Novel treatment strategies in congenital adrenal hyperplasia. Curr Opin Endocrinol Diabetes Obes. 2016;23(3):225-232. doi:10.1097/MED.0000000000000256
  4. Schröder MAM, Claahsen-van der Grinten HL. Novel treatments for congenital adrenal hyperplasia. Rev Endocr Metab Disord. 2022;23(3):631-645. doi:10.1007/s11154-022-09717-w
  5. Bancos I, Kim H, Cheng HK, et al. Glucocorticoid therapy in classic congenital adrenal hyperplasia: traditional and new treatment paradigms. Expert Rev Endocrinol Metab. 2025;20(1):33-49. doi:10.1080/17446651.2025.2450423
  6. Trainer P, Ferrara-Cook, C, Ayala A, et al. CRN04894: an oral, nonpeptide adrenocorticotropic hormone (ACTH) receptor antagonist decreases basal and stimulated cortisol secretion in healthy volunteers. Endocr Abstracts. 2022;86:PL344. Selected articles from Society for Endocrinology BES 2022. doi:10.1530/endoabs.86.P344