WHAT THE C@H?!

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.