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Trends in Congenital Adrenal Hyperplasia (CAH) Research

Expanding the Phenotype of CAH

New Endocrine Abnormalities
Adrenomedullary Dysfunction: Cortisol is necessary for the normal development and functioning of the adrenal medulla. Cortisol turns on the enzyme necessary for the production of epinephrine (adrenaline), which is a major regulator of blood glucose and suppresses insulin, by the medulla. Classic CAH not only affects cortisol, aldosterone and androgen production in the adrenal cortex, but also severely compromises the adrenal medulla. The implications of this dysfunction are impaired epinephrine response during short-term high-intensity exercise with no increase in blood glucose. More studies are needed on the risk of low blood glucose in CAH as well as the function of the adrenal medulla in patients with NCAH.

Insulin Resistance: Insulin resistance in patients with CAH is most likely due to a combination of chronic adrenomedullary hypofunction and glucocorticoid therapy. Insulin resistance puts patients at a higher risk for cardiovascular disease, Type 2 Diabetes, and infertility. Research is being conducted to study the use of Metformin in patients with CAH and insulin resistance (see below).

Psychological Effects of CAH
Relationship between hormones and physical effects on the brain: In NIH studies involving MRIs in patients with CAH, researchers have found that the structure and function of the amygdala (the part of the brain that regulates emotion and fear) is affected. The effects of these changes are relevant to issues of anxiety and mood disorders, risk-taking behaviors and decision making. While amygdala response in girls with CAH is similar to the normal male response, suggesting an androgen effect, behavioral implications need to be further studied.

New Treatment Approaches—Clinical

Adrenalectomy (removal of the adrenal glands) should only be considered when conventional therapy is failing and long-term follow-up can be secured. This therapy requires life-long monitoring and vigilance in administering medication.
Related Newsletter Article: Adrenalectomy: My Personal Story

Aromatase inhibitors (medications that inhibit the conversion of androgens to estrogens) and Anti-Androgens (medications that block androgen receptors) used with hydrocortisone and fludrocortisone have shown some benefit in short-term (2 year) studies. Children receiving new treatment regimens had normalization of growth rate, normalization and slowing of bone maturation, and less weight gain. However, no long-term safety data is available and liver function must be monitored carefully.

GH, LHRHa have been shown to improve final height by 1 standard deviation in 14 children but it needs more investigation.

Calcium channel blockers (Amlodipine) have been shown to decrease ACTH secretion.

Metformin has proven effective with insulin resistance and decreasing ovarian and adrenal hormone secretion in patients with PCOS. Studies are ongoing to investigate the effects of Metformin on insulin resistance and adrenal hormone production in patients with CAH and confirmed insulin resistance.

Preimplantation genetic diagnosis

DHEA replacement is being studied in Addison’s patients, but it is unclear whether this holds any relevance to CAH.

11 beta-HSD inhibitors are not recommended, but may have potential to decrease the dose of glucocorticoids (i.e., hydrocortisone) needed for treatment.

Growth hormone combined with depot leuprolide acetate (Lupron) treatment has been studied in a small group of CAH patients with short-stature. Growth rate and final height appear to be significantly improved.

The Pump for Hydrocortisone: Researchers and clinicians in the UK have successfully used an insulin pump to deliver a continuous infusion of hydrocortisone in one patient with CAH.

New Treatment Approaches—Preclinical Studies

CRH antagonists for adrenal suppression have shown promise in animal studies but need further investigation before they are applied to patient treatment.

Gene therapy represents a potential cure for CAH, but achieving safe and effective methods has proven challenging. There is much debate about the ethical and moral issues involved with this research.