Treating congenital adrenal hyperplasia with an underestimated hormone

August 25, 2016 § Leave a comment

Image of adipocytes with lipids labelled in red and corticosterone in green.

 

In healthy people, the adrenal glands putter away atop the kidneys, releasing hormones as needed. For most people with congenital adrenal hyperplasia, the adrenal glands produce the glucocorticoid class of hormones, such as cortisol and corticosterone, in greatly diminished quantities.

The standard treatment for the disorder is hormone replacement therapy with hydrocortisone, the pharmaceutical version of cortisol. However, this tends to cause unpleasant side effects, such as obesity, hypertension and cardiovascular disease. In a paper just out in the journal Science Translational Medicine, researchers at the University of Edinburgh have found that using corticosterone can be just as effective as standard hydrocortisone, with fewer side effects.

Congenital adrenal hyperplasia affects about 1 out of every 10,000 people. When left unchecked, it can manifest as adrenal insufficiency, which can cause fatigue, depression, vomiting, severe abdominal pains and mood disorders. It can also lead to increased synthesis of adrenal androgens because adrenal androgens and glucocorticoids share precursor building blocks, which can have adverse effects on the development of primary or secondary sex characteristics in women.

Most cases of congenital adrenal hyperplasia are the result of a deficiency in 21-hydroxylase, which participates in the pathways that produce cortisol. Under stressful conditions, the anterior pituitary gland releases a molecule called adrenocorticotropic hormone, or ACTH. The ACTH travels to the kidney’s adrenal glands and stimulates the production of 17-hydroxyprogesterone, which is modified by 21-hydroxylase to ultimately become the stress-response hormone cortisol.

When glucocorticoid production is insufficient, as it is in congenital adrenal hyperplasia, 17-hydroxyprogesterone starts to accumulate and is diverted to the synthesis of adrenal androgens, such as testosterone. This also causes a buildup of ACTH, a precursor to the adrenal androgen, and also can cause unnatural darkening of the skin.

Treatment for these glucocorticoid deficiencies involves capsules of hydrocortisone, the pharmaceutical version of cortisol. But the treatment treads a fine line with cortisol cytotoxicity, according to Brian Walker, a professor at the University of Edinburgh and the primary investigator on the Science Translational Medicine paper.

The best way to suppress the overproduction of androgens “is to suppress this ACTH, but if you suppress the ACTH you almost always end up giving a dose that produces adverse side effects,” says Walker.

Because those side effects are mediated in the adipose tissue, the researchers decided to scrutinize the presence of cortisol and corticosterone in human adipocytes, the cells that store energy as fat.

After examining the adipocytes’ expression of the ATP-binding cassette transporters ABCB1 and ABCC1, which were known to export cortisol and corticosterone respectively, the researchers found that ABCC1 was dominant in the adipocytes. The transporter clears the cells of corticosterone. This suggested corticosterone, not cortisol, would be the better choice for replacement therapy; corticosterone wouldn’t stimulate activity in the cells and cause side effects.

To test this, Walker and his colleagues recruited two groups of six individuals with Addison’s disease, a disease similar to congenital adrenal hyperplasia. The investigators chose Addison’s disease patients over those with congenital adrenal hyperplasia to avoid any confounding effects of high androgen concentrations in the adipose tissues. They gave the patients either cortisol or corticosterone via short-term infusions.

Walker and colleagues found that while corticosterone treatments weren’t any more effective at suppressing circulating ACTH than cortisol treatments, they did reduce the presence of biomarkers for pathways in adipose tissues that lead to fat accumulation and hypertension.

Based on these results, Walker says, “We think it would be worth developing a treatment using corticosterone rather than cortisol or hydrocortisone. We are anticipating that that would have fewer side effects mediated in the adipose tissue for a dose that is equally efficacious in other tissues.”

At present, the researchers are working on developing such a therapy, Walker says, “because it doesn’t exist at present. We only have hydrocortisone tablets.”

 

This post was written by John Arnst, ASBMB Today’s science writer. 

 

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