The finding appears in the November 9 New England Journal of Medicine. It has long been known that, in addition to producing excess male hormones, patients with the disorder fail to produce enough cortisol, a key hormone in the body’s response to stress. The new finding means that, in addition to reducing excess male hormones and replacing cortisol in severely affected patients, physicians may need to find ways to replace adrenaline in these people as well. Currently, physicians lack the technology to administer adrenaline in doses matching the release of the hormone by the body. The finding may also mean that, in severe cases, it may be more appropriate to remove the defective adrenals and administer cortisol and other adrenal hormones artificially.
"This study offers important new information for the understanding and treatment of the severe form of the disorder," said NICHD Director Duane Alexander, M.D. "This knowledge may provide the medical community with the means to prevent the unexpected seizures and shock reactions that threaten people with severe 21-hydroxylase deficiency."
The research team was led by Deborah P. Merke, M.D., a researcher at NICHD’s pediatric endocrinology branch when the study was conducted, now Chief of Pediatric Services at the National Institutes of Health’s Warren Grant Magnuson Clinical Center.
According to the study’s senior author, Stefan R. Bornstein, M.D., of NICHD’s pediatric endocrinology branch, 21-hydroxylase deficiency is the most common form of a group of disorders known as congenital adrenal hyperplasia (CAH). People with these disorders typically lack functioning copies of any one of a number of enzymes needed to produce the hormone cortisol and related hormones. Among their many functions, these hormones “switch off” production of adrenaline and other hormones produced in response to stress, play a role in healing and fighting infection, and regulate the body’s salt content. People with CAH are susceptible to dehydration and sometimes, sudden, unexpected collapse. They may also have abnormally low levels of blood sugar placing them at risk for coma, seizures, or even death. In some cases, a simple infection may lead to shock.
Depending on the defect in the enzyme 21-hydroxylase, people with the condition may have mild, moderate, or severe forms of the disorder. In the U.S., 1 out of 60 people can transmit the severe form of the disease.
In the disorder, the “precursor” compounds that the enzyme 21-hydroxylase normally converts to cortisol and related hormones instead accumulate within the body. These precursors are then converted to androgens testosterone-like hormones that prompt facial and body hair growth, physical strength and other masculine features. Women with 21-hydroxylase deficiency may be infertile or even lack the ability to menstruate.
Because of the excess androgens, children with 21-hydroxylase deficiency typically grow faster than do other children if their condition is undiagnosed. However, because they enter puberty earlier than do other children, they reach their final adult height early, and so tend to be shorter than other adults. In boys, milder forms of 21-hydroxylase deficiency are typically undetected. Girls with the condition are more likely to be diagnosed, because the excess androgens often result in bodily hair growth as well as masculinized genitals.
For their study, Dr. Merke and her colleagues examined the adrenal hormone levels of 38 children with 21-hydroxylase deficiency. As compared to 39 normal children of the same age, the children with 21-hydroxylase deficiency produced from 40 to 80 percent less adrenaline and a related hormone, metanephrine. Children with the more severe form of the disorder those who had the lowest cortisol levels also tended to have the lowest adrenaline levels.
The researchers next compared adrenal glands previously removed from 3 patients with severe 21-hydroxylase deficiency, and compared them to the adrenal glands of 8 children who had died of either trauma or some other cause unrelated to 21-hydroxylase deficiency. The investigators found that the adrenal glands of the 21-hydroxylase deficient patients were structurally very different from the adrenals of other children. In addition to being poorly formed, they also lacked the adrenaline producing structures, or vesicles, found in normal adrenal glands.
The research team concluded that, since people with severe cases of 21-hydroxylase deficiency fail to produce enough adrenaline, it is probably more effective in severe cases to treat their excess androgen production by removing the adrenals, and then artificially replacing the necessary adrenal hormones.
Other authors of the paper were: George P. Chrousos, M.D., Martina Weise, M.D., Margaret F. Keil, R.N., of NICHD’s pediatric endocrinology branch, Graeme Eisenhofer, Ph.D, NIH’s National Institute of Neurological Disorders and Stroke, Alan D. Rogol, M.D., Ph.D., the University of Virginia Health System, and Judson J. Van Wyk, M.D., the University of North Carolina School of Medicine.
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