Congenital adrenal hyperplasia (CAH) in children, adolescents, and young adults is associated with an increased risk of obesity and metabolic-related dysfunction, particularly insulin resistance and hypertension. Previous studies have indicated a relationship among levels of adipokine, excess androgen, and metabolic markers. However, adipokine levels are not well established in the CAH population and evidence is scarce related to thedegree of metabolic dysregulation. To this end, Oksana Lekarev, D.O., a pediatric endocrinologist and associate medical director of the Comprehensive Care Center for CAH at NewYork-Presbyterian and Weill Cornell Medicine, and her colleagues, conducted a study to help clarify how adiponectin, leptin, and visfatin levels impact metabolic risk factors and androgen levels. Karen Lin Su, M.D., a pediatric endocrinologist and co-medical director of the Comprehensive Care Center for CAH at NewYork-Presbyterian and Weill Cornell Medicine, was the senior author on this paper.
Below, Dr. Lekarev discusses how their research findings provide insighton the association between insulin resistance and glucocorticoid dosing for treatment to adequately control hyperandrogenemia.
We looked at the long-term implications of adrenal androgens and glucocorticoid dosing related to cardiovascular and metabolic health. Would there be any additional markers that could be used clinically as predictors that could be correlated to future outcomes?
— Dr. Oksana Lekarev
Predicting Risk Factors for CAH Outcomes
As the first center of excellence for CAH in the country designated by CARES Foundation more than a decade ago, we have acquired a very large population of patients with CAH. This has enabled us to remain at the forefront of research in this area. I believe we have a responsibility to continue stage-related research. This includes our most recent study, where we looked at the long-term implications of adrenal androgens and glucocorticoid dosing related to cardiovascular and metabolic health. Would there be any additional markers that could be used clinically as predictors that could be correlated to future outcomes?
We need to think about good adrenal control in children and young adults in order to not only optimize their growth but also preserve their fertility. We also want to make sure that young women do not develop significant hirsutism and acne. While these are important reasons to control the androgens in young people, we wanted to determine other clinical concerns that might be influenced by androstenedione levels and what individuals with CAH might face going forward.
Study Parameters and Results
We conducted a prospective cross-sectional observational study of 17 patients, ages 7 to 22, with a diagnosis of CAH (15 classical, 2 non-classical) due to 21-hydroxylase deficiency who were recruited from our pediatric endocrinology clinic. To assess adrenal control, we obtained fasting blood for visfatin, leptin, adiponectin, glucose, insulin, CRP, lipid panel, total cholesterol, triglycerides, and HbA1c, as well as performed standard laboratory tests. Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) was calculated based on fasting glucose and insulin.
The data was fairly strong, even for this rare condition and a small number of study subjects. Our findings showed:
- Adiponectin and androstenedione were inversely correlated
- A positive correlation between leptin and BMI percentile as well as leptin and HOMA-IR
- Glucocorticoid dose had a significant correlation with HOMA-IR
- Visfatin was inversely correlated with HDL cholesterol and total cholesterol
- Overweight children and young adults had significantly higher leptin than non-overweight children and young adults
Implications for Treatment
The inverse relationship between adiponectin and androstenedione indicates that better control of CAH can reduce the risk of insulin resistance and metabolic syndrome. However, there is a delicate balance at play in treatment in that a high glucocorticoid dose appears to increase the risk of insulin resistance.
In our study, we also found a direct correlation between higher glucocorticoid doses and HOMA-IR, thereby indirectly increasing the risk for metabolic syndrome and type 2 diabetes. It is possible that patients with insulin resistance require higher doses of glucocorticoid to adequately suppress adrenal androgens. Or, it may also be that a higher glucocorticoid dose is an independent risk factor for insulin resistance. In treating children with CAH, we want to balance normalization of androgens with optimal glucocorticoid dosing. Glucocorticoid is used in children to lower their androgen levels, but you certainly don't want to overdo it with higher dosing because that can cause weight gain and, in children, slow their growth.
As children with CAH grow up, it's very important to be able to assess the most appropriate dosing, weighing that against their hormone control and possible long-term adverse effects.
— Dr. Oksana Lekarev
Before the discovery of steroid treatment in the 1950s, patients with classical CAH did not survive. They had such severe adrenal insufficiency that without steroids the disease was not compatible with life. Now, we are seeing these patients growing into adulthood and senior years. So, as children with CAH grow up, it's very important to be able to assess the most appropriate dosing, weighing that against their hormone control and possible long-term adverse effects.
As we continue to optimize treatment, newer adjunct FDA-approved medications are becoming available; most recently they just approved crinecerfont for classical CAH for which we were a study site. These novel treatments are aimed at improving the patient's adrenal control and decreasing their total daily glucocorticoid dose. This is another validation how important adrenal control is, how important androgens are, particularly androstenedione, when it comes to metabolic health, and how important it is to minimize glucocorticoid doses as much as possible.
