Natural History Study of Patients with Excess Androgen

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Abstract

Our recruitment of patients continues to be excellent and to date, we have enrolled over 500 patients with various forms of congenital adrenal hyperplasia (CAH) and other genetic causes of abnormal puberty. This Natural History study allows for longitudinal characterization of disease-related and treatment-related clinical manifestations and timely referral to clinical trials of novel treatments. Comprehensive clinical phenotyping of patients with CAH due to 21-hydroxylase deficiency has been performed. Detailed clinical evaluations reveal great variation in treatment approaches of referred patients, especially among adults, with only 30% of patients in acceptable disease control based on adrenal hormones. Adult short stature, abnormal growth and development of children, cardiovascular risk factors, reduced bone mineral density and adrenal and testicular tumor formation are common. Children with CAH are at risk for early puberty. In a retrospective study of data from our Natural History study, we evaluated the effect of gonadotropin releasing hormone analogue (GnRHa) therapy on bone health in the CAH population. Childhood GnRHa therapy for an average of 4.5 years in patients with CAH did not affect bone mineral density (BMD) at attainment of adult height or during early adulthood when peak BMD occurs in healthy individuals and is expected. However, an overall decrease in BMD occurred during the second and third decades of life, regardless of GnRHa therapy, a possible effect of chronic supraphysiologic doses of glucocorticoids. Patients with CAH and other forms of adrenal insufficiency have been reported to have poor quality-of-life. Cognition, emotional processing, memory and quality-of-life is being evaluated. As part of this Natural History Study, we developed the first validated patient reported outcome (PRO) instrument to capture disease-specific health-related quality of life outcomes in CAH, named CAHQL. The instrument will be valuable in the clinical management of adults with CAH and could be used to assess the efficacy of novel treatments in development. There is no consensus on what hormones to measure, when, how often and how to interpret results to optimize the hormonal control of patients with CAH. Through modeling of steroid profiles, we were able to provide guidance regarding the use and interpretation of commonly used biomarkers. In a separate study, we estimated residual enzymatic activity based on hormonal measurements in the untreated state and found that model-based estimated enzymatic activity was higher than genotype predicted enzyme activity. The estimation of individual residual enzymatic activity allowed for evaluating individual dosing regimens and represents a novel step towards optimizing therapy through individualizing glucocorticoid replacement therapy. Studies are underway to better define the clinical, molecular and biochemical aspects of CAH.