Congenital Adrenal Hyperplasia in Adults

Congenital adrenal hyperplasia (CAH) is an autosomal recessive disorder affecting adrenal steroid synthesis. More than 95% of CAH cases are caused by reduced 21hydroxylase function leading to variable extent of cortisol and aldosterone deficiency in addition to androgen excess. The foundation of CAH treatment is the use of glucocorticoids. However, overtreatment leads to Cushing’s syndrome and undertreatment to hyperandrogenism and Addisonian crisis. The aims of this thesis has been to evaluate the impact of CAH and its treatment on some factors that could lead to a reduced quality of life and increased morbidity or mortality during adult life. In total 93 patients (32 males) with CAH and 93 (32 males) ageand sex-matched controls were studied. Subgroups of different ages (<30 years or older), phenotypes and the three most common genotype groups (null, I2 splice and I172N) were studied. Focus was on cardiovascular and metabolic risk, bone health in females and fertility in males. Cardiovascular and metabolic risk: Younger female and male patients and controls had similar waist/hip ratio, lean and fat mass and insulin values. Older females had higher waist/hip ratio, lean mass and insulin values than controls. Fat mass was similar to controls but higher than in younger patients. Lipid profiles were slightly more favourable in older patients than in controls. Gestational diabetes was more common in patients. Few older female patients had hypertension, cardiovascular disease or diabetes. Despite moderate glucocorticoid doses, most patients had suppressed androgens. Serum liver enzymes were elevated in patients compared to controls. In patients, liver enzymes were correlated with waist circumference and with total body and trunk fat. Liver enzymes were increased even in non-obese patients mainly attributed to the patients ≥30 years who also demonstrated elevated insulin levels and HOMA-indices. In older males, waist/hip ratio, fat mass, and gamma-glutamyl transpeptidase were higher and heart rate faster than in controls. Insulin levels were increased during oral glucose tolerance test in all and older patients. Homocysteine was lower in all and in younger male patients which may be cardioprotective. Adverse cardiovascular profiles were mainly found in the mild genotype I172N. This group had normal urinary epinephrine concentrations whereas the more severe genotypes null and I2 splice had low levels. Few old male patients had cardiovascular disease and no patient had diabetes. Bone health in females: Patients had lower bone mineral density (BMD) than controls at all measured sites. In patients ≥30 years old 73% were osteopenic or osteoporotic vs 21% in controls. BMD was similar in the two classic forms and had no obvious relationship to genotypes. More fractures were reported in patients than controls. Fertility in males: Compared to national data the fertility was impaired in CAH males. The lifetime number of partners was smaller in all patients, in older patients and in the null group. Testicular tumours (TARTs) were found in 86% and 47% had pathological semen. Those with pathological semen had increased total and truncal fat mass, fat/lean mass ratio and heart rate. FSH was elevated and correlated negatively with sperm count and concentration. Conclusions: Adult CAH females and males have a number of issues due to the disease and to corticoid supplementation. However, the findings in this thesis are more positive than many of the previous reports on CAH. Many parameters studied in our CAH individuals <30 years were not different from ageand sex-matched controls. This is likely to reflect improvements in management. LIST OF PUBLICATIONS I. Falhammar H, Filipsson H, Holmdahl G, Janson PO, Nordenskjöld A, Hagenfeldt K, Thorén M. Metabolic profile and body composition in adult women with congenital adrenal hyperplasia due to 21-hydroxylase deficiency. J Clin Endocrinol Metab 2007 92:110-116 II. Falhammar H, Filipsson H, Holmdahl G, Janson PO, Nordenskjöld A, Hagenfeldt K, Thorén M. Increased liver enzymes in adult women with congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Endocr J 2009 56:601-608 III. Falhammar H, Filipsson Nyström H, Wedell A, Thorén M. Cardiovascular risk, metabolic profile, and body composition in adult males with congenital adrenal hyperplasia 21-hydroxylase deficiency.