Endocrinologic and Psychologic Evaluation of 21-Hydroxylase Deficiency Carriers and Matched Normal Subjects: Evidence for Physical and/or Psychologic Vulnerability to Stress

Abstract

Carriers of congenital adrenal hyperplasia due to 21-hydroxylase (21-OH) deficiency demonstrate increased secretion of cortisol precursors after ACTH stimulation, suggestive of impaired cortisol production and compensatory increases in hypothalamic CRH secretion. Because both cortisol and CRH have behavioral effects, and hypothalamic CRH hypersecretion has been associated with chronic states of anxiety and depression, we performed endocrine and psychologic studies in consecutively admitted parents of patients with classic congenital adrenal hyperplasia due to 21-OH deficiency and parents of children with other chronic endocrine disorders. The number of excluded carriers because of pathologic reasons was higher than that of controls (P = 0.05). Carriers of 21-OH deficiency had a lower mean 24-h urinary free cortisol excretion (26.4 +/- 3.4 vs. 42.7 +/- 6.4 microg/d, P = 0.03) and higher peak ACTH (75.7 +/- 8.1 vs. 54.2 +/- 5.9 pg/ml, P = 0.04) and 17-hydroxyprogesterone (224.2 +/- 28.1 vs. 107.1 +/- 12.5 ng/dl, P < 0.001) concentrations post CRH stimulation than control subjects. Cortisol and androstenedione responses were similar in the two groups. Psychometric assessment performed by administering the State-Anxiety Inventory, Beck Depression Inventory, Profile of Mood States, Symptom Checklist-90R, and Temperament and Character Inventory revealed no differences between the two subject groups. Interestingly, a stepwise multiple linear regression model analysis in each population sample revealed that in carriers of 21-OH deficiency but not in the control subjects, a lower mean 24-h urinary free cortisol excretion and a higher ACTH response to ovine CRH stimulation predicted predisposition to obsessive-compulsive behavior, novelty seeking, reward dependence, and harm avoidance. We conclude that carriers of 21-OH deficiency appear to have mild hypocortisolism and compensatory changes of CRH secretion secondary to lower cortisol concentrations. These changes might predict mild predisposition of these subjects to physical and psychologic pathology, suggesting that larger studies are necessary.

Psychological vulnerability to stress in carriers of congenital adrenal hyperplasia due to 21-hydroxylase deficiency

“…Moreover, their 24-hour UFC concentrations correlated negatively with obsessive-compulsive behavior, novelty seeking and reward dependence. 7 Although a similar finding was not shown in the present study, a relative hypocortisolemic state of carriers of 21-OHD owing to their enzymatic defect can be postulated. This mild hypocortisolism might contribute to the decreased ability of these subjects to cope adequately with stress, both physically and emotionally.…”

“…7 Moreover, the higher-though not statistically significant-mean ACTH values at baseline (at -15 and 0 min) may point towards the same direction, most likely reflecting a state of mild chronic ACTH hypersecretion.…”

“…Furthermore, they demonstrate increased 17-hydroxyprogesterone (17-OHP) concentrations following ACTH stimulation, and higher mean and peak ACTH and 17-OHP concentrations following ovine (o) CRH stimulation. 1,6,7 These findings are likely to reflect chronic mild hypothalamic CRH and/or AVP hypersecretion secondary to mild impairment in cortisol biosynthesis, which is compensated for by the increased activity of the hypothalamic-pituitary axis. 7 The hypothalamic-pituitary-adrenal (HPA) axis represents a major component of the stress system and plays an important role in maintaining basal and stress-related homeostasis.…”

“…1,6,7 These findings are likely to reflect chronic mild hypothalamic CRH and/or AVP hypersecretion secondary to mild impairment in cortisol biosynthesis, which is compensated for by the increased activity of the hypothalamic-pituitary axis. 7 The hypothalamic-pituitary-adrenal (HPA) axis represents a major component of the stress system and plays an important role in maintaining basal and stress-related homeostasis. [8][9][10] CRH, a 41-amino-acid neuropeptide secreted by the parvocellular neurons of the paraventricular nucleus of the hypothalamus, is the primary regulator of HPA axis activity and the central coordinator of the endocrine, autonomic, immune and behavioral responses to stress.…”

A Favorable Metabolic and Antiatherogenic Profile in Carriers of <i>CYP21A2</i> Gene Mutations Supports the Theory of a Survival Advantage in This Population

“…The fact that basal cortisol values did not differ in the two groups does not support such a mechanism. However, higher cortisol response to adrenocorticotropic hormone stimulation and lower free cortisol concentrations in 24-hour urine have been detected in carriers of CYP21A2 mutations and, consequently, the role of cortisol concentrations in PAI-1 values remains uncertain [28]. …”