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Title: Congenital adrenal hyperplasia : the influence of puberty on cortisol pharmacokinetics
Author: Charmandari, Evangelia
ISNI:       0000 0001 3530 0183
Awarding Body: University of London
Current Institution: University College London (University of London)
Date of Award: 2001
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In Congenital Adrenal Hyperplasia (CAH) due to 21-hydroxylase deficiency, appropriate glucocorticoid substitution does not often result in adequate suppression of the hypothalamic-pituitary-adrenal (HPA) axis. Suboptimal control is especially observed in pubertal patients, despite adherence to medical treatment. The clinical studies described in this thesis were performed to address the effect of puberty on cortisol pharmacokinetics and HPA axis activity in patients with CAH due to 21-hydroxylase deficiency. Six studies were conducted on forty patients (14 prepubertal, 20 pubertal and 6 postpubertal) with classical 21-hydroxylase deficiency. They revealed: i) An alteration in the pharmacokinetic parameters of total and free cortisol at puberty: There was an increase in cortisol clearance and volume of distribution but no change in half life. The half life of free cortisol was shorter in females compared to males. ii) An increase in cortisol clearance and a decrease in half life in association with specific alterations in the endocrine milieu at puberty, including alterations in the growth hormone (GH) ~ insulin-like growth factors and 11β-hydroxysteroid dehydrogenase activity. Also, a decrease in cortisol half life in association with elevated adrenocorticotrophic hormone (ACTH) concentrations. iii) Essentially complete bioavailability of oral hydrocortisone tablets used as substitution therapy in these patients. iv) A significant negative correlation between cortisol and 17-hydroxyprogesterone concentrations. Also, a difference in the activity of HPA axis between daytime and night-time, with the minimal activity observed between 1600h and 0400h. v) No alteration in the negative feedback effect of cortisol at the pituitary level. vi) A significant positive correlation between serum cortisol and GH concentrations. The above findings may explain the difficulties encountered in the management of CAH patients at puberty and suggest that replacement therapy should be with frequent doses of glucocorticoid substitution in all pubertal patients, particularly females. Management should also aim at providing adequate HPA axis suppression between 0400h and 1600h, as well as preventing and/or treating hyperandrogenism.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available