We report the case of a 53 year old woman with a history of refractory focal epilepsy with complex partial and secondary generalised seizures. She has been on multiple anti-epileptic drugs since childhood. At 42 years of age she was referred to the Endocrinology Department complaining of capital hair loss and hirsutism. At this time her epilepsy was controlled on phenytoin and carbamazepine.
A diagnosis of congenital adrenal hyperplasia (CAH) was made, with genetic analysis showing her to be homozygous/hemizygous for the Val281Leu point mutation in the CYP21 (21-hydroxylase) gene, a mutation usually associated with a mild, non-classical form of CAH. Basal 17-hydroxyprogesterone (17OHP) is often only marginally elevated or even within the normal reference range in patients with the non-classical variant of 21-hydroxylase deficiency. In our patient biochemical analysis showed a basal17OHP of 83 nmol/l (0.611.1) with an androstenedione of 28.4 nmol/l (4.010.0), more consistent with severe forms of 21-hydroxylase deficiency.
Phenytoin and carbamazepine are known to be potent inducers of hepatic cytochrome P450 enzymes, and will increase the metabolism of glucocorticoids and adrenal androgens. This increased metabolism of cortisol acts to further increase the stimulation of the adrenal cortex by corticotrophin. This results in an increase in cortisol precursors prior to the partial enzyme deficiency, and an increase in biosynthesis of adrenal androgens. Was it therefore possible that concomitant phenytoin and carbamazepine therapy in this patient was exacerbating the clinical phenotype of a mild form of 21-hydroxylase deficiency?
Subsequently, phenytoin was withdrawn and replaced with leviteracetam which does not induce cytochrome P450 enzymes. Following this change in anti-epileptic therapy the patient noted an improvement in her hair loss and less hirsutism. Biochemistry analysis showed a marked improvement in her adrenal androgens, with a 17OHP of 26 nmol/l and an androstenedione of 1.4 nmol/l.
01 - 05 Apr 2006
European Society of Endocrinology