339optimal treatment often subsequently results in induction of GDPP. This happens
because rapid reduction of androgens with optimal glucocorticoid treatment results
in withdrawal of inhibitory effects (of androgens) on androgen-primed GnRH–
gonadotropin axis. Patient was started on GnRH agonist, which was continued for
the next 2 years. With this therapy, the growth velocity remained in prepubertal range
(6 cm/year), and after 3 months of discontinuation of GnRH agonist, she had men-
arche with Tanner stage A +, P 5, B 4. Six months later, she presented with worsening of
hyperpigmentation, secondary amenorrhea, and deepening of voice, and serum
17(OH)P and testosterone were markedly elevated. Sudden worsening of clinical
symptoms related to androgen excess is usually observed during peripubertal period.
This is a consequence of increased ACTH drive as a result of augmented cortisol
clearance during peripubertal period. This occurs due to increased IGF1 during peri-
pubertal period, as serum IGF1 inhibits 11β-hydroxysteroid dehydrogenase type 1
(11β-HSD1), thereby decreasing t½ of cortisol. This mandates the increase in dose
and frequency of hydrocortisone administration. Other options in this scenario
include the use of potent glucocorticoids (e.g., dexamethasone or prednisolone;
either alone or in combination with hydrocortisone), modifi ed release preparations of
hydrocortisone, and the use of hydrocortisone infusion pump. Hydrocortisone
replacement in reverse circadian rhythm has also been tried without any substantial
benefi ts. In the index patient, dexamethasone alone could not control 17(OH)P and
testosterone; therefore, hydrocortisone was also added to dexamethasone akin to the
“basal–bolus” regimen in diabetes.
10.3 Clinical Rounds
- What is congenital adrenal hyperplasia?
Congenital adrenal hyperplasia (CAH) includes a group of autosomal recessive
disorders due to defi ciency of enzymes required for cortisol synthesis in adrenal
cortex and consequently results in adrenal hyperplasia due to adrenocortico-
tropic hormone (ACTH) overdrive.- What are the enzymes involved in cortisol biosynthesis?
The enzymes involved in cortisol biosynthesis include side-chain cleavage
(20,22 desmolase or CYP11A1), 17α-hydroxylase (CYP17A1),
3 β-hydroxysteroid dehydrogenase type 2 (3β-HSD2), 21α-hydroxylase
(CYP21A2), and 11β-hydroxylase (CYP11B1). In addition, steroidogenic
acute regulatory protein (StAR) is required for the transport of cholesterol into
mitochondria for cortisol synthesis. All these enzymes are cytochrome P450
dependent except 3β-HSD2. Inherited defi ciencies of any of these enzymes or
StAR protein result in CAH. 21α-hydroxylase defi ciency is the most common
cause of CAH and accounts for 95 % of patients. The enzymes involved in cor-
tisol biosynthesis are depicted in the fi gure given below (Fig. 10.2 ).10 Congenital Adrenal Hyperplasia