Challenges in treatment of patients with non-classic congenital adrenal hyperplasia

Abstract

Congenital adrenal hyperplasia (CAH) due to 21α-hydroxylase deficiency (21OHD) or 11β-hydroxylase deficiency (11OHD) are congenital conditions with affected adrenal steroidogenesis. Patients with classic 21OHD and 11OHD have a (nearly) complete enzyme deficiency resulting in impaired cortisol synthesis. Elevated precursor steroids are shunted into the unaffected adrenal androgen synthesis pathway leading to elevated adrenal androgen concentrations in these patients. Classic patients are treated with glucocorticoid substitution to compensate for the low cortisol levels and to decrease elevated adrenal androgens levels via negative feedback on the pituitary gland. On the contrary, non-classic CAH (NCCAH) patients have more residual enzymatic activity and do generally not suffer from clinically relevant glucocorticoid deficiency. However, these patients may develop symptoms due to elevated adrenal androgen levels, which are most often less elevated compared to classic patients. Although glucocorticoid treatment can lower adrenal androgen production, the supraphysiological dosages also may have a negative impact on the cardiovascular system and bone health. Therefore, the benefit of glucocorticoid treatment is questionable. An individualized treatment plan is desirable as patients can present with various symptoms or may be asymptomatic. In this review, we discuss the advantages and disadvantages of different treatment options used in patients with NCCAH due to 21OHD and 11OHD.

Keywords: 11-hydroxylase deficiency (11OHD); 21-hydroxylase deficiency (21OHD); Non-classic congenital adrenal hyperplasia (NCCAH); glucocorticoid treatment; treatment options.

Figure 1

Schematic overview of adrenal steroidogenesis. NCCAH patients with 21OHD have impaired 21α-hydroxylase activity (CYP21A2) and NCCAH patients with 11OHD have impaired 11β-hydroxylase activity (CYP11B1). Precursor steroids prior to the enzymatic block increase and are shunted into androstenedione that can be converted into testosterone and dihydrotestosterone in the gonads. Steroids depicted in a red box have mainly glucocorticoid activity, steroids in a green box have mainly mineralocorticoid activity, and steroids in a blue box have mainly androgen activity. DHEA, dehydroepiandrosterone; CYP11B1, 11β-hydroxylase; CYP11B2, aldosterone synthase; CYP17A1, 17α-hydroxylase/17,20-lyase; CYP21A2, 21α-hydroxylase; HSD3B2, 3β-hydroxysteroid dehydrogenase type 2; OH-, hydroxy-.

Figure 2

In NCCAH, different gene mutations can lead to decreased activity of the effected enzyme. Symptoms can present during childhood, adolescence, and adulthood and are influenced by the residual enzymatic activity. Elevated androgen concentrations can lead to various clinical symptoms (blue box). Side effects of supraphysiological glucocorticoid treatment are common (red box). Symptoms in the purple box occur due to elevated androgens or glucocorticoid treatment.