By far, 21- hydroxylase deficiency (21OHD) is the most common form of CAH, both classic at ~1:16 000 worldwide and non- classic, ~1:1000 or more prevalent in certain populations. The genetics and diagnosis of 21OHD is reviewed in detail in Chapter 5.9.1. Upstream of the defective CYP21A2 enzyme, 17- hydroxyprogesterone (17OHP), progesterone, and other cortisol precursors accumulate, and some of these steroids are metabolized to androgens (Figure 1). Patients with classic 21OHD require cortisol replacement, and most also benefit from mineralocorticoid therapy, even those who make some aldosterone. In addition, treatment must also control the androgen excess to the extent that is clinically indicated. In non- classic 21OHD, treatment is employed to control androgen excess and reproductive dysfunction in children and women with these clinical manifestations. Based on conservative estimates from population studies, <10% of females and <1% of males with non- classic 21OHD are ever diagnosed with the condition, and of these roughly 70% are compound heterozygotes for classic and non- classic 21OHD alleles and thus carriers for classic 21OHD.
Fig1. Altered steroidogenesis in classic 21OHD. The block at P450 21A2 (double crossed lines on dotted arrows) causes deficient synthesis of aldosterone and cortisol. Underlined steroid names in large font indicate major adrenal products in 21OHD: 17OHP, 21- deoxycortisol, and 11OHA4. Lack of substrate production also precludes downstream conversions, also indicated with dotted arrows. Note that pregnenolone sulphate (PregS) accumulates comparably to DHEAS in classic 21OHD, and progesterone (underlined in normal size font) is also elevated.
While 17OHP, androstenedione (A4), and testosterone (T) measurements have been traditionally used to diagnose and monitor therapy for 21OHD, these steroids also derive from the gonads, limiting their specificity. For example, diagnostic testing for non- classic 21OHD must be performed in the follicular phase avoid the contribution of ovarian 17OHP, and men with 21OHD in very poor control or very good control can both have a ‘normal’ male- range T. In addition, dehydroepiandrosterone sulphate (DHEAS), the most abundant steroid in the circulation through most of life, is elevated in non- classic 21OHD but normal or low in classic 21OHD, contrary to simple predictions by inspection of Figure 2.
Fig2. Composite diagram of adrenal steroid biosynthesis, highlighting the genetic defects causing the congenital adrenal hyperplasias (enzyme names in white on black boxes). Underlined steroid names in large font indicate major adrenal products: aldosterone, cortisol, and DHEAS. Minor pathways, either due to poor enzyme activity or limited substrate availability, are shown with dashed arrows. The 11- oxyandrogen pathways, which in part are due to conversions in peripheral tissues, are indicated at right.
The adrenals of patients with 21OHD, however, still contain the enzyme 11- hydroxylase (CYP11B1), and most of the 3- keto- Δ4- steroids that accumulate in 21OHD are substrates for CYP11B1. For example, CYP11B1 converts 17OHP to the 11- oxygenated steroid 21- deoxycortisol (21dF), and 21dF is more specific than 17OHP for diagnosis of non- classic 21OHD and for de termination of carrier status. The 3β- hydroxy- Δ5- steroids pregnenolone and 17- hydroxypregnenolone, which also accumulate in 21OHD, are substrates for the sulfotransferase SULT2A1, and pregnenolone sulphate rises in classic 21OHD to about 40% the abundance of DHEAS. More importantly, A4 is an excel lent substrate for CYP11B1, and circulating concentrations of 11β- hydroxyandrostenedione (11OHA4) exceed those of A4 in treated patients with classic 21OHD by twofold. Via two consecutive intra- adrenal and/ or peripheral enzymatic steps, 11OHA4 is converted to 11- ketotestosterone (11KT), which is a biologically relevant androgen, particularly in 21OHD. In teleost (bony) fishes and some reptiles, 11KT is the major gonadal androgen, and 11KT activates the human androgen receptor nearly as potently and effectively as T, depending on model system used. Furthermore, serum 11KT is roughly twice as high as T in treated patients with classic 21OHD, suggesting that 11KT is the dominant androgen in most patients with classic 21OHD. The 11KT correlates directly with T in women with classic 21OHD, as both steroids derive entirely or mostly from the adrenals. Conversely, 11KT correlates inversely with T in men with classic 21OHD, reflecting the testicular origin of T in well- controlled men and primarily adrenal origin of both T and 11KT in those with poor disease control.
