Non-Classic Disorder of Adrenal Steroidogenesis and Clinical Dilemmas in 21-Hydroxylase Deficiency Combined with Backdoor Androgen Pathway. Mini-Review and Case Report

Abstract

Congenital adrenal hyperplasia (CAH) is the most common cause of primary adrenal insufficiency in children and adolescents. It comprises several clinical entities associated with mutations in genes, encoding enzymes involved in cortisol biosynthesis. The mutations lead to considerable (non-classic form) to almost complete (classic form) inhibition of enzymatic activity, reflected by different phenotypes and relevant biochemical alterations. Up to 95% cases of CAH are due to mutations in CYP21A2 gene and subsequent 21α-hydroxylase deficiency, characterized by impaired cortisol synthesis and adrenal androgen excess. In the past two decades an alternative ("backdoor") pathway of androgens' synthesis in which 5α-androstanediol, a precursor of the 5α-dihydrotestosterone, is produced from 17α-hydroxyprogesterone, with intermediate products 3α,5α-17OHP and androsterone, in the sequence and with roundabout of testosterone as an intermediate, was reported in some studies. This pathway is not always considered in the clinical assessment of patients with hyperandrogenism. The article describes the case of a 17-year-old female patient with menstrual disorders and androgenization (persistent acne, advanced hirsutism). Her serum dehydroepiandrosterone sulfate and testosterone were only slightly elevated, along with particularly high values for 5α-dihydrotestosterone. In 24 h urine collection, an increased excretion of 16α-OHDHEA-a dehydroepiandrosterone metabolite-and pregnanetriolone-a 17α-hydroxyprogesterone metabolite-were observed. The investigations that we undertook provided evidence that the girl suffered from non-classic 21α-hydroxylase deficiency with consequent enhancement of the androgen "backdoor" pathway in adrenals, peripheral tissues or both, using adrenal origin precursors. The paper presents diagnostic dilemmas and strategies to differentiate between various reasons for female hyperandrogenism, especially in childhood and adolescence.

Keywords: 16α-hydroxydehydroepiandrosterone (16α-OHDHEA); 21-hydroxylase deficiency; backdoor androgen pathway; non-classic congenital adrenal hyperplasia; pregnanetriolone (PTN).

Figure 1

Androgen “backdoor” steroidogenesis pathway. The orange boxes bear the names of the steroid precursors at early stages of steroidogenesis and for 17OHP and its derivatives; reddish boxes for the cortisol pathway and its metabolite; blue areas (and mixed orange/blue) are background for androgens and their precursors; and finally gray boxes bear names of enzymes, which are involved in consecutive steps of steroidogenesis. The bluish arrows depict steps of the androgen backdoor pathway. The left side of the figure presents a few steps of steroidogenesis leading to cortisol synthesis (steroidogenesis beginning from cholesterol towards mineralocorticoid pathway is omitted), which are adjacent the rectangle area displaying the irreversible pathway from 17OH-progesterone to pregnanetriolone, a marker of adrenal origin of 17OHP. The upper row (from 17OH-pregnenolone) presents canonical steroidogenic steps to dehydroepiandrosterone (and its sulfate), which initiate progression of so-called classic androgen pathways toward testosterone and thereafter, to 5α-dihydrotestosterone. The main substrate appears to be 17OH-progesterone, which fuels (broad bluish arrows) the ”androgen backdoor pathway" and eventually reaches 5α-dihydrotestosterone with omission of testosterone as an intermediate step. The abbreviations of the enzymes involved in each step are displayed in gray boxes: AKR1C1/4 aldo-keto reductase 1C1/1C4 (3αHSD), AKR1C2/4 aldo-keto reductase 1C2/1C4 (3αHSD), AKR1C3 aldo-keto reductase 1C3 (17β-hydroxysteroid dehydrogenase type 5), CYB5 cytochrome b5, CYP11B1 cytochrome P450 11β-hydroxylase, CYP17A1 cytochrome P450 17α-hydroxylase/17,20-lyase, CYP21A2 cytochrome P450 21α-hydroxylase, HSD11B1 11β-hydroxysteroid dehydrogenase type 1 (mainly reductase 11BHSD), HSD11B2 11β-hydroxysteroid dehydrogenase type 2 (mainly oxidase 11BHSD), HSD3B2 3b-hydroxysteroid dehydrogenase type 2, HSD17B3/5 17β-hydroxysteroid dehydrogenase type 3/type 5, HSD17B6 17β-hydroxysteroid dehydrogenase type 6, 3αHSD 3α-hydroxysteroid dehydrogenase, 20αHSD 20α-hydroxysteroid dehydrogenase, SRD5A1 steroid 5α-reductase type 1, SRD5A2 steroid 5α-reductase type 2, SRD5B steroid 5β-reductase (AKR1D1 5b-reductase), SULT2A1 sulfotransferase 2A1 (DHEA sulfotransferase). Steroid metabolites usually estimated in urines are indicated in red letters close to their steroid precursors.