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

Int J Mol Sci. 2020 Jun 29;21(13):4622. doi: 10.3390/ijms21134622.


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).

Publication types

  • Case Reports
  • Review

MeSH terms

  • Adolescent
  • Adrenal Glands / metabolism
  • Adrenal Hyperplasia, Congenital / genetics
  • Adrenal Hyperplasia, Congenital / metabolism*
  • Adrenal Hyperplasia, Congenital / physiopathology*
  • Androgens / metabolism
  • Dihydrotestosterone / metabolism
  • Female
  • Humans
  • Steroid 17-alpha-Hydroxylase / metabolism
  • Steroid 21-Hydroxylase / genetics
  • Steroid 21-Hydroxylase / metabolism*
  • Steroids / metabolism
  • Testosterone / metabolism


  • Androgens
  • Steroids
  • Dihydrotestosterone
  • Testosterone
  • CYP21A2 protein, human
  • Steroid 21-Hydroxylase
  • Steroid 17-alpha-Hydroxylase

Supplementary concepts

  • Congenital adrenal hyperplasia due to 21 hydroxylase deficiency