Altered Transcription Profiles of Key-Enzymes of Androgen Biosynthesis in Genital Skin Fibroblasts from Patients with 46,XY Disorders of Sex Development (DSD)

Abstract

Normal synthesis and action of androgens is essential for normal male sex differentiation. 17β-hydroxysteroid dehydrogenase (17β-HSD) and 5α-reductase isoenzymes play essential roles in normal androgen biosynthesis. We hypothesized that differences in expression of these enzymes in genital skin could contribute to the pathogenesis of 46,XY disorders of sex development (DSD). We investigated the mRNA transcription patterns of 17β-hydroxysteroid dehydrogenase-isoenzymes type 1, 2, 3, 4, 5, 7, and 10, 5α-reductase type 1 and 2 and the androgen receptor in genital skin fibroblasts from foreskin and scrotal skin obtained from healthy males and patients with unclassified 46,XY DSD. mRNA expression was semi-quantified by real-time PCR. Although no systematic differences of gene expression of any enzyme between normal controls and hypospadias patients could be detected, we found in nearly half of all investigated patients’ samples noticeable differences in the transcription profiles of 17β-hydroxysteroid dehydrogenase type 5. In scrotal skin samples of patients a significantly higher transcription of the androgen receptor was detected. A role for an altered expression pattern of different enzymes of steroidogenesis in the etiology of genital malformations in some patients may be postulated.

Testosterone Synthesis in Patients with 17β-Hydroxysteroid Dehydrogenase 3 Deficiency

“…Hence, if these patients have relevant amounts of testosterone and the concurrent clinical effects at puberty, testosterone synthesis must be through alternative pathways. It has been postulated that elevated amounts of androstenedione are converted to testosterone in peripheral tissues [Andersson et al, 1996;Boehmer et al, 1999;Luu-The, 2001;Hoppe et al, 2007]. In our investigations of patient ARD1853, we could demonstrate that both testosterone and androstenedione took a sharp drop within 48 h after gonadectomy ( table 1 ).…”

46,XY Disorder of Sex Development in a Sudanese Patient Caused by a Novel Mutation in the <b><i>HSD17B3</i></b> Gene

“…At the time of puberty, severe virilization is seen as a consequence of the presence of T in the circulation as a result of the conversion of A to T through alternative pathways in the testes, most likely the 17β-HSD5 pathway [Werner et al 2012]. Another hypothesis is that elevated amounts of An are converted to T in peripheral tissues [Andersson et al, 1996;Boehmer et al, 1999;Luu-The, 2001;Hoppe et al, 2007].…”

The differential role of androgens in early human sex development

“…The effects on the cellular androgen milieu are so far not elucidated, but it can be perceived that the composition of androgenic metabolites can be quite variable, depending on the expression pattern of steroidogenic enzymes within the cell. In this regard it is of interest that different cell types have different expression patterns of steroidogenic enzymes that are also age dependent [29,30]. Furthermore, additional alternative pathways for androgen synthesis may aggravate androgenic effects due to selective expression patterns of isoenzymes or alternate enzymes.…”