Six Decades of Research on Human Fetal Gonadal Steroids

Abstract

Human fetal gonads acquire endocrine steroidogenic capabilities early during their differentiation. Genetic studies show that this endocrine function plays a central role in the sexually dimorphic development of the external genitalia during fetal development. When this endocrine function is dysregulated, congenital malformations and pathologies are the result. In this review, we explain how the current knowledge of steroidogenesis in human fetal gonads has benefited from both the technological advances in steroid measurements and the assembly of detailed knowledge of steroidogenesis machinery and its expression in human fetal gonads. We summarise how the conversion of radiolabelled steroid precursors, antibody-based assays, mass spectrometry, ultrastructural studies, and the in situ labelling of proteins and mRNA have all provided complementary information. In this review, our discussion goes beyond the debate on recommendations concerning the best choice between the different available technologies, and their degrees of reproducibility and sensitivity. The available technologies and techniques can be used for different purposes and, as long as all quality controls are rigorously employed, the question is how to maximise the generation of robust, reproducible data on steroid hormones and their crucial roles in human fetal development and subsequent functions.

Activin A and Sertoli Cells: Key to Fetal Testis Steroidogenesis

“…Interestingly, human scRNASeq data suggest that only a small subset of human fetal Leydig cells produce androgen precursors between weeks 14–18 of gestation [ Supplementary Figure 1 ( 35 )]. This speculation is aligned with evidence that human fetal interstitial and Leydig-like cells are a heterogenous population ( 49 ).…”

“…The first trimester human testes can produce low levels of T via the Δ4 pathway prior to a switch to the Δ5 pathway at the beginning of the second trimester ( 48 ). Thereafter, the human fetal testis produces high levels of T during the second trimester via the classical Δ5 steroidogenic pathway ( Figure 1B , blue lines) ( 48 , 49 ). This switch coincides with the maturation of fetal Leydig cells as they acquire their capacity to produce androgen precursors ( 48 ).…”

“…Leydig cells are the major steroidogenic cells of the human fetal testis, expressing a wide range of steroid biosynthetic enzymes, and their differentiation coincides with elevated testicular T levels ( 49 ). Thus, these cells are often assumed to be responsible for androgen biosynthesis.…”

Endocrine Disruptors and Prostate Cancer

“…About 95% of T is produced and secreted by Leydig cells in the testis, and the remaining 5% is produced in adrenal glands by conversion of precursors (e.g., DHEA, DHEA sulfate, and androstenedione) [18]. T is converted to DHT and 17β-estradiol (E2, the main active estrogen), by the enzymes 5α-reductase (SRD5A) and aromatase, respectively [18,29]. There are three different isoforms of SRD5A, encoded by separate genes (SRD5A1, SRD5A2, and SRD5A3) and, among these, the most prevalent and biologically active isoenzyme is the SRD5A1.…”

Acetaminophen (APAP, Paracetamol) Interferes With the First Trimester Human Fetal Ovary Development in an Ex Vivo Model

“…Several experimental studies have demonstrated the endocrine disrupting capacity of APAP in fetal testis ( 5-8 ). Although studies showed that elements of the steroidogenic pathway are present in the human fetal ovary (hFO) ( 9-12 ) and that it displays endocrine activity ( 13 ), the effect of APAP on fetal ovarian endocrine capability has not been reported.…”