Alternative (backdoor) androgen production and masculinization in the human fetus

Abstract

2Masculinization of the external genitalia in humans is dependent on formation of 5α-3 dihydrotestosterone (DHT) through both the canonical androgenic pathway and an alternative 4 (backdoor) pathway. The fetal testes are essential for canonical androgen production but little 5 is known about the synthesis of backdoor androgens despite their known critical role in 6 masculinization. In this study, we have measured plasma and tissue levels of endogenous 7 steroids in second trimester human male fetuses using multi-dimensional and high-resolution formed primarily in non-gonadal tissue with placental progesterone the likely substrate. 16Masculinization of the human fetus depends, therefore, on androgen synthesis by both the 17 fetal testes and non-gonadal tissues leading to DHT formation at the genital tubercle. Our 18 findings provide, for the first time, a solid basis to explain why placental insufficiency is

GC‐MS‐based metabolic signatures reveal comparative steroidogenic pathways between fetal and adult mouse testes

“…Here, no 7α‐OHT was found in adult testes, while 5α‐DHT was undetectable in fetal testes (Table 1). The lack of fetal testicular DHT is concurrent with a study indicating the absence of DHT in fetal plasma 27 . Metabolic activities of both 3α‐HSD and 5α‐reductase are inhibited by 7α‐OHT and 7α‐Adione in adult rat testes, 28 which might explain ααβ‐diol catalyzed by 3α‐HSD was not detected here.…”

“…The lack of fetal testicular DHT is concurrent with a study indicating the absence of DHT in fetal plasma. 27 Metabolic activities of both 3α-HSD and 5α-reductase are inhibited by 7α-OHT and 7α-Adione in adult rat testes, 28 which might explain ααβ-diol catalyzed by 3α-HSD was not detected here. In addition, 7α-Adione in a Leydig cell was significantly higher in fetus than in adults (P < .04).…”

Ablation of the canonical testosterone production pathway via knockout of the steroidogenic enzyme HSD17B3, reveals a novel mechanism of testicular testosterone production

“…Whether this is the case, or indeed whether this explains the apparent dispensability of Hsd17b3 for basal testosterone production requires further investigation. A further explanation could be that, in humans, masculinization requires that both canonical and alternative (backdoor) androgen pathways are intact and the alternative pathway may also be dependent on a functional HSD17B3 38,39 . This alternative pathway does not appear to be of importance in fetal masculinization in the mouse 40 …”

Sex hormones and acne: State of the art

“…The alternative (backdoor) androgen synthesis pathway has been reported in human hyperandrogenic disorders, such as prenatal virilization/masculinization in girls with congenital adrenal hyperplasia (CAH), or with prepubertal acne [5]. Studies have demonstrated that androsterone is the principal backdoor androgen in the human fetus, and its circulating level is sex‐dependent.…”

“…The backdoor androgens are primarily synthesized from the placental progesterone in several nontesticular tissues, with little de novo biosynthesis in the testis. This explains the relationship between placental insufficiency and sex development disorders [5]. The expression of aldo‐keto reductases (AKR1C1‐1C4), 5α‐reductases (SRD5A1/2), and retinol dehydrogenase (RoDH) in the ovarian theca cells is enhanced in the polycystic ovary syndrome (PCOS), revealing that backdoor DHT biosynthesis occurs in the ovary and plays significant roles in androgen overproduction and clinical hyperandrogenism (HA) [6].…”