Figure 2.

Male reproductive hormone levels and fetal sex differentiation. (A) Ontogeny of male reproductive hormone levels from fetal to adult periods of life. In the early fetal stage, the initiation of testicular hormones secretion is independent of luteinizing hormone (LH) and follicle-stimulating hormone (FSH). In the second and third trimesters, LH and FSH are the main regulators of Sertoli and Leydig cell hormone production. For ~6 months after birth, LH, FSH, and testicular hormone levels remain at high levels. Afterwards, in infancy and childhood, gonadotropins, testosterone (T), and insulin-like factor 3 (INSL3) levels decrease, while those of anti- Müllerian hormone (AMH) and inhibin B continue to be high. During puberty, gonadotropins, T and INSL3 increase again to attain adult levels. AMH is inhibited by testosterone, and inhibin B is stimulated by FSH. Reprinted, with permission, from Salonia et al. (4). © 2019 Springer Nature Limited. (B) The undifferentiated gonad is exposed to pro-testicular and pro-ovarian factors. In the XY fetus, SRY expression regulated by MAP3K1, GATA4, SF1, and WT1 shifts the balance toward the pro-testicular factors, like SOX9, inducing testis differentiation. Sertoli cells produce anti-Müllerian hormone (AMH), which provokes Müllerian duct regression upon binding to its receptor AMHR2. Leydig cells express the LHCG receptor and steroidogenic proteins involved in androgen synthesis; testosterone acts on Wolffian ducts, the urogenital sinus, and the external genitalia, either directly or after metabolization to the more potent androgen dihydrotestosterone (DHT), to virilize them. In the XX fetus, where SRY is absent, the pro-ovarian factors WNT4, RSPO1, FOXL2, and DAX1 control the differentiation of the ovaries. The latter do not produce androgens or AMH, which results in feminization of the internal and external genitalia. Modified with permission from Rey et al. (13) © 2016 Elsevier Saunders.