In early fetal development, the testis secretes -independent of pituitary gonadotropinsandrogens and anti-Müllerian hormone (AMH) that are essential for male sex differentiation. In the second half of fetal life, the hypothalamic-pituitary axis gains control of testicular hormone secretion. Follicle-stimulating hormone (FSH) controls Sertoli cell proliferation, responsible for testis volume increase and AMH and inhibin B secretion, whereas luteinizing hormone (LH) regulates Leydig cell androgen and INSL3 secretion, involved in the growth and trophism of male external genitalia and in testis descent. This differential regulation of testicular function between early and late fetal periods underlies the distinct clinical presentations of fetal-onset hypogonadism in the newborn male: primary hypogonadism results in ambiguous or female genitalia when early fetal-onset, whereas it becomes clinically undistinguishable from central hypogonadism when established later in fetal life. The assessment of the hypothalamic-pituitary-gonadal axis in male has classically relied on the measurement of gonadotropin and testosterone levels in serum. These hormone levels normally decline 3-6 months after birth, thus constraining the clinical evaluation window for diagnosing male hypogonadism. The advent of new markers of gonadal function has spread this clinical window beyond the first 6 months of life. In this review, we discuss the advantages and limitations of old and new markers used for the functional assessment of the hypothalamic-pituitary-testicular axis in boys suspected of fetal-onset hypogonadism. Keywords: hypopituitarism, cryptorchidism, micropenis, disorder of sex development, testosteroneThe concept of male hypogonadism is usually associated with the adult patient, and rarely thought of as a condition in the prepubertal boy. Furthermore, male hypogonadism is most frequently equated to hypoandrogenism. Androgens are the dean of testicular hormones, and the normal testis produces very little or no testosterone during most of infancy and childhood. It is therefore easy to understand why the term hypogonadism is almost absent from the pediatrician's terminology. However, many hypogonadal states in the male bear their origin in fetal life. With the advent of direct markers of Sertoli cell function, hypogonadism can be identified in boys beyond the early postnatal critical window of pituitary-gonadal activation (1) -called "mini-puberty" by some authors -and before pubertal age. In this review, we address the diagnostic approaches of fetal-onset male hypogonadism based on the physiology and pathophysiology of the hypothalamic-pituitary-testicular axis ontogeny. ONTOGENY OF THE HYPOTHALAMIC-PITUITARY-TESTICULAR AXIS FETAL LIFE: THE FIRST VERSUS THE SECOND AND THIRD TRIMESTERSThe gonadotropin-releasing hormone (GnRH) neurons derive from cells present in the nasal placode in the sixth fetal week (2), which migrate together with olfactory axons and blood vessels through the cribriform plate and arrive in the developing forebrain...

The persistent Müllerian duct syndrome (PMDS) is a 46,XY disorder of sexual development characterized by the persistence of Müllerian duct derivatives, uterus and tubes, in otherwise normally masculinized males. The condition, transmitted as a recessive autosomal trait, is usually due to mutations in either the anti-Müllerian hormone (AMH) gene or its main receptor. Many variants of these genes have been described, all targeting the coding sequences. We report the first case of PMDS due to a regulatory mutation. The AMH promoter contains two binding sites for steroidogenic factor 1 (SF1), one at −102 and the other at −228. Our patient carries a single base deletion at −225, significantly decreasing its capacity for binding SF1, as measured by the electrophoresis mobility shift assay. Furthermore, by linking the AMH promoter to the luciferase gene, we show that the transactivation capacity of the promoter is significantly decreased by the mutation, in contrast to the disruption of the −102 binding site. To explain the difference in impact we hypothesize that SF1 could partially overcome the lack of binding to the −102 binding site by interacting with a GATA4 molecule linked to a nearby response element. We show that disruption of both the −102 SF1 and the −84 GATA response elements significantly decreases the transactivation capacity of the promoter. In conclusion, we suggest that the distance between mutated SF1 sites and potentially rescuing GATA binding motifs might play a role in the development of PMDS.

Anti-Müllerian hormone (AMH) is secreted by Sertoli cells of the testes from early fetal life until puberty, when it is downregulated by androgens. In conditions like complete androgen insensitivity syndrome (CAIS), AMH downregulation does not occur and AMH increases at puberty, due in part to follicle-stimulating hormone (FSH) effect. However, other conditions like Peutz-Jeghers syndrome (PJS), characterised by low FSH, also have increased AMH. Because both CAIS and PJS may present as hyperoestrogenic states, we tested the hypothesis that oestradiol (E2) upregulates AMH expression in peripubertal Sertoli cells and explored the molecular mechanisms potentially involved. The results showed that E2 is capable of inducing an upregulation of endogenous AMH and of the AMH promoter activity in the prepubertal Sertoli cell line SMAT1, signalling through ERα binding to a specific ERE sequence present on the hAMH promoter. A modest action was also mediated through the membrane oestrogen receptor GPER. Additionally, the existence of ERα expression in Sertoli cells in patients with CAIS was confirmed by immunohistochemistry. The evidence presented here provides biological plausibility to the hypothesis that testicular AMH production increases in clinical conditions in response to elevated oestrogen levels.