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...

During childhood, the pituitary-testicular axis is partially dormant: testosterone secretion decreases following a drop in luteinising hormone levels; follicle-stimulating hormone (FSH) levels also go down. Conversely, Sertoli cells are most active, as revealed by the circulating levels of anti-Müllerian hormone (AMH) and inhibin B. Therefore, hypogonadism can best be evidenced, without stimulation tests, if Sertoli cell function is assessed. Serum AMH is high from fetal life until mid-puberty. Testicular AMH production increases in response to FSH and is potently inhibited by androgens. Inhibin B is high in the first years of life, then decreases partially while remaining clearly higher than in females, and increases again at puberty. Serum AMH and inhibin B are undetectable in anorchid patients. In primary or central hypogonadism affecting the whole gonad established in fetal life or childhood, all testicular markers are low. Conversely, when hypogonadism only affects Leydig cells, serum AMH and inhibin B are normal. In males of pubertal age with central hypogonadism, AMH and inhibin B are low. Treatment with FSH provokes an increase in serum levels of both Sertoli cell markers, whereas human chorionic gonadotrophin (hCG) administration increases testosterone levels. In conclusion, measurement of serum AMH and inhibin B is helpful in assessing testicular function, without need for stimulation tests, and orientates the aetiological diagnosis of paediatric male hypogonadism.

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