Abstract
In early fetal development, the testis secretes – independent of pituitary gonadotropins – androgens 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.
Highlights
In early fetal development, the testis secretes – independent of pituitary gonadotropins – androgens and anti-Müllerian hormone (AMH) that are essential for male sex differentiation
We address the diagnostic approaches of fetal-onset male hypogonadism based on the physiology and pathophysiology of the hypothalamic–pituitary–testicular axis ontogeny
The definition should be extended to all situations characterized by a decreased testicular function, as compared to what is expected for age, involving an impaired hormone secretion by Leydig cells and/or Sertoli cells (AMH, inhibin B) and/or a disorder of spermatogenesis (Table 1)
Summary
Serum AMH peaks during the second year and remains fairly stable during childhood [22, 26] These data clearly indicate that Sertoli cells are functionally active during infancy and childhood. LH induces Leydig cells androgen production again: intratesticular testosterone concentration increases and acts on Sertoli cells, which express the androgen receptor They acquire a mature phenotype characterized by the development of the blood–testis barrier and a down-regulation of AMH production [reviewed in Ref. The definition should be extended to all situations characterized by a decreased testicular function, as compared to what is expected for age, involving an impaired hormone secretion by Leydig cells (androgens, INSL3) and/or Sertoli cells (AMH, inhibin B) and/or a disorder of spermatogenesis (Table 1). LEVEL OF THE AXIS PRIMARILY AFFECTED: CENTRAL, PRIMARY, OR COMBINED HYPOGONADISM In central (or hypothalamic–pituitary) hypogonadism, testicular failure is secondary to a disorder affecting the secretion of GnRH www.frontiersin.org
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