Spreading the clinical window for diagnosing fetal-onset hypogonadism in boys

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.

Keywords: cryptorchidism; disorder of sex development; hypopituitarism; micropenis; testosterone.

Figure 1

Schematic representation of the pituitary–testicular axis hormone levels and of sexual differentiation and development of male internal and external genitalia. WD diff., Wolffian duct differentiation; MD regr., Müllerian duct regression; EG diff., differentiation of the external genitalia.

Figure 2

Serum levels of gonadotropins and testicular hormones in male newborns. Data obtained from Ref. (15).

Figure 3

Serum levels of gonadotropins in anorchid boys. Reproduced from Ref. (29), ©2012 Blackwell Publishing Ltd., with permission from Blackwell Publishing Ltd., John Wiley and Sons.

Figure 4

A schematic guide for the interpretation of serum hormone levels in patients with fetal-onset male hypogonadism. IHH, isolated hypogonadotropic hypogonadism; Inh B, inhibin B; MPHD, multiple pituitary hormone deficiency; Nx, normal. Levels are considered as high, normal, or low as compared to the reference levels for newborns or prepubertal boys.