What Does AMH Tell Us in Pediatric Disorders of Sex Development?

Abstract

Disorders of sex development (DSD) are conditions where genetic, gonadal, and/or internal/external genital sexes are discordant. In many cases, serum testosterone determination is insufficient for the differential diagnosis. Anti-Müllerian hormone (AMH), a glycoprotein hormone produced in large amounts by immature testicular Sertoli cells, may be an extremely helpful parameter. In undervirilized 46,XY DSD, AMH is low in gonadal dysgenesis while it is normal or high in androgen insensitivity and androgen synthesis defects. Virilization of a 46,XX newborn indicates androgen action during fetal development, either from testicular tissue or from the adrenals or placenta. Recognizing congenital adrenal hyperplasia is usually quite easy, but other conditions may be more difficult to identify. In 46,XX newborns, serum AMH measurement can easily detect the existence of testicular tissue, leading to the diagnosis of ovotesticular DSD. In sex chromosomal DSD, where the gonads are more or less dysgenetic, AMH levels are indicative of the amount of functioning testicular tissue. Finally, in boys with a persistent Müllerian duct syndrome, undetectable or very low serum AMH suggests a mutation of the AMH gene, whereas normal AMH levels orient toward a mutation of the AMH receptor.

Keywords: Klinefelter syndrome; Leydig cell; Sertoli cell; Turner syndrome; gonadal dysgenesis; ovary; persistent Müllerian duct syndrome; testis.

Figure 1

Upregulation of AMH production in testicular Sertoli cells. Left: onset of AMH expression in early fetal life is independent of gonadotropins and depends on transcription factors SOX9, which triggers AMH expression, and SF1, GATA4, and WT1, which further increase AMH transcription by binding to specific response elements on the proximal AMH promoter. Right: increase of testicular AMH production in response to FSH, involving the FSH receptor-Gsα protein-adenylate cyclase (AC)-cyclic AMP (cAMP) pathway, which activates protein kinase A (PKA)-mediated induction of SOX9, SF1, NFκB, and AP2. These factors bind to their specific response elements on the AMH promoter. Reproduced with permission from ref. (11). Copyright^© 2011 the American Physiological Society and ^© 2020 MDText.com, Inc.

Figure 2

Downregulation of AMH production in testicular Sertoli cells by androgens. In the absence of androgens (e.g., normal childhood and DSD with impaired androgen production) or androgen receptor (AR, e.g., normal fetal and neonatal periods and DSD due to androgen insensitivity syndromes), SF1 binds to its response elements on the AMH promoter and increases AMH transcription. When androgen action on the AR is effective in the Sertoli cell (e.g., at puberty), the ligand-activated AR could either block SF1 binding to the AMH promoter (blockage by competition) or interact with site-bound-SF1 and prevent it from exerting its stimulatory effect on AMH promoter (blockage by interaction). Modified with permission from (17). Copyright ^© The Author(s) 2018.

Figure 3

Serum AMH levels in normal males. The dotted lines represent the 97, 50, and 3rd percentiles. To obtain serum AMH in ng/mL, divide by 7.14. Reproduced with permission from ref. (22). Copyright ^© The Author(s) 2011.

Figure 4

(A) Undifferentiated stage of fetal sex development. (B) Male differentiation in normal 46,XY individuals and patients with 46,XX testicular DSD or Klinefelter syndrome. (C) Female external genitalia in patients with 46,XY DSD due to impaired androgen synthesis or action. (D) Female genital differentiation in normal 46,XX individuals and patients with dysgenetic DSD associated with 46,XX, 45,X or 46,XY genotypes. (E) Ambiguous external genitalia in patients with testicular or ovotesticular dysgenesis with different karyotypes. (F) Ambiguous external genitalia in patients with 46,XY DSD due to impaired androgen synthesis or action. (G) Male external genitalia and persistence of Müllerian ducts in 46,XY patients with AMH or AMHR2 gene defects.

Figure 5

Steroidogenesis steps in testicular Leydig cells (within the dotted blue box) and in the adrenals, ovaries, and placenta (outside the box). Reproduced with permission from (49). Copyright^© 2020 Grinspon, Bergadá and Rey.

Figure 6

Schematic of AMH levels in various types of disorders of sex development (DSD) in relationship to the aspect of the external genitalia and age. The shaded area represents reference levels for AMH, as obtained from ref. (22).