Androgens, by signaling through the androgen receptor (AR), mediate a wide range of male developmental processes. Complete androgen insensitivity syndrome (CAIS), a X-linked disorder caused by AR gene mutations, represents an in vivo model to study the role of androgens in sexual development. Here, we reported a case with CAIS at 20 weeks of gestational age harbouring a novel AR missense mutation (D767V), which was predicted to prevent androgen binding and action. Morphological examination and immunostaining were carried out in the index case, three male and one female normal 20-week-old fetuses for comparison. CAIS fetus showed complete female external genitalia, intrabdominal testis and persistence of Müllerian derivatives, as a uterus and the upper portion of vagina, developed to a similar extent in the CAIS fetus than in normal 20-week-old female fetus, were found. The testis showed a dramatic increase in the size and number of Leydig cells, resulting in doubling of the CAIS testis volume compared with the normal male fetuses. Semineferous tubules and Sertoli cells were normally developed. Leydig cells hyperplasia and persistence of Müllerian duct were described both in CAIS and persistent Müllerian duct syndrome. Direct sequencing of AMH and AMHR2 genes did not identify genomic variants. AMH protein was expressed in the Sertoli cells of both CAIS and normal male fetuses, though the immunostaining in CAIS Sertoli cells was more intense. AMHR2 immunostaing was present in the mesenchymal peritubular cells, which were definitely reduced in the CAIS testis compared with normal male fetuses. Finally, Leydig cells expressed bone morphogenetic receptor type 1A (BMPR1A) at high levels both in CAIS and normal male fetuses. These data suggested that AR deletion did not affect the testicular expression of genes relevant for Müllerian duct regression and that Leydig cells hyperplasia might be sustained by LH and BMPR1A-mediated AMH hyperstimulations.
Prague, Czech Republic
24 - 28 Apr 2010
European Society of Endocrinology