IMPAIRED GONOCYTE TRANSFORMATION DUE TO ANDROGEN RECEPTOR DEFECT

Background: A sharp increase in serum gonadotropins and testosterone and a simultaneous transformation of gonocytes (the fetal stem cell pool) into adult dark spermatogonia (the adult stem cell pool) occurs in normal male infants between 2-4 months of postnatal life. Previous studies suggest that the testicular histology of prepubertal boys with complete androgen insensitivity syndrome (AIS) is normal. This study examines the testicular development in prepubertal and early pubertal patients with complete AIS. Methods: Fifteen patients with complete AIS were studied. The ages ranged from 1 month to 40 years. Twelve were prepubertal or early pubertal boys. All had intraabdominal or high inguinal undescended testes. All had bilateral testicular biopsies. The tissue was fixed in 1% glutaraldehyde, embedded in Epon for semithin light microscopy and electron microscopy. Results: All 12 of the prepubertal/early pubertal patients had abnormal testicular development which was obvious even in the one month old. Ten (80%) of the 12 had complete absence of adult dark spermatogonia despite the fact that the total germ cell counts were all within the lower limits of normal. This abnormality indicates a failure of gonocytes to transform into adult dark spermatogonia. None developed primary spermatocytes between 3 and 6 years of age when transient mieiosis normally appears. All had severe Leydig cell hyperplasia and normal Sertoli cell number and structure. Ten (80%) of the older prepubertal/early pubertal patients progressed to Sertoli cell-only syndrome. Two (20%) had a few adult dark spermatogonia; these may represent the "incomplete variant" of complete AIS. Conclusion: Both complete AIS and cryptorchidism are associated with failure of transformation of gonocytes (the fetal germ cell pool) into adult dark spermatogonia (the adult germ cell pool) which normally occurs at 2-4 months postnatally and which is probably testosterone dependent. In AIS, the "injury" is the androgen receptor defect on Sertoli cells which blocks the paracrine effect of normal or increased intratesticular testosterone levels and leads to hyperplasia of Leydig cells. In crytporchidism, the "injury" is hypogonadotropic hypogonadism which causes hypoplasia of Leydig cells and reduced levels of intratesticular testosterone. The histomorphometric pathology seen in semithin sections of testicular biopsies in these two conditions are mutually supportive of the hypothesis that the transformation of gon