A Common Polymorphism in the Human Relaxin-Like Factor (RLF) Gene: No Relationship with Cryptorchidism

Impaired testicular descent (cryptorchidism) is one of the most frequent congenital abnormalities in humans, involving 2% of male births. Cryptorchidism can result in infertility and increases risk for development of germ-cell tumours. Testicular descent from abdomen to scrotum occurs in two distinct phases: the trans-abdominal phase and the inguino-scrotal phase. Currently, little is known about the factors that regulate the trans-abdominal phase of testicular descent. Leydig insulin-like hormone (Insl3) is a member of the insulin hormone superfamily expressed in the developing testis. We show here that mice mutant for Insl3 are viable, but exhibit bilateral cryptorchidism due to developmental abnormalities of the gubernaculum, resulting in abnormal spermatogenesis and infertility. Female homozygotes have impaired fertility associated with deregulation of the oestrus cycle. These findings reveal roles for Insl3 in the development of the urogenital tract and in female fertility. Insl3 may act as a hormone to regulate the growth and differentiation of the gubernaculum, thereby mediating intra-abdominal testicular descent.

The Abdominal B (AbdB) genes constitute a distinct subfamily of homeobox genes that exhibit posterior domains of expression, including the genital imaginal disc in Drosophila and the developing urogenital system in vertebrates. We have mutated the AbdB gene Hoxa10 in mice. We report here that homozygotes are fully viable and show an anterior homeotic transformation of lumbar vertebrae. All male homozygotes manifest bilateral cryptorchidism resulting in severe defects in spermatogenesis and increasing sterility with age. Female homozygotes ovulate normally, but about 80% are sterile because of death of embryos between days 2.5 and 3.5 post coitum. This coincides spatially and temporally with expression of maternal Hoxa10 in distal oviductal and uterine epithelium. These results indicate a role for AbdB Hox genes in male and female fertility and suggest that maternal Hoxa10 is required to regulate the expression of a factor that affects the viability of preimplantation embryos.

We studied risk factors for cryptorchidism and hypospadias. We performed a register based, case control study of 6,177 boys with cryptorchidism, 1,345 with hypospadias and 23,273 male controls born live in Denmark from 1983 to 1992 to determine the effects of cryptorchidism and hypospadias on the presence of the other abnormality in an individual, the presence of the abnormalities in an older brother, birth weight, weeks of gestation, maternal history of stillbirth, parity, twin birth, parental age, nationality and professional status. Unconditional logistic regression analysis was used to estimate odds ratios. In an individual simultaneous cryptorchidism and hypospadias were more common than expected. There was an increased risk of both entities when the same abnormality was present in an older brother. The risk of cryptorchidism and hypospadias increased with decreasing birth weight independent of weeks of gestation. Twins were at lower risk than singletons for both entities in all lower birth weight groups. An increased risk of hypospadias was noted in the sons of women who had had a previous stillbirth. The risk of cryptorchidism and hypospadias slightly increased with decreasing parity. Birth weight was the principal determinant of cryptorchidism and hypospadias. Twins were at lower risk for both abnormalities than singletons in the same birth weight classes. There are indications of separate genetic as well as common environmental causes of cryptorchidism and hypospadias.