HOME :: CHAPTER 15  :: 15.4 INSULIN-LIKE HORMONE 3 :: INSULIN-LIKE HORMONE-3 AND SECONDARY MALE SEX DETERMINATION

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Insulin-like Hormone-3 and Secondary Male Sex Determination

One of the differences between the testes and the ovaries is their position within the body. The ovaries are located near the kidneys, well within the body. The testes, however, have descended such that they are outside the main body, residing in the scrotum. The testes descend in two steps, the first step is within the abdomen, and the second step is from the abdomen to the scrotum. This sexual dimorphic position of the gonads in mammals is dependent on differential development of two ligaments, the cranial suspensory ligament (CSL) and the gubernaculum. During male embryogenesis, the gubernaculum grows and the CSL regresses. This results in the transabdominal descent of the testes. In the female, CSL develops while the gubernaculum regresses. The CSL holds the ovaries in a position lateral to the kidneys.

Recent evidence suggests that the regression of the CSL and the induction of gubernaculum development are mediated by testosterone and Insl-3, respectively. The Insl3 gene (insulin-like hormone-3; originally designated Ley I-L), a member of the insulin-like superfamily, is specifically expressed in Leydig cells of the fetal and postnatal testis. When male mice were made homozygous for a targeted deletion of the Insl3 locus (Nef and Parada, 1999; Zimmerman et al., 1999), the testes failed to descend, remaining freely floating in the abdominal cavity. These malformations were due to failure of gubernaculum development during embryogenesis. The deficiency of Insl3 appeared to stop gubernaculum growth, while testosterone inhibited the CSL growth. There was no ligament to hold the testes. In double-mutant male mice lacking both the Insl3 and androgen receptor genes, the testes were positioned adjacent to the kidneys and steadied in the abdomen by the CSL, just like ovaries. These findings demonstrate that Insl3 induces gubernaculum development in an androgen-independent way, while androgen-mediated regression of the CSL occurs independently from Insl3. Therefore, in addition to producing testosterone and anti-Müllerian duct hormone, the testes also produce insulin-like hormone-3, a hormone necessary for a part of the secondary male phenotype.

While the knockout mice show that these two testicular hormones are necessary for testes descent within the abdomen, mutations in the Insl-3 gene may not be that important for human conditions where the testes fail to descend (Krausz et al., 2000). In a study of 31 men with undescended testes, none of them showed any mutations in their Insl-3 genes.

Literature Cited

Krausz, C., Quintana-Murci, L., Fellous, M., Siffroi, J. P., and McElreavey, K. 2000. Mol. Hum. Reprod. 6: 298-302.

Nef, S. and Parada, L. F. 1999. Cryptorchidism in mice mutant for Insl3. Nat Genet. 22: 295-299.

Zimmermann, S., Steding, G., Emmen, J. M., Brinkmann, A. O., Nayernia, K., Holstein, A. F., Engel, W., and Adham, I. M. 1999. Targeted disruption of the Insl3 gene causes bilateral cryptorchidism. Mol. Endocrinol. 13: 681-691.

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