The Molecular Basis for IntersexualityPart One: The Developing Testis

Intersex disorders are the result of an adverse event which occurs at some stage along the pathway of normal sexual differentiation. We owe our understanding of this pathway largely to the pioneering intrauterine experiments carried out by Alfred Jost in wartime France during the 1940's. He showed that by removing the gonadal ridges in the early rabbit embryo before the stage of sexual differentiation both the internal and external genitalia went on to develop along female lines irrespective of the genetic sex. In a second series of experiments, he inserted a crystal of testosterone where the ridges had been and observed that the external genitalia in all cases masculinized although the Mullerian ducts persisted and went on to form fallopian tubes and a uterus. Jost concluded from these studies that in sexual differentiation female was the pathway of default but for normal masculinization to occur, the testes must secrete, in addition to testosterone, another substance which was responsible for suppression of the Mullerian ducts which he called ilihormone inhibitrice.i We now know this as Mullerian inhibiting substance or anti-Mullerian hormone (AMH), a TGF-betalike growth factor which is produced by the Sertoli cells early in testicular development. We have subsequently come to appreciate that testosterone, produced by the Leydig cells, is converted in the peripheral tissues by the enzyme 5 alpha reductase to dihydrotestosterone which is actually responsible for the masculinizing process and that the effectiveness of these hormones depends on the integrity of testosterone receptors in the target cells. Nonetheless, it is clear that the testis occupies a central role in the pathway of male sexual differentiation. The gonads in the early embryo are identical in both sexes and initially appear as swellings in the central portion of the urogenital ridges on either side of the dorsal midline. The first signs of testicular organization can be recognized at 42 days when cells in the medial portion of the mesonephros aggregate into cords of primordial Sertoli cells which come to envelope inflowing germ cells to form primordial tubules. Leydig cells migrate into the developing testicular interstitium where they come to rest as clusters between the tubules. These events are clearly genetically determined but the precise mechanisms responsible for initiating these steps in testicular development were, until recently, unknown.