GENETICS AND BIOLOGY OF EARLY REPRODUCTIVE TRACT DEVELOPMENT
Most living species have some form of sex-determination system that drives the development and expression of sexual characteristics in that organism. Sex determination can be genetic or can be a consequence of environmental or social variables. In humans, sex determination is genetic and is governed by speciﬁc genes and chromosomes. It is believed that the two human sex chromosomes (X and Y) evolved from other nonsex chromosomes (autosomes) 300 million years ago. Human females have two of the same kind of sex chromosome (XX), whereas males have two distinct sex chromosomes (XY). However, both male and female features can rarely be found in one individual, and it is possible to have XY women and XX men. Analysis of such individuals has revealed the genes of sex determination, including SRY (sex-determining region Y gene) on the short arm of the Y chromosome, which is important for maleness. The SRY gene product is a protein that harbors a high-mobility group box (HMG) sequence, a highly conserved DNA-binding motif that kinks DNA. This DNA-bending effect alters gene expression, leading to formation of a testis and subsequently to the male phenotype. Notably, XY individuals who lack the SRY gene on the Y chromosome are phenotypic females.
It is now clear that the SRY gene does not act in isolation to determine human sex. Other genes in other locations are also important for complete male sexual differentiation. DAX1, a nuclear hormone receptor, can alter SRY activity during development by suppressing genes downstream to SRY that would normally induce testis differentiation. A second gene, WNT4, largely conﬁned to the adult ovary, may also serve as an “anti-testis” gene. Indeed, the discovery of these genes has signiﬁcantly altered theories of sex determination. Previously, SRY gene presence was thought to determine male gonadal development from the bipotential gonad. The female genotype was considered the “default” developmental pathway for gonads. It is now clear that genes such as WNT4 and DAX1 can proactively induce female gonadal development, even in the presence of SRY.
Once gonadal sex is determined, several other events must occur for normal male sexual differentiation. Within the testis, Leydig cells make testosterone, a hormone that is critical for development of the internal genitalia, including the vas deferens, epididymis, and seminal vesicles through wolfﬁan duct differentiation. Leydig cells also synthesize insulin-like-3 to promote transabdominal testis migration that begins testis descent into the scrotum. Dihydrotestosterone (DHT), a testosterone metabolite, masculinizes the genital anlage to form the external genitalia, including the penis and scrotum as well as the prostate. In addition, Sertoli cells within the developing testis synthesize anti-müllerian hormone (AMH or MIF), which prevents the müllerian duct from developing into uterus and fallopian tubes and helps the early germ cells remain quiescent in the developing testis. Deﬁciencies in any of these developmental pathways generally results in either birth defects or intersex disorders. Such development disorders, formerly termed true or pseudo-hermaphroditism, can include chromosomal abnormalities, ambiguous genetalia, phenotypic sex anomalies, or true intersex states.