Sex determination and differentiation (human)
Human sex refers to the processes by which an individual becomes either a male or female during development.
The Jost Paradigm
Under typical circumstances, the sex of an individual will be determined and expressed through the following mechanisms:
- Chromosomal Sex (genetic): Presence or absence of Y chromosome
- Gonadal Sex (Primary Sex Determination): Controlled by presence or absence of testis determining factor (TDF)
- Phenotypic Sex (Secondary Sex Differentiation): Determined by the hormonal products produced by the gonads.
Sex differentiation
Sex differentiation refers to the expression of phenotypic attributes specific to the sex of an individual. While gonad development is a result of the presence or absence of the sex determination gene SRY on the Y chromosome, sex differentiation is determined by the hormonal products produced by the gonads.
Testosterone
In the 1930s, Alfred Jost determined that the presence of testosterone was required for Wolffian duct development in the male rabbit.[1]
Müllerian inhibiting substance
Jost also observed that while testosterone was required for Wolffian duct development, the regression of the Müllerian duct was due to another substance. This was later determined to be Müllerian inhibiting substance (MIS), a 140 kD dimeric glycoprotein that is produced by sertoli cells. MIS blocks the development of Müllerian ducts, promoting their regression.
5-alpha dihydrotestosterone (DHT)
Testosterone is converted to the more potent DHT by 5-alpha reductase. DHT is necessary to exert androgenic effects farther from the site of testosterone production, where the concentrations of testosterone are too low to have any potency. A 5-alpha reductase deficiency results in an androgen disorder characterized by female phenotype or severely undervirilized male phenotype with development of the epididymis, vas deferens, seminal vesicle, and ejaculatory duct, but also a pseudovagina.
Pathologies
The following disorders are caused by a malfunction in the sex determination and differentiation process:[2]
- Congenital adrenal hyperplasia - Inability of adrenal to produce sufficient cortisol, leading to increased production of testosterone resulting in severe masculinization of 46 XX females.
- Persistent müllerian duct syndrome - A rare type of pseudohermaphroditism that occurs in 46 XY males, caused by either a mutation in the Müllerian inhibiting substance (MIS) gene, on 19p13, or its type II receptor, 12q13. Results in a retention of Müllerian ducts (persistence of rudimentary uterus and fallopian tubes in otherwise normally virilized males), unilateral or bilateral undescended testes and sometimes causes infertility.
- Male pseudohermaphroditism - Failure of androgen production or inadequate androgen response, which can cause incomplete masculinization in XY males. Varies from mild failure of masculinization with undescended testes to complete sex reversal and female phenotype (Androgen insensitivity syndrome)
- Swyer syndrome. A form of complete gonadal dysgenesis, mostly due to mutations in the first step of sex determination; the SRY genes.
See also
References
- ^ A. Jost, D. Price, R. G. Edwards (1970). "Hormonal Factors in the Sex Differentiation of the Mammalian Foetus [and Discussion]". Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences 259(828): 119-131. link to article abstract
- ^ MacLaughlin and Donahoe N (2004). "Mechanisms of Disease: Sex Determination and Differentiation". New England Journal of Medicine 350 (4): 367–378. doi:10.1056/NEJMra022784. PMID 14736929.