Human sex refers to the processes by which an individual becomes either a male or female during development.
Complex mechanisms are responsible for male sex determination and differentiation. The steps of formation of the testes are dependent on a series of Y-linked, X-linked and autosomal genes actions and interactions. After formation of testes the gonads secrete hormones, which are essential for the formation of the male genitalia. Hormones are transcription regulators, which function by specific receptors. Ambiguous genitalia are result of disruption of genetic interaction. This review describes the mechanisms, which lead to differentiation of male sex and ways by which the determination and differentiation may be interrupted by naturally occurring mutations, causing different syndromes and diseases.
Sex determination: Initial event that determines whether the gonads will develop as testes or ovaries. Sex is determined by “the heat of the male partner during intercourse” –Aristotle (335 B.C.) Today: both environmental and internal mechanisms of sex determination can operate in different species.
Sex differentiation: Subsequent events that ultimately produce either the male or female sexual phenotype. Sexual differentiation is conformed in the human during four successive steps: the constitution of the genetic sex, the differentiation of the gonads, the differentiation of the internal and the external genital tractus and the differentiation of the brain and the hypothalamus.
Under typical circumstances, the sex of an individual will be determined and expressed through the following mechanisms:
Sex determination is associated with sex chromosomes that are different between male and female individuals. Many Species have heteromorphous sex chromosomes (different in size and gene content). Three important chromosomal sex-determining systems:
DNA that has been altered as a result of the recombination of genes; the formation of new combinations of different alleles of each gene on a chromosome; the result of crossing over.
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.
The combination of sex chromosomes that determine the sex of an offspring; in humans the sex chromosomes of a normal female are XX and the sex chromosomes of a normal male are XY.
XY system in mammals: Sex is determined by presence of Y. "Female" is the default sex; due to the absence of the Y. XXY: Klinefelter's syndrome: > same phenotype when testosterone receptor is defect. Turner syndrome: one X-chromosome > women produce no eggs
In the 1930s, Alfred Jost determined that the presence of testosterone was required for Wolffian duct development in the male rabbit.
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.
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.
The following disorders are caused by a malfunction in the sex determination and differentiation process:
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