Establishment Of Chromosomal Sex Research Articles

The Molecular Genetics of Sex Determination and Sex Reversal in Mammals

The process of sex determination in mammals normally unfolds in three distinct stages: (1) establishment of chromosomal sex at fertilization (XX or XY); (2) commitment to the appropriate pathway of gonadal differentiation with respect to chromosomal sex, through the action (or absence) of the Y chromosome gene SRY; and (3) correct development of secondary sexual characteristics, including internal and external genitalia, in accordance with gonadal sex. At any of these three steps, the process of sex determination can go awry, leading to disorders of sexual development. In this article, we review the typical mechanism and process of mammalian sex determination, with an emphasis on the well-characterized mouse and human models. We also consider aberrant mammalian sex determination, focusing on examples of sex reversal stemming from gene defects.

Challenges in clinical and laboratory diagnosis of androgen insensitivity syndrome: a case report

IntroductionAndrogen is a generic term usually applied to describe a group of sex steroid hormones. Androgens are responsible for male sex differentiation during embryogenesis at the sixth or seventh week of gestation, triggering the development of the testes and penis in male fetuses, and are directed by the testicular determining factor: the gene SRY (sex determining region on Y chromosome) located on the short arm of chromosome Y. The differentiation of male external genitalia (penis, scrotum and penile urethra) occurs between the 9th and 13th weeks of pregnancy and requires adequate concentration of testosterone and the conversion of this to another more potent androgen, dihydrotestosterone, through the action of 5α-reductase in target tissues.Case presentationThis report describes the case of a teenage girl presenting with a male karyotype, and aims to determine the extension of the mutation that affected the AR gene. A Caucasian girl aged 15 was referred to our laboratory for genetic testing due to primary amenorrhea. Physical examination, karyotype testing and molecular analysis of the androgen receptor were critical in making the correct diagnosis of complete androgen insensitivity syndrome.ConclusionsSex determination and differentiation depend on a cascade of events that begins with the establishment of chromosomal sex at fertilization and ends with sexual maturation at puberty, subsequently leading to fertility. Mutations affecting the AR gene may cause either complete or partial androgen insensitivity syndrome. The case reported here is consistent with complete androgen insensitivity syndrome, misdiagnosed at birth, and consequently our patient was raised both socially and educationally as a female. It is critical that health care providers understand the importance of properly diagnosing a newborn manifesting ambiguous genitalia. Furthermore, a child with a pseudohermaphrodite phenotype should always undergo adequate endocrine and genetic testing to reach a conclusive diagnosis before gender is assigned and surgical interventions are carried out. Our results show that extreme care must be taken in selecting the genetic tools that are utilized for the diagnosis for androgen insensitivity syndrome.

Hormonal abnormalities leading to disorders of sexual development

Normal human sexual development occurs in a highly regulated process that comprises three distinct phases: establishment of chromosomal sex, development of the sex-specific gonads and phenotypic differentiation of the internal ductal anatomy and external genitalia. The latter two phases are mediated by specific hormonal effector molecules, including anti-Müllerian hormone and testosterone, and their dysregulation often leads to the development of a phenotypic disorder of sexual differentiation. This review describes the hormonal mediators that are involved in sexual development and the disorders of sexual differentiation that arise from their dysfunction.

Mechanisms of Disease: normal and abnormal gonadal development and sex determination in mammals

Sex differentiation in mammals occurs in three steps. The first is the establishment of chromosomal sex at fertilization, followed by the differentiation of the gonad into an ovary or testis, and finally the establishment of the phenotypic sex of the embryo and adult, which is regulated by the gonad. Disruption of any of these stages gives rise to sexual ambiguities that include 46,XY pure gonadal dysgenesis, 46,XX true hermaphroditism, and variable degrees of intersexuality. In this review, we focus on the development of the mammalian gonad from a bipotential primordium that differentiates into either an ovary or a testis. We describe the recent increase in our knowledge of the genetic defects that directly affect gonadal development, sex determination, and sex differentiation, with emphasis on the comparison of genetic studies in mice with studies of naturally occurring mutations in humans.

Origin, proliferation and differentiation of Leydig cells.

Mammalian sex determination involves complex interacting networks of cellular and hormonal signals leading to the development of male or female phenotypes. Three main sequential processes are involved: first, the establishment of chromosomal sex at fecundation (genetic sex); second, the development of the undifferentiated gonad into either testes or ovaries (gonadal sex); and third, differentiation of male or female internal and external genitalia (phenotypic sex). Male phenotype is controlled by two testicular hormones, the anti-Mullerian hormone (AMH) secreted by fetal Sertoli cells which induces regression of the Mullerian ducts, and testosterone produced by Leydig cells which induces differentiation of the Wolffian ducts into male reproductive organs, although conversion of testosterone into dehydrotestosterone is required for masculinization of the external genitalia. In the absence of testes, and therefore in the absence of both AMH and testosterone, the Wolffian ducts regress, creating a permissive environment for the differentiation of the Mullerian ducts and, thereby, female reproductive organs.

Regulation of sexual dimorphism in mammals.

Sexual dimorphism in humans has been the subject of wonder for centuries. In 355 BC, Aristotle postulated that sexual dimorphism arose from differences in the heat of semen at the time of copulation. In his scheme, hot semen generated males, whereas cold semen made females (Jacquart, D., and C. Thomasset. Sexuality and Medicine in the Middle Ages, 1988). In medieval times, there was great controversy about the existence of a female pope, who may have in fact had an intersex phenotype (New, M. I., and E. S. Kitzinger. J. Clin. Endocrinol. Metab. 76: 3-13, 1993.). Recent years have seen a resurgence of interest in mechanisms controlling sexual differentiation in mammals. Sex differentiation relies on establishment of chromosomal sex at fertilization, followed by the differentiation of gonads, and ultimately the establishment of phenotypic sex in its final form at puberty. Each event in sex determination depends on the preceding event, and normally, chromosomal, gonadal, and somatic sex all agree. There are, however, instances where chromosomal, gonadal, or somatic sex do not agree, and sexual differentiation is ambiguous, with male and female characteristics combined in a single individual. In humans, well-characterized patients are 46, XY women who have the syndrome of pure gonadal dysgenesis, and a subset of true hermaphrodites are phenotypic men with a 46, XX karyotype. Analysis of such individuals has permitted identification of some of the molecules involved in sex determination, including SRY (sex-determining region Y gene), which is a Y chromosomal gene fulfilling the genetic and conceptual requirements of a testis-determining factor. The purpose of this review is to summarize the molecular basis for syndromes of sexual ambiguity seen in human patients and to identify areas where further research is needed. Understanding how sex-specific gene activity is orchestrated may provide insight into the molecular basis of other cell fate decisions during development which, in turn, may lead to an understanding of aberrant cell fate decisions made in patients with birth defects and during neoplastic change.

Body Politics

Sexual differentiation is a sequential process beginning with the establishment of chromosomal sex at the moment of fertilization and finding a preliminary completion with the formation of a gender identity/role. Disturbances of this process can interfere with normal development in a male or female direction at different stages, leading to ambiguity. Only a narrow window of time exists for each phase of the differentiation process, during which there is sensitivity to particular stimuli. The residual effect is immutable and cannot be induced at a later point. While there is a close parallel between the paradigm of sexual differentiation of humans and other mammals from the chromosomal through the genital sex determination stages, this parallel becomes less manifest in the mechanism of sexual differentiation of the brain believed to be the substrate of gender identity/role. Money, after extensive research efforts, concluded that the future gender identity/role of a child with a defective sexual differentiation is best prognosticated by 'non-biological' factors such as the sex of assignment and rearing. Much to his regret, the terms gender and gender identity/role have subsequently become divorced from their bodily aspects. In transsexualism there is a conflict between gender identity/role and the body. The only way out for transsexuals is that their body follows their identity. This substantiates that gender identity/ role cannot be viewed as an entity discontinuous of one's bodily existence.