Normal function of the<unk>  receptor: Testosterone (T) enters the cell and, if 5-alpha-reductase is present, is converted into dihydrotestone (DHT). Upon steroid binding, the<unk>  receptor (AR) undergoes a conformational change and releases heat shock proteins (hsps). Phosphorylation (P) occurs before or after steroid binding. The AR translocates to the nucleus where dimerization, DNA binding, and the recruitment of coactivators occur. Target genes are transcribed (mRNA) and translated into proteins.<unk> s and the<unk>  receptor The effects that<unk> s have on the human body (virilization, masculinization, anabolism, etc.) are not brought about by<unk> s themselves, but rather are the result of<unk> s bound to<unk>  receptors; the<unk>  receptor mediates the effects of<unk> s in the human body. Likewise, the<unk>  receptor itself is generally inactive in the cell until<unk>  binding occurs. The following series of steps illustrates how<unk> s and the<unk>  receptor work together to produce<unk> ic effects: In this way,<unk> s bound to<unk>  receptors regulate the expression of target genes, thus produce<unk> ic effects. Theoretically, certain mutant<unk>  receptors can function without<unk> s; in vitro studies have demonstrated that a mutant<unk>  receptor protein can induce transcription in the absence of<unk>  if its steroid binding domain is deleted. Conversely, the steroid-binding domain may act to repress the AR transactivation domain, perhaps due to the AR's unliganded conformation. Sexual differentiation: The human embryo has indifferent sex accessory ducts until the seventh week of development.<unk> s in fetal development Human embryos develop similarly for the first six weeks, regardless of genetic sex (46,XX or 46,XY karyotype); the only way to tell the difference between 46,XX or 46,XY embryos during this time period is to look for Barr bodies or a Y chromosome. The gonads begin as bulges of tissue called the genital ridges at the back of the abdominal cavity, near the midline. By the fifth week, the genital ridges differentiate into an outer cortex and an inner medulla, and are called indifferent gonads. By the sixth week, the indifferent gonads begin to differentiate according to genetic sex. If the karyotype is 46,XY, testes develop due to the influence of the Y chromosome’s SRY gene. This process does not require the presence of<unk> , nor a functional<unk>  receptor. Until around the seventh week of development, the embryo has indifferent sex accessory ducts, which consist of two pairs of ducts: the Müllerian ducts and the Wolffian ducts. Sertoli cells within the testes secrete anti-Müllerian hormone around this time to suppress the development of the Müllerian ducts, and cause their degeneration. Without this anti-Müllerian hormone, the Müllerian ducts develop into the female internal genitalia (uterus, cervix, fallopian tubes, and upper vaginal barrel). Unlike the Müllerian ducts, the Wolffian ducts will not continue to develop by default. In the presence of testosterone and functional<unk>  receptors, the Wolffian ducts develop into the epididymides, vasa deferentia, and seminal vesicles. If the testes fail to secrete testosterone, or the<unk>  receptors do not function properly, the Wolffian ducts degenerate. Masculinization of the male genitalia is dependent on both testosterone and dihydrotestosterone. Masculinization of the male external genitalia (the penis, penile urethra, and scrotum), as well as the prostate, are dependent on the<unk>  dihydrotestosterone. Testosterone is converted into dihydrotestosterone by the 5-alpha reductase enzyme. If this enzyme is absent or deficient, then dihydrotestosterone is not created, and the external male genitalia do not develop properly. As is the case with the internal male genitalia, a functional<unk>  receptor is needed for dihydrotestosterone to regulate the transcription of target genes involved in development. Pathogenesis of<unk>  Mutations in the<unk>  receptor gene can cause problems with any of the steps involved in<unk> ization, from the synthesis of the<unk>  receptor protein itself, through the transcriptional ability of the dimerized,<unk> -AR complex.<unk>  can result if even one of these steps is significantly disrupted, as each step is required for<unk> s to activate the AR successfully and regulate gene expression. Exactly which steps a particular mutation will impair can be predicted, to some extent, by identifying the area of the AR in which the mutation resides. This predictive ability is primarily retrospective in origin; the different functional domains of the AR gene have been elucidated by analyzing the effects of specific mutations in different regions of the AR. For example, mutations in the steroid binding domain have been known to affect<unk>  binding affinity or retention, mutations in the hinge region have been known to affect nuclear translocation, mutations in the DNA-binding domain have been known to affect dimerization and binding to target DNA, and mutations in the transactivation domain have been known to affect target gene transcription regulation. Unfortunately, even when the affected functional domain is known, predicting the phenotypical consequences of a particular mutation (see Correlation of genotype and phenotype) is difficult. Some mutations can adversely impact more than one functional domain. For example, a mutation in one functional domain can have deleterious effects on another by altering the way in which the domains interact. A single mutation can affect all downstream functional domains if a premature stop codon or framing error results; such a mutation can result in a completely unusable (or unsynthesizable)<unk>  receptor protein. The steroid binding domain is particularly vulnerable to the effects of a premature stop codon or framing error, since it occurs at the end of the gene, and its information is thus more likely to be truncated or misinterpreted than other functional domains. Other, more complex relationships have been observed as a consequence of mutated AR; some mutations associated with male phenotypes have been linked to male breast cancer, prostate cancer, or in the case of spinal and bulbar muscular atrophy, disease of the central nervous system. The form of breast cancer seen in some men with PAIS is caused by a mutation in the AR's DNA-binding domain. This mutation is thought to cause a disturbance of the AR's target gene interaction that allows it to act at certain additional targets, possibly in conjunction with the estrogen receptor protein, to cause cancerous growth. The pathogenesis of spinal and bulbar muscular atrophy (SBMA) demonstrates that even the mutant AR protein itself can result in pathology. The trinucleotide repeat expansion of the polyglutamine tract of the AR gene that is associated with SBMA results in the synthesis of a misfolded AR protein that the cell fails to proteolyze and disperse properly. These misfolded AR proteins form aggregates in the cell cytoplasm and nucleus. Over the course of 30 to 50 years, these aggregates accumulate and have a cytotoxic effect, eventually resulting in the neurodegenerative symptoms associated with SBMA.
Androgen insensitivity syndrome
Mild androgen insensitivity syndrome
Partial androgen insensitivity syndrome
Complete androgen insensitivity syndrome
Estrogen insensitivity syndrome
Kallmann syndrome
Klinefelter syndrome
Turner syndrome