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PubMed · 17161333

Androgen resistance.

Ieuan A Hughes·Asma Deeb
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Abstract

Androgen resistance causes the androgen insensitivity syndrome in its variant forms and is a paradigm of clinical syndromes associated with hormone resistance. In its complete form, the syndrome causes XY sex reversal and a female phenotype. Partial resistance to androgens is a common cause of ambiguous genitalia of the newborn, but a similar phenotype may result from several other conditions, including defects in testis determination and androgen biosynthesis. The biological actions of androgens are mediated by a single intracellular androgen receptor encoded by a gene on the long arm of the X chromosome. Mutations in this gene result in varying degrees of androgen receptor dysfunction and phenotypes that often show poor concordance with the genotype. Functional characterization and three-dimensional modelling of novel mutant receptors has been informative in understanding the mechanism of androgen action. Management issues in syndromes of androgen insensitivity include decisions on sex assignment, timing of gonadectomy in relation to tumour risk, and genetic and psychological counselling.

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Androgen-Insensitivity SyndromeAndrogensChorionic GonadotropinDisorders of Sex DevelopmentDrug ResistanceFemaleFollicle Stimulating HormoneHormone Replacement TherapyHumansInfantInfant, NewbornLuteinizing HormoneMaleMutationPedigreePhenotypeReceptors, AndrogenTestosteroneJournal ArticleResearch Support, Non-U.S. Gov'tReview

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Ieuan A Hughes, Asma Deeb. 2006. Androgen resistance.. https://doi.org/10.1016/j.beem.2006.11.003

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[Incomplete androgen insensitivity].

In the androgen insensitivity syndrome (AIS) the androgen effect is decreased in the fetus and the youth despite the adequate testosterone production. Usually the mutation of the androgen receptor is responsible for the disease. In the presented case the external genitalia were similar to female genitalia but masses were palpable in the labioscrotal fold. The karyotype was 46,XY. There was no increase in the testosterone level during the first three months of life. The stimulation test by stanazolol and the androgen receptor gene analysis verified the androgen insensitivity. The mutation was absent in the mother's leukocytes. This fact makes the genetic advising difficult in this family.

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PubMed2006

Androgen receptor gene mutations in androgen insensitivity syndrome cause distinct patterns of reduced activation of androgen-responsive promoter constructs.

Assessment of quantitative impairment of reporter gene activation is an important strategy proving pathogenetic relevance of androgen receptor (AR)-gene mutations in androgen insensitivity syndrome (AIS). We hypothesized the additional existence of mutation-specific patterns of reduced target gene activation. Four AR-gene mutations causing AIS, L712F, M780I, R855H, and V866M, respectively, were recreated in an AR-expression plasmid. Activation of three structurally different androgen-dependent promoters (MMTV, (ARE)2TATA, and GRE-OCT) was measured in transfected CHO-cells in response to dihydrotestosterone (DHT), testosterone, androstenedione and stanozolol (S). V866M showed the lowest activity across all conditions. R855H exhibited strikingly high activation of MMTV in response to DHT. M780I showed markedly low activation of (ARE)2TATA by S. L712F demonstrated high activation of GRE-OCT. In essence, each mutation was characterized in this model by a specific pattern of reduced reporter gene activation. Our AR crystal structure analyses showed that L712 and M780 may cause distinct alterations of AR-ligand- and AR-coregulator interaction interfaces supporting the experimental observations. Our data support the hypothesis that mutations of the AR-gene in AIS induce mutation-specific patterns of reduced promoter activation in vitro. Considering the diversity of natural androgen-regulated promoters, mutation-specific differences of androgen response patterns may be of relevance in vivo and consequently may influence the AIS-phenotype. Assessment of transactivation patterns in vitro may be an interesting concept to extend functional description of AR-gene mutations in AIS.

Androgen-Insensitivity Syndrome↗