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  • 1
    ISSN: 1432-1076
    Keywords: Key words Sex hormone-binding globulin ; Androgen receptor ; Mutations ; Androgen insensitivity syndrome ; Pseudohermaphroditism
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract In the genetic male, mutations of the androgen receptor (AR) gene cause phenotypes ranging from female to subfertile male. Binding assays on genital skin fibroblasts and DNA analysis alone provide incomplete information about receptor function. We used the sex hormone-binding globulin (SHBG) response to stanozolol as a measure of AR function and correlated the results with phenotypes which were classified according to the degree of defective masculinization. Of the 34 patients investigated, 9 had complete, and 14 had partial androgen insensitivity syndrome (AIS) with predominantly female, ambiguous, or predominantly male phenotype. Eleven subjects served as controls. Mutations were characterized using polymerase chain reaction-single strand conformation polymorphism analysis and direct DNA sequencing. DNA analysis revealed two major deletions, two minor defects leading to premature stop codons in exon 1, and 19 point mutations in the DNA- and hormone-binding domains of the AR gene. After stanozolol, SHBG remained unchanged in patients with complete AIS (102.0 ± 3.8 [SE]%; range 92.4%–129% of the initial value). The SHBG decrease was diminished in partial AIS with predominantly female (83.8% ± 1.7%; range 81.3%–87.0%), ambiguous (80.4% ± 4.4%, range 68.4%–89.1%), and predominantly male (mean 65.9% ± 4.9%, range 48.6%– 80.8%) phenotypes, and normal in controls (51.4% ± 2.1%, range 35.6%–62.1%). Differences between controls and each AIS group were statistically significant (P〈 〈 0.05 – 〈 0.0001). A close correlation was found between the degree of undermasculinization (AIS phenotype) and the SHBG response. Conclusions The SHBG test provides functional information about the severity of the receptor defect in vivo and hence adds to the structural information provided by DNA analysis. It detects receptor defects due to mutations within the entire gene, including the DNA-binding domain, and is a rapid, simple, and cost effective procedure. It may provide useful information for the diagnosis and management of affected children.
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  • 2
    ISSN: 1432-1076
    Keywords: Key words Androgen receptor ; Androgen insensitivity syndrome ; Somatic mosaicism ; Pseudohermaphroditism
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Recently, we demonstrated a previously unknown high rate of de novo mutations of the androgen receptor (AR) gene in androgen insensitivity syndrome (AIS) with some resulting in somatic mosaicism of mutant and wild type AR alleles. However, data on the genotype-phenotype relationship in the latter patients are sparse. We present here a 46,XY newborn with ambiguous genitalia carrying a mosaic of an 866 GTG (Val) → ATG (Met) mutation with the wild type AR gene. This mutation has usually been associated with complete AIS. Accordingly, we found markedly impaired transactivation due to the mutant Met866 AR. Essential information arose from Scatchard analysis of methyltrienolone binding on cultured genital skin fibroblasts. We demonstrated for the first time the expression of two functionally different ARs (Kd1: 5.58 nM = mutant, Kd2: 0.06 nM = wild type) in one AIS individual. This finding not only represents an important confirmation for the presence of the somatic mosaicism in the patient, it also indicates the most likely molecular mechanism responsible for the unexpectedly strong virilization of the patient: Androgen action through the wild type AR expressed by part of the somatic cells. Conclusions The present case clearly demonstrates the molecular mechanism by which somatic mosaicism of the androgen receptor gene can modulate in vivo androgen action. It underlines the importance of particular notice on somatic mosaicism in all androgen insensitivity syndrome patients carrying de novo mutations of the androgen receptor gene.
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  • 3
    ISSN: 0003-276X
    Keywords: Rat male accessory sex glands ; Coagulating gland ; Transglutaminase ; Stecretion ; Stroma ; Hormonal regulation ; Life and Medical Sciences ; Cell & Developmental Biology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine
    Notes: The effects of androgen deprivation and estrogen stimulation on rat coagulating gland were determined by immunohistochemistry and morphometric quantification of different tissue compartments. In castrated or estrogen-treated or estrogen-treated castrated animals, the reduction of the glandular lumen is the most obvious morphological alteration, which is accompanied by an increase in stromal tissue, especially within the lamina propria. Regressive changes occur most rapidly in castrated animals (already by the end of the first week), slower in estrogen-treated castrated animals, and still slower in estrogen-treated normal animals. In castrated animals, epithelium shows a reduction of rough endoplasmic reticulum, loss of secretory blebs, and a decrease of cell size and immunoreactivity for secretory transglutaminase. The reduction of glandular lumen results from an impressive increase in connective tissue of the lamina propria. Smooth muscle cells become atrophic in castrated animals, less so in estrogen-treated animals and in castrated estrogen-treated animals. A relative increase in thickness of the smooth muscle cell layer occurs in all experimental groups and is most obvious in estrogen-treated normal animals. The proportion of myofilament and intermediate filament proteins (smooth muscle-specific actin and desmin immunoreactivities) remains nearly unaltered in these cells after hormonal challenge. A redistribution of intermediate filaments occurs forming thicker bundles within the cells. No indication for increased mitotic activity of estrogenized smooth muscle cells has been found. After castration, and after estrogen treatment, the fibroblasts and the smooth muscle cells, respectively, appear responsible for the architectural changes within the coagulating gland. Reactions of the stroma are differentially regulated after estrogen treatment and androgen deprivation. No indication for increased biosynthetic activities of smooth muscle cells has been observed in any of the experimental conditions. © 1993 Wiley-Liss, Inc.
    Additional Material: 8 Ill.
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