The Experts below are selected from a list of 1866 Experts worldwide ranked by ideXlab platform
Olaf Hiort - One of the best experts on this subject based on the ideXlab platform.
-
Epigenetic Repression of Androgen Receptor Transcription in Mutation-Negative Androgen Insensitivity Syndrome (AIS Type II).
The Journal of clinical endocrinology and metabolism, 2018Co-Authors: Nadine Hornig, Pascal Rodens, Helmuth G. Dörr, Nina C. Hubner, Alexandra Kulle, H. U. Schweikert, Maik Welzel, Susanne Bens, Olaf Hiort, Ralf WernerAbstract:Context: Inactivating mutations within the AR gene are present in only ~40% of individuals with clinically and hormonally diagnosed Androgen Insensitivity Syndrome (AIS). Previous studies revealed the existence of an AR gene mutation-negative group of patients with AIS who have compromised Androgen receptor (AR) function (AIS type II). Objective: To investigate whether AIS type II can be due to epigenetic repression of AR transcription. Design: Quantification of AR mRNA and AR proximal promoter CpG methylation levels in genital skin-derived fibroblasts (GFs) derived from patients with AIS type II and control individuals. Setting: University hospital endocrine research laboratory. Patients: GFs from control individuals (n = 11) and patients with AIS type II (n = 14). Main Outcome Measure(s): Measurement of AR mRNA and AR promoter CpG methylation as well as activity of AR proximal promoter in vitro. Results: Fifty-seven percent of individuals with AIS type II (n = 8) showed a reduced AR mRNA expression in their GFs. A significant inverse correlation was shown between AR mRNA abundance and methylation at two consecutive CpGs within the proximal AR promoter. Methylation of a 158-bp-long region containing these CpGs was sufficient to severely reduce reporter gene expression. This region was bound by the runt related transcription factor 1 (RUNX1). Ectopic expression of RUNX1 in HEK293T cells was able to inhibit reporter gene expression through this region. Conclusions: Aberrant CpGs methylation within the proximal AR promoter plays an important role in the control of AR gene expression and may result in AIS type II. We suggest that transcriptional modifiers, such as RUNX1, could play roles therein offering new perspectives for understanding Androgen-mediated endocrine diseases.
-
gonadectomy in complete Androgen Insensitivity Syndrome why and when
Sexual Development, 2017Co-Authors: Ulla Dohnert, Lutz Wunsch, Olaf HiortAbstract:Prophylactic gonadectomy has been recommended in complete Androgen Insensitivity Syndrome (CAIS) because of an increased risk for the development of malignant germ cell tumors in the intra-abdominal gonads. No reliable screening parameters are available to detect early (pre-)malignant changes. Because the tumor risk before puberty is very low, the timing of gonadectomy has been postponed to allow spontaneous puberty and involvement of the patients in important decisions affecting their body and health. Gonadectomy after puberty is still discussed controversially. There are difficulties in determining the absolute malignancy risk for individuals with CAIS, difficulties with hormone therapy, and lack of studies supporting different protocols. In contrast, endogenous hormone profiles show very specific features that influence bone health, psychosocial well-being, and many other aspects which still have to be investigated. For women with CAIS who wish to keep their gonads, we propose a biannual screening program which has to be evaluated in a prospective multi-center trial.
-
the long term outcome of boys with partial Androgen Insensitivity Syndrome and a mutation in the Androgen receptor gene
The Journal of Clinical Endocrinology and Metabolism, 2016Co-Authors: Angela K Lucasherald, Anders Juul, S Bertelloni, Jillian Bryce, Jipu Jiang, Martina Rodie, Richard O Sinnott, M A Boroujerdi, Lindhardt M Johansen, Olaf HiortAbstract:Background: In boys with suspected partial Androgen Insensitivity Syndrome (PAIS), systematic evidence that supports the long-term prognostic value of identifying a mutation in the Androgen receptor gene (AR) is lacking. Objective: To assess the clinical characteristics and long-term outcomes in young men with suspected PAIS in relation to the results of AR analysis. Methods: Through the International Disorders of Sex Development Registry, clinical information was gathered on young men suspected of having PAIS (n = 52) who presented before the age of 16 years and had genetic analysis of AR. Results: The median ages at presentation and at the time of the study were 1 month (range, 1 day to 16 years) and 22 years (range, 16 to 52 years), respectively. Of the cohort, 29 men (56%) had 20 different AR mutations reported. At diagnosis, the median external masculinization scores were 7 and 6 in cases with and without AR mutation, respectively (P = .9), and median current external masculinization scores were 9 an...
-
Androgen Insensitivity Syndrome
Seminars in Reproductive Medicine, 2012Co-Authors: Ieuan A Hughes, Ralf Werner, Trevor Bunch, Olaf HiortAbstract:The Androgen Insensitivity Syndromes (AIS) fall within the generic category of 46,XY DSD (disorder of sex development) and present as phenotypes associated with complete or partial resistance to the action of Androgens. Three categories are recognized: complete Androgen Insensitivity Syndrome (CAIS), partial Androgen Insensitivity Syndrome (PAIS), mild Androgen Insensitivity Syndrome (MAIS). The Androgen receptor (AR) is encoded by an 8 exon gene on the X chromosome long arm. More than 800 mutations in the AR gene have been reported in AIS patients ( www.Androgendb.mcgill.ca/ ). They are distributed throughout the gene with a preponderance located in the ligand binding domain. The most severe mutations are generally associated with a CAIS phenotype, but the correlation is less defined in PAIS. CAIS presents typically as primary amenorrhoea in an adolescent female and less commonly in infancy with bilateral inguinal/labial swellings due to testes. The differential diagnosis in CAIS is limited, whereas in PAIS, numerous other causes of DSD can also produce the typical phenotype of micropenis, severe hypospadias and bifid scrotum. Management issues in CAIS involve timing of gonadectomy, appropriate hormone replacement therapy and assessment of the need for vaginal dilation or rarely, vaginal surgery. The risk of gonadal germ cell tumor is low during childhood and adolescence but increases in later adulthood. Expert psychological counseling is mandatory to manage the disconnect between chromosomal, gonadal and phenotypic sex and to choreograph the evolving process of disclosure from late childhood through to maturity. It is implicit that management in AIS requires a multidisciplinary team and engagement with patient advocacy groups.
-
hormonal management of complete Androgen Insensitivity Syndrome from adolescence onward
Hormone Research in Paediatrics, 2011Co-Authors: S Bertelloni, Eleonora Dati, Giampiero I Baroncelli, Olaf HiortAbstract:Complete Androgen Insensitivity Syndrome (CAIS) represents a main disorder of sex development. Women with CAIS may have their gonads removed before, during or after adolescence, thus requiring hormonal replacement therapy to induce puberty and/or maintain secondary sexual characteristics, to optimize bone mass accrual, and to promote physical and social well-being. Usually estrogens are used for this purpose, but formulations and doses should be better defined in multicentric prospective studies. Some women started testostosterone as hormonal replacement therapy, but this practice remains anecdotal. Bone health remains a crucial aspect in the management of persons with CAIS, but few sound data are available to guide clinical practice.
Ieuan A Hughes - One of the best experts on this subject based on the ideXlab platform.
-
Androgen Insensitivity Syndrome
Best Practice & Research Clinical Endocrinology & Metabolism, 2015Co-Authors: Nigel P Mongan, Rieko Tadokorocuccaro, Trevor Bunch, Ieuan A HughesAbstract:Androgen Insensitivity Syndrome (AIS) results from Androgen receptor dysfunction and is a common cause of disorder of sex development. The AIS phenotype largely depends on the degree of residual Androgen receptor (AR) activity. This review describes the molecular action of Androgens and the range of Androgen receptor gene mutations, essential knowledge to understand the pathogenesis of the complete and partial forms of this Syndrome. A multidisciplinary approach is recommended for clinical management from infancy through to adulthood. Hormone replacement therapy is needed following gonadectomy. Patients who choose to retain the gonads are at risk of developing germ cell tumors for which sensitive circulating tumor markers may soon become available. Whilst the contribution of AR dysfunction to complete AIS is well understood, the involvement of the AR and associated proteins as contributors to partial AIS is an area of active research. Disorders of sex development such as AIS which are related to AR dysfunction offer a breadth of manifestations for the clinician to manage and opportunities for further research on the mechanism of Androgen action.
-
promoter dependent activity on Androgen receptor n terminal domain mutations in Androgen Insensitivity Syndrome
Sexual Development, 2014Co-Authors: Rieko Tadokorocuccaro, Trevor Bunch, Nigel P Mongan, John Davies, Rosalind S Brown, Laura Audi, Kate Watt, Iain J Mcewan, Ieuan A HughesAbstract:Androgen receptor (AR) mutations are associated with Androgen Insensitivity Syndrome (AIS). Missense mutations identified in the AR-N-terminal domain (AR-NTD) are rare, and clinical phenotypes are typically mild. We investigated 7 missense mutations and 2 insertion/deletions located in the AR-NTD. This study aimed to elucidate the pathogenic role of AR-NTD mutants in AIS and to use this knowledge to further define AR-NTD function. AR-NTD mutations (Q120E, A159T, G216R, N235K, G248V, L272F, and P380R) were introduced into AR-expression plasmids. Stably expressing cell lines were established for del57L and ins58L. Transactivation was measured using luciferase reporter constructs under the control of GRE and Pem promoters. Intrinsic fluorescence spectroscopy and partial proteolysis studies were performed for mutations which showed reduced activities by using a purified AR-AF1 protein. Pem-luciferase reporter activation was reduced for A159T, N235K, and G248V but not the GRE-luciferase reporter. Protein structure analysis detected no significant change in the AR-AF1 region for these mutations. Reduced cellular expression and transactivation activity were observed for ins58L. The mutations Q120E, G216R, L272F, P380R, and del57L showed small or no detectable changes in function. Thus, clinical and experimental analyses have identified novel AR-signalling defects associated with mutations in the structurally disordered AR-NTD domain in patients with AIS.
-
Androgen Insensitivity Syndrome
Current Opinion in Endocrinology Diabetes and Obesity, 2014Co-Authors: Rieko Tadokorocuccaro, Ieuan A HughesAbstract:Purpose of review Androgen Insensitivity Syndrome (AIS) can present with a wide range of phenotypes, and its management requires a multidisciplinary approach from diagnosis in infancy to adulthood. This review provides an update on some clinical and genetic aspects in AIS. Additional outcome data on surgical and psychosexual findings are presented, together with a discussion on the risk of development of gonadal tumours in AIS. Recent findings This review covers clinical features of AIS, including recent trends in sex of rearing, aspects of Androgen receptor gene mutations and longer term outcomes in both complete and partial forms of AIS. Summary More follow-up studies are needed to optimize management in AIS, especially in the partial form. Predicting the risk of gonadal tumours is key to determining the timing of gonadectomy or whether to retain the gonads in the long term.
-
Androgen Insensitivity Syndrome
The Lancet, 2012Co-Authors: Ieuan A Hughes, John D Davies, Trevor Bunch, Vickie Pasterski, Kiki Mastroyannopoulou, Jane MacdougallAbstract:Summary Androgen Insensitivity Syndrome in its complete form is a disorder of hormone resistance characterised by a female phenotype in an individual with an XY karyotype and testes producing age-appropriate normal concentrations of Androgens. Pathogenesis is the result of mutations in the X-linked Androgen receptor gene, which encodes for the ligand-activated Androgen receptor—a transcription factor and member of the nuclear receptor superfamily. This Seminar describes the clinical manifestations of Androgen Insensitivity Syndrome from infancy to adulthood, reviews the mechanism of Androgen action, and shows examples of how mutations of the Androgen receptor gene cause the Syndrome. Management of Androgen Insensitivity Syndrome should be undertaken by a multidisciplinary team and include gonadectomy to avoid gonad tumours in later life, appropriate sex-hormone replacement at puberty and beyond, and an emphasis on openness in disclosure.
-
Androgen Insensitivity Syndrome
Seminars in Reproductive Medicine, 2012Co-Authors: Ieuan A Hughes, Ralf Werner, Trevor Bunch, Olaf HiortAbstract:The Androgen Insensitivity Syndromes (AIS) fall within the generic category of 46,XY DSD (disorder of sex development) and present as phenotypes associated with complete or partial resistance to the action of Androgens. Three categories are recognized: complete Androgen Insensitivity Syndrome (CAIS), partial Androgen Insensitivity Syndrome (PAIS), mild Androgen Insensitivity Syndrome (MAIS). The Androgen receptor (AR) is encoded by an 8 exon gene on the X chromosome long arm. More than 800 mutations in the AR gene have been reported in AIS patients ( www.Androgendb.mcgill.ca/ ). They are distributed throughout the gene with a preponderance located in the ligand binding domain. The most severe mutations are generally associated with a CAIS phenotype, but the correlation is less defined in PAIS. CAIS presents typically as primary amenorrhoea in an adolescent female and less commonly in infancy with bilateral inguinal/labial swellings due to testes. The differential diagnosis in CAIS is limited, whereas in PAIS, numerous other causes of DSD can also produce the typical phenotype of micropenis, severe hypospadias and bifid scrotum. Management issues in CAIS involve timing of gonadectomy, appropriate hormone replacement therapy and assessment of the need for vaginal dilation or rarely, vaginal surgery. The risk of gonadal germ cell tumor is low during childhood and adolescence but increases in later adulthood. Expert psychological counseling is mandatory to manage the disconnect between chromosomal, gonadal and phenotypic sex and to choreograph the evolving process of disclosure from late childhood through to maturity. It is implicit that management in AIS requires a multidisciplinary team and engagement with patient advocacy groups.
Ralf Werner - One of the best experts on this subject based on the ideXlab platform.
-
Epigenetic Repression of Androgen Receptor Transcription in Mutation-Negative Androgen Insensitivity Syndrome (AIS Type II).
The Journal of clinical endocrinology and metabolism, 2018Co-Authors: Nadine Hornig, Pascal Rodens, Helmuth G. Dörr, Nina C. Hubner, Alexandra Kulle, H. U. Schweikert, Maik Welzel, Susanne Bens, Olaf Hiort, Ralf WernerAbstract:Context: Inactivating mutations within the AR gene are present in only ~40% of individuals with clinically and hormonally diagnosed Androgen Insensitivity Syndrome (AIS). Previous studies revealed the existence of an AR gene mutation-negative group of patients with AIS who have compromised Androgen receptor (AR) function (AIS type II). Objective: To investigate whether AIS type II can be due to epigenetic repression of AR transcription. Design: Quantification of AR mRNA and AR proximal promoter CpG methylation levels in genital skin-derived fibroblasts (GFs) derived from patients with AIS type II and control individuals. Setting: University hospital endocrine research laboratory. Patients: GFs from control individuals (n = 11) and patients with AIS type II (n = 14). Main Outcome Measure(s): Measurement of AR mRNA and AR promoter CpG methylation as well as activity of AR proximal promoter in vitro. Results: Fifty-seven percent of individuals with AIS type II (n = 8) showed a reduced AR mRNA expression in their GFs. A significant inverse correlation was shown between AR mRNA abundance and methylation at two consecutive CpGs within the proximal AR promoter. Methylation of a 158-bp-long region containing these CpGs was sufficient to severely reduce reporter gene expression. This region was bound by the runt related transcription factor 1 (RUNX1). Ectopic expression of RUNX1 in HEK293T cells was able to inhibit reporter gene expression through this region. Conclusions: Aberrant CpGs methylation within the proximal AR promoter plays an important role in the control of AR gene expression and may result in AIS type II. We suggest that transcriptional modifiers, such as RUNX1, could play roles therein offering new perspectives for understanding Androgen-mediated endocrine diseases.
-
minor hypospadias the tip of the iceberg of the partial Androgen Insensitivity Syndrome
PLOS ONE, 2013Co-Authors: Nicolas Kalfa, Ralf Werner, Pascal Philibert, Francoise Audran, Anu Bashamboo, Helene Lehors, Myriam Haddad, Jean Michel Guys, Rachel Reynaud, Pierre AlessandriniAbstract:Background Androgens are critical in male external genital development. Alterations in the Androgen sensitivity pathway have been identified in severely undermasculinized boys, and mutations of the Androgen receptor gene (AR) are usually found in partial or complete Androgen Insensitivity Syndrome (AIS). Objective The aim of this study was to determine whether even the most minor forms of isolated hypospadias are associated with AR mutations and thus whether all types of hypospadias warrant molecular analysis of the AR. Materials and Methods Two hundred and ninety-two Caucasian children presenting with isolated hypospadias without micropenis or cryptorchidism and 345 controls were included prospectively. Mutational analysis of the AR through direct sequencing (exons 1–8) was performed. In silico and luciferase functional assays were performed for unreported variants. Results Five missense mutations of the AR were identified in 9 patients with glandular or penile anterior (n = 5), penile midshaft (n = 2) and penile posterior (n = 2) hypospadias, i.e., 3%: p.Q58L (c.173A>T), 4 cases of p.P392S (c.1174C>T), 2 cases of p.A475V (c.1424C>T), p.D551H (c.1651G>C) and p.Q799E (c.2395C>G). None of these mutations was present in the control group. One mutation has never been reported to date (p.D551H). It was predicted to be damaging based on 6 in silico models, and in vitro functional studies confirmed the lowered transactivation function of the mutated protein. Three mutations have never been reported in patients with genital malformation but only in isolated infertility: p.Q58L, p.P392S, and p.A475V. It is notable that micropenis, a cardinal sign of AIS, was not present in any patient. Conclusion AR mutations may play a role in the cause of isolated hypospadias, even in the most minor forms. Identification of this underlying genetic alteration may be important for proper diagnosis and longer follow-up is necessary to find out if the mutations cause differences in sexual function and fertility later in life.
-
Androgen Insensitivity Syndrome
Seminars in Reproductive Medicine, 2012Co-Authors: Ieuan A Hughes, Ralf Werner, Trevor Bunch, Olaf HiortAbstract:The Androgen Insensitivity Syndromes (AIS) fall within the generic category of 46,XY DSD (disorder of sex development) and present as phenotypes associated with complete or partial resistance to the action of Androgens. Three categories are recognized: complete Androgen Insensitivity Syndrome (CAIS), partial Androgen Insensitivity Syndrome (PAIS), mild Androgen Insensitivity Syndrome (MAIS). The Androgen receptor (AR) is encoded by an 8 exon gene on the X chromosome long arm. More than 800 mutations in the AR gene have been reported in AIS patients ( www.Androgendb.mcgill.ca/ ). They are distributed throughout the gene with a preponderance located in the ligand binding domain. The most severe mutations are generally associated with a CAIS phenotype, but the correlation is less defined in PAIS. CAIS presents typically as primary amenorrhoea in an adolescent female and less commonly in infancy with bilateral inguinal/labial swellings due to testes. The differential diagnosis in CAIS is limited, whereas in PAIS, numerous other causes of DSD can also produce the typical phenotype of micropenis, severe hypospadias and bifid scrotum. Management issues in CAIS involve timing of gonadectomy, appropriate hormone replacement therapy and assessment of the need for vaginal dilation or rarely, vaginal surgery. The risk of gonadal germ cell tumor is low during childhood and adolescence but increases in later adulthood. Expert psychological counseling is mandatory to manage the disconnect between chromosomal, gonadal and phenotypic sex and to choreograph the evolving process of disclosure from late childhood through to maturity. It is implicit that management in AIS requires a multidisciplinary team and engagement with patient advocacy groups.
-
apolipoprotein d apod is a putative biomarker of Androgen receptor function in Androgen Insensitivity Syndrome
Journal of Molecular Medicine, 2009Co-Authors: Mahesh Appari, Olaf Hiort, Ralf Werner, Lutz Wunsch, Gunnar Cario, Janos Demeter, Felix G Riepe, James D Brooks, Paul-martin HolterhusAbstract:Androgen Insensitivity Syndrome (AIS) is the most common cause of disorders of sex development usually caused by mutations in the Androgen receptor (AR) gene. AIS is characterized by a poor genotype–phenotype correlation, and many patients with clinically presumed AIS do not seem to have mutations in the AR gene. We therefore aimed at identifying a biomarker enabling the assessment of the cellular function of the AR as a transcriptional activator. In the first step, we used complementary DNA (cDNA) microarrays for a genome-wide screen for Androgen-regulated genes in two normal male primary scrotal skin fibroblast strains compared to two labia majora fibroblast strains from 46,XY females with complete AIS (CAIS). Apolipoprotein D (APOD) and two further transcripts were significantly upregulated by dihydrotestosterone (DHT) in scrotum fibroblasts, while CAIS labia majora cells were unresponsive. Microarray data were well correlated with quantitative real-time polymerase chain reaction (qRT-PCR; R = 0.93). Subsequently, we used qRT-PCR in independent new cell cultures and confirmed the significant DHT-dependent upregulation of APOD in five normal scrotum strains [13.5 ± 8.2 (SD)-fold] compared with three CAIS strains (1.2 ± 0.7-fold, p = 0.028; t test) and six partial Androgen Insensitivity Syndrome strains (2 ± 1.3-fold, p = 0.034; t test). Moreover, two different 17s-hydroxysteroid dehydrogenase III deficiency labia majora strains showed APOD induction in the range of normal scrotum (9.96 ± 1.4-fold), supporting AR specificity. Therefore, qRT-PCR of APOD messenger RNA transcription in primary cultures of labioscrotal skin fibroblasts is a promising tool for assessing AR function, potentially allowing a function-based diagnostic evaluation of AIS in the future.
Berenice B Mendonca - One of the best experts on this subject based on the ideXlab platform.
-
partial Androgen Insensitivity Syndrome due to somatic mosaicism of the Androgen receptor
Journal of Pediatric Endocrinology and Metabolism, 2018Co-Authors: Rafael Loch Batista, Mirian Yumie Nishi, Elaine Maria Frade Costa, Berenice B Mendonca, Andresa De Santi Rodrigues, Aline Zamboni Machado, Flavia Siqueira Cunha, Rosana Barbosa Silva, Sorahia DomeniceAbstract:Background Androgen Insensitivity Syndrome (AIS) is the most frequent etiology of 46,XY disorders of sex development (DSDs), and it is an X-linked disorder caused by mutations in the Androgen receptor (AR) gene. AIS patients present a broad phenotypic spectrum and individuals with a partial phenotype present with different degrees of undervirilized external genitalia. There are more than 500 different AR gene allelic variants reported to be linked to AIS, but the presence of somatic mosaicisms has been rarely identified. In the presence of a wild-type AR gene, a significant degree of spontaneous virilization at puberty can be observed, and it could influence the gender assignment, genetic counseling and the clinical and psychological management of these patients and the psychosexual outcomes of these patients are not known. Case presentation In this study, we report two patients with AR allelic variants in heterozygous (c.382G>T and c.1769-1G>C) causing a partial AIS (PAIS) phenotype. The first patient was raised as female and she had undergone a gonadectomy at puberty. In both patients there was congruency between gender of rearing and gender identity and gender role. Conclusions Somatic mosaicism is rare in AIS and nonsense AR variant allelic can cause partial AIS phenotype in this situation. Despite the risk of virilization and prenatal Androgen exposure, the gender identity and gender role was concordant with sex of rearing in both cases. A better testosterone response can be expected in male individuals and this should be considered in the clinical management.
-
a recurrent synonymous mutation in the human Androgen receptor gene causing complete Androgen Insensitivity Syndrome
The Journal of Steroid Biochemistry and Molecular Biology, 2017Co-Authors: Rafael Loch Batista, Andresa Rodrigues, Mirian Yumie Nishi, Nathalia Lisboa Gomes, Jose Antonio Diniz Faria, Daniela Rodrigues De Moraes, Luciani R Carvalho, Elaine Maria Frade Costa, Sorahia Domenice, Berenice B MendoncaAbstract:Androgen Insensitivity Syndrome (AIS) is the most common cause of 46,XY disorders of sex development (46,XY DSD). This Syndrome is an X-linked inheritance disease and it is caused by mutations in the human Androgen receptor (AR) gene. Non-synonymous point AR mutations are frequently described in this disease, including in the complete phenotype. We present a novel synonymous mutation in the human AR gene (c.1530C > T) in four 46,XY patients from two unrelated families associated with complete Androgen Insensitivity Syndrome (CAIS). The analysis of mRNA from testis showed that synonymous AR mutation changed the natural exon 1 donor splice site, with deletion of the last 92 nucleotides of the AR exon 1 leading to a premature stop codon 12 positions ahead resulting in a truncate AR protein. Linkage analyses suggested a probable founder effect for this mutation. In conclusion, we described the first synonymous AR mutation associated with CAIS phenotype, reinforcing the disease-causing role of synonymous mutations.
-
heterozygous nonsense mutation in the Androgen receptor gene associated with partial Androgen Insensitivity Syndrome in an individual with 47 xxy karyotype
Sexual Development, 2017Co-Authors: Rafael Loch Batista, Andresa Rodrigues, Mirian Yumie Nishi, Nathalia Lisboa Gomes, Elaine Maria Frade Costa, Sorahia Domenice, Alina C R Feitosa, Jose Antonia F, Berenice B MendoncaAbstract:There are only 2 patients with 47,XXY karyotype and Androgen receptor (AR) gene mutation reported in the literature, and both are diagnosed as complete Androgen Insensitivity Syndrome (CAIS). We report a 22-year-old female with 47,XXY karyotype and atypical external genitalia. Sequencing of AR revealed the heterozygous p.Asn849Lys*32 mutation, and extensive X chromosome microsatellite analysis showed homozygosity for Xp and heterozygosity for Xq, suggesting partial X maternal isodisomy. Partial Androgen Insensitivity Syndrome (PAIS) developed in this case, probably because of the presence of the heterozygous AR mutation and random X- inactivation of the healthy allele. This is the first report of a female patient with 47,XXY karyotype and PAIS phenotype.
-
height and bone mineral density in Androgen Insensitivity Syndrome with mutations in the Androgen receptor gene
Osteoporosis International, 2007Co-Authors: Debora Lucia Seguro Danilovic, Elaine Maria Frade Costa, Berenice B Mendonca, Pedro Henrique Silveira Correa, Karla F S Melo, I J P ArnholdAbstract:Androgen Insensitivity Syndrome (AIS) constitutes a natural model to study effects of Androgens and estrogens on growth and bone density. We evaluated height and bone density in patients with AIS with mutations in the Androgen receptor (AR) gene. A retrospective analysis was conducted of eight subjects with complete AIS (CAIS) and four with partial AIS (PAIS) submitted to gonadectomy followed by estrogen replacement, and three with PAIS who did not undergo gonadectomy. Standing height and bone mineral apparent density (BMAD) by DXA were measured and compared with male (z m) and female (z f) reference populations. The z-scores were compared with a value of zero using the one-sample t-test. Final heights of patients with CAIS and PAIS were intermediate between those predicted for females and males. BMAD of the lumbar spine in CAIS and PAIS after gonadectomy and estrogen replacement (z f = − 1.56 ± 1.04, P = 0.006, and z m = − 0.75 ± 0.89, P = 0.04) indicated vertebral bone deficit, whereas BMAD at the femoral neck was normal. No patient reported fractures. Subjects with AIS had mean final height intermediate between mean normal male and female, and decreased bone mineral density in the lumbar spine. These data suggest an important role for Androgens in normal male growth and bone density not replaced by estrogens.
Gerard S Conway - One of the best experts on this subject based on the ideXlab platform.
-
bone mineral density in complete Androgen Insensitivity Syndrome and the timing of gonadectomy
Clinical Endocrinology, 2017Co-Authors: Thomas F J King, Sarah M Creighton, Winnie Z M Wat, Gerard S ConwayAbstract:Objective Low bone mineral density (BMD) has been reported in complete Androgen Insensitivity Syndrome (CAIS), but the impact of timing of gonadectomy is not known. We aimed to assess the relationship between age of gonadectomy and BMD in women with CAIS. Design Retrospective analysis of pre- and post-gonadectomy parameters in women with CAIS attending an adult Disorders of Sex Development (DSD) clinic in a tertiary centre. Patients One hundred and thirteen women with CAIS. Measurements Dual-energy x-ray absorptiometry (DXA) before and after gonadectomy; and pre-gonadectomy hormone profile. Results Mean BMD was reduced (95%CI); T-score -1.34 (-1.55 to -1.13; P < 0.001) at the lumbar spine and -0.3 (-0.49 to -0.12; P = 0.001) at the hip. There was no relationship between age of gonadectomy and BMD. Thirty-two subjects had BMD measured before or within 2 years of gonadectomy, and mean BMD was reduced (95%CI) at the lumbar spine; T-score: -1.05 (-1.54 to -0.57; P < 0.001), but was normal at the hip; T-score -0.04 (-0.35 to 0.28; P = 0.8). There was no relationship between BMD and history of hernia, testosterone, oestradiol or follicle stimulating hormone levels. Twelve subjects had DXA both before and after gonadectomy, and after 4.3 (1.7 to 12.8) years there was no change in BMD. Conclusions We found reduced BMD at the spine and hip in subjects with CAIS. We found no relationship between age of gonadectomy and BMD, and we also found no drop in BMD in subjects followed up after gonadectomy. This article is protected by copyright. All rights reserved.
-
evaluation of retained testes in adolescent girls and women with complete Androgen Insensitivity Syndrome
Radiology, 2013Co-Authors: Rola S Nakhal, M A Hallcraggs, Alex Freeman, Alex Kirkham, Gerard S Conway, Rupali Arora, Christopher Woodhouse, Dan Wood, Sarah M CreightonAbstract:The results of this study confirm that MR imaging can accurately depict testicular findings in complete Androgen Insensitivity Syndrome and that these findings correlate well with histologic descriptions.
-
timing of gonadectomy in adult women with complete Androgen Insensitivity Syndrome cais patient preferences and clinical evidence
Clinical Endocrinology, 2012Co-Authors: Rebecca Deans, Sarah M Creighton, Lihmei Liao, Gerard S ConwayAbstract:OBJECTIVE: Adult women with complete Androgen Insensitivity Syndrome (CAIS) are increasingly likely to defer or decline gonadectomy despite counselling about malignancy risk. The objectives of this study were to review the evidence on the risk of gonadal malignancy in adult women with CAIS and to explore women's reasons for deferring gonadectomy. STUDY DESIGN: A case series and literature review. PATIENTS: Sixteen women with CAIS over the age of 18 years who have elected to defer gonadectomy. RESULTS: Sixty-two relevant papers were identified. Of these, 14 confirmed that tumours had been reported in 98 adults. Taking into account the limitations of combining historic case series, this review estimates a risk of gonadal malignancy of 14% (range 0% and 22%) in adults with CAIS. The most common reasons women offered for deferring gonadectomy included inconvenience of surgery, concern about surgical risk and reluctance to take hormone replacement therapy. CONCLUSIONS: Perceived benefits for retaining gonads in women with CAIS are prompting more women to keep their gonads in situ. An accurate estimate for adult malignancy risk is unavailable, and the risks currently quoted may be falsely reassuring.
-
sexual function in women with complete Androgen Insensitivity Syndrome
Fertility and Sterility, 2003Co-Authors: Catherine L Minto, Gerard S Conway, Lihmei K Liao, Sarah M CreightonAbstract:Abstract Objective To investigate sexual function in women with complete Androgen Insensitivity Syndrome (CAIS) and to investigate the prevalence of factors that might contribute to sexual difficulties. Design Cross sectional survey and clinical examination. Setting Tertiary hospital multidisciplinary intersex clinic and an international peer support group for CAIS. Patient(s) Sixty-six adult women with CAIS. Intervention(s) Self-completed survey of sexual function, genital normality perceptions, and compliance and satisfaction with vaginal hypoplasia treatments. Hospital case notes review, and genital examination for prevalence of vaginal and clitoral hypoplasia. Main outcome measure(s) Golombok-Rust Inventory of Sexual Satisfaction (GRISS) scores of study participants were compared against the scores of the test validation population (as control). In physical examination participants, anatomical dimensions were assessed against published normal values for clitoral and vaginal sizes. Result(s) We found that 90% of women with CAIS in this study had sexual difficulties when compared with the general female population, most commonly sexual infrequency and vaginal penetration difficulty; 77% perceived their vagina as small, but on genital examination only 35% had vaginal hypoplasia. Conclusion(s) Androgen deficiency leads to sexual problems. Vaginal hypoplasia and negative psychological adaptation to living with an intersex condition are likely to have contributed to the high rates of sexual problems found in this study. Treatments for vaginal hypoplasia need to be evaluated with outcome studies of long-term sexual function, quality of life, and satisfaction. Clinical services for the management of intersex conditions need to be multidisciplinary and aim to optimize the patient's physical and psychological health.