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Ieuan A Hughes

Publications and source records attributed to Ieuan A Hughes.

At least 19 recordsLinked to original sources
PubMed2007

Heterozygous missense mutations in steroidogenic factor 1 (SF1/Ad4BP, NR5A1) are associated with 46,XY disorders of sex development with normal adrenal function.

CONTEXT: Steroidogenic factor 1 (SF1/AdBP4/FTZF1, NR5A1) is a nuclear receptor transcription factor that plays a key role in regulating adrenal and gonadal development, steroidogenesis, and reproduction. Targeted deletion of Nr5a1 (Sf1) in the mouse results in adrenal and gonadal agenesis, XY sex-reversal, and persistent Müllerian structures in males. Consistent with the murine phenotype, human mutations in SF1 were described initially in two 46,XY individuals with female external genitalia, Müllerian structures (uterus), and primary adrenal failure. OBJECTIVE: Given recent case reports of haploinsufficiency of SF1 affecting testicular function in humans, we aimed to identify SF1 mutations in a cohort of individuals with a phenotypic spectrum of 46,XY gonadal dysgenesis/impaired androgenization (now termed 46,XY disorders of sex development) with normal adrenal function. METHODS AND PATIENTS: The study included mutational analysis of NR5A1 in 30 individuals with 46,XY disorders of sex development, followed by functional studies of SF1 activity. RESULTS: Heterozygous missense mutations in NR5A1 were found in four individuals (four of 30, 13%) with this phenotype. These mutations (V15M, M78I, G91S, L437Q) were shown to impair transcriptional activation through abnormal DNA binding (V15M, M78I, G91S), altered subnuclear localization (V15M, M78I), or disruption of the putative ligand-binding pocket (L437Q). Two mutations appeared to be de novo or germline changes. The other two mutations appeared to be inherited in a sex-limited dominant manner because the mother is heterozygous for the change. CONCLUSIONS: These studies demonstrate that SF1 mutations are more frequent than previously suspected causes of impaired fetal and postnatal testicular function in 46,XY individuals.

Adolescent↗
PubMed2006

Regulation of Wolffian duct development.

Wolffian ducts (WDs) are the embryonic structures that form the male internal genitalia. These ducts develop in both the male and female embryo. However, in the female they subsequently regress, whereas in the male they are stabilised by testosterone. The WDs then develop into separate but contiguous organs, the epididymis, vas deferens and seminal vesicles. Recently, considerable progress has been made in identifying genes that are involved in these different stages of development which is described in this review. In addition, WD development in (atypical forms of) cystic fibrosis and intersex disorders, such as the complete androgen insensitivity syndrome, 17beta-hydroxysteroid dehydrogenase deficiency and LH-receptor defects, is discussed. The apparent increase in male reproductive tract disorders is briefly discussed from the perspective of the potential endocrine-disrupting effects of the numerous chemicals in the environment to which the developing male foetus can be exposed.

Androgens↗
PubMed2006

A wider perspective on puberty.

The mechanisms that control the onset of puberty remain within the purview of the neurobiologists who first recognised the concept of removal of a restraint factor to permit reawakening of puberty. The discovery of a ligand-activated G protein receptor-signalling pathway upstream of the GnRH pulse generator adds further weight to the role of the hypothalamus in the central regulation of puberty. The physical pointers to puberty are the mainstay of assessing timing and tempo in a clinical setting but non-invasive and indirect methods of assessment only are appropriate for population studies in normal children. That puberty can be regarded as a sensor recognises the observation of secular changes in pubertal timing and perhaps qualitative aspects of tempo. The influences on the sensor include marked changes in nutrition and an environmental exposure to low-dose chemical mixtures interacting with a polygenic background.

Breast↗
PubMed2006

Changes in gene expression during Wolffian duct development.

BACKGROUND: Wolffian ducts (WDs) are the embryonic precursors of the male reproductive tract. Their development is induced by testosterone, which interacts with the androgen receptor (AR). The molecular pathways underlying androgen-dependent WD development are largely unknown. We aimed to identify AR target genes important in this process. METHODS: RNA was isolated from rat WDs at E17.5 and E20.5. Affymetrix GeneChip expression arrays were used to identify transcripts up- or downregulated more than 2-fold. Regulation of seven transcripts was confirmed using quantitative PCR. RESULTS: Transcripts from 76 known genes were regulated, including modulators of insulin-like growth factor and transforming growth factor-beta signalling. By controlling these modulators, androgens may indirectly affect growth factor signalling pathways important in epithelial-mesenchymal interactions and organ development. Caveolin-1, also upregulated, may play a role in modifying as well as mediating AR signalling. Differentiation of WD epithelium and smooth muscle, innervation and extracellular matrix synthesis were reflected in regulation of other transcripts. Several genes were previously suggested to be regulated by androgens or contained functional or putative androgen/glucocorticoid response elements, indicating they may be direct targets of androgen signalling. CONCLUSION: Our results suggest novel cohorts of signals that may contribute to androgen-dependent WD development and provide hypotheses that can be tested by future studies.

Androgens↗
PubMed2006

Five novel androgen receptor gene mutations associated with complete androgen insensitivity syndrome.

Mutations in the androgen receptor (AR) gene result in androgen insensitivity syndrome (AIS). We have identified five novel mutations that result in a complete loss in AR function and are associated with complete AIS. The mutations span all three AR major functional domains. In two cases, the loss of AR function could be explained on the basis of the current knowledge of AR molecular structure and function. N-terminal mutation c.256C>T (p.Gln86X) leads to an early stop codon and abolishes all DNA and ligand binding. The DNA-binding domain mutation c.1685G>A (p.Cys562Tyr) is located in the N-terminal part of the first zinc finger; a mutation in this position is likely to impair the association of the mutated AR with the androgen response element of target genes. The splice site mutation at intron 2/exon 3 junction (c.1766-1G>A) is shown to lead to c.1765_1766 ins69 (p.[Gly589_Lys590ins23;Gly589Glu]). The two novel ligand-binding domain mutations identified were recreated by site-directed mutagenesis. Both mutations c.2171G>T (p.Gly724Val) and c.2435T>C (p.Leu812Pro) abolished AR ligand binding and severely impaired AR mediated transactivation. Residue p.Gly724 is located in the ligand binding domain, between helices 3 and 4. This region is known to be involved not only in ligand binding but also in AR N/C-terminal interactions. The mutation p.Leu812Pro is located in the C-terminal end of helix 8. This domain is highly conserved and critical for ligand binding. This study extends current understanding of AR mutations associated with CAIS.

Adolescent↗
PubMed2006

Androgen resistance.

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.

Androgen-Insensitivity Syndrome↗
PubMed2005

Genetic mechanisms of fetal male undermasculinization: a background to the role of endocrine disruptors.

Fetal male sex development proceeds along an orderly sequence of events coordinated by an interplay of genetic and hormonal events. These operate in a time- and concentration-dependent manner. Once a testis is formed (the female sex being constitutive in nature), differentiation of the internal and external male genitalia is androgen dependent. A number of genetic syndromes of sex reversal are well characterized at the biochemical and molecular levels. They fall into three principal categories: defects in formation of the testis, defects in production of androgens, and defects in the action of androgens. In many instances, the precise cause is not established, although the investigative evidence points in the direction of one of the three stated classifications. Polymorphic variants in several of the genes involved in male development are associated with certain degrees of male undermasculinization. While the genetic background is essentially static, it is plausible that the effect of endocrine disruptors during fetal life acting through epigenetic mechanisms may partly explain the observed changing trends in male reproductive tract disorders.

Animals↗
PubMed2005

Inguinal hernia in female infants: a cue to check the sex chromosomes?

OBJECTIVES: To review the clinical presentation of complete androgen insensitivity syndrome (CAIS) and assess the current practice of considering the diagnosis of CAIS in female infants presenting with inguinal hernia. PATIENTS AND METHODS: AIS arises from target tissue resistance to the actions of androgens due to molecular abnormalities in the androgen receptor. Patients with CAIS are born with normal external female genitalia, and although inguinal hernias are uncommon in female infants, they are a well-known presentation of CAIS. Such patients were identified from the Cambridge Intersex Database and details of presentation, presence and laterality of inguinal hernia and contents, and family history of CAIS, were recorded. A questionnaire detailing different indications for considering CAIS in female infants with a hernia was distributed to members of the British Association of Paediatric Surgeons and the British Society for Paediatric Endocrinology and Diabetes. RESULTS: More than half of patients with CAIS presented with inguinal hernia, of which half were bilateral and a third contained gonads. Completed questionnaires were returned by 87 surgeons and 64 endocrinologists, and most of the surgeons and endocrinologists would consider CAIS in all female infants with a hernia. Bilateral hernias, hernias containing gonads and a family history of CAIS would prompt clinicians to consider the diagnosis. CONCLUSION: Most clinicians agreed that CAIS should be considered in all female infants with inguinal hernia, as this is the commonest mode of presentation in childhood. Macroscopic inspection of the internal genital structures coupled, perhaps, with gonadal biopsy is recommended. Fluorescence in situ hybridization offers a rapid and reliable method to check the sex chromosomes. Liaison between the paediatric surgeon and endocrinologist is essential in management of infants with CAIS.

Adolescent↗
PubMed2004

Congenital adrenal hyperplasia: transitional care.

Congenital adrenal hyperplasia (CAH) is a life-long disorder which poses management problems that are age- and sex-specific. The condition merits an organised, multi-disciplinary transitional care format similar to the kind that is now well established for Turner's syndrome in many centres. In the eyes of the paediatrician, achieving optimal growth is the primary target of CAH management during infancy and childhood. Fixation on this objective can be to the detriment of the patient because it may result in failure to appreciate the significance of metabolic disturbances that occur in later childhood, particularly in females, and which may be the progenitor of chronic problems with obesity, insulin resistance and infertility in adult life. Similarly, the care of the adult patient with CAH comprises more than just prescribing steroid replacement for primary adrenal insufficiency. The transition period between childhood and adulthood is an opportune time for review of the various management options and to assess the efficacy of steroid replacement, to consider alternative novel treatment modalities and to apply a checklist to the multi-faceted aspects of the medical, surgical and psychological needs of the patient.

Adolescent↗
PubMed2004

Residual activity of mutant androgen receptors explains wolffian duct development in the complete androgen insensitivity syndrome.

Development of the Wolffian ducts (WD) into epididymides and vasa deferentia is dependent on testosterone. Patients with the complete androgen insensitivity syndrome (CAIS) are therefore not expected to develop these structures. However, WD derivatives have been described in cases of CAIS. It is thought that these may be remnants. This study assesses the degree of WD development in 33 patients with CAIS and investigates whether this development was androgen dependent. Epididymides and vasa deferentia were identified in 70% of patients with substitution mutations in the androgen receptor ligand-binding domain. They were more developed than epididymides and vasa deferentia from 16- to 20-wk-old male fetuses, suggesting that the WD had been stimulated to grow, rather than failed to regress. Receptors with substitutions in the ligand-binding domain were normally expressed and showed residual response to androgens in transactivation assays. Patients with premature stop codons or frameshift mutations, which prevented androgen receptor expression, or DNA-binding domain mutations that abolished transcriptional activity did not have epididymides or vasa deferentia. We hypothesize that mutant receptors with residual activity in vitro respond to high local testosterone concentrations in vivo, thereby stimulating WD development. The classification of androgen insensitivity in such patients should be considered severe rather than complete.

Adolescent↗
PubMed2004

A perspective on stem cells by a clinician.

Stem cell terminology has entered the lexicon of medical practitioners even though the application of harvesting stem cells to treat diseases other than haematological disorders is not yet a reality in clinical practice. All branches of medicine will be affected by the new technology, more so those related to regenerative cell-based therapy for disorders such as Parkinson's disease, Alzheimer's disease, multiple sclerosis and traumatic injuries to the nervous system. Endocrinology is not a branch of medicine that carries a burden of disease that merits priority for the early application of stem cell therapy once the technique becomes safe and practical to do so. However, the allied disorder of diabetes is, sine qua non, an ideal example of how stem cell therapy has the potential to cure a chronic disabling condition. It is logical therefore to have included a number of articles on stem cells in this special issue of this journal, publishing papers on a range of endocrine-related topics.

Animals↗
PubMed2003

Psychological outcomes and gender-related development in complete androgen insensitivity syndrome.

We evaluated psychological outcomes and gender development in 22 women with complete androgen insensitivity syndrome (CAIS). Participants were recruited through a medical database (n = 10) or through a patient support group (n = 12). Controls included 14 males and 33 females, of whom 22 were matched to women with CAIS for age, race, and sex-of-rearing. Outcome measures included quality of life (self-esteem and psychological general well-being), gender-related psychological characteristics (gender identity, sexual orientation, and gender role behavior in childhood and adulthood), marital status, personality traits that show sex differences, and hand preferences. Women recruited through the database versus the support group did not differ systematically, and there were no statistically significant differences between the 22 women with CAIS and the matched controls for any psychological outcome. These findings argue against the need for two X chromosomes or ovaries to determine feminine-typical psychological development in humans and reinforce the important role of the androgen receptor in influencing masculine-typical psychological development. They also suggest that psychological outcomes in women with CAIS are similar to those in other women. However, additional attention to more detailed aspects of psychological well-being in CAIS is needed.

Adaptation, Psychological↗
PubMed2003

Androgen receptor gene CAG repeat polymorphism in the development of ovarian hyperandrogenism.

Ovarian hyperandrogenism, a key feature of polycystic ovary syndrome, is preceded by precocious pubarche (PP) (pubic hair < 8 yr) in some populations. We hypothesized that this earlier presentation may relate to increased androgen sensitivity, indicated by androgen receptor gene CAG repeat length. This polymorphism was genotyped in 181 Barcelona girls (age, 10.9 yr; range, 4-19 yr) who had presented with PP, and in 124 Barcelona control girls. PP girls had shorter mean CAG number than Barcelona controls (PP vs. controls: mean, range: 21.3, 7-31 repeats vs. 22.0, 15-32, P = 0.003) and greater proportion of short alleles 20 repeats or less (37.0% vs. 24.6%, P = 0.002). Among post-menarcheal PP girls (n = 69), shorter CAG number (biallelic mean </=20) was associated with higher 17-hydroxy-progesterone levels post leuprolide (P = 0.009), indicative of ovarian hyperandrogenism, higher testosterone levels (P = 0.02), acne (P = 0.03) and hirsutism scores (P = 0.01), and more menstrual cycle irregularities (P = 0.04). In multiple regression, ovarian hyperandrogenism risk was related to both low birth weight (SD <-1.5: odds ratio = 17.0; 95% confidence interval: 4.2-69.2) and shorter mean CAG number (20 or less repeats: odds ratio = 7.3; 1.3-42.0). In summary, shorter androgen receptor gene CAG number, indicative of increased androgen sensitivity, increases risks for PP and subsequent ovarian hyperandrogenism. Shorter CAG repeat alleles in Barcelona compared with United Kingdom women could lead to higher prevalences of these conditions.

Adolescent↗
PubMed2002

The genetics of male undermasculinization.

A review of the genetics of male undermasculinization must encompass a description of the embryology of the genital system. The dimorphism of sex development consequent upon the formation of a testis and the subsequent secretion of hormones to impose a male phenotype is highlighted. Thus, an understanding of the causes of male undermasculinization (manifest as XY sex reversal, complete and partial) includes reviewing the genetic factors which control testis determination and the production and action of testicular hormones. The study of disorders of male sex development has contributed substantially to knowledge of normal male development before birth. This knowledge has been complimented in recent years by the use of targeted murine gene disruption experiments to study the sex phenotype, although murine and human phenotypes are not always concordant. The investigation of disorders associated with male undermasculinization of prenatal onset is described briefly to complete the review.

Animals↗