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IA Hughes

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.

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Abstract. The clinical and endocrine features of the syndromes of androgen insensitivity which display a wide phenotypic spectrum are reviewed. A simple, dispersed whole cell assay to study androgen receptor binding in genital skin fibroblasts has been used to determine the pathogenesis of androgen insensitivity. Classification of the disorders based on in vitro studies does not show absolute concordance with the clinical sub-groups. Androgen-induced augmentation of basal specific binding is proposed as a possible functional test of androgen responsiveness in disorders such as partial androgen insensitivity, isolated hypospadias and micropenis. Understanding the cause of androgen insensitivity in many receptor-positive patients awaits identification and isolation of DNA probes for the X-linked gene locus for the androgen receptor.

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NP Mongan, IA Hughes and HN Lim

BACKGROUND: The luteinising hormone receptor (LHR) is necessary for the stimulation of androgen production and male genital development. It contains three protein polymorphisms: a leucine and glutamine insertion between codons 8 and 9 (LQ+) and two amino acid substitutions (N291S, N312S). OBJECTIVES: To determine whether these LHR polymorphisms are associated with male genital undermasculinisation or the androgen receptor polyglutamine repeat polymorphism (AR(Q)n), which contributes in some cases to the cause of genital undermasculinisation. METHODS: The LHR polymorphisms were assessed by PCR amplification of genomic DNA, followed by restriction enzyme analysis. The frequency of the LHR polymorphisms were compared between an undermasculinised male group (n=75) and a control group (n=55). RESULTS: LQ+ was not independently associated with the undermasculinised group (P=0.09), but it was associated with increased AR(Q)n within the undermasculinised group (P=0.02), particularly for AR(Q)n lengths >or=26 (P=0.002). In the undermasculinised group, homozygosity for N291 (872A/A) was more frequent (P=0.05), whereas homozygosity for N312 (935A/A) was less frequent (P=0.05). The combination of the presence of 872A/A and the absence of 935A/A showed a stronger association with the undermasculinised group than either polymorphism independently (P=0.006). The odds ratio of this genotype compared with any other, between the undermasculinised and control groups was 3.28 (95% confidence interval (CI) 1.33 to 8.08). CONCLUSION: LHR polymorphisms may contribute to genital undermasculinisation.

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NP Mongan, J Jaaskelainen, S Bhattacharyya, RM Leu and IA Hughes

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HN Lim, E Raipert-de Meyts, NE Skakkebaek, Hawkins JR and IA Hughes

OBJECTIVE: Testicular maldescent is important because it is a common congenital disorder that is associated with an increased risk of infertility and testicular cancer. Murine studies indicate that testicular maldescent can result from disruption of insulin-like factor 3 (INSL3) activity and that it may be more severe when there is concurrent undermasculinisation. Therefore, the INSL3 gene was screened for mutations and polymorphisms that may contribute to testicular maldescent in patients with undermasculinisation as well as those with isolated testicular maldescent. METHODS AND RESULTS: The patient groups consisted of individuals with isolated testicular maldescent (n=28) and patients with undermasculinised genitalia and intra-abdominal (n=24) or inguinal gonads (n=33). The three control groups were: normal males (n=15), males with undermasculinised genitalia and scrotal gonads (n=29) and females (n=82). SSCP/HA mutation screening detected eight variants, five of which were predicted to alter the protein sequence (A-1G, V19L, P25S, A36T, R78H). Three of the amino acid changes (A-1G, V19L, R78H) each occurred in a single control sample and one was identified in a male with undermasculinised genitalia and intra-abdominal testes (P25S). The A36T amino acid polymorphism was found in both patient and control groups at a similar frequency. CONCLUSIONS: The evidence suggests that INSL3 mutations and polymorphisms are not a major cause of testicular maldescent with or without associated undermasculinisation.