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Biomedical subjects

R M Martin

Publications and source records attributed to R M Martin.

At least 19 recordsLinked to original sources
PubMed2006

Combined pituitary hormone deficiency (CPHD) due to a complete PROP1 deletion.

OBJECTIVE: PROP1 mutations are the most common cause of genetic combined pituitary hormone deficiency (CPHD). The aim of this study was to investigate the PROP1 gene in two siblings with CPHD. DESIGN: Pituitary function and imaging assessment and molecular analysis of PROP1. PATIENTS: Two siblings, born to consanguineous parents, presented with GH deficiency associated with other pituitary hormone deficiencies (TSH, PRL and gonadotrophins). The male sibling also had an evolving cortisol deficiency. METHODS: Pituitary size was evaluated by magnetic resonance imaging (MRI). PROP1 gene analysis was performed by polymerase chain reaction (PCR), automatic sequencing and Southern blotting. Amplification of sequence tag sites (STS) and the Q8N6H0 gene flanking PROP1 were performed to define the extension of PROP1 deletion. RESULTS: MRI revealed a hypoplastic anterior pituitary in the girl at 14 years and pituitary enlargement in the boy at 18 years. The PROP1 gene failed to amplify in both siblings, whereas other genes were amplified. Southern blotting analysis revealed the PROP1 band in the controls and confirmed complete PROP1 deletion in both siblings. The extension of the deletion was 18.4 kb. The region flanking PROP1 contains several Alu core sequences that might have facilitated stem-loop-mediated excision of PROP1. CONCLUSIONS: We report here a complete deletion of PROP1 in two siblings with CPHD phenotype.

Adolescent↗
PubMed2006

Haemoglobin A1c is not a surrogate for glucose and insulin measures for investigating the early life and childhood determinants of insulin resistance and Type 2 diabetes in healthy children. An analysis from the Avon Longitudinal Study of Parents and Children (ALSPAC).

AIMS: Research into early life and childhood determinants of insulin resistance and Type 2 diabetes are complicated by requirements for fasting blood samples and glucose tolerance tests. We investigated haemoglobin A(1c) (HbA(1c)), a marker of glycaemia measured in non-fasting blood, as an alternative. METHODS: HbA(1c) was measured in 1645 children aged 9-11 years without diabetes from the Avon Longitudinal Study of Parents and Children. Thirty-nine children had two HbA(1c) measurements. Data on parental, child and potential confounding factors were collected prospectively from questionnaires, medical records and direct examination. Data from a shortened 30-min oral glucose tolerance test were available for 431 children at age 8 years. Body composition was measured by dual-energy X-ray absorptiometry. RESULTS: Mean (sd) HbA(1c) was 4.91(0.29)%. HbA(1c) increased with age and was higher in boys compared with girls, non-white compared with white children, and in children with anaemia. Mean difference between repeated HbA(1c) measurements was 0.01%. HbA(1c) was weakly positively associated with fasting glucose (beta = 0.066%/mmol/l, P = 0.05), but was not associated with 30-min glucose, fasting or 30-min insulin, or homeostasis model assessment-insulin resistance. HbA(1c) was weakly inversely associated with weight sd score (beta =-0.02%/unit, P = 0.004), body mass index sd score (beta = -0.02%/unit, P = 0.002), and total body fat (beta = -0.003%/kg, P = 0.06) and lean mass (beta = -0.011%/kg, P = 0.01), but was not associated with birthweight or breastfeeding. CONCLUSIONS: HbA(1c) is not a good marker of fasting or post-load glucose and insulin measures in healthy children, and is not a viable alternative to these measures for investigating the determinants of insulin resistance and Type 2 diabetes in children.

Biomarkers↗
PubMed2005

Neuropathology of fragile X-associated tremor/ataxia syndrome (FXTAS).

Fragile X-associated tremor/ataxia syndrome (FXTAS) is an adult-onset neurodegenerative disorder that affects carriers, principally males, of premutation alleles (55-200 CGG repeats) of the fragile X mental retardation 1 (FMR1) gene. Clinical features of FXTAS include progressive intention tremor and gait ataxia, accompanied by characteristic white matter abnormalities on MRI. The neuropathological hallmark of FXTAS is an intranuclear inclusion, present in both neurons and astrocytes throughout the CNS. Prior to the current work, the nature of the associations between inclusion loads and molecular measures (e.g. CGG repeat) was not defined. Post-mortem brain and spinal cord tissue has been examined for gross and microscopic pathology in a series of 11 FXTAS cases (males, age 67-87 years at the time of death). Quantitative counts of inclusion numbers were performed in various brain regions in both neurons and astrocytes. Inclusion counts were compared with specific molecular (CGG repeat, FMR1 mRNA level) and clinical (age of onset, age of death) parameters. In the current series, the three most prominent neuropathological characteristics are (i) significant cerebral and cerebellar white matter disease, (ii) associated astrocytic pathology with dramatically enlarged inclusion-bearing astrocytes prominent in cerebral white matter and (iii) the presence of intranuclear inclusions in both brain and spinal cord. The pattern of white matter pathology is distinct from that associated with hypertensive vascular disease and other diseases of white matter. Spongiosis was present in the middle cerebellar peduncles in seven of the eight cases in which those tissues were available for study. There is inclusion formation in cranial nerve nucleus XII and in autonomic neurons of the spinal cord. The most striking finding is the highly significant association between the number of CGG repeats and the numbers of intranuclear inclusions in both neurons and astrocytes, indicating that the CGG repeat is a powerful predictor of neurological involvement in males, both clinically (age of death) and neuropathologically (number of inclusions).

Age of Onset↗
PubMed2005

Prostate cancer: screening approaches.

Introducing screening for prostate cancer requires evidence that this would do more good than harm. Current evidence about the impact and natural history of prostate cancer, screening and diagnostic tests, and the effectiveness of treatments is reviewed below.

Evidence-Based Medicine↗
PubMed2003

Clinical studies in patients with solid tumors using a second-generation antisense oligonucleotide (GEM 231) targeted against protein kinase A type I.

GEM 231 is a second-generation antisense oligonucleotide targeted against the RIalpha regulatory subunit of cAMP-dependent protein kinase type I (PKA-I). Excessive expression of PKA-I is associated with cell proliferation and transformation, and increased levels of secreted extracellular PKA (ECPKA) are found in the serum of cancer patients. Preclinical studies have demonstrated single-agent antitumor activity of GEM 231 in a variety of human cancer xenograft models, and additive or synergistic antitumor activity has been observed with taxane and/or camptothecin-based combinations. Based on prior safety (MTD) data demonstrating dose-dependent, reversible, and cumulative transaminitis, and high peak plasma concentration (Cmax)-dependent changes in activated partial thromboplastin time (aPTT) with GEM 231 2-h twice-weekly infusions, an alternative schedule of GEM 231 given as a single agent was evaluated in patients with advanced solid tumors. Fourteen patients (median age approximately 60 yrs) with advanced solid malignancies received a total of 78 weeks of therapy. GEM 231 was infused via a CADD pump at 80 mg/m2/day (d) for 3 d/wk (n = 1), then for 5 d/wk at 80 (n = 3), 120 (n = 8), and 180 mg/m2/d (n = 2). One cycle was defined as 4 weeks of therapy. Apparent dose dependency for the occurrence of transaminitis was readily reversible. At 180 mg/m2/d, 2 of 2 patients had cycle 1 dose-limiting toxicity (DLT) transaminitis. One patient treated at 120 mg/m2/d experienced grade 3 transaminase elevations after 8 weeks of therapy, but when serum transaminase values rapidly improved he resumed treatment at 80 mg/m2/d for 6 weeks until tumor progression was documented. Another patient at 120 mg/m2/d developed grade 3 esophagitis after 3 weeks, limiting further dosing. One patient (lung cancer) demonstrated stable disease for 9 weeks. Overall, plasma aPTT was minimally prolonged and changes were transient, peaked at the end of each infusion, and were not associated with spontaneous bleeding. A constitutive symptom (e.g., low-grade fatigue) was common, cumulative, and reversible following discontinuation of therapy. Serum ECPKA was measured by enzymatic assay and Western blotting from blood drawn at the beginning and end of each infusion. Serum ECPKA levels demonstrated a trend to decline with the treatment. In addition to single agent schedules, combination trials were undertaken to assess safety and possible interaction of GEM 231 with taxanes (paclitaxel, docetaxel), given once every 3 weeks (one cycle). While trials using the 2-h twice-weekly GEM 231 infusions are ongoing, preliminary results from both studies show that it is safe to combine paclitaxel or docetaxel with GEM 231. Overall, it is also feasible to administer GEM 231 in combination with taxane or nontaxane chemotherapy (e.g., camptothecins). Phase I combination studies are currently underway to further explore the clinical, pharmacokinetic, and biologic profile of GEM 231 with chemotherapy.

Antineoplastic Agents↗
PubMed2002

Association between breast feeding and growth: the Boyd-Orr cohort study.

OBJECTIVE: To investigate the association of breast feeding with height and body mass index in childhood and adulthood. DESIGN: Historical cohort study, based on long term follow up of the Carnegie (Boyd-Orr) survey of diet and health in pre-war Britain (1937-1939). SETTING: Sixteen urban and rural districts in Britain. SUBJECTS: A total of 4999 children from 1352 families were surveyed in 1937-1939. Information on infant feeding and childhood anthropometry was available for 2995 subjects. MAIN OUTCOME MEASURES: Mean differences in childhood and adult anthropometry between breast and bottle fed subjects. RESULTS: Breast feeding was associated with the survey district, greater household income, and food expenditure, but not with number of children in the household, birth order, or social class. In childhood, breast fed subjects were significantly taller than bottle fed subjects after controlling for socioeconomic variables. The mean height difference among boys was 0.20 standard deviation (SD) (95% confidence interval (CI) 0.07 to 0.32), and among girls it was 0.14 SD (95% CI 0.02 to 0.27). Leg length, but not trunk length, was the component of height associated with breast feeding. In males, breast feeding was associated with greater adult height (difference: 0.34 SD, 95% CI 0.13 to 0.55); of the two components of height, leg length (0.26 SD, 95% CI 0.02 to 0.50) was more strongly related to breast feeding than trunk length (0.16 SD, 95% CI -0.04 to 0.35). Height and leg length differences were in the same direction but smaller among adult females. There was no association between breast feeding and body mass index in childhood or adulthood. CONCLUSIONS: Compared with bottle fed infants, infants breast fed in the 1920s and 1930s were taller in childhood and adulthood. As stature is associated with health and life expectancy, the possible long term impact of infant feeding on adult mortality patterns merits further investigation.

Adolescent↗
PubMed2002

Population need for coronary revascularisation: are national targets for England credible?

OBJECTIVE: To estimate the need for coronary revascularisation, by using an incidence of indications approach, among 45-84 year olds with stable angina, unstable angina, and acute myocardial infarction. DESIGN: Modelling exercise. Six key steps along the pathway of care from initial diagnosis in primary or secondary care to revascularisation were defined and the frequency of indications estimated using routine data from hospital admissions and data from studies in the general population, and primary and secondary care. SETTING AND PATIENTS: Mid-1998 population of England. INTERVENTION: Coronary revascularisation. MAIN OUTCOME MEASURE: Ability to benefit (need), defined by randomised trials, expert panel ratings from the ACRE (appropriateness of coronary revascularisation) study, or by informal consensus. RESULTS: The need for coronary revascularisation was estimated to be 92 000 procedures, equivalent to a rate of 1861 per million population. Overall, the model of need exceeded current provision by 3.3:1, although among people aged 75 years and over the ratio was 7.7:1. A plausible upper estimate of need--obtained by assuming that 90% of patients with stable angina were referred from primary care and that angiography would be performed in 65% of patients with acute myocardial infarction and 75% of patients with unstable angina--was 2626 per million population. CONCLUSIONS: The national target of 1500 revascularisation procedures per million population is credibly related to population need, although upper estimates of need are considerably higher. Better understanding is required of the benefits of referring patients with specific indications from primary care. The greatest relative increase in provision is required for those aged 75 and older, among whom trial evidence of benefit is scant.

Aged↗
PubMed2001

An inherited mutation outside the highly conserved DNA-binding domain of the p53 tumor suppressor protein in children and adults with sporadic adrenocortical tumors.

Mutations of the p53 tumor suppressor gene are the single most common genetic alterations in human cancers. Recently, a distinct nucleotide substitution was identified in exon 10 of the p53 gene, leading to an Arg337His mutation in 97% of children with adrenocortical tumors from Southern Brazil. In the present study, we investigated the presence of this mutation in a larger series of 55 patients (37 adults and 18 children) with benign and malignant sporadic adrenocortical tumors. None of the patients had family cancer histories that conformed to the criteria for Li-Fraumeni syndrome. Twenty-one asymptomatic close relatives of patients with p53 mutations and 60 normal unrelated individuals were also studied. The missense Arg337His mutation was identified in 19 patients (14 children and 5 adults), and 8 of 11 cases studied had LOH. Among the 19 patients with the Arg337His mutation, only one boy and three adults showed fatal evolution or recurrent metastases. This mutation was also identified in heterozygous state in asymptomatic first-degree relatives of the patients, indicating that Arg337His mutation was inherited in most cases. In contrast, this mutation was not found in 120 alleles of normal unrelated controls. In conclusion, the germ line Arg337His mutation of p53 protein is present at a high frequency (77.7%) in children with benign or malignant sporadic adrenocortical tumors, but it is not restricted to the pediatric group, since 13.5% of adults with adrenocortical tumors also had this mutation. The presence of this mutation was related to unfavorable prognosis in most of the adults, but not in the children with adrenocortical tumors.

Adolescent↗
PubMed2001

Age- and gender-specific asthma death rates in patients taking long-acting beta2-agonists: prescription event monitoring pharmacosurveillance studies.

OBJECTIVE: Prescription event monitoring is a national drug safety surveillance scheme in which prescribers are prompted to report events and deaths following prescription of newly marketed drugs. This paper presents age- and gender-specific asthma death rates in patients prescribed the long-acting beta2-agonists salmeterol and bambuterol. DESIGN AND SETTING: Pharmacosurveillance cohort study of general practice patients in England. PATIENTS AND PARTICIPANTS: 15 406 patients prescribed salmeterol between December 1990 and May 1991, and 8098 patients prescribed bambuterol between February 1993 and December 1995. METHODS: Patients prescribed these drugs by general practitioners in England were identified using the national pharmacovigilance system of prescription event monitoring, in which details of all dispensed prescriptions were provided in confidence by the Prescription Pricing Authority. Questionnaires were sent to the prescriber asking for details of events occurring after the first prescription. In each study an attempt was made to establish the cause of all deaths reported on the questionnaires, via retrieval of the patients' medical notes or examination of death certificates. OUTCOME MEASURES AND RESULTS: There was little evidence of heterogeneity in the drug-specific death rates and we therefore present the combined age- and gender-specific death rates for the 2 cohorts. Overall, there were 85 asthma deaths among people taking the long-acting beta2-agonists studied (bambuterol and salmeterol cohorts combined). The overall death rate was 2.33 [95% confidence interval (CI) 1.84 to 2.84] per 10000 months of observation. There were 37 asthma deaths among male patients (rate 2.40 per 10000 months of observation; 95% CI 1.74 to 3.40) and 48 asthma deaths among female patients (rate 3.08 per 10000 months of observation; 95% CI 2.21 to 3.98). There was no difference in death rates when male and female patients were compared (rate ratio 0.78; 95% CI 0.49 to 1.22; p = 0.26). CONCLUSION: Prescription event monitoring is a form of prompted surveillance allowing rapid, uniform, national and practical assessment of newly marketed drugs on large cohorts of patients in England. These data provide benchmark rates from which to assess the performance of newly prescribed anti-asthma drugs and generate hypotheses for later analytical investigation in which confounding by indication and asthma severity can be controlled for. Any differences in these rates should be considered as a source of signal generation within the context of a surveillance programme, rather than as robust evidence of any mortality differential between drugs.

Adrenergic beta-Agonists↗
PubMed2000

Local production of anti-CD4 antibody by transgenic allogeneic grafts affords partial protection.

BACKGROUND: Immunosuppressive drugs and anti-lymphocyte antibody are used clinically to suppress cellular rejection responses. However, these systemic regimens often led to general immunodeficiency and thus increased susceptibility to opportunistic infection and neoplasia. Immunosuppressive molecules delivered locally may be a way of inhibiting rejection responses, whereas systemic immunity is preserved. To achieve protective local immunosuppression, we produced a graft secreting its own immunomodulator, by deriving transgenic mice expressing a chimeric anti-CD4 antibody (GK2c) in the pancreas. METHODS AND RESULTS: Transgenic mice in bml genetic background expressing a modified anti-mouse CD4 antibody (GK2c) under two promoters have been produced. Tissue expression of GK2c was detected by immunoperoxidase staining. Under the cytomegalovirus promoter, there was abundant GK2c expression in pancreatic exocrine tissue. Under the rat preproinsulin II promoter, there was abundant GK2c expression in pancreatic endocrine tissue only. High-expression transgenic lines had 10-100 microg/ml GK2c in blood plasma. By flow cytometry, these transgenic mice were devoid of CD4+ cells in their peripheral lymphoid organs. To test transgenic mice as donors, fetal pancreata from transgenic mice were grafted into fully allogeneic CBA mice under the kidney capsule, transgenic grafts had prolonged survival compared with control non-transgenic grafts. Furthermore, GK2c transgenic grafts had reduced infiltration with an absence of CD4+ cells at the graft site without any effect on the cell composition in lymphatic tissues. CONCLUSION: Transgenic grafts that secrete anti-CD4 antibody can afford some protection against graft rejection, while only affecting the CD4 population at the graft site.

Animals↗
PubMed2000

SPAK, a STE20/SPS1-related kinase that activates the p38 pathway.

We have cloned a member of the STE20/SPS1 protein kinase family from a transformed rat pancreatic beta cell line. SPAK (STE20/SPS1-related, proline alanine-rich kinase) belongs to the SPS1 subfamily of STE20 kinases and is highly conserved between species. SPAK is expressed ubiquitously, although preferentially in brain and pancreas. Biochemical characterization of SPAK catalytic activity demonstrates that is a serine/threonine kinase that can phosphorylate itself and an exogenous substrate in vitro. SPAK is immunoprecipitated from transfected mammalian cells as a complex with another, as yet uncharacterized, serine/threonine kinase which is capable of phosphorylating catalytically-inactive SPAK and myelin basic protein in an in vitro kinase assay. SPAK specifically activates the p38 pathway in cotransfection assays. Like MST1 and MST2, SPAK contains a putative caspase cleavage site at the junction of the catalytic domain and the C-terminal region. Full-length SPAK is expressed in the cytoplasm in transfected cells, while a mutant corresponding to caspase-cleaved SPAK is expressed predominantly in the nucleus. The similarity of SPAK to other SPS1 family members, its ability to activate the p38 pathway, in addition to its putative caspase cleavage site, provide evidence that SPAK may act as a novel mediator of stress-activated signals. Oncogene (2000) 19, 4290 - 4297

Amino Acid Sequence↗
PubMed2000

Metallization of molecular hydrogen: predictions from exact-exchange calculations.

We study metallization of molecular hydrogen under pressure using exact-exchange (EXX) Kohn-Sham density-functional theory in order to avoid well-known underestimates of band gaps associated with standard local-density or generalized-gradient approximations. Compared with the standard methods, the EXX approach leads to considerably (1-2 eV) higher gaps and significant changes in the relative energies of different structures. Metallization is predicted to occur at a density of greater, approximately greater than 0.6 mol/cm(3) (corresponding to a pressure of greater, approximately greater than 400 GPa), consistent with all previous measurements.

Journal Article↗
PubMed2000

Local secretion of a chimeric anti-CD4 antibody protects against graft rejection in the NOD mouse.

BACKGROUND: Engineering a graft to secrete its own immunosuppressive antibodies may minimize the risks associated with current high dose systemic immunosuppression. METHODS AND RESULTS: A beta cell insulinoma cell line (NIT-1) was transfected with genes encoding a chimeric anti-CD4 antibody. The NIT-1 cells secreted functional chimeric anti-CD4 antibody that bound to the CD4 molecule on mouse thymocytes and inhibited in vitro proliferation of CD4+ve T cells. Both test and control transfected cell lines grew at a similar rate in immunodeficient mice. In immunocompetent NOD mice, NIT-1 cells are normally rejected by a cellular immune response against the SV40 T antigen. Although control transfected NIT-1 cells were rapidly rejected by NOD mice, anti-CD4 secreting NIT-1 cells grew significantly better and were able to form tumors at the site of injection. CONCLUSIONS: The local secretion of chimeric anti-CD4 antibody from transfected cells can contribute to graft survival in our transplantation model.

Animals↗
PubMed2000

The incidence of adverse events and risk factors for upper gastrointestinal disorders associated with meloxicam use amongst 19,087 patients in general practice in England: cohort study.

AIMS: Meloxicam is a novel nonsteroidal anti-inflammatory drug (NSAID) which may be associated with fewer adverse upper gastrointestinal events than other NSAIDs because it preferentially inhibits the inducible enzyme cyclo-oxygenase-2 relative to the constitutive isoform, cyclo-oxygenase-1. The aims of the study were to: determine the rate of adverse events associated with meloxicam in general practice, stratify these rates by selected risk factors, and to identify signals of previously unsuspected adverse events associated with meloxicam. METHODS: As part of the national prescription-event monitoring pharmacovigilance system for newly launched drugs in general practice, all patients prescribed meloxicam in England between December 1996 and March 1997 were identified by the central Prescription Pricing Authority. We sent short questionnaires to all prescribers asking about adverse events experienced within 6 months of the first prescription. RESULTS: There were 19 087 patients in the study. The rate of dyspepsia during the first month of exposure was 28.3 per 1000 patient-months. There were 33 reports of upper gastrointestinal haemorrhage during treatment (rate: 0.4 per 1000 months). A history of gastrointestinal disorder in the previous year was associated with an increased rate of dyspepsia (rate ratio: 3.0; 95% confidence interval: 2.6, 3.4), abdominal pain (2.1; 1.6, 2.6), and peptic ulcer (4.0; 1.4, 13.2). Prior NSAID use was associated with a 20-30% decrease in the rate of dyspepsia and abdominal pain in patients starting meloxicam, while patients prescribed concomitant gastroprotective agents had a two to three-fold increased rate of dyspepsia, abdominal pain and peptic ulceration. Other rare events were thrombocytopenia (n = 2); interstitial nephritis (n = 1) and idiosyncratic liver abnormalities (n = 1). CONCLUSIONS: In the absence of gastro-intestinal risk factors the incidence of gastro-intestinal disturbance was low. Such risk factors should be carefully reviewed prior to prescribing meloxicam.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed2000

The rates of common adverse events reported during treatment with proton pump inhibitors used in general practice in England: cohort studies.

AIMS: To estimate the rates of common adverse events in patients treated with the proton pump inhibitors omeprazole, lansoprazole and pantoprazole in general practice in England. METHODS: In prescription-event monitoring cohort studies, data on dispensed prescriptions prescribed by general practitioners in England soon after each drug was launched were linked to subsequent clinical events recorded by the prescriber. 16 205 patients prescribed omeprazole between June 1989 and June 1990, 17 329 patients prescribed lansoprazole between May and November 1994, and 11 541 patients prescribed pantoprazole between December 1996 and June 1997 were studied. RESULTS: The commonest adverse events in the omeprazole, lansoprazole and pantoprazole cohorts were diarrhoea (incidence: 0. 18, 0.39 and 0.23 per 1000 days of exposure, respectively); nausea/vomiting (incidence: 0.16, 0.22 and 0.18 per 1000 days of exposure, respectively); abdominal pain (incidence: 0.17, 0.21 and 0. 17 per 1000 days of exposure, respectively); and headache (incidence rates: 0.10, 0.17 and 0.15 per 1000 days of exposure, respectively). The remaining adverse events occurred at rates of less than 0.11 per 1000 days of exposure. There were little absolute differences in the rates of most events between the three proton pump inhibitors. However, diarrhoea was more commonly associated with lansoprazole compared with omeprazole (rate difference: 0.21 per 1000 days of exposure; 95% CI 0.17, 0.25; rate ratio: 2.11; 1.78, 2.51), and there was a clear age-response relationship. CONCLUSIONS: Adverse events occurred relatively infrequently in all three cohorts. There were only small absolute differences in event rates between the three drugs, although these data suggest the hypothesis that lansoprazole is associated with more frequent occurrence of diarrhoea, particularly in the elderly.

2-Pyridinylmethylsulfinylbenzimidazoles↗
PubMed2000

Male pseudohermaphroditism due to 17 beta-hydroxysteroid dehydrogenase 3 deficiency. Diagnosis, psychological evaluation, and management.

Ten male pseudohermaphrodites with 17 beta-hydroxysteroid dehydrogenase 3 (17 beta-HSD3) deficiency were evaluated in 1 clinic with an average follow-up of 10.1 years. The diagnoses were made by demonstrating low to normal serum testosterone levels, high androstenedione levels, and high ratios of serum androstenedione to testosterone in the basal state or after treatment with human chorionic gonadotropin. The molecular features of the underlying mutations were identified in all 7 families. Two additional males in the same families are believed to be affected on the basis of history obtained from family members. All of the 46,XY individuals in these families were registered at birth and raised as females (despite the presence of ambiguous genitalia in all or most), and all virilized after the time of expected puberty due to a rise in serum testosterone to or toward the normal male range. The age at diagnosis varied from 4 to 37 years. Ten individuals were studied by the same psychologist, and change of gender role (social sex) from female to male occurred in 3 subjects and in the 2 presumed affected subjects not studied. The individual with the highest serum testosterone level maintained female sexual identity, and in 2 families some of the affected males changed gender role and others did not. Thus, while androgen action plays a role in the process, additional undefined psychological, social, and/or biologic factors must be determinants of gender identity/role behavior. Management of the 7 individuals who chose to maintain female sex roles included castration, clitoroplasty, vaginal enlargement procedures when appropriate, treatment of hirsutism, cricoid cartilage reduction, and estrogen replacement. Three of the 7 are married (2 twice), 1 is involved in a long-term heterosexual relationship, 1 is engaged to be married, and the other 2 are not married and not believed to be sexually active. The 3 subjects who changed gender role behavior to male underwent hypospadias repair, and 1 was given supplemental testosterone therapy. One of these men is divorced, and the other 2 (aged 29 and 35 years) are unmarried. The diagnosis in 8 of these subjects was made after the time of expected puberty; it is unclear whether the functional and social outcomes would have been different if the diagnosis had been made and therapy begun earlier in life.

17-Hydroxysteroid Dehydrogenases↗