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Biomedical subjects

G S Conway

Publications and source records attributed to G S Conway.

At least 37 records · Page 2Linked to original sources
PubMed2000

Mapping of the POF1 locus and identification of putative genes for premature ovarian failure.

We have identified a breakpoint on the X chromosome which is associated with premature ovarian failure (POF). Using polymerase chain reaction (PCR) probes of polymorphic microsatellites and fluorescent in-situ hybridization (FISH), this breakpoint has been narrowed to a region of 300 kb spanned by two P1 artificial chromosomes (PAC). Computer exon prediction and gene homology programs revealed three genes in this area. Our results suggest that two of these genes, HS6ST and E2F, and LINE 1 elements may be involved in ovarian development. Interruption of these genes could be the cause of POF. This study demonstrates how various molecular techniques and bioinformatic searches can complement each other in order to solve a clinical problem.

Carrier Proteins↗
PubMed2000

The effect of hormone replacement therapy on cardiovascular hemodynamics in women with Turner's syndrome.

Women with Turner's syndrome, the majority of whom are estrogen deficient, have an increased incidence of coronary artery disease. The aim of this study was to assess the effects of hormone replacement therapy (HRT) on central arterial hemodynamics, insulin sensitivity, and lipids in adults with Turner's syndrome. Twenty-one women with Turner's syndrome were studied prospectively, on and off 3 months of estradiol valerate in combination with levonorgestrel. The following measurements were made: body mass index, waist/hip ratio, serum lipids, fasting insulin and glucose, and mean arterial blood pressure. Aortic root pressure and waveforms were estimated noninvasively and the augmentation index (AI), a measure of aortic stiffness, was calculated. The AI was significantly lower during estrogen therapy (22% vs. 15%; P = 0.008), suggesting a reduction in central arterial stiffness. Fasting insulin and glucose concentrations were also significantly lower during HRT (P = 0.01 and P = 0.0004, respectively). There was no difference in body mass index, serum lipids, or brachial and aortic blood pressures on and off treatment. Total cholesterol was correlated with the AI (r = 0.4; P = 0.03). These results suggest that HRT in women with Turner's syndrome has a favorable effect on central arterial hemodynamics and insulin sensitivity. The lack of effect on serum lipids suggests that the effects of HRT on aortic compliance may be mediated by an improvement in endothelial function.

Adolescent↗
PubMed2000

Premature ovarian failure.

On average, the menopause occurs at the age of 50 years, with 1% of women continuing to menstruate beyond the age of 60 years and 1% whose menopause occurs before 40 years. Arbitrarily, a menopause before the age of 40 years is defined as 'premature'.

Addison Disease↗
PubMed2000

Premature menopause and psychological well-being.

This study aimed to investigate the psychological well-being of women who had experienced menopause before the age of 40 years. Participants were women known to the reproductive endocrinology service of a London teaching hospital. They were contacted and invited to participate in the questionnaire study by post. Sixty-four women (41.6%) who completed and returned their questionnaires formed a usable sample. Participants reported high levels of depression and perceived stress, and low levels of self-esteem and life satisfaction, compared to the general population. Self-reports on several dimensions of sexuality were significantly more negative. The following factors could affect the degree of reported distress: age, age at diagnosis, time since diagnosis, already having children, being in a long-term relationship, or having psychological treatment in the past or present. The results suggest that premature menopause could pose significant psychological difficulty for a sizeable proportion of those who have the condition. It is argued that the provision of psychological care should be an integral part of clinical management.

Adaptation, Psychological↗
PubMed1999

Serum vascular endothelial growth factor (VEGF) in the normal menstrual cycle: association with changes in ovarian and uterine Doppler blood flow.

OBJECTIVE: To investigate whether changes in circulating serum vascular endothelial growth factor (VEGF) concentrations during the menstrual cycle are associated with changes in blood flow within the ovaries and uterus. PATIENTS AND MEASUREMENTS: Serum VEGF concentrations were measured and pulsed and colour Doppler blood flow waveforms recorded within the ovarian stroma and uterine arteries during the early follicular, the immediate preovulatory and the mid-luteal phases of the menstrual cycle of 14 healthy women. RESULTS: Mean (+/- SD) serum VEGF concentrations rose from 2.44 +/- 0.1 ng/ml in the early follicular phase to 3 +/- 0.8 ng/ml in the pre-ovulatory phase and to 4.4 +/- 0.9 ng/ml in the mid-luteal phase (P < 0.0001) of the menstrual cycle. Mean peak systolic blood flow velocity (PSV) and time-averaged maximum flow velocity (TAMXV) were higher within the ovarian stroma of the ovary bearing the dominant follicle and the uterine arteries in the pre-ovulatory and mid-luteal phase than in the same sites during the early follicular phase of the menstrual cycle. PSV rose significantly from the early follicular phase (11 +/- 6 cm/s) to 14 +/- 4 cm/s in the pre-ovulatory phase and further in the mid-luteal phase (26 +/- 7 cm/s, P = 0.0001). Within the uterine arteries, mean PSV rose significantly from 28 +/- 9 cm/s in the early follicular phase to 31 +/- 8 cm/s in the pre-ovulatory phase and further in the mid-luteal phase (44 +/- 11 cm/s, P < 0.005). Serum VEGF correlated with serum progesterone concentrations in the luteal phase (r = 0.85, P < 0.001), with serum oestradiol concentrations in the early follicular (r = 0.67, P = 0.009), pre-ovulatory (r = 0.57, P = 0.03) and luteal phases (r = 0.68, P < 0.005) and with serum testosterone in the early follicular phase (r = 0.63, P = 0.01). CONCLUSIONS: Cyclical changes in serum vascular endothelial growth factor concentrations are associated with coincident changes in ovarian and uterine blood flow.

Adult↗
PubMed1999

Mutation screening and isoform prevalence of the follicle stimulating hormone receptor gene in women with premature ovarian failure, resistant ovary syndrome and polycystic ovary syndrome.

OBJECTIVE: To determine whether mutations in the FSH receptor gene are associated with premature ovarian failure (POF) or resistant ovary syndrome (ROS) in women in the UK. To determine whether an allelic variant of the FSH receptor gene affects fertility parameters in women with polycystic ovary syndrome (PCOS). DESIGN: A mutation screen using DNA from women with POF and ROS. Restriction digest of amplified DNA from women with POF, ROS, PCOS and controls to determine allelic variant status. Fertility parameters were compared between allelic variant subgroups of women with PCOS. PATIENTS: The study population comprised 49 women with POF, 5 with ROS, 93 with PCOS and 51 controls. MEASUREMENTS: In women with PCOS, fertility and menstrual status was recorded and serum FSH and ovarian volume were measured. RESULTS: No mutation of the FSH receptor gene was found in women with POF or ROS. The allelic variant Thr307/Ser680 was found to be similarly prevalent in all study groups. The Thr307/Ser680 variant was found to have no phenotype in terms of fertility parameters in women with PCOS. CONCLUSIONS: Mutations of the FSH receptor gene are rare in women with premature ovarian failure or resistant ovary syndrome in the UK. Polymorphisms of the FSH receptor gene do not appear to have pathophysiological significance with regard to ovarian function.

Adult↗
PubMed1999

Lipid profile, glucose tolerance and insulin sensitivity after more than four years of growth hormone therapy in non-growth hormone deficient adolescents.

OBJECTIVE: To study the effects of long-term (> 4 years) growth hormone (GH) therapy on insulin sensitivity, glucose tolerance and lipid profile in non-GH deficient adolescents at completion of their growth. SUBJECTS: Thirty non-GH deficient (15 'idiopathic' short stature, 8 intrauterine growth retardation, 7 partial GH deficiency in childhood but normal on retesting) were recruited, median (range) age 16.9 years (15-20.3) prior to ceasing their GH therapy. Their median (range) duration of GH treatment was 7.9 years (4-11). Insulin sensitivity was also recorded in 10 normal controls with a median (range) age of 20.5 years (18.4-22.3). METHODS: Insulin sensitivity was assessed by a short insulin tolerance test in 18 patients on GH therapy and controls. It was repeated in 14 patients six months after stopping their GH therapy. A 3-h standard oral glucose tolerance test (OGTT) was performed in 19 patients on GH therapy, and repeated after 6 months off GH in 10 patients. Fasting lipids were also measured. RESULTS: Insulin sensitivity index was significantly lower in the patients on GH therapy than in the controls, (median (range)) 3.7%/min (1.2-5.3) and 5.3%/min (3.8-6.2), respectively. Six months after termination of GH therapy, insulin sensitivity increased significantly from 3.6%/min (1.2-5) to 4. 8%/min (2.8-5.6). Fasting plasma insulin decreased significantly off GH therapy from 10.1 to 3.6 mU/l. The area under the insulin curve during the OGTT was also significantly higher on GH therapy. Apart from one patient with impaired glucose tolerance on GH treatment, plasma glucose concentrations remained within the normal range. No lipid abnormalities were recorded. CONCLUSIONS: These data suggest that long-term GH therapy may cause insulin resistance in non GH deficient adolescents, but usually with neither impaired glucose tolerance nor hyperlipidaemia.

Adolescent↗
PubMed1999

Serum concentrations of follicle stimulating hormone may predict premature ovarian failure in FRAXA premutation women.

It is now recognized that female carriers of fragile X premutations are at increased risk of premature ovarian failure. We have studied 51 premenopausal women from fragile X families, to determine whether premutation carriers have variations in the hormonal markers of menopause, compared to full mutations and controls. We found a significant increase in serum follicle stimulating hormone in premutation carriers, suggesting that as a group they will enter menopause before full mutation carriers and unaffected controls. These results have important implications for fertility in these women.

Adolescent↗
PubMed1999

Human leukocyte antigen-DQB1* genotypes encoding aspartate at position 57 are associated with 3beta-hydroxysteroid dehydrogenase autoimmunity in premature ovarian failure.

Premature ovarian failure (POF) has an autoimmune pathogenesis in a significant proportion of cases. Autoantibodies to the steroid cell enzyme, 3beta-hydroxysteroid dehydrogenase (3betaHSD) are present in one fifth of patients and may identify an autoimmune subgroup. As autoimmune diseases are associated with alleles of the human leukocyte antigen (HLA) genes, we examined the distribution of HLA-DRB1 and -DQB1 genotypes in 118 women with POF, of whom 21% had 3betaHSD autoantibodies, and 134 racially matched control subjects. Two HLA-DQB1 alleles, 0301 and 0603, were associated with 3betaHSD autoantibody positivity (P = 0.04 and P = 0.006, respectively). As the DQB1*0301 and -0603 genes share an identical codon at position 57 (aspartate, Asp), we analyzed the frequency of DQbeta-Asp57 encoding DQB1 genes in our series. Eighteen of 21 POF patients with 3betaHSD autoantibodies had DQbeta-Asp57-encoding genotypes (haplotype frequency, 27 of 42; 64%) compared with 92 of 134 control subjects (haplotype frequency, 109 of 268; 41%; P = 0.004), and 9 of 21 (43%) cases were homozygous for codon 57 genotypes compared with 17 of 134 (13%) control subjects (P = 0.0006). These probability values were not significant after correction for multiple testing, and these trends will therefore require confirmation in larger cohorts. HLA class II molecules present antigenic peptides to CD4+ T lymphocytes. DQbeta57 occupies a key site at the boundary of the peptide binding groove, with a major impact on peptide binding. Our preliminary demonstration of an association between POF, 3betaHSD autoimmunity, and a distinctive HLA-DQ molecule supports the hypothesis that autoantibodies to this steroid cell enzyme may be markers of autoimmune ovarian failure and suggests that presentation of autoantigenic or external peptides to T lymphocytes by HLA-DQ molecules with Asp57-beta-chains is important in the pathogenesis of this disease.

3-Hydroxysteroid Dehydrogenases↗
PubMed1999

Medical problems in adult women with Turner's syndrome.

Turner's syndrome, the most common chromosome abnormality in females, is the consequence of complete absence or partial deletion of one X chromosome. It is associated with a wide spectrum of clinical features of which short stature and gonadal dysgenesis are almost invariably present. Women with Turner's syndrome have a reduced life expectancy primarily as a result of cardiovascular disease. They are also susceptible to a number of other disorders including autoimmune thyroiditis, osteoporosis, renal and gastrointestinal disease. Thus, women with Turner's syndrome should be followed up by a multidisciplinary team of physicians with an interest in the disorder following discharge from paediatric care. This review aims to highlight the problems associated with Turner's syndrome in adulthood and to discuss important management strategies.

Adult↗
PubMed1998

Genotype-phenotype analysis in late onset 21-hydroxylase deficiency in comparison to the classical forms.

OBJECTIVE: To establish the type and frequency of mutations causing late onset 21-hydroxylase deficiency and associated clinical and biochemical phenotypes and to compare these findings to those from heterozygotes and homozygotes for classical 21-hydroxylase deficiency. DESIGN: Analysis of the 21-hydroxylase genes by DNA amplification and mutation detection. Measurement of serum 17-hydroxyprogesterone following stimulation with adrenocorticotrophic hormone. PATIENTS: Fifteen patients with late onset congenital adrenal hyperplasia, 18 obligate heterozygotes for classical congenital adrenal hyperplasia, 95 patients with classical 21-hydroxylase deficiency. MEASUREMENTS: 17-hydroxyprogesterone following adrenal stimulation with adrenocorticotrophic hormone; frequency of 10 common mutations in the 21-hydroxylase gene. RESULTS: Of alleles from patients with late onset CAH 46% carried V281L and 10% P30L mutations compared to 2.6% and 1.1% respectively of alleles from patients with the classical disease where the most common mutations are a splice site mutation in intron 2 (34%), deletions (25%) and I172N (15%). Serum 17-hydroxyprogesterone following Synacthen stimulation reliably differentiated the late onset patients from carriers for the classical disease, whereas there was overlap of the basal 17-hydroxyprogesterone concentration between these two conditions. CONCLUSIONS: Normal basal serum 17-hydroxyprogesterone levels cannot exclude late onset CAH, although response to adrenocorticotrophic stimulation clearly distinguished this disorder from carriers of the classical disease. The frequency of mutations causing less severe enzyme deficiency was higher in the late onset patients than in a group of classical patients, although other genes or environmental pressures may determine the age of onset of disease.

17-alpha-Hydroxyprogesterone↗
PubMed1998

The impact of obesity on cardiovascular risk factors in Turner's syndrome.

OBJECTIVE: To evaluate risk factors for coronary artery disease in women with Turner's syndrome which may contribute to the increased incidence of premature cardiovascular death noted in this disorder. DESIGN: Comparison of clinical and biochemical parameters in women with Turner's syndrome with those in women with normal karyotype. PATIENTS: Ninety-one women with Turner's syndrome attending a dedicated adult Turner's syndrome clinic and 22 control subjects were studied. MEASUREMENTS: Recumbent blood pressure, body mass index (BMI), fasting total cholesterol, triglycerides and high density lipoproteins (HDL) were measured in both study groups. RESULTS: Women with Turner's syndrome were more obese compared with women with a normal karyotype. They were more likely to be hypertensive and the obese patients had higher serum triglyceride concentrations. Hypertension was independent of obesity and may be under-recognized because of failure to compare with age-matched normal ranges. Lipoprotein changes were accounted for by the obesity. CONCLUSIONS: Women with Turner's syndrome may be at increased risk of developing coronary artery disease as a result of the higher frequency of hypertension and obesity. Routine screening of this population for risk factors for ischaemic heart disease is recommended.

Adolescent↗
PubMed1998

Cytogenetic and molecular investigations of Y chromosome sequences and their role in Turner syndrome.

It has been proposed that all live born females with Turner syndrome carry a cell line containing two sex chromosomes, which may be present at a low level of mosaicism (Hook & Warburton, 1983; Hassold et al. 1985; 1988; Connor & Loughlin, 1989). If the second sex chromosome is a Y, these patients are at risk of developing gonadoblastoma. In this study, 50 patients found to have a 45,X karyotype by conventional cytogenetic analysis, were screened by the polymerase chain reaction (PCR), for the presence of Y chromosome sequences. Two patients were positive for six of the eight Y chromosome loci tested and additional cytogenetic analysis confirmed the presence of a marker chromosome, in 8% and 3% of cells respectively. Fluorescence in situ hybridization (FISH) was used to confirm that the markers were of Y chromosome origin and helped to elucidate their structure. In addition, four other patients were found to have a Y chromosome by initial routine cytogenetic analysis. FISH, in conjunction with PCR, elucidated the structure of the Y chromosomes. This study illustrates the value of using a combination of cytogenetic and molecular techniques, to identify Y chromosome sequences in Turner syndrome.

Cytogenetics↗
PubMed1998

A familial case of X chromosome deletion ascertained by cytogenetic screening of women with premature ovarian failure.

The association between X chromosome deletions and premature ovarian failure is well established. Previous anecdotal reports however, have not documented the prevalence of X deletions in women with premature ovarian failure. We therefore performed cytogenetic analyses on 79 women with primary or secondary amenorrhoea to assess the utility of screening for a genetic marker for familial premature ovarian failure. A normal karyotype was found in 77 women. One woman with primary amenorrhoea had an XY karyotype and a woman with secondary amenorrhoea had a deletion at Xq 26.1. This second case had a family history of premature ovarian failure, and her mother who underwent premature ovarian failure at 28 years shared this deletion. The early diagnosis of familial X deletions causing premature ovarian failure allowed for the prediction of impending menopause and the implementation of manoeuvres to advance conception. Although cytogenetic aberrations are rare in secondary amenorrhoea, the ability to predict premature ovarian failure can be vital.

Adult↗
PubMed1998

Serum vascular endothelial growth factor concentrations and ovarian stromal blood flow are increased in women with polycystic ovaries.

The aim of this study was to determine basal serum vascular endothelial growth factor (VEGF) concentrations and Doppler blood flow changes within the ovarian stroma of women with polycystic ovaries (PCO) and women with normal ovaries. Pulsed and colour Doppler blood flows within the ovarian stroma were recorded, and serum VEGF concentrations measured, in the early follicular phase (days 2-3 of a menstrual cycle) in 60 women undergoing ovarian stimulation for in-vitro fertilization. 36 women had normal ovaries, 14 women had PCO as seen on pelvic ultrasound examination and 10 had polycystic ovarian syndrome (PCOS). Mean+/-SD serum VEGF concentrations were significantly higher (P < 0.001) in women with PCO and PCOS (3.4+/-0.7 and 3.2+/-0.66 ng/ml respectively) compared with women with normal ovaries (2.3+/-0.5 ng/ml). Mean peak systolic blood flow velocity (PSV) and time-averaged maximum flow velocity (TAMXV) were significantly higher (P < 0.001) in women with PCO and PCOS compared with women with normal ovaries. The mean PSV were 15+/-4 and 16+/-4 cm/s in women with PCO and PCOS respectively, compared with 9+/-2 cm/s in women with normal ovaries. The TAMXV were 9+/-3 and 11+/-3 cm/s in women with PCO and PCOS respectively compared with women with normal ovaries (5.8+/-1.5 cm/s). Serum VEGF concentrations were positively correlated with PSV (r=0.44, P=0.001) and TAMXV (r=0.45, P < 0.000) in all three groups of women. Higher serum concentrations of VEGF in women with PCO and PCOS may relate to the increased vascularity that underlies the increased blood flow demonstrated by Doppler blood flow velocity measurements in these women. The results may explain the higher risk of ovarian hyperstimulation syndrome in programmes of ovarian stimulation in patients with PCO compared with those with normal ovaries.

Adult↗