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Biomedical subjects

A S Bates

Publications and source records attributed to A S Bates.

At least 19 recordsLinked to original sources
PubMed2004

Growth hormone and pituitary radiotherapy, but not serum insulin-like growth factor-I concentrations, predict excess mortality in patients with acromegaly.

Increased mortality in patients with acromegaly has been confirmed in a number of retrospective studies, but causative factors and relationship to serum IGF-I remain uncertain. The West Midlands Pituitary database contains details of 419 patients (241 female) with acromegaly. Serum IGF-I data from the Regional Endocrine Laboratory were available for 360 patients (86%). At diagnosis, mean age was 47 yr (range, 12-84) and mean duration of follow-up was 13 yr (0.5-48). Sixty-one percent were treated by surgery and 39% by nonsurgical means. Radiotherapy was used alone or as adjuvant therapy in 50%. All patients were registered with the Office of National Statistics to obtain information on deaths. At the date of analysis (31 December 2001), 95 of the 419 patients had died (43 males), giving a standardized mortality ratio of 1.26 [confidence interval (CI), 1.03-1.54; P = 0.046]. After controlling for age and sex, data indicated that mortality was increased in subjects with posttreatment GH levels more than 2 micro g/liter, compared with those with levels less than 2 micro g/liter [ratio of mortality rates (RR), 1.55 (range, 0.97-2.50); P = 0.068]. By contrast, a much smaller increase was observed for subjects with elevated posttreatment IGF-I levels compared with those with normal levels [RR, 1.20 (range, 0.71-2.03); P = 0.50]. Treatment with radiotherapy was associated with increased mortality [RR, 1.67 (range, 1.09-2.56); P = 0.018], with cerebrovascular disease the predominant cause of death [standardized mortality ratio, 4.42 (range, 2.71-7.22); P = 0.005]. These results confirm the increased mortality in acromegaly and suggest that reduction of GH levels to less than 2 micro g/liter is beneficial in terms of improving long-term outcome. The sole use of IGF-I as a marker for effective treatment of acromegaly is not justified by this data. This study also highlights the potential deleterious effect of radiotherapy.

Acromegaly↗
PubMed2001

Association between premature mortality and hypopituitarism. West Midlands Prospective Hypopituitary Study Group.

BACKGROUND: Four retrospective studies have reported premature mortality in patients with hypopituitarism with standard mortality ratios (SMRs) varying between 1.20 and 2.17. Patients with hypopituitarism have complex endocrine deficiencies, and the mechanisms underpinning any excess mortality are unknown. Furthermore, the suggestion has emerged that endogenous growth-hormone deficiency might account for any excess mortality. We aimed to clarify these issues by doing a large prospective study of total and specific-cause mortality in patients with hypopituitarism. METHODS: We followed up 1014 UK patients (514 men, 500 women) with hypopituitarism from January, 1992, to January, 2000. 573 (57%) patients had non-functioning adenomas, 118 (12%) craniopharyngiomas, and 93 (9%) prolactinomas. SMRs were calculated as the ratio of observed deaths to the number of deaths in an age-matched and sex-matched UK population. FINDINGS: The number of observed deaths was 181 compared with the 96.7 expected (SMR 1.87 [99% CI 1.62-2.16], p<0.0001). Univariate analysis indicated that mortality was higher in women (2.29 [1.86-2.82]) than men (1.57 [1.28-1.93], p=0.002), in younger patients, in patients with an underlying diagnosis of craniopharyngioma (9.28 [5.84-14.75] vs 1.61 [1.30-1.99], p<0.0001), and in the 353 patients treated with radiotherapy (2.32 [1.71-3.14] vs 1.66 [1.30-2.13], p=0.004). Excess mortality was attributed to cardiovascular (1.82 [1.30-2.54], p<0.0001), respiratory (2.66 [1.72-4.11], p<0.0001), and cerebrovascular (2.44 [1.58-4.18], p<0.0001) causes. There was no effect of hormonal deficiency on mortality, except for gonadotropin deficiency, which, if untreated was associated with excess mortality (untreated 2.97 [2.13-4.13] vs treated 1.42 [0.97-2.07], p<0.0001). Multiple regression analyses identified age at diagnosis, sex, a diagnosis of craniopharyngioma, and untreated gonadotropin deficiency as independent significant factors affecting mortality. INTERPRETATION: Patients with hypopituitarism have excess mortality, predominantly from vascular and respiratory disease. Age at diagnosis, female sex, and above all, craniopharyngioma were significant independent risk factors. Specific endocrine-axis deficiency, with the exception of untreated gonadotropin deficiency, does not seem to have a role.

Adenoma↗
PubMed2000

Restricting medicaid payments for transportation: effects on inner-city patients' health care.

BACKGROUND: Prior approval programs have been used to control spiraling costs of Medicaid, but they are rarely formally assessed. We evaluated the effect of a change in Indiana Medicaid's policy (effective October 1, 1993) requiring prior approval to pay transportation costs. METHODS: We performed a historical cohort study comparing the health care utilization of Medicaid patients during the first 6 months of 1993 versus the first 6 months of 1994. Subjects included all Medicaid patients who visited any inpatient or outpatient site affiliated with an inner-city public hospital in the first 6 months of 1993 (N = 23,015) and 1994 (N = 23,707). RESULTS: These Medicaid patients made 82,961 visits in the first 6 months of 1993 and 79,809 visits in the first 6 months of 1994. Visits to hospital-based primary care clinics declined 16% (P < 0.001), which was partially offset by a 7% increase in visits to neighborhood health centers (P < or = 0.001). Emergency and urgent visits fell by 8%; visits for medication refills fell by 18% (P < 0.001 for each). Hospitalizations increased slightly in 1994, with no change in the number of inpatient days. There was no change in inpatient or outpatient nontransportation charges. There were no systematic reductions in selected aspects of preventive care. However, there were fewer emergency and urgent visits among patients with reactive airway disease. CONCLUSIONS: Requiring prior approval for transportation was associated with reductions in visits for primary care visits and refilling prescriptions without measurable short-term effects on charges or selected clinical parameters. Neighborhood health centers partially ameliorated the decline in primary care visits.

Adolescent↗
PubMed1999

Life expectancy following surgery for pituitary tumours.

OBJECTIVE: Hypopituitarism, predominantly although not exclusively due to nonfunctioning pituitary tumours, has been associated with reduced life expectancy. Mortality from vascular diseases contributed significantly to the overall increase in mortality in some, but not all of the studies published to date. The aim of this study was to contribute further data to the debate regarding the putative association of vascular mortality with hypopituitarism. DESIGN AND PATIENTS: A retrospective case note review of patients undergoing pituitary surgery in Birmingham, between 1/1/70 and 1/1/92. Subjects were identified from neurosurgical and neuropathology records. 348 patients were identified of which 197 were male (median age at surgery 48.4, range 11-79 years) and 151 female (median age at surgery 47.8, range 9-78 years). All cause mortality and mortality from vascular disease was compared to the general population of the UK using the Person Years computer programme. RESULTS: There was a small increase in all cause mortality (SMR 1.2; 95% CI 0.95-1.55), but this was not statistically significant in this study (P = 0.06). Mortality from vascular disease was reduced (SMR 0.7; 95% CI 0.5-1.1; P = 0.03) particularly in the female cohort (SMR 0.5; 95% CI 0.2-1.0; P < 0.01) with the male subjects having similar mortality to that expected in an age and sex matched control population (SMR 0.9; 95% CI 0.5-1.4; P = 0.26). CONCLUSION: Although patients with pituitary deficiency may be subject to a small increase in all cause mortality, the results of this study do not support the view that hypopituitarism is associated with a significant increase in vascular disease. There is a pressing need for a large prospective study with comprehensive data collection, including both endocrine data and information regarding clinical outcome, to clarify this issue. In the interim it would seem prudent to base the need for GH replacement therapy on quality of life issues rather than any potential for increased longevity.

Adolescent↗
PubMed1998

Instant electronic imaging systems are superior to Polaroid at detecting sight-threatening diabetic retinopathy.

Polaroid photography in diabetic retinopathy screening allows instant image availability to enhance the results of ophthalmoscopy. Retinal cameras are now being developed which use video/digital imaging techniques to produce an instant enlarged retinal image on a computer monitor screen. We aimed to compare one such electronic imaging system, attached to a Canon CR5 45NM, with standard Polaroid retinal photography. Two hundred and thirteen eyes from 107 diabetic patients were photographed through dilated pupils by both systems in random order and the images were analysed blind. Diabetic retinopathy was present in 58 eyes of which 55/58 (95%) were detected on the electronic image and only 49/58 (84%) on the Polaroid. Of 34 eyes requiring ophthalmologist referral according to standard European criteria, 34/34 (100%) were detected on the electronic image and only 24/34 (71%) on the Polaroid. Side by side comparisons showed electronic imaging to be superior to Polaroid at lesion detection. Using linear analogue scales, the patients assessed the electronic imaging photographic flash as less uncomfortable than the Polaroid equivalent (p < 0.0001). Other advantages of electronic imaging include: ready storage of the images with other patient clinical data on the diabetes computerized register/database; potential for image enhancement and analysis using image analysis software and electronic transfer of images to ophthalmologist or general practitioner. Electronic imaging systems represent a potential major advance for the improvement of diabetic retinopathy screening.

Diabetic Retinopathy↗
PubMed1998

Radiotherapy for non-function pituitary tumours.

OBJECTIVE: Pituitary radiotherapy (RT) is often used as adjuvant treatment in the post-operative period for patients with clinically non-functioning pituitary tumours (NFTs). There is a distinct lack of objective data, however, describing the efficacy of RT in preventing the regrowth of these tumours. We have therefore determined whether the recurrence rate for NFTs is significantly lower in patients treated with post-operative RT compared with that observed in patients not treated with RT. PATIENTS AND METHODS: A retrospective case notes review was performed on 126 patients with NFTs treated at two institutions in the UK. One hospital routinely administered RT within 12 months of initial pituitary surgery whereas the other used post-operative RT only rarely. The main outcome measure was regrowth of pituitary tumours following surgery in patients who did or did not receive post-operative RT. RESULTS: There was no significant difference between patients who received RT versus those who did not in terms of age, sex, initial tumour size or mode of operation. The actuarial progression-free survival was 93% at both 10 years and at 15 years for the RT treated group, and was 68% and 33%, respectively, for the non-RT-treated group. Using Cox's model for proportional hazard analysis, we found the only prognostic factor for NFT regrowth was the administration of pituitary RT (P < 0.00005). CONCLUSIONS: Radiotherapy administered within 12 months of initial pituitary surgery for non-functioning pituitary tumours significantly reduces the risk of tumour regrowth. It remains to be determined whether sequential MRI scanning can help delineate those patients who should receive radiotherapy following pituitary surgery for non-functioning pituitary tumours.

Adult↗
PubMed1998

Dimensions and correlates of physician work satisfaction in a midwestern city.

OBJECTIVES: The purpose of this study was to examine the dimensions of physician work satisfaction across a variety of medical specialties and practice settings. METHODS: A modified version of the Scheckler et al survey instrument was mailed to all physicians in Marion County, Indiana. Forty-two percent (777) of the eligible physicians responded. Exploratory factor analysis and internal consistency measures were used to assess the instrument's validity and reliability. Multivariable linear regression was used to predict global and summary scale scores. RESULTS: Four dimensions of physician work satisfaction were identified: relationships with patients (k = 6, alpha = 0.81), autonomy in clinical decision-making (k = 8, alpha = 0.81), office resources (k = 7, alpha = 0.87), and professional relationships (k = 5, alpha = 0.82). Most (73%) of the physicians were satisfied with their overall practice, and the majority were also satisfied with their income. Significant differences were observed in the sources and magnitude of physician work satisfaction across medical specialty, practice setting, and financial arrangement. Physicians in private practice were most satisfied with their overall practice and office resources, whereas physicians in health maintenance organizations (HMOs) were most satisfied with their autonomy in clinical decision-making. Physicians not working in HMOs but having a large percentage of patients with capitated reimbursement were not enthusiastic about the effect of managed care on their medical practice. Among primary care physicians, family practitioners and general internists were generally less satisfied, and general pediatricians were generally more satisfied with most aspects of their medical practices. CONCLUSIONS: The modified version of the Scheckler et al instrument is a reliable and valid measure of physician work satisfaction. Increases in the market share of managed care have differentially affected the work satisfaction of physicians based on their medical specialty, practice setting, and financial arrangements.

Adult↗
PubMed1998

Personal, financial, and structural barriers to immunization in socioeconomically disadvantaged urban children.

OBJECTIVE: To evaluate personal, financial, and structural barriers to vaccination in socioeconomically disadvantaged urban children in the first 2 years of life. DESIGN: Prospective cohort study. SETTING: A large municipal teaching hospital in the Midwest. PARTICIPANTS: Healthy term newborns discharged to the care of their mothers. Mothers were interviewed 24 to 72 hours postpartum regarding personal and financial barriers, and 2 years later regarding personal, financial, and structural barriers to care. MAIN OUTCOME MEASURE: Vaccination status at age 2 years. RESULTS: Of 399 children with documented vaccination status, 47% had not received all recommended vaccinations by 2 years of age. After adjusting for mother's age, race, and education, mothers who were unmarried (adjusted odds ratio [AOR] 1.74; 95% confidence interval [CI]: 1.05, 2.90), multiparous (AOR 2.10; 95% CI: 1.26, 3.52), not coresident with the child's grandmother (AOR 1.75; 95% CI: 1.01, 3.03), had not received adequate prenatal care (AOR 1.78; 95% CI: 1.12, 2.84), or lived in poverty (AOR 2.62; 95% CI: 1.44, 4.75) were more likely to have undervaccinated children, as were mothers who perceived less satisfaction with their child's health care (AOR 1.63; 95% CI: 1.01, 2.61), less control over their lives (AOR 2.01; 95% CI: 1.03, 3.94), or more benefit of medical care to prevent vaccine-related diseases (AOR 1.76; 95% CI: 1.25, 2.48). CONCLUSIONS: Family environment, a mother's history of prenatal care use, and financial barriers are important factors related to vaccination receipt among socioeconomically disadvantaged children at age 2 years. These factors, however, do not fully explain the variation in vaccination status.

Adult↗
PubMed1997

Chromosome 9p deletions in invasive and noninvasive nonfunctional pituitary adenomas: the deleted region involves markers outside of the MTS1 and MTS2 genes.

We have screened 57 cases of primary, nonfunctional, pituitary adenomas for loss of heterozygosity of markers on chromosome 9p. Using a panel of 11 microsatellite markers, we found hemizygous deletion with at least one of the markers in 18 tumors (31.5%). The frequency of loss was similar in both noninvasive (8 of 26; 31%) and invasive tumors (10 of 31; 32%), suggesting that loss on this chromosome might be an early event in pituitary tumorigenesis. Two discrete areas of loss were punctuated by a region of retention of heterozygosity between the markers D9S171 and IFNA, indicative of homozygous deletion. However, multiplex PCR analysis (MTS1 and MTS2) and the presence of a 3' untranslated region polymorphism in MTS1 suggested that neither of these tumor suppressor genes was homozygously deleted. In 6 of the 18 tumors showing LOH, sufficient DNA was also available for Southern blot analysis and, in all cases, showed retention of MTS1. Cell mixing experiments of tumor cell DNA homozygously deleted for MTS1 with DNA in which neither copy of the gene was deleted only gave rise to a signal at contamination levels greater than 30% and could discriminate homozygous and hemizygous loss. These studies support the recent findings that mechanisms other than hemi- and homozygous deletion are most likely responsible for the loss of MTS1 gene product in pituitary tumors (M. Woloschak et al., Cancer Res., 56: 2493-2486, 1996.). These data show that losses on either side of 9p21-22, both or either of which may be deleted, are involved in pituitary tumorigenesis and provide evidence for distinct suppressor gene loci, in addition to MTS1, on chromosome 9p.

Adenoma↗
PubMed1997

Tumour suppressor genes in the pathogenesis of human pituitary tumours.

Abnormal cell proliferation is controlled by opposing actions of oncogene products (stimulatory) and tumour suppressor gene (TSG) products (inhibitory). The former are dominantly acting, i.e. only one copy needed for tumorigenesis, whilst for TSG both copies of the gene must be inactivated so these are recessive at a cellular level. For anterior pituitary tumours only one oncogene (Gsp) has been identified in a variable proportion (4-40%) of a single tumour subtype (somatotrophinomas). Contrariwise, allelic deletion studies, using a PCR-based microsatellite polymorphism analysis of DNA extracted from archival specimens, have shown significant loss of heterozygosity in 20-40% of all tumour subtypes at the locus of the putative MEN-1 gene (chr. 11q13); the retinoblastoma gene (chr. 13q 12-14), and 10q26. Moreover, these DNA microdeletions were concentrated in radiologically invasive tumours compared to noninvasive tumours (modified Hardy gdes 3 and 4 vs. 1 + 2). In addition, 50% of Cushing's adenomas showed presence of p53 immunopositivity, though no point mutations in exons 4-9 were found, by SSCP analysis, to account for this. These studies show that analysis of TSGs in pituitary adenomas may provide clues to their pathogenesis, and more importantly relate to clinical behaviour of the tumour, and hence aid decisions regarding management.

Cell Division↗
PubMed1997

Allelic deletion in pituitary adenomas reflects aggressive biological activity and has potential value as a prognostic marker.

Tumors of the pituitary gland are usually benign adenomas and account for 10% of all intracranial neoplasms. Five pituitary tumors have previously been reported to harbor multiple allelic deletions. Of these, three displayed particularly aggressive biological behavior, whereas there were no clinical details provided for the others. This study was designed to test the hypothesis that genetic deletions are a marker of invasive behavior and to identify the loci most commonly involved. Accordingly, we studied two cohorts of pituitary tumors, classified radiologically as invasive or noninvasive, for loss of heterozygosity (LOH). There is a significantly higher frequency of LOH in invasive tumors (10.8% of all loci examined) compared to noninvasive tumors (2.4%; P < 0.001). Of the 11 loci investigated, 75% of the allelic deletions identified in invasive tumors were found at 4 loci: 11q13, 13q12-14, 10q, and 1p. Twenty of 47 invasive tumors had evidence of at least 1 allelic deletion, whereas 14 of 20 had more than 1. Of the 6 tumors with only 1 deletion, 5 involved the 11q13 locus, suggesting that this is an early change in the transition from noninvasive to invasive adenoma. Comparison of invasive and noninvasive tumors demonstrates a significantly higher frequency of deletions affecting 11q13 (P < 0.001), 13q12-14 (P < 0.05), and 10q26 (P < 0.05) in invasive tumors. In addition, allelic deletion correlates with increasingly invasive behavior (modified Hardy classification), as 73% of grade 4 tumors compared to 33% of grade 3 and 9.5% of grade 1 and 2 tumors demonstrated LOH at any locus. Furthermore, in some tumors we identified a breakpoint between markers intragenic and extragenic to the retinoblastoma gene (Rb1) on chromosome 13q, suggesting that tumor suppressor genes other than or in addition to Rb1 may be involved in pituitary tumorigenesis. This was further supported by the presence of Rb protein in two of four tumors where the genetic loss extended to include the intragenic marker D13S153. Early identification of tumors with likely invasive potential by means of genetic analysis (LOH) may provide useful information on potential tumor behavior and aid tumor management in a manner that is not possible using routine histological methods. A large prospective study is required in patients without radiological evidence of invasion to assess the value of LOH in predicting outcome and for planning treatment.

Adenoma↗
PubMed1996

The effect of hypopituitarism on life expectancy.

One hundred and seventy-two patients with partial or complete hypopituitarism diagnosed between 1967 and 1994 were studied retrospectively. Those with acromegaly or Cushing's disease were excluded. One hundred and two patients were male (median age at, diagnosis, 53 yr; range, 12-78 yr) and 70 female (median age at diagnosis, 51 yr; range, 1-74 yr). In 131 patients the cause of hypopituitarism was a pituitary tumor or the effects of its treatment, as the majority underwent surgery and/or radiotherapy. In 22, the cause was an extrapituitary tumor, 14 were termed idiopathic, 2 developed hypopituitarism as a result of basal sarcoid, 2 were due to trauma, and 1 was the result of Sheehan's syndrome. The patients were treated with standard replacement therapy. Mortality due to all causes was higher than expected in an age- and sex-matched control population (ratio of observed/expected deaths, 1.73; 95% confidence interval, 1.28-2.28; P < 0.01). Females tended to have a worse prognosis (ratio of observed/expected deaths, 2.29; 95% confidence interval, 1.37-3.58; P < 0.01) than their male counterparts (ratio of observed/expected deaths, 1.50; 95% confidence interval, 1.02-2.13; P < 0.01). There was a small but nonsignificant increase in the number of deaths due to vascular disease (ratio of observed/expected deaths, 1.35; 95% confidence interval, 0.84-2.07; P = 0.11). The only significant independent predictive factors for survival were age at diagnosis and hypogonadism. The majority of the male hypogonadal cohort received replacement therapy (79%), but fewer of the females did so (27%). Hypogonadal patients had a better prognosis than their eugonadal counterparts (log rank, 6.85; P < 0.01). Our data confirmed that mortality in patients with hypopituitarism is significantly increased. However, the contribution of vascular disease to this poor prognosis was not as great as previously reported, and overall, our results favor a multifactorial explanation of the poor long term outcome.

Adolescent↗
PubMed1995

GSTM1 and CYP2D6 genotype frequencies in patients with pituitary tumours: effects on P53, ras and gsp.

We describe studies to determine if susceptibility to pituitary tumours is associated with the putatively high risk GSTM1 null and CYP2D6 EM genotypes. Frequency distributions of these genotypes were similar in cases and controls though the frequency of CYP2D6 PM and GSTM1 B tended to be lower (P = 0.072 and P = 0.095 respectively) in the tumour group. Immunopositivity for p53 was found in 18/97 tumours. In these samples GSTM1 null (39%) and CYP2D6 EM (56%) frequencies were not different to those in controls. The frequencies of CYP2D6 PM and GSTM1 B in the p53 immunonegative tumours tended to be lower (P = 0.055 and P = 0.1185 respectively) than in controls. Mutations in gsp and ras were studied using the polymerase chain reaction and allele specific oligonucleotide analysis. Eight of 19 somatotrophinomas demonstrated mutations in gsp; frequencies of GSTM1 null and CYP02D6 EM were similar to controls. No ras mutations were identified in 55-tumour studies. The data indicate the GSTM1 null and CYP2D6 EM genotypes are not associated with altered expression of p53 or, mutation of gsp and ras in these adenomas and, suggest the CYP2D6 PM genotype is associated with a reduced risk of pituitary adenomas and, that GSTM1*B confers greater protection than GSTM1*A.

Adult↗
PubMed1995

Assessment of GH status in acromegaly using serum growth hormone, serum insulin-like growth factor-1 and urinary growth hormone excretion.

OBJECTIVE: It is still not clear what is the most suitable method for monitoring progress of acromegaly. The aim of this study was to assess the relative merits of serum GH, serum IGF-I and urinary GH (uGH) excretion in the follow-up of acromegalic subjects. SUBJECTS AND METHODS: Thirty-six acromegalic patients each had a GH day series performed consisting of five serum GH measurements, together with an estimate of serum IGF-I and uGH. The first sample taken for serum GH was fasting (basal) whilst the third (1430h) was arbitrarily chosen as a random value. uGH was measured from two overnight collections and the mean value used for subsequent data analysis. MEASUREMENTS: Serum GH and IGF-I were measured by radioimmunoassay whilst uGH was estimated by an immunoradiometric assay using commercially available reagents. RESULTS: There is a highly significant linear correlation between serum GH and IGF-I following log transformation of these two variables (r = 0.85; P < 0.0001). Analysis of the raw data shows that the relation is in fact curvilinear rendering IGF-I less useful as a surrogate for integrated GH secretion at high levels of serum GH. There is a strong linear correlation between both a singleton basal serum GH and uGH (r = 0.78; P < 0.001) and the mean of five measurements (day series) and uGH (r = 0.81; P < 0.0001). Both uGH and IGF-I are excellent predictors of those patients with persistent elevation of serum GH, identifying 95 and 96% respectively with serum GH > 5mU/l. We have identified a number of patients, however, with persistent elevation of IGF-I in the presence of serum GH < 5mU/l and normal uGH. Until the significance of these findings with respect to long-term outcome is known, serum GH should continue to be used in the follow-up of these patients. An alternative, which reflects integrated overnight GH secretion, is uGH which is convenient and easy to collect as an outpatient and correlates strongly with serum GH. CONCLUSION: Acromegalic patients can be conveniently followed on an outpatient basis using a combination of uGH and serum IGF-I. Measurements of serum GH can be reserved for those with discrepant results.

Acromegaly↗
PubMed1995

Assessment of GH status in adults with GH deficiency using serum growth hormone, serum insulin-like growth factor-I and urinary growth hormone excretion.

OBJECTIVES: The benefits of treating adults with GH deficiency are now well recognized although the criteria for deciding which patients to treat are still not clear. At present the 'gold standard' is the insulin stress test (IST) which is unpleasant and potentially dangerous, particularly in patients with hypopituitarism. The aim of this study was to determine whether alternative methods of assessing GH status are reliable in predicting GH deficiency. SUBJECTS AND METHODS: Forty-four patients with unequivocal GH deficiency (peak IST < 2 mU/l) and 17 with partial deficiency (peak IST 2-10 mU/l) were studied. Each patient was assessed clinically with respect to the number of other pituitary axes affected and biochemically with an estimate of urinary GH excretion (uGH) and serum IGF-I. These markers were then related to GH status as defined by insulin stress testing. MEASUREMENTS: Insulin stress tests were performed using 0.1 units/kg i.v. and accepted with a blood glucose < 2 mmol/l. Serum GH and IGF-I were measured by radioimmunoassay whilst uGH was estimated by an immunoradiometric assay using commercially available reagents. uGH was estimated from the mean of two overnight urine collections which consisted of all urine passed from last voiding through to the first morning sample. RESULTS: The presence of unequivocal GH deficiency (peak IST < 2 mU/l) was predictable if 2 or more other pituitary axes were affected (90%). uGH declined significantly with the level of peak IST response (P < 0.001) and almost so with the number of other deficient hypothalamic-pituitary axes affected (P = 0.057). Thus, uGH accurately reflected GH status and showed good separation from normal controls in patients less than 40 years (specificity 79%) and between 40 and 60 years (specificity 67%). Above this age the method is less specific (36%). Patients excreted significantly less GH than controls in all three age groups (P < 0.01). Subnormal levels of IGF-I were strongly predictive of unequivocal GH deficiency (91% with subnormal IGF-I have a peak IST GH < 2 mU/l) although a normal value does not reliably exclude the diagnosis. CONCLUSIONS: A diagnosis of adult GH deficiency can be reliably made without the need for an insulin stress test by using a combination of low urinary GH excretion, subnormal IGF-I levels and clinical assessment with regard to the number of other pituitary axes affected.

Adolescent↗
PubMed1995

Clinical and genetic changes in a case of a Cushing's carcinoma.

A 30-year-old presented in 1984 with a clinically nonfunctional tumour which subsequently developed into a metastatic corticotrophinoma from which he died despite surgery in 1984, 1986 and 1991 and external radiotherapy in 1986. Molecular genetic analysis of tumour and metastatic tissue revealed loss of heterozygosity at loci on the autosomes 1p, 3p, 10q26, 11q13 and 22q12. Tissue taken at surgery in 1986 also revealed positive cytoplasmic immunostaining for p53 protein. No such staining was evident in tissue taken at first surgery in 1984. Further analysis of invasive pituitary adenomas may reveal loci associated with such behaviour, enabling better prediction of subsequent clinical outcome than is possible using standard histological techniques, and delivery of early, aggressive treatment to those tumours which show molecular markers associated with a poor prognosis.

Adenoma↗
PubMed1995

P53 protein accumulates in Cushings adenomas and invasive non-functional adenomas.

The p53 protein, a negative regulator of cell growth, plays an important role in the pathogenesis of many human tumours following gene mutation and/or deletion. We screened a large number of sporadic pituitary tumours for p53 protein accumulation suggestive of gene mutation. Samples were divided into benign adenomas (n = 95) and invasive tumours with local or distant invasion (n = 26). All main tumour classes were represented. Putative p53 mutations were detected by immunohistochemistry on paraffin-embedded sections using polyclonal CM-1 and monoclonal DO-7 and PAb1801 antibodies. Results were compared to normal post-mortem pituitary tissue controls (n = 17). p53 protein accumulation was detected in invasive tumours (16%), but only in corticotrophinomas (2/4) and non-functional tumours (4/15). In non-invasive adenomas, protein accumulation was observed only in ACTH-secreting tumours where 50% were positive (16/32). No protein accumulation was identified in any control tissue. These results indicate that p53 protein accumulation may play a role in the development of Cushings adenomas and in the progression of non-functional tumours to the invasive state.

Adenoma↗