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Biomedical subjects

M C Sheppard

Publications and source records attributed to M C Sheppard.

At least 19 recordsLinked to original sources
PubMed2006

Serum thyrotropin concentration as a novel predictor of malignancy in thyroid nodules investigated by fine-needle aspiration.

CONTEXT: Thyroid nodules and goiter are common, and fine-needle aspiration biopsy (FNAB) is the first investigation of choice in distinguishing benign from malignant disease. OBJECTIVE: The objective of the study was to assess whether simple clinical and biochemical parameters can predict the likelihood of thyroid malignancy in subjects undergoing FNAB. DESIGN: The design was a prospective cohort. SETTING: The study was conducted at a single secondary/tertiary care clinic. PARTICIPANTS: One thousand five hundred consecutive patients without overt thyroid dysfunction (1304 females and 196 males, mean age 47.8 yr) presenting with palpable thyroid enlargement between 1984 and 2002 were evaluated by FNAB of the thyroid. INTERVENTION(S): There were no interventions. MAIN OUTCOME MEASURES: Goiter type was assessed clinically and classified as diffuse in 183, multinodular in 456, or solitary nodule in 861 cases. Serum TSH concentration at presentation was measured in a sensitive assay in patients presenting after 1988 (n = 1183). The final cytological or histological diagnosis was determined after surgery (n = 553) or a minimum 2-yr clinical follow-up period (mean 9.5 yr, range 2-18 yr). RESULTS: The overall sensitivity and specificity of FNAB in predicting malignancy were 88 and 84%, respectively. The risk of diagnosis of malignancy rose in parallel with the serum TSH at presentation, with significant increases evident in patients with serum TSH greater than 0.9 mU/liter, compared with those with lower TSH. Binary logistic regression analysis revealed significantly increased adjusted odds ratios (AORs) for the diagnosis of malignancy in subjects with serum TSH 1.0-1.7 mU/liter, compared with TSH less than 0.4 mU/liter [AOR 2.72, 95% confidence interval (CI) 1.02-7.27, P = 0.046], with further increases evident in those with TSH 1.8-5.5 mU/liter (AOR 3.88, 95% CI 1.48-10.19, P = 0.006, compared with TSH < 0.4 mU/liter) and greater than 5.5 mU/liter (AOR 11.18, 95% CI 3.23-8.63, P < 0.001, compared with TSH < 0.4 mU/liter). Males (AOR 1.8, 95% CI 1.04-3.1, P = 0.04), younger patients (AOR 1.1, 95% CI 1.01-1.15, P = 0.025), and those with clinically solitary nodules (AOR 2.53, 95% CI 1.5-4.28, P = 0.001) were also at increased risk. Based on these findings, a formula to predict the risk of the diagnosis of thyroid malignancy in individual patients, taking into account their gender, age, goiter type determined clinically, and serum TSH, was calculated. CONCLUSIONS: The risk of malignancy in a thyroid nodule increases with serum TSH concentrations within the normal range. In addition to patient's gender, age, and goiter type, the serum TSH concentration at presentation is an independent predictor of the presence of thyroid malignancy. We propose that these simple clinical and biochemical factors can serve as an adjunct to FNAB in predicting risk of malignancy.

Adolescent↗
PubMed2006

Lack of association between serum TSH or free T4 and body mass index in euthyroid subjects.

BACKGROUND: There is ongoing debate regarding the influence of minor changes in thyroid status within the normal range and body mass index (BMI). Overt thyroid dysfunction is well recognized to affect weight, but the influence of minor perturbations of thyroid function remains unclear. AIM OF THE STUDY: To examine in euthyroid subjects the association of serum concentrations of TSH and free T4 within the normal range and BMI. To compare serum TSH and free T4 concentrations in nonobese and obese subjects. SUBJECTS AND METHODS: A cohort of 401 euthyroid subjects with normal serum TSH (361 females, 40 males, mean age 48.2 years) who had been referred to a Thyroid Clinic due to the presence of a thyroid nodule or goitre. Measurements of serum TSH and free T4 were recorded, together with BMI (calculated from weight and height). Associations between measures of TSH, free T4 and BMI were investigated. RESULTS: There was no association between either serum TSH or free T4 concentration when considered as a continuous variable and BMI, and no difference in BMI when subjects were categorized according to serum TSH or free T4. There was also no difference in serum TSH or free T4 between lean and obese euthyroid subjects. Evidence of thyroid autoimmunity indicated by the presence of antibodies to thyroid peroxidase was likewise not associated with a difference in BMI. CONCLUSION: This study provides no evidence for an association between thyroid status within the normal range and BMI.

Antibodies↗
PubMed2006

Growth hormone and its disorders.

Growth hormone (GH) is synthesised and secreted by the somatotroph cells of the anterior lobe of the pituitary gland. Its actions involve multiple organs and systems, affecting postnatal longitudinal growth as well as protein, lipid, and carbohydrate metabolism. GH hypersecretion results in gigantism or acromegaly, a condition associated with significant morbidity and mortality, while GH deficiency results in growth retardation in children and the GH deficiency syndrome in adults. This article, aimed at non-paediatric physicians, examines the clinical features, diagnosis, and current concepts in the management of these conditions.

Acromegaly↗
PubMed2005

Consensus statement: medical management of acromegaly.

In November 2003, the Pituitary Society and the European Neuroendocrine Association sponsored a consensus workshop in Seville to address challenging issues in the medical management of acromegaly. Participants comprised 70 endocrinologists and neurosurgeons with international expertise in managing patients with acromegaly. All participants participated in the workshop proceedings, and the final document written by the scientific committee reflects the consensus opinion of the interactive deliberations. The meeting was supported by an unrestricted educational grant from Ipsen. No pharmaceutical representatives participated in the program planning or in the scientific deliberations.

Acromegaly↗
PubMed2005

The critical parameters in GH excess.

Effective biochemical control of GH and IGF-I levels in subjects with acromegaly can reduce mortality to that of the general population. Post-treatment mean GH values <2 or 2.5 microg/l are associated with mortality which is not different from the general population. Virtually all evidence from epidemiological studies has related GH and not IGF-I values to long-term mortality; controversy remains regarding relative importance of GH and IGF-I values in determining post-treatment control status. Current approaches to management of acromegaly (surgery, radiotherapy, SRIF analogues) rely on post-treatment monitoring of GH and IGF-I levels. Development of GH receptor antagonist therapy, which inhibits GH activity and normalizes circulating IGF-I, GH levels remaining elevated, requires re-analysis of relationship between GH and IGF-I. Studies have reported that normalization of IGF-I is associated with normalization of SMR, a significant association of IGF-I with survival, that IGF-I is not an independent predictor of mortality, and, in the largest study (419 patients), that there is no increase in mortality in patients with raised serum IGF-I levels. Post-operative subjects with acromegaly, with normal IGF-I levels but persistently abnormal nadir GH levels after glucose, have an increased risk of disease recurrence. Discordant values for GH and IGF-I estimations may be seen in up to 30% of patients following treatment, without knowledge of the impact on morbidity and mortality of this discordance. An optimal level of both GH and IGF-I appears to be required to maintain normal health, emphasizing the need for a clearer understanding of relationship between these two parameters.

Acromegaly↗
PubMed2005

GH and mortality in acromegaly.

Effective biochemical control of GH and IGF-I levels in subjects with acromegaly can reduce mortality to that of the general population. Several retrospective studies have reported that the increased mortality is improved if GH levels are reduced to <2.5 microg/l, measured as mean of GH day profile or random GH level. It has been proposed that control or "cure" of disease is achieved when mean GH levels are <2.5 microg/l, nadir GH after an oral glucose load is <1 microg/l, and circulating IGF-I is reduced to an age- and sex-adjusted normal range. However, virtually all evidence from epidemiological studies has related GH values and not IGF-I values to long-term morbidity and mortality; controversy remains regarding the relative importance of these 2 parameters in determining post-treatment control status. Review of the West Midlands Acromegaly Database (419 patients) revealed that mortality was increased in the subgroup of patients with GH levels >2 microg/l (measured either as mean GH day profile or GH values across an oral glucose tolerance test, or random GH level). Factors influencing mortality in acromegaly were analyzed in a study from New Zealand of 208 acromegalic subjects. Serum GH at last follow-up was the most significant predictor of mortality, with mortality rates reduced to normal by achieving GH concentrations <1-2 microg/l. A nationwide survey of mortality in 334 patients with acromegaly from Finland has reported no difference in overall mortality between patients and general population; however, patients with last known basal serum GH >2.5 microg/l showed excess mortality (SMR 1.61, p<0.001). These 3 analyses of 961 patients indicate unequivocally that a GH value of 1-2 microg/l is an appropriate therapeutic target, as values above this level are associated with increased mortality.

Acromegaly↗
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↗
PubMed2003

Abnormal expression of 11 beta-hydroxysteroid dehydrogenase type 2 in human pituitary adenomas: a prereceptor determinant of pituitary cell proliferation.

The physiological effects of glucocorticoids (GCs) are, at least in part, mediated by inhibition of cell proliferation. Two isozymes of 11 beta-hydroxysteroid dehydrogenase (11 beta-HSD) interconvert cortisol (F) and inactive cortisone (E), and are thus able to modulate GC action at an autocrine level. Previously, we have demonstrated absent expression of 11 beta-HSD2 in normal pituitaries; however, in a small number of pituitary tumors analysed, 11 beta-HSD2 was readily demonstrable. Here we have used real-time RT-PCR to quantify expression of mRNA for 11 beta-HSD1 and 2 in 105 human pituitary tumors and have performed enzyme expression and activity studies in primary pituitary cultures. Overall, pituitary tumors expressed lower levels of 11 beta-HSDl mRNA compared with normals (0.2-fold, P<0.05). In contrast, expression of 11 beta-HSD2 mRNA was 9.8-fold greater in tumors than in normals (P<0.001). Enzyme assays showed significant 11 beta-HSD2 activity (71.9+/-22.3 pmol/h/mg protein (mean+/-s.d.)) but no detectable 11 beta-HSDl activity. Proliferation assays showed that addition of glycyrrhetinic acid (an 11 beta-HSD2 inhibitor) resulted in a 30.3+/-7.7% inhibition of cell proliferation. In summary, we describe a switch in expression from 11 beta-HSDl to 11 beta-HSD2 in neoplastic pituitary tissue. We propose that abnormal expression of 11 beta-HSD2 acts as a proproliferative prereceptor determinant of pituitary cell growth, and may provide a novel target for future tumor therapy.

11-beta-Hydroxysteroid Dehydrogenases↗
PubMed2003

Expression of pituitary tumour transforming gene (PTTG) and fibroblast growth factor-2 (FGF-2) in human pituitary adenomas: relationships to clinical tumour behaviour.

OBJECTIVE: Pituitary tumour transforming gene (PTTG) encodes a multifunctional protein that is implicated in initiating and perpetuating pituitary adenoma growth. PTTG appears to have key regulatory functions in determining control of many fundamental cellular events including mitosis, cell transformation, DNA repair and gene regulation. Several of these events are mediated through interactions with PTTG binding factor (PBF) and fibroblast growth factor-2 (FGF-2). Given this background, we have determined the expression of PTTG, PBF, FGF-2 and its receptor FGF-R-1 in a large cohort of pituitary adenomas and have sought associations between levels of gene expression and clinical markers of tumour behaviour. PATIENTS AND METHODS: We used real-time reverse transcriptase-polymerase chain reaction (RT-PCR) and Western blot analyses to measure PTTG, PBF, FGF-2 and FGF-R-1 expression in ex vivo pituitary tumours (N = 121). Clinical data, including accurate radiological assessment of tumour characteristics, were used to determine any associations between gene expression and tumour behaviour. RESULTS: PTTG was increased significantly (fivefold, P = 0.005) in adenomas compared with normal pituitaries. We also demonstrated that PBF was similarly raised in adenomas (sixfold, P = 0.0001), and was significantly correlated with PTTG expression. FGF-2 and its receptor FGF-R-1 were also raised in adenomas compared with normal pituitary tissue. Moreover, significantly enhanced expression of FGF-R-1 was observed in invasive adenomas compared with other pituitary tumours. CONCLUSIONS: Our data support a fundamental role for PTTG-mediated upregulation of FGF-2 signalling in pituitary tumorigenesis and growth, and suggest that receptor-mediated mechanisms of growth factor action may be critically important. Further prospective studies are required to determine whether measurement of FGF-R-1 mRNA will be of clinical use as a prognostic marker in patients with pituitary adenomas.

Adenoma↗
PubMed2003

Pituitary tumor transforming gene and fibroblast growth factor-2 expression: potential prognostic indicators in differentiated thyroid cancer.

Differentiated thyroid cancers are the most common endocrine cancers, but there are no reliable molecular markers of prognosis. Pituitary tumor transforming gene (PTTG) plays several potential roles in tumor initiation and progression, including regulating mitosis and stimulating expression of fibroblast growth factor (FGF)-2. Increased expression of PTTG has been demonstrated in follicular thyroid lesions, and expression of this oncogene has been identified as a potential prognostic marker in pituitary adenomas and colon carcinomas. We assessed the expression of PTTG and FGF-2 and its receptor FGF-R-1 in 27 differentiated thyroid cancers, and we compared this with expression in 11 normal thyroids, 25 multinodular goiters, and 13 Graves' disease specimens. We also examined the relationship between gene expression and clinical markers of tumor behavior. PTTG and FGF-2 were overexpressed in thyroid carcinomas (9.5-fold increase, P = 0.003, and 5.0-fold increase, P < 0.001, respectively) compared with normal thyroid. Increased FGF-2 mRNA expression was independently associated with the findings of lymph node invasion (R(2) = 0.71; P < 0.001) and distant metastasis (R(2) = 0.55; P = 0.009) at tumor presentation, after taking into account known prognostic factors such as age and gender of the patient and size and type of the tumor. High PTTG expression was independently associated with tumor recurrence (R(2) = 0.64; P = 0.003). We conclude that PTTG and FGF-2 expression are potential prognostic markers (and perhaps therapeutic targets) for differentiated thyroid cancer.

Adult↗
PubMed2002

Dysregulation of iodothyronine deiodinase enzyme expression and function in human pituitary tumours.

OBJECTIVE: Thyroid hormones (THs) perform essential roles in pituitary function. They regulate anterior pituitary hormone secretion and are also key determinants of pituitary cell proliferation and differentiation. The critical role of deiodinase enzymes, which serve as prereceptor regulators of TH action, remains largely unexplored. Three deiodinase enzymes metabolize active and inactive THs and thereby determine tissue concentrations of the biologically active ligand, tri-iodothyronine (T3). We hypothesized that aberrant expression of deiodinase enzymes and/or altered enzyme activity in pituitary tumours may change tissue concentrations of THs and influence their growth and secretory characteristics. STUDY DESIGN AND PATIENTS: We studied 105 pituitary tumours and 10 normal pituitaries for expression of deiodinase enzyme mRNAs encoding types 1 (D1), 2 (D2) and 3 (D3) using real-time RT-PCR. Enzyme activity data from 20 pituitary samples were also obtained. RESULTS: Pituitary tumours expressed significantly increased D3 mRNA (6.5-fold, P < 0.0005) compared with normal pituitaries. D2 mRNA was also increased 2.6-fold (P = 0.005) in pituitary tumours compared with normals. The rare TSH-secreting pituitary tumour subtype expressed a 13.1-fold excess of D3 mRNA and reduced D2 mRNA (0.1-fold of normal pituitaries). D2 mRNA expression in ACTH-secreting tumours was similarly reduced to 0.1-fold that in normal pituitaries. CONCLUSIONS: Pituitary adenomas express abnormal levels of deiodinase enzymes compared to normal pituitaries. These abnormalities may have functional consequences on pituitary tumour growth. In the case of TSH-secreting pituitary adenomas, the observed pattern of deiodinase mRNA expression may explain the 'resistance' of this tumour type to TH feedback.

Adenoma↗
PubMed2002

Vascular endothelial growth factor, its receptor KDR/Flk-1, and pituitary tumor transforming gene in pituitary tumors.

Pituitary tumorigenesis is a poorly understood process involving dysregulation of the cell cycle, proliferation, and angiogenesis. The novel securin pituitary tumor transforming gene (PTTG) disrupts cell division and stimulates fibroblast growth factor (FGF)-2-mediated angiogenesis. We investigated expression of the angiogenic vascular endothelial growth factor (VEGF) and its receptor KDR/Flk-1 in 103 human pituitary tumors, and we assessed functional relationships between these genes in vitro. Nonfunctioning tumors (n = 81) demonstrated markedly raised VEGF mRNA (3.2-fold, P < 0.05) and protein concentrations, compared with normal pituitaries (n = 10). KDR was also highly induced in nonfunctioning tumors (14-fold, P < 0.001, n = 78) as well as in the whole cohort of pituitary tumors, compared with normal pituitary samples (14-fold, P < 0.0001, n = 100). In vitro, PTTG induced VEGF, but not KDR, expression in fetal neuronal NT2 cells (2.7-fold, P < 0.001, n = 8), MCF-7 breast carcinoma cells (1.9-fold, P = 0.03, n = 10), and choriocarcinoma JEG-3 cells (P = 0.0002, n = 8). A mutated PTTG construct that cannot be phosphorylated showed identical VEGF up-regulation (2.9-fold, P < 0.001, n = 8) in NT2 cells, compared with wild-type PTTG, but a further mutated construct with abrogation of the key protein:protein interaction domain of PTTG resulted in a significant reduction in VEGF stimulation, compared with wild-type (0.37-fold reduction, P < 0.001, n = 8). FGF-2 findings mirrored those of VEGF, although antibody depletion of secreted FGF-2 in the cell medium failed to influence VEGF up-regulation by PTTG. Overall, our findings implicate altered VEGF and KDR signaling in pituitary tumorigenesis, and we propose that PTTG stimulation of FGF-2 and VEGF expression in the presence of up-regulated growth factor receptors may account for angiogenic growth and progression of human pituitary tumors.

Adenoma↗
PubMed2001

Prediction of all-cause and cardiovascular mortality in elderly people from one low serum thyrotropin result: a 10-year cohort study.

BACKGROUND: Low serum thyrotropin, in combination with normal concentrations of circulating thyroid hormones, is common, especially in elderly people and in individuals with a history of thyroid disease. We aimed to assess the long-term effects of subclinical hyperthyroidism on mortality. METHODS: We did a population-based study of mortality in a cohort of 1191 individuals not on thyroxine or antithyroid medication. All participants were aged 60 years or older. We measured concentration of thyrotropin in serum at baseline in 1988-89. We recorded vital status on June 1, 1999, and ascertained causes of death for those who had died. We compared data for causes of death with age-specific, sex-specific, and year-specific data for England and Wales. We also compared mortality within the cohort according to initial thyrotropin measurement. RESULTS: During 9733 person-years of follow-up, 509 of 1191 people died, the expected number of deaths being 496 (standardised mortality ratio [SMR] 1.0, 95% CI 0.9-1.1). Mortality from all causes was significantly increased at 2 (SMR 2.1), 3 (2.1), 4 (1.7), and 5 (1.8) years after first measurement in those with low serum thyrotropin (n471). These increases were largely accounted for by significant increases in mortality due to circulatory diseases (SMR 2.1, 2.2, 1.9, 2.0, at years 2, 3, 4, and 5 respectively). Increases in mortality from all causes in years 2-5 were higher in patients with low serum thyrotropin than in the rest of the cohort (hazard ratios for years 2, 3, 4, and 5 were 2.1, 2.2, 1.8, and 1.8, respectively). This result reflects an increase in mortality from circulatory diseases (hazard ratios at years 2, 3, 4, and 5 were 2.3, 2.6, 2.3, 2.3), and specifically from cardiovascular diseases (hazard ratios at years 2, 3, 4, and 5 were 3.3, 3.0, 2.3, 2.2). INTERPRETATION: A single measurement of low serum thyrotropin in individuals aged 60 years or older is associated with increased mortality from all causes, and in particular mortality due to circulatory and cardiovascular diseases.

Age Distribution↗
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↗
PubMed2001

Expression of 11 beta-hydroxysteroid dehydrogenase in rat osteoblastic cells: pre-receptor regulation of glucocorticoid responses in bone.

11 beta-hydroxysteroid dehydrogenase (11 beta-HSD) acts as a pre-receptor signaling mechanism for corticosteroids by regulating the access of active glucocorticoids to both glucocorticoid (GR) and mineralocorticoid receptors (MR). To examine the relationship between endogenous glucocorticoid metabolism and osteoblast function, we have characterized the expression of 11 beta-HSD isozymes in rat osteosarcoma cells. Analysis of mRNA from ROS 25/1, UMR 106 and ROS 17/2.8 cells revealed transcripts for both 11 beta-HSD type 1 (11 beta-HSD1) and type 2 (11 beta-HSD2) in all three cell lines. However, enzyme activity studies showed only high affinity dehydrogenase activity (inactivation of corticosterone (B) to 11-dehydrocorticosterone (A)), characteristic of 11 beta-HSD2; conversion of B to A was higher in ROS 25/1> UMR 106 cells>ROS 17/2.8. Although all three cell lines had similar numbers of GR (50,000/cell), glucocorticoid modulation of alkaline phosphatase activity and cell proliferation was only detectable in ROS 17/2.8 cells. Further studies showed that 11 beta-HSD2 activity in each of the cells was potently stimulated by both A and B, but not by synthetic dexamethasone. This effect was blocked by the 11 beta-HSD inhibitor, 18 beta-glycyrrhetinic acid (but not by GR or MR antagonists) suggesting direct, allosteric regulation of 11 beta-HSD2 activity. These data indicate that in osteosarcoma cells 11 beta-HSD2 plays a key role in controlling GR-mediated responses; cells with relatively high levels of 11 beta-HSD2 activity were insensitive to glucocorticoids, whilst cells with low levels showed functional responses to both dexamethasone and B. In addition to the established effects of 11 beta-HSD2 in protecting MR in the kidney and colon, our data suggest that 11 beta-HSD2 in bone represents an important pre-receptor mechanism in determining ligand availability to GR.

11-beta-Hydroxysteroid Dehydrogenase Type 1↗
PubMed2001

An audit of management of differentiated thyroid cancer in specialist and non-specialist clinic settings.

OBJECTIVE: Thyroid cancer is the most common endocrine malignancy but is none the less rare. Some aspects of its management remain controversial. Previous audits of patient management in the United Kingdom have revealed deficiencies, especially in communication between specialists. We have audited patient management in a large university-associated teaching hospital, assessing points of good practice identified from published guidelines and reviews, and have compared findings in groups of patients managed jointly by specialists with an interest in thyroid cancer (including surgeon, endocrinologist and oncologist) with a group managed by other clinicians outside that setting. DESIGN AND PATIENTS: Retrospective case-note review of 205 patients with differentiated (papillary or follicular) cancer including group A (n = 134; managed in a specialist multi-disciplinary clinic setting) and group B (n = 71; managed in other clinic settings). Points of good practice investigated were adequacy of surgery, surgical complications, prescription and adequacy of T4 treatment, adequacy of monitoring by measurement of serum thyroglobulin and action taken and appropriate administration of ablative radioiodine. RESULTS: Deficiencies in management of the cohort as a whole were identified, including inadequate surgery and inadequate TSH suppression in approximately one-fifth of the cases. Monitoring with thyroglobulin measurements and action when serum thyroglobulin was high were also inadequate in some cases and ablative radioiodine was not given, despite being indicated in 11.7% of the cohort. Inadequate surgery and failure to administer radioiodine were less common in those managed in a specialist clinic setting than in those managed in other clinic settings. CONCLUSIONS: The findings highlight the need for locally agreed protocols in managing relatively rare endocrine disorders such as thyroid cancer and argue in favour of centralization of expertise and patient management in multi-disciplinary specialist clinic settings.

Adolescent↗
PubMed2001

Weight gain following treatment of hyperthyroidism.

OBJECTIVE: Patients frequently express concern that treating hyperthyroidism will lead to excessive weight gain. This study aimed to determine the extent of, and risk factors for, weight gain in an unselected group of hyperthyroid patients. DESIGN AND SUBJECTS: We investigated 162 consecutive hyperthyroid patients followed for at least 6 months. Height, weight, clinical features, biochemistry and management were recorded at each clinic visit. RESULTS: Documented weight gain was 5.42 +/- 0.46 kg (mean +/- SE) and increase in BMI was 8.49 +/- 0.71%, over a mean 24.2 +/- 1.6 months. Pre-existing obesity, Graves' disease causing hyperthyroidism, weight loss before presentation and length of follow-up each independently predicted weight gain. Patients treated with thionamides or radioiodine gained a similar amount of weight (thionamides, n = 87, 5.16 +/- 0.63 kg vs. radioiodine, n = 62, 4.75 +/- 0.57 kg, P = 0.645), but patients who underwent thyroidectomy (n = 13) gained more weight (10.27 +/- 2.56 kg vs. others, P = 0.007). Development of hypothyroidism (even transiently) was associated with weight gain (never hypothyroid, n = 102, 4.57 +/- 0.52 kg, transiently hypothyroid, n = 29, 5.37 +/- 0.85 kg, on T4, n = 31, 8.06 +/- 1.42 kg, P = 0.014). This difference remained after correcting for length of follow-up. In the whole cohort, weight increased by 3.95 +/- 0.40 kg at 1 year (n = 144) to 9.91 +/- 1.62 kg after 4 years (n = 27) (P = 0.008), representing a mean weight gain of 3.66 +/- 0.44 kg/year. CONCLUSION: We have demonstrated marked weight gain after treatment of hyperthyroidism. Pre-existing obesity, a diagnosis of Graves' disease and prior weight loss independently predicted weight gain and weight continued to rise with time. Patients who became hypothyroid, despite T4 replacement, gained most weight.

Adolescent↗