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Showing papers in "Clinical Endocrinology in 1996"


Journal ArticleDOI
TL;DR: The measurement of urinary free cortisone (UFE) excretion in normals and in patients with disorders of the pituitary‐adrenal axis is validated in an attempt to more accurately measure the activity of 11β‐HSD2 in vivo.
Abstract: OBJECTIVE Two isoforms of 11 beta-hydroxysteroid dehydrogenase (11 beta-HSD) catalyse the interconversion of cortisol to hormonally inactive cortisone; defects in the 11 beta-HSD2 isoform result in hypertension. The kidney, expressing high levels of 11 beta-HSD2, is the principal source of cortisone in man. We have validated the measurement of urinary free cortisone (UFE) excretion in normals and in patients with disorders of the pitultary-adrenal axis in an attempt to more accurately measure the activity of 11 beta-HSD2 in vivo. SUBJECTS Forty-one normal adults, 12 normal children < 12 years of age, 15 patients with Cushing's syndrome, 12 with hypopitultarism on replacement hydrocortisone, 12 with the syndrome of apparent mineralocorticoid excess (AME) and 7 volunteers consuming liquorice. MEASUREMENTS A complete 24-hour urine collection was analysed by gas chromatography/mass spectrometry for "A-ring' reduced cortisol and cortisone metabolites, i.e. tetrahydrocortisols (THF and allo-THF) and tetrahydrocortisone (THE). In addition, urinary free cortisol (UFF) and urinary free cortisone were quantified using deuterium-labelled internal standards. RESULTS In normal adults and children, UFE excretion exceeded that of UFF (UFF 30.4 +/- 2.4 micrograms/24h (mean +/- SE), UFE 54.6 +/- 4.1 micrograms/24h, adults) (for conversion to nmol/24h multiply E by 2.78 and F by 2.76 respectively). Thus the normal UFF/UFE ratio was 0.54 +/- 0.05 in contrast to the (THF + allo-THF)/THE ratio of 1.21 +/- 0.06. UFE excretion was normal in hypopituitary patients on replacement hydrocortisone. Although UFE was elevated in all forms of Cushing's syndrome, the UFF/UFE ratio was grossly elevated in patients with the ectopic ACTH syndrome (14.0 +/- 6.7, n = 6). UFE was below the lower limit of the assay (< 1 microgram/24h) in most patients with the so-called type 1 variant of AME and significantly reduced in 4 patients described as having the type 2 variant of AME (10.5 +/- 3.5 micrograms/h, P < 0.05) and in 7 volunteers consuming liquorice (26.8 +/- 10.0 micrograms/24h, P < 0.01). In ectopic ACTH syndrome, AME, and liquorice ingestion the UFF/UFE ratio was more deranged than the (THF + allo-THF)/THE ratio. CONCLUSION In normals the discrepant THF + allo-THF/ THE and UFF/UFE ratio suggests that much more of the UFE is derived from the kidney. Reduction in UFE excretion is seen following liquorice ingestion and in both variants of AME, though it is more profound in AME1. The high UFF/UFE ratio in the mineralocorticoid excess state seen in the ectopic ACTH syndrome is compatible with substrate-saturation of renal 11 beta-HSD2. The measurement of UFE and the UFF/UFE ratio is a significant advance in the analysis of human 11 beta-HSD activity in vivo; in particular, the UFF/UFE ratio appears to be a more sensitive index than the (THF + allo-THF)/THE ratio of renal 11 beta-HSD2 activity.

273 citations


Journal ArticleDOI
TL;DR: The frequency of specific mutations in the RET proto‐oncogene in sporadic medullary thyroid carcinomas in MTCs are determined and the presence or absence of a codon 918 mutation with the clinical characteristics of these tumours is correlated.
Abstract: OBJECTIVE We have determined the frequency of specific mutations in the RET proto-oncogene in sporadic medullary thyroid carcinomas (MTCs) and correlated the presence or absence of a codon 918 mutation with the clinical characteristics of these tumours. DESIGN Thirty paraffin-embedded sporadic MTCs and two frozen MTCs were collected for analysis of specific mutations in the RET proto-oncogene in codons 609, 611, 618 and 620 (exon 10); 630 and 634 (exon 11); 768 (exon 13); 883 (exon 15) and 918 (exon 16). A novel primer was designed which introduced a restriction site for RsaI in the presence of the specific codon 918 mutation (ATG → ACG) in these tumour samples. A ‘clinical-genetic’ correlation was performed comparing the presence or absence of the codon 918 mutation with the following clinical characteristics: age at diagnosis, tumour size, presence or absence of metastases, MTC related morbidity, and base line calcitonin levels at diagnosis or most recent follow-up. PATIENTS Patients were classified as having sporadic MTC if there was no family history of C-cell hyperplasia, MTC, phaeochromocytoma or parathyroid disease. Retrospective review of patient records enabled complete clinical data to be obtained in 28 of 32 patients. MEASUREMENTS Base line calcitonin levels were measured by radioimmunoassay or calcitonin enzyme linked immunoassay. Cysteine codons in exons 10 and 11, specifically codons 609, 611, 618, 620, 630 and 634, were screened for the presence of mutations by sequence analysis. Specific mutations occurring at codons 768, 883 and 918 were screened for by restriction endonuclease digestion of PCR products. RESULTS The mutation at codon 918ATG → ACG was found in 21 of 32 (66%) MTCs and the mutation at codon 883GCT → TTT was found in one of 32 MTCs. Where possible, the presence of ‘germline-type’ mutations in codons 609, 611, 618, 620, 630 and 634 were excluded. Ten MTCs did not have a mutation in codons 768, 883 or 918 of the RET proto-oncogene. The presence or absence of the somatic mutation at codon 918 did not correlate with any of the above clinical characteristics. CONCLUSION Somatic mutations in the RET proto-oncogene occur frequently in sporadic MTCs.

272 citations


Journal ArticleDOI
TL;DR: The ITT has been compared to a low dose ACTH stimulation test and the standard ACTH stimulating test to assess the hypothalamic–pituitary–adrenal axis.
Abstract: OBJECTIVE The insulin tolerance test (ITT) has long been used to assess the hypothalamic-pituitary-adrenal axis, but may be hazardous. The standard synthetic ACTH (Synacthen) test has been advocated as a substitute but is sometimes insensitive. In this study the ITT has been compared to a low dose ACTH stimulation test (1 microg) and the standard ACTH stimulation test (250 microg). SUBJECTS Twenty-seven subjects were studied, 24 with verified or suspected hypothalamic-pituitary disorders and three on long-term glucocorticoid therapy. DESIGN Insulin tolerance, low dose ACTH and standard ACTH tests were performed in all patients. The ITT was performed less than 48 hours after the ACTH tests. Synacthen was administered as an intravenous bolus. MEASUREMENTS Serum cortisol values were determined by radioimmunoassay. The peak cortisol value during ITT was compared to the cortisol levels during the ACTH tests. RESULTS There was a highly significant correlation between peak cortisol values during ITT and cortisol levels after 20-60 minutes in the low dose ACTH test (r(s) = 0.91-0.93; P < 0.0001) and after 30 and 60 minutes in the standard ACTH test (r(s) = 0.85 and 0.89 respectively; P < 0.0001). Four patients showed discrepancies between the three tests. CONCLUSIONS The 1-microg ACTH test follows the ITT more closely and may be more sensitive than the standard ACTH test in detecting more subtle insufficiency of the hypothalamic-pituitary-adrenal axis. The standard ACTH test and the insulin tolerance test may thus be replaced by the 1-microg ACTH test in screening for secondary cortisol insufficiency. We recommend that serum cortisol is measured before and 30 and 40 minutes after the ACTH injection.

240 citations


Journal ArticleDOI
TL;DR: The prevalence of thyroid autoantibodies and autoimmune thyroid disorders in patients with chronic hepatitis C before and during interferon therapy is assessed.
Abstract: BACKGROUND AND AIMS Hepatitis C virus is involved in the induction of autoimmunity and interferon can also induce hepatic and non-hepatic autoimmune reactions. This study assessed the prevalence of thyroid autoantibodies and autoimmune thyroid disorders in patients with chronic hepatitis C before and during interferon therapy. PATIENTS AND METHODS We studied prospectively 207 patients positive for anti-HCV and viral RNA. One hundred and forty-four of them received a therapeutic trial of one year with interferon-α. Free thyroxine, TSH and autoantibodies to thyroglobulin and thyroid microsomes were systematically tested at entry and at weeks 12 and 24 in both untreated and treated patients. RESULTS Sixteen of the 207 patients (7.7%) had thyroid dysfunction, including positive antithyroid antibodies in 14 (6.7%) and hypothyroidism in 10 (4.8%) prior to interferon therapy. In addition, during pretreatment evaluation one patient developed clinical hyperthyroidism after transient subclinical hypothyroidism and another had subclinical hyperthyroidism. Prevalences of positive antithyroid antibodies and hypothyroidism were significantly higher in women (14.7 and 10.5%, respectively, vs 0% in men, P < 0.01) and were directly associated with increasing age (P < 0.01). The incidence of thyroid dysfunction was also significantly higher in patients with other autoantibodies such as anti-nuclear (ANA) (P < 0.01). A trial with interferon was initiated in 144 patients and 8 of 142 (5.6%) without previous thyroid abnormalities developed thyroid dysfunction, including positive antithyroid antibodies in 7 (4.9%) and hypothyroidism in 4 (2.8%) with a prevalence again significantly higher in women (12.7 and 8.3%, respectively, vs 1% in men, P < 0.01) and also directly related to increasing age (P < 0.01). An association was found between the development of thyroid dysfunction during interferon therapy and the presence of other autoantibodies, including ANA, anti-DNA and anti-Sjogren’s antibodies (P < 0.01), as well as with the induction of autoimmune hepatitis and Sjogren's syndrome (P < 0.01 and < 0.05 respectively). Thyroid abnormalities were reversed in all patients when interferon therapy was discontinued. CONCLUSIONS No significant association was found between chronic hepatitis C and the presence of thyroid autoimmunity in female patients. On the contrary, interferon therapy induced antithyroid autoantibodies and thyroid dysfunction de novo in patients with chronic hepatitis C without pre-existing thyroid abnormalities. Thyroid dysfunction secondary to interferon was reversible after discontinuation of therapy.

207 citations


Journal ArticleDOI
TL;DR: Size at birth is related to the urinary excretion of adrenal androgen and glucocorticoid metabolites in a population sample of 9‐year‐old children to test the mechanisms underlying the association between reduced size at birth and cardiovascular disease and non‐insulin‐dependent diabetes mellitus in adult life.
Abstract: OBJECTIVE The mechanisms underlying the association between reduced size at birth and cardiovascular disease and non-insulin-dependent diabetes mellitus in adult life are not known. One possibility is that the intra-uterine environment has permanent effects on the function or activity of the hypothalamo-pituitary-adrenal axis. We tested this by relating size at birth to the urinary excretion of adrenal androgen and glucocorticoid metabolites in a population sample of 9-year-old children. SUBJECTS AND METHODS One hundred and ninety children (89 boys and 101 girls) of known present height, weight and size at birth collected a 24-hour urine sample. The urinary breakdown products of dehydroepiandrosterone sulphate and of cortisol and cortisone were measured by gas chromatography and their respective breakdown products summed (‘adrenal androgen metabolites’ and ‘glucocorticoid metabolites’). Excretion was expressed in μg/day. RESULTS Urinary adrenal androgen metabolite excretion was higher in children who had been light at birth. A 1-kg decrease in birthweight was associated with a 40% (95% CI 9–79%) increase in metabolite excretion. Excretion was positively associated with current weight and age, but the relation with birth weight was independent of weight, age or sex. Urinary glucocorticoid metabolite excretion was positively associated with current weight, but not independently with age. The urinary excretion of total glucocorticoid metabolites was higher in children who had been light at birth, but the relation was best described as U-shaped, with the highest average urinary glucocorticoid metabolite excretion being found in children who had been either light or heavy at birth. The U-shaped (quadratic) relation persisted after adjustment for sex and current weight (P for quadratic term 0.006). CONCLUSION These findings suggests that the intra-uterine environment, as measured by fetal size at birth, has long-lasting effects on the function of the hypothalamo-pituitary-adrenal axis.

206 citations


Journal ArticleDOI
TL;DR: The results of transsphenoidal pituitary surgery for acromegaly were analyzed to assess the longer‐term outcome for patients not offered further treatment when post‐operative levels of GH < 5 mU/l were achieved.
Abstract: OBJECTIVE Previous studies of surgical treatment for acromegaly have used varied criteria for ‘cure’, but elevated GH levels are considered to be associated with continuing disease activity. We wished to analyse the results of transsphenoidal pituitary surgery for acromegaly and assess the longer-term outcome for patients not offered further treatment when post-operative levels of GH < 5 mU/l were achieved. DESIGN We studied a retrospective group of patients who underwent transsphenoidal surgery for acromegaly at St Bartholomew’s Hospital between 1985 and 1993. PATIENTS One hundred consecutive patients (53 male, mean age 46 years, range 18–68 years) undergoing transsphenoidal surgery for acromegaly were assessed. The patients were followed for a mean of 3.8 years (range 0.5–8 years) after operation. MEASUREMENTS GH levels are represented as a mean value from a four-point day curve taken at 0830, 1300, 1700 and 1900h. ACTH reserve was assessed basally and, if this was normal, with the insulin tolerance or glucagon tests. TSH, T4, PRL, LH, FSH, testosterone or oestradiol and plasma and urine osmolality were also measured. RESULTS Post-operatively, 42% of patients achieved a mean GH level of 100 mU/l achieved post-operative GH values < 5mU/l. In addition, tumour size influenced the outcome of surgery with 61% of patients with a microadenoma but only 23% of patients with a macroadenoma achieving post-operative GH levels of < 5 mU/l. Of the 42 patients considered in remission postoperatively (mean GH < 5 mU/l), 32 were available for long-term follow-up and were not offered any further treatment: only one of these has shown evidence of mild biochemical recurrence after a mean follow-up of 3.8 years (range 0.5–8). There were no peri-operative deaths. Two patients required surgical repair for CSF leaks and there were eight documented cases of meningitis. Permanent diabetes insipidus was noted in eight patients post-operatively. New anterior pituitary deficiency occurred in 21% of patients following surgery; 73% had unaltered pituitary function and in 6% recovery of partial hypopituitarism was noted. CONCLUSIONS The stated outcome of surgery depends on the criteria adopted. Safe GH levels (mean levels < 5 mU/l) can be achieved in 42% of an unselected series of patients with acromegaly and if the tumour is a microadenoma this figure rises to 61%. Based on the current evidence it is safe not to offer further treatment to those patients in whom post-operative GH < 5 mU/l are achieved.

199 citations


Journal ArticleDOI
TL;DR: The relation between smoking severity and the incidence of endocrine ophthalmopathy symptoms in patients with Graves’ hyperthyroidism was examined.
Abstract: OBJECTIVE Smoking has been associated with an increased incidence of endocrine ophthalmopathy (EO). In this study we examined the relation between smoking severity and the incidence of EO symptoms in patients with Graves’ hyperthyroidism. DESIGN Patients were prospectively followed for at least one year after the onset of hyperthyroidism. Smoking and EO status were evaluated at 3−6- months intervals. PATIENTS Two hundred and fifty-three ambulatory patients with recent onset of Graves’ hyperthyroidism were studied. MEASUREMENTS The incidence of total EO symptoms, proptosis, and diplopia at any time point before and after the occurrence of Graves’ hyperthyroidism was assessed by interview and physical examination. RESULTS Smoking was associated with a 1.3-fold increase in the overall incidence of symptomatic EO, and a 2.6 and 3.1-fold increase in the incidence of proptosis and diplopia, respectively. The relative risk increased in parallel with the current number of cigarettes smoked per day. In contrast, lifetime tobacco use was not an independent risk factor for the development of EO symptoms. Former smokers had a significantly lower risk for the occurrence of proptosis and diplopia than active smokers with a comparable lifetime cigarette consumption. CONCLUSIONS Our data suggest that current, but not lifetime, tobacco consumption constitutes a risk for the incidence of proptosis and diplopia in patients with Graves’ hyperthyroidism, and that this risk increases with smoking severity.

194 citations


Journal ArticleDOI
TL;DR: The prevalence of pre‐clinical CS among obese patients with uncontrolled diabetes is assessed and autonomous cortisol secretion without clinical stigmata of Cushing's syndrome is recognized.
Abstract: OBJECTIVE Autonomous cortisol secretion without clinical stigmata of Cushing's syndrome (CS) has been recently recognized and termed pre-clinical or sub-clinical CS. The common assumption is that CS is an extremely rare cause of uncontrolled diabetes; however, the prevalence of this entity has not been studied. We assessed the prevalence of pre-clinical CS among obese patients with uncontrolled diabetes. PATIENTS AND DESIGN (1) In a retrospective analysis, the medical records of 63 patients with endogenous CS were reviewed. (2) In a cross-sectional study, 90 obese patients (BMI > 25 kg/m2) followed in a University Hospital and the local Health Fund endocrine and diabetes clinics, with poorly controlled diabetes (glycosylated haemoglobin > 9%), underwent an overnight 1 mg dexamethasone suppression. In patients with non-suppressible cortisol levels (> 140 nmol/l), Liddle's 2 and 8 mg dexamethasone suppression tests and imaging studies were performed. MEASUREMENTS The prevalence of poorly controlled diabetes, the major presenting symptom of CS, was assessed in the retrospective analysis. The prevalence of "true' CS and the false positive rate in the overnight dexamethasone suppression test were calculated. The endocrine evaluation of the patients with pre-clinical CS and the effects of surgical cure on glycaemic control are described. RESULTS In the retrospective analysis, 11 (17.5%) had diabetes and 2 (3.2%) lacked the classic physical characteristics of the syndrome. In the cross-sectional study, 4 patients failed to suppress plasma cortisol (< 140 nmol/l). In one patient the diagnosis of CS was not confirmed by a standard Liddle's test and was therefore considered false positive. In the other 3, the diagnosis of CS was confirmed (prevalence of 3.3%, 95% confidence interval 1-9%). In all other patients the overnight cortisol suppression test was normal (cortisol level 47.3 +/- 2.5 nmol/l (mean +/- SEM)). After surgical treatment of CS, glycaemic control was markedly improved in all 5 patients (2 from retrospective and 3 from cross-sectional studies). CONCLUSIONS The prevalence of pre-clinical Cushing's syndrome in obese patients with poorly controlled diabetes appears to be considerably higher than previously believed. The overnight dexamethasone suppression test proved to be a simple, sensitive and highly specific screening test for Cushing's syndrome despite the presence of obesity and hyperglycaemia.

190 citations


Journal ArticleDOI
TL;DR: Assessment of lipids and lipoproteins in women with PCOS is compared with weight matched controls, and the findings are related to indices of insulin secretion and action, and to menstrual history.
Abstract: OBJECTIVE Polycystic ovary syndrome (PCOS) is characterized by hyperinsulinaemia and insulin resistance. Previous reports of lipid abnormalities in the syndrome have produced conflicting results which may, in part, be related to the lack of appropriate controls for the obese women with PCOS. Only one study has related lipid levels to insulin sensitivity. The objective of this study was to assess lipids and lipoproteins in women with PCOS, to compare the results with weight matched controls, and to relate the findings to indices of insulin secretion and action, and to menstrual history. DESIGN A cross-sectional study of insulin sensitivity and lipids in a cohort of PCO subjects compared to weight and ethnic group matched controls. PATIENTS AND METHODS We have therefore investigated glucose tolerance, plasma lipids and lipoproteins in 19 lean (LP) and 55 obese (OP) patients with PCO and compared the results with those in 22 lean (LC) and 15 obese (OC) control women. Insulin sensitivity was measured in the same subjects with a short insulin (0.05 U/kg i.v. insulin) tolerance test (LP, n = 18; OP, n = 20; LC, n = 19; OC, n = 11). RESULTS Results are expressed as mean +/- SEM or median (interquartile range). Fasting plasma glucose levels were similar in the four groups but the plasma glucose area was higher after oral glucose (75 g) in both the lean and obese PCOS groups than in their controls (LC 32.4 +/- 0.7 vs LP 35.2 +/- 1.2, P < 0.01; OC 34.7 +/- 1.8 vs OP 37.8 +/- 1.5 mmol/l/3 h, P < 0.01). Insulin sensitivity was significantly reduced in obese PCOS women (LC 196 +/- 9 vs LP 179 +/- 9, NS; OC 168 +/- 12 vs OP 133 +/- 9 mmol/l/min, P < 0.01). Total serum cholesterol levels were similar in the four groups but HDL2-cholesterol was reduced in both obese and lean PCOS (LC 0.42 (0.38-0.62), LP 0.31 (0.26-0.44), P < 0.05; OC 0.34 (0.21-0.47), OP 0.21 (0.12-0.32) mmol/l, P < 0.01). Total HDL-cholesterol was decreased significantly only in the obese PCOS group. Body mass index correlated significantly and negatively with total HDL-cholesterol and with HDL2-cholesterol levels both within the PCOS group and the control women. Using multiple regression insulin insensitivity contributes significantly beyond BMI to the low HDL-cholesterol in women with polycystic ovaries. CONCLUSION Polycystic ovary syndrome is associated with biochemical risk factors for premature vascular disease, which cannot be explained by obesity alone.

184 citations


Journal ArticleDOI
TL;DR: Hyperinsulinaemic women with the polycystic ovary syndrome (PCOS) may be at increased risk of vascular disease later in life, mediated by blood pressure or lipid abnormalities or by elevated plasma levels of plasminogen activator inhibitor‐1 (PAI‐1) activity.
Abstract: OBJECTIVE Hyperinsulinaemic women with the polycystic ovary syndrome (PCOS) may be at increased risk of vascular disease later in life, mediated by blood pressure or lipid abnormalities or by elevated plasma levels of plasminogen activator inhibitor-1 (PAI-1) activity. PAI-1 may also be involved in ovarian follicle development and ovarian connective tissue remodelling. We measured plasma PAI-1 activity and 24-hour ambulatory blood pressure records in women with and without PCOS. DESIGN Cross-sectional study of three groups. PATIENTS Twenty-four non-obese women with a classic ovarian ultrasound appearance of PCO and extreme menstrual disturbance (Group 1), 26 matched controls with a normal menstrual cycle and an ultrasound appearance of PCO (Group 2) and 10 matched controls with a normal menstrual cycle and normal ovarian ultrasound (Group 3). MEASUREMENTS Twenty-four hour ambulatory blood pressure recordings (Spacelabs 90207), ovarian ultrasonography, fasting plasma insulin and glucose, plasma PAI-1 activity, HDL and total cholesterol, triglycerides, gonadotrophins and testosterone. Family history of premature vascular disease. RESULTS Median fasting plasma insulin was significantly higher in Group 1 (45 .8 pmol/l, range 12.9–161.9) than in Group 2 (28.1 pmol/l; range 13.6–91; P <0.05) or Group 3 (26.0 pmol/l; range 13.5–63.3; P <0.05). There were no differences between groups in 24-hour, daytime or night-time ambulatory blood pressure measurements, and no relation between plasma insulin and any blood pressure variable. Mean plasma PAI-1 activity was higher in Group 1 (10.0 ±7.1 AU/l) than in Group 2 (6.0 ±4.6 AU/l P < 0.05) or Group 3 (5.1 ± 3.5 AU/l; P =0.06). There was a significant independent direct relation between fasting plasma insulin and PAI-activity (r = 0.41, R2 = 0.154; F1,59 = 11.38; P = 0.001). Groups did not differ in parental history of premature vascular disease, or in mean HDL or fasting triglyceride levels. CONCLUSIONS The only measurable vascular risk factor associated with hyperinsulinaemia and menstrual disturbance in non-obese women with PCOS is an elevated plasma PAI-1 activity. These women did not differ from controls in ambulatory blood pressure profiles, lipid measurements or in a parental history of premature vascular disease. PAI-1 and plasminogen are involved in ovarian follicle maturation and the present finding suggests a biologically plausible link between hyperinsulinaemia, anovulation and vascular risk in PCOS.

184 citations


Journal ArticleDOI
TL;DR: The association between hypercholesterolaemia and subclinical hypothyroidism is described and the effect of thyroid substitution therapy is quantified by an analysis of previously published intervention studies.
Abstract: OBJECTIVE The significance of mild hypercholesterolaemia in subclinical hypothyroidism and whether there is beneficial reduction after thyroxine replacement, remain controversial. We aimed to describe the association between hypercholesterolaemia and subclinical hypothyroidism, and to quantify the effect of thyroid substitution therapy by an analysis of previously published intervention studies. DATA SOURCES Intervention studies cited in the Medline database from January 1976 until January 1995, with index terms cholesterol, hypercholesterolaemia, hyperlipidaemia, thyrotrophin (TSH), hypothyroidism, thyroid and human. A total of 148 studies were reviewed. DATA EXTRACTION We recorded the year of publication, study design, number of patients enrolled, mean age, duration of thyroid substitution, normal range of TSH levels, TSH levels pre and post-substitution treatment and total cholesterol in plasma before and after treatment. DATA ANALYSIS (1) Qualitative description of studies on the relationship between hypercholesterolaemia and hypothyroidism, both subclinical and clinical. (2) Precision weighted pooled estimates of the effect of thyroid substitution therapy on the plasma levels of total cholesterol, in patients with subclinical and overt hypothyroidism. RESULTS Subclinical hypothyroidism was two to three times more frequent in people with an elevated total plasma cholesterol. In addition, the total plasma cholesterol levels were slightly elevated in patients with subclinical dysfunction of the thyroid. Thyroid substitution therapy in patients with subclinical hypothyroidism, restoring the TSH levels to normal, decreased total cholesterol by 0.4 mmol/l (95% confidence interval (CI) 0.2-0.6 mmol/l) independently of the initial plasma level. The effect of thyroid substitution therapy on HDL-cholesterol in patients with subclinical hypothyroidism was not consistent. The effect of thyroid substitution in patients with overt hypothyroidism was highly dependent on the pretreatment levels of total cholesterol. In these patients substitution therapy decreased total cholesterol by 1.2 mmol/l (95% CI 0.9-1.5 mmol/l) when the plasma levels were elevated up to 8 mmol/l, and by 3.4 mmol/l (95% CI 3.0-3.7) when plasma levels were higher than 8 mmol/l. The high density lipoprotein (HDL)-cholesterol level decreased and amounted to 0.16 mmol/l (95% CI 0.07-0.24). CONCLUSIONS Thyroid substitution treatment in patients with hypercholesterolaemia and subclinical hypothyroidism decreases total plasma cholesterol by 0.4 mmol/l, but plasma levels remain elevated in most patients. Further treatment with dietary restriction and cholesterol synthesis inhibitors should then be considered.

Journal ArticleDOI
TL;DR: It is aimed to establish normal ranges with current assays, for both the short Synacthen (SST) and insulin stress tests (IST), and to examine whether the SST can satisfactorily substitute for the IST in assessment of the hypothalamic–pituitary–adrenal axis.
Abstract: OBJECTIVE The best dynamic test for the assessment of the hypothalamic–pituitary–adrenal axis and the interpretation of the cortisol levels, remain a matter of controversy. We aimed to establish normal ranges with current assays, for both the short Synacthen (SST) and insulin stress tests (IST) and then to use these data to examine whether the SST can satisfactorily substitute for the IST in assessment of the hypothalamic–pituitary–adrenal axis. DESIGN Thirty SSTs and 27 ISTs were performed on different healthy volunteers. The results of all paired tests performed on patients in the last three years are reviewed. SETTING Programmed Investigation Unit. SUBJECTS Fifty-seven healthy volunteers and 166 patients. MAIN OUTCOME MEASURES Basal serum cortisol concentration and cortisol values obtained at 30 and 60 minutes during the SST compared to the maximum obtained with adequate hypoglycaemia (plasma glucose < 2mmol/l) during an IST. RESULTS From normal data the mean-2SD 30-minute value during the SST was 392 nmol/l and 60-minute value was 497 nmol/l. The maximal cortisol response (mean − 2SD) during the IST was 519 nmol/l. Sixty patients failed the IST, none of whom had a basal cortisol > 450 nmol/l and only six (10%) had a 30-minute cortisol value > 600 nmol/l. The 30-minute value provided a better index than the 60-minute value. The basal, 30 and 60-minute values during the SST all correlated positively and significantly with the maximal cortisol on IST. The correlations persisted for all microadenomas and macroadenomas secreting prolactin, gonadotrophins or growth hormone, patients undergoing either pre or post-adenomectomy evaluation, and in those patients who had received long-term steroids provided that the medication had been reduced and stopped two days prior to admission. CONCLUSIONS Using a 30-minute cortisol value > 600 nmol/l as a cut-off, the short Synacthen test provides a suitable substitute for the insulin stress test. Adopting this policy will decrease the number of insulin stress tests performed by one-quarter and thus provide a substantial saving without detriment to patient care.

Journal ArticleDOI
TL;DR: The third trimester of pregnancy is characterized by a mildly hyperactive hypothalamic–pituitary–adrenal (HPA) axis, possibly driven by elevated circulating levels of corticotrophin releasing hormone (CRH) of placental origin.
Abstract: OBJECTIVE The third trimester of pregnancy is characterized by a mildly hyperactive hypothalamic–pituitary–adrenal (HPA) axis, possibly driven by elevated circulating levels of corticotrophin releasing hormone (CRH) of placental origin. In-vitro studies have demonstrated that glucocorticoids and oestrogen stimulate while progesterone inhibits the expression of CRH mRNA and/or protein, suggesting that several potential interactions between the placenta and the HPA axis may exist. DESIGN AND PATIENTS To investigate the detailed pattern of circulating immunoreactive (ir) CRH, ACTH, cortisol, oestradiol and progesterone during the third trimester of pregnancy, plasma samples were drawn serially every 30 minutes from 22 healthy pregnant women (age 32.0 ± 1.1 years, mean ± SE) between the 34th and 36th week of gestation. Ten women had plasma samples drawn between 0800 h and 2000 h (daytime group), and 12 between 2000 h and 0800 h (night-time group). The hormone concentrations obtained were analysed for pulsatility by the Detect program, for detection of circadian rhythmicity by comparison between the first and second 6-hour periods within each group by Student's t-test, and for time-dependent correlations by cross-correlation analysis. RESULTS All five hormones were secreted in a pulsatile fashion. There was no apparent circadian rhythm of CRH or oes tradiol secretion, whereas there was a clear circadian rhythm in plasma ACTH, cortisol and progesterone secretion, with the latter in reverse phase (P<0.05). No significant correlations were observed between CRH and ACTH, whereas, as expected, ACTH and cortisol concentrations were strongly correlated with each other over time (r=0.32 and 0.70 at lag time 30 minutes for the daytime and night-time groups, respectively), with ACTH leading cortisol. A weak positive correlation was observed between CRH and cortisol concentrations for the night-time group at lag time 0 minute, suggesting that the latter may have a positive effect on the former in vivo CONCLUSIONS These data suggest that placental CRH, although pulsatile, drives quantitatively the maternal HPA axis in the third trimester of pregnancy in a non-circadian, non-pulsatile fashion. The maternal HPA axis is probably driven in a circadian and pulsatile fashion by another major ACTH secretagogue, most likely AVP of parvocellular paraventricular nucleus origin.

Journal ArticleDOI
TL;DR: In adults, there are few data regarding GH responses to provocative stimuli other than insulin‐induced hypoglycaemia, so this work compares the GH response to four different growth hormone secretagogues and placebo in normal healthy adult males.
Abstract: OBJECTIVE In adults, there are few data regarding GH responses to provocative stimuli other than insulin-induced hypoglycaemia. We have compared the GH response to four different growth hormone secretagogues and placebo in normal healthy adult males. DESIGN This was a prospective, randomized, placebo-controlled study in 18 normal male subjects. After an overnight last, an intravenous cannula was inserted into the arm of each subject and a blood sample was taken for GH at -30, -15, and 0 minutes. Four provocative agents (intravenous insulin 0.2 IU/kg; intravenous arginine 20 g/m2 as an infusion over 30 minutes; oral clonidine, either 100 or 200 micrograms; intramuscular glucagon 1 mg) and placebo were administered to each subject in a randomized manner on different days. Further blood samples were taken at 15-minute intervals for 180 minutes for GH estimation. RESULTS The median (range) GH peak response for each agent was insulin 107.7 (28.1-200) mU/l; arginine 22.3 (3.1-72.9) mU/l; glucagon 42 (11.8-200) mU/l; 100 micrograms clonidine 7.2 ( 20 mU/l to glucagon, arginine and clonidine respectively. In complete contrast only one subject achieved a peak response of less than 40 mU/l (28.1 mU/l) to ITT. CONCLUSIONS The most profound GH release is seen after insulin-induced hypoglycaemia. Glucagon appears to be more effective at inducing GH release than arginine. Clonidine at a dose of 100 or 200 micrograms is no more effective than placebo.

Journal ArticleDOI
TL;DR: This study monitored the development of cortisol daily rhythm using non‐invasive salivary cortisol determination and found that the age of appearance of such rhythm in infancy is determined by the day of the week.
Abstract: Objective Although an outstanding characteristic of the adrenocortical function of children and adults is its circadian rhythm, little information is available about the age of appearance of such rhythm in infancy. The main obstacle has been the ethical difficulty in obtaining serial blood samples from healthy infants. We monitored the development of cortisol daily rhythm using noninvasive salivary cortisol determination. Design and patients A longitudinal study of a group of 9 healthy infants was performed. Salivary samples were obtained in the morning, afternoon and night at 2, 4, 8, 12, 16, 20 and 24 post-natal weeks from all infants. Measurements Cortisol was determined by RIA in 25-microl salivary samples. Two techniques based on assay coefficients of variation were employed to characterize a normal circadian pattern of cortisol. Results Five infants (55%) established and maintained their cortisol rhythm as early as at 2, 4 and 8 weeks of age. In the remaining 4 infants the age of appearance was 12 and 20 weeks. This rhythm emerged in the group as a whole at a mean age of 8 weeks. Conclusions Our data suggest that, in most normal infants, the development of hypothalamic-pituitary-adrenal axis circadian maturation may occur at a much earlier age than previously described.

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TL;DR: Binding sites specific for growth hormone have been identified in the brain, but the action of GH on the central nervous system is still poorly understood.
Abstract: Objective Binding sites specific for growth hormone have been identified in the brain, but the action of GH on the central nervous system is still poorly understood. Design In a double-blind, placebo-controlled 21-month trial with a cross-over design, with each treatment period lasting for 9 months, we investigated the long-term effect of GH on the cerebrospinal fluid (CSF) concentrations of some brain neurotransmitters and thyroid hormones of importance for mood and cognition. Patients Twenty-four patients with documented GH deficiency acquired in adult life took part. Results Analysis of CSF collected at the end of the two treatment periods showed that the GH concentration was related to the administered dose of rhGH (r = 0.56, P = 0.0044). After rhGH treatment the concentration of the dopamine metabolite homovanillic acid (HVA) had decreased from 218 +/- 80 to 193 +/- 82 nmol/l (P = 0.002) and that of the excitatory acid aspartate had increased from 233 +/- 81 to 313 +/- 116 nmol/l (P = 0.032). No effects were observed on the concentrations of 5-hydroxyindoleacetic acid (the serotonin metabolite) and of 3-methoxy-4-hydroxyphenyl glycol (the noradrenaline metabolite), or on those of glutamate, glycine and beta-endorphin. However, both CSF and serum levels of free T4 decreased, from 19.8 +/- 6.1 to 16.6 +/- 5.7 nmol/l (P = 0.0002) and 17.0 +/- 5.0 to 13.7 +/- 4.3 nmol/l (P = 0.0001), respectively. The concentration of total T3 was not measurable in CSF but increased in serum from 1.41 to 1.53 nmol/l (P = 0.01). Conclusion The study demonstrates a passage of GH from the circulation into the CSF. The observed changes in homovanillic acid and free T4 are similar to those reported after successful treatment of depressive disorders with antidepressant drugs, and may reflect a beneficial effect of GH on mood and behaviour.

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TL;DR: End‐points such as physical fitness and body composition may be subject to a considerable placebo effect which weakens the validity of open studies, and GH (2 IU/m2 per day) versus placebo treatment for 12 months was tested.
Abstract: OBJECTIVE Studies with GH substitution in GH-deficient (GHD) adults lasting more than 6 months have so far been uncontrolled. End-points such as physical fitness and body composition may be subject to a considerable placebo effect which weakens the validity of open studies. We therefore tested GH (2 IU/m2 per day) versus placebo treatment for 12 months. DESIGN Twenty-nine patients (mean age 45.5 +/- 2.0 years) with adult-onset GHD were studied in a double-blind, parallel design. Measurements of body composition by means of conventional anthropometry, bioelectrical impedance (BIA), CT scan and DEXA scan, exercise capacity, and isometric muscle strength were performed at baseline and after 12 months treatment. For body composition measurements a control group of 39 healthy, age and sex-matched subjects was included. RESULTS Sum of skinfolds (SKF) at 4 sites decreased significantly after GH treatment. Total body fat (TBF) as assessed by DEXA and BIA was elevated at baseline but normalized after GH. TBF assessed by SKF revealed significantly higher levels compared to DEXA and BIA, although all estimates intercorrelated closely. Visceral and subcutaneous abdominal fat decreased by 25 and 17%, respectively after GH (P < 0.01) to levels no longer different from the control group. CT of the mid thigh revealed a significant reduction in fat tissue and a significant increase in muscle volume after GH treatment, both of which resulted in a normalization of the muscle: fat ratio (%) (placebo: 58:42 (baseline) vs 58:42 (12 months); GH: 66:34 (baseline) vs 72:28 (12 months) (P = 0.002); normal subjects: 67:33 (P < 0.05 when compared to 12 months placebo data)). Total body resistance and resistance relative to muscle volume decreased significantly after GH treatment suggesting over-hydration as compared to normal subjects. Exercise capacity (kJ) increased significantly after GH treatment (placebo: 54.7 +/- 9.8 (baseline) vs 51.6 +/- 8.2 (12 months); GH: 64.9 +/- 13.3 (baseline) vs 73.5 +/- 13.6 (12 months) (P < 0.05)). Isometric quadriceps strength increased after GH but no treatment effect could be detected owing to a small increase in the placebo group. Serum IGF-I levels (microgram/l) were low baseline and increased markedly after GH treatment to a level exceeding that of normal subjects (270 +/- 31 (12 months GH) vs 156 +/- 8 (normal subjects (P < 0.01)). The levels of serum electrolytes and HbA1c remained unchanged. The number of adverse effects were higher in the GH group after 3 months, but not after 6 and 12 months. CONCLUSIONS (1) The reduction in excess visceral fat during GH substitution is pronounced and sustained; (2) beneficial effects on total body fat, muscle volume and physical fitness can be reproduced during prolonged placebo-controlled conditions; (3) uncontrolled data on muscle strength must be interpreted with caution; (4) a daily GH substitution dose of 2 IU/m2 seems too high in many adult patients.

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TL;DR: The study was designed to identify the clinical and biochemical features of patients with pituitary macroadenomas in whom a high dose PRL hook effect was documented.
Abstract: OBJECTIVE Large amounts of antigen may produce falsely low values in immunoradiometric assays due to the so-called high dose, hook effect. The study was designed to identify the clinical and biochemical features of patients with pituitary macroadenomas in whom a high dose PRL hook effect was documented. DESIGN The clinical and biochemical features of four patients with the high dose PRL hook effect were compared with those of 54 patients with pituitary non-functioning adenomas and 11 with macroprolactinomas who underwent transsphenoidal microsurgery between 1989 and 1994. MEASUREMENTS The presence of the high dose PRL hook effect was confirmed by an increase in the initial PRL concentration when the immunoradiometric assay was processed after dilutions of the serum. This phenomenon was observed in 5.8% (4/69) of patients with pituitary macroadenomas. Undiluted median (range) PRL levels were 9140 (1530-83850), 1530 (162-3210) and 2110 mU/l (1470-45,000) in patients with macroprolactinoma, non-functioning macroadenoma and the hook effect, respectively. In patients with the hook effect, the median PRL levels increased to 384,720 (317,520-950,000) mU/l when the assay was performed after serum dilution. The proportion of males was 9.9% (1/11) in the macroprolactinoma group, 46.3% (25/54) in the non-functioning macroadenoma group and 100% (4/4) in patients with the hook effect. Patients with prolactinoma and non-functioning adenoma had mean tumour sizes of 20 +/- 9 and 27 +/- 11 mm (SD), respectively, while in the hook effect group it was 51 +/- 10 mm. CONCLUSION This study suggests that the high dose PRL hook effect is observed particularly in patients with very large tumours. The immunoradiometric PRL assay must be performed with serum dilution in order to overcome the high dose PRL hook effect in all new patients with pituitary macroadenomas who may have a prolactinoma.

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TL;DR: Oestrogen replacement therapy is associated with a marked reduction in coronary event rates in post‐menopausal women, and HRT with oestrogen alone, or Oestrogen and progesterone combined, isassociated with improved endothelial function in healthy women after the menopause.
Abstract: OBJECTIVE Oestrogen replacement therapy is associated with a marked reduction in coronary event rates in post-menopausal women. As older age is associated with progressive arterial endothelial damage, a key event in atherosclerosis, we assessed whether hormone replacement therapy (HRT) with oestrogen alone, or oestrogen and progesterone combined, is associated with improved endothelial function in healthy women after the menopause. DESIGN Using high resolution external vascular ultrasound, brachial artery diameter was measured at rest and in response to reactive hyperaemia, with increased flow causing endothelium-dependent dilatation (flow-mediated dilatation). PATIENTS We investigated 135 healthy women; 40 were pre-menopausal (mean +/- SD age/26 +/- 6 years, group 1), 40 were post-menopausal and had never taken HRT (aged 58 +/- 3 years; group 2) and 55 were age-matched post-menopausal women who had taken HRT for > or = 2 years, from within 2 years of the menopause (aged 57 +/- 4 years; group 3). In group 3, 40 women were on combined oestrogen and progesterone and 15 on oestrogen-only HRT. RESULTS In group 2, flow-mediated dilatation was significantly reduced compared with group 1 (4.4 +/- 3.4 vs 9.6 +/- 3.6%, P < 0.001), consistent with a decline in arterial endothelial function after the menopause. In group 3, however, flow-mediated dilatation was significantly better than group 2 (6.2 +/- 3.3 vs 4.4 +/- 3.4%, P = 0.01), suggesting a protective effect of HRT. Flow-mediated dilatation was similar in women taking oestrogen alone and in those on combined HRT (5.5 +/- 2.8 vs 6.5 +/- 3.4%, P = 0.40). CONCLUSIONS Long-term HRT is associated with improved arterial endothelial function in healthy post-menopausal women. This benefit was observed in both the combined hormone replacement and unopposed oestrogen therapy groups. This may explain some of the apparent cardioprotective effect of HRT after the menopause.

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TL;DR: To determine how many patients who received GH replacement therapy in childhood until completion of growth have GH deficiency severe enough to be considered for GH Replacement therapy in adult life, this study surveys young adults treated with GH therapy for childhood GH deficiency.
Abstract: OBJECTIVE The few previous studies in which reassessment of GH status has been carried out in young adults treated with GH therapy for childhood GH deficiency concentrated on determining the incidence of 'transient GH deficiency'. As the benefits of GH replacement therapy in adults become increasingly appreciated, it is likely that GH therapy started in childhood for GH deficiency will be continued into adult life in many of those with severe GH deficiency. The aim of this study is to determine how many patients who received GH replacement therapy in childhood until completion of growth have GH deficiency severe enough to be considered for GH replacement therapy in adult life. DESIGN Retrospective analysis of the peak GH responses to provocative stimuli performed at the time of diagnosis of GH deficiency in childhood and at the completion of growth after GH replacement therapy had been stopped. PATIENTS Eighty-eight adults (49 male, 39 female) who had received GH therapy in childhood for a diagnosis of GH deficiency. The aetiology of the GH deficiency included craniopharyngioma, radiation induced associated with either a cerebral tumour or acute lymphoblastic leukaemia, histiocytosis-X and idiopathic. MEASUREMENTS In childhood the original diagnosis of GH deficiency was based biochemically on the failure of the peak GH response to reach 20 mU/l during two provocative tests in 59 of the 88 patients and to a single test in the remaining 29. A total of 147 tests were performed, the most common being an insulin tolerance test (ITT, n = 72) and an arginine stimulation test (AST, n = 53). At reassessment in young adult life 146 tests were performed (74 ITT, 64 AST). Severe GH deficiency was defined arbitrarily as a peak GH response of less than 9 mU/l to a single (n = 33) or to two (n = 55) pharmacological stimuli. RESULTS By definition all patients were considered GH deficient at the time of initial diagnosis. A peak GH response of less than 9 mU/l was seen in 64.8% at initial assessment and 60.2% at reassessment. Analysis in aetiological terms, however, showed that between assessments the incidence of severe GH deficiency increased in the group of radiation induced (48.8 vs. 55.8%) but decreased in the idiopathic group (78.1 vs. 53.1%). Out of the 55 patients who underwent two tests at reassessment, 47.3% of those with a GH peak less than 9 mU/l at one test had a GH peak greater than 9 mU/l at the second test. Fifteen of the 55 patients had additional pituitary hormone deficiencies and all 15 had a GH peak below 9 mU/l in both tests. CONCLUSIONS Our study suggests that all children who have received GH replacement therapy in childhood should undergo reassessment of GH status in young adult life. Between 40 and 60% of such patients merit consideration for GH therapy in adult life depending on the definition of severe GH deficiency in use. Patients with isolated GH deficiency should undergo two provocative tests of GH secretion, but those with additional anterior pituitary hormone deficiencies require only one test at reassessment.

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TL;DR: To determine the frequency with which hyperprolactinaemic illnes tends to resolve with time, a method called AIM’s “AIM ” is used.
Abstract: AIM To determine the frequency with which hyperprolactinaemic illnes tends to resolve with time. STUDY DESIGN A retrospective case-notes review from a specialist endocrine unit in a provincial teaching hospital and tertiary referral centre. PATIENTS Seventy women with hyperprolactinaemia referred to the unit in the 15 year period between May 1979 and May 1994. All those with a non-pituitary cause or with macroadenoma had been excluded, as were those who did not have high-resolution imaging, or who were on treatment at the time of referral. INTERVENTION Intermittent course of treatment with dopamine receptor agonists according to individual need. ENDPOINTS Latest serum PRL concentration in those who had discontinued treatment, and whether serum PRL tended to be lower in any particular group RESULTS There was a significant fall in median PRL concentration from 2000 (714–8000) to 1000 mU/l (220–5600) in the 31 women who had discontinued therapy (P<0.0005), and serum PRL was normal (<700 mU/l) in 11 of them. Serum PRL also fell to normal in three of ten women who had no treatment at all. Final PRL concentration was normal in 35% of women who had had at least one pregnancy during the period of follow-up compared to 14% who had not (P<0.05). CONCLUSIONS These data confirm the findings of others that hyperprolactinaemia will prove self-limiting in up to one-third of women, and that pregnancy may be one factor which triggers a return to normal function

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TL;DR: The aim of this study was to ascertain the extent of mental illness in patients before and after treatment for Cushing's syndrome.
Abstract: OBJECTIVE Cushing's syndrome is associated with psychiatric and psychological disturbances. The aim of this study was to ascertain the extent of mental illness in patients before and after treatment for Cushing's syndrome. DESIGN AND PATIENTS Patients with Cushing's syndrome were identified for a prospective study. Control patients were selected with pituitary adenomas secreting GH or PRL. The aim was to reassess patients after Cushing's syndrome had been treated. MEASUREMENTS Psychiatric symptoms were measured and classified using the Present State Examination (PSE), and analysed on the Catego Programme. The Hamilton Rating Scale (HRS) was used to measure depression. The Crown-Crisp Experiential Index was used to measure common psychoneurotic symptoms (anxiety, phobia, obsession, somatic, depression and hysteria scales). The Eysenck Personality Inventory was used to assess extroversion and neuroticism. Cortisol, ACTH, and other hormones were measured by conventional methods. Parametric and non-parametric tests were used where appropriate. RESULTS Catego analysis of psychiatric ratings showed only 8 patients of 43 with active Cushing's syndrome (19%) were normal. Psychiatric diagnoses were obtained as follows: neurotic depression in 20 (46%), possible neurotic depression in 1 (2%), reactive depression in 6 (14%), and non-specific neurotic symptoms in 8 (19%). Additional Catego ratings of suspected other psychoses were made for 3 patients who were also depressed. None of these 43 patients with active Cushing's syndrome had ratings of schizophrenia or mania, obsessional neurosis or pathological anxiety. In the control group 13 (87%) were normal, 1 patient with acromegaly had an anxiety state and one patient with a prolactinoma had neurotic depression. It was possible to reassess the Present State Examination after treatment in 25 patients, when cortisol levels had been substantially reduced (to normal in 88%), the percentage rated as psychiatrically normal increased from 19 to 68 (chi 2 = 11.7, 1 d.f., P < 0.01). Hamilton Rating Scale scores for depression showed significant improvements after treatment for Cushing's syndrome (mean decrease from 9.2 to 2.4, n = 36, P < 0.001). Crown-Crisp experiential index data showed significant improvements in anxiety, somatic symptoms, and depression (n = 25, P < 0.05). Eysenck Personality Inventory assessments showed a significant improvement in neuroticism score (n = 26 P = 0.016), but no significant change in extroversion (P = 0.5) or lie score (P = 0.6). CONCLUSIONS Most patients with Cushing's syndrome had significant psychiatric pathology, usually depressive illness. As cortisol levels were returned to normal there were significant improvements in scores for depression and anxiety. Management of patients with Cushing's syndrome should include careful assessment of psychological and psychiatric illness.

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TL;DR: The ob gene product, leptin, is considered to be a marker of adipose tissue mass and a possible homeostatic regulator of body mass and is examined for its role in adult hypopituitarism.
Abstract: OBJECTIVE The ob gene product, leptin, is considered to be a marker of adipose tissue mass and a possible homeostatic regulator of body mass. Our objective was to examine the effect of GH replacement on adipose tissue stores and leptin in adult hypopituitarism. SUBJECTS Twenty adults, mean age 47 years (range 20–69) with proven GH deficiency were randomly allocated to either GH (up to 0.25 U/kg/week in daily doses) or placebo for 3 months before cross-over to the opposite treatment. MEASUREMENTS Body composition was measured by dual-energy X-ray absorptiometry (DEXA) in the whole body, trunk and limbs. Plasma leptin was measured by radioimmunoassay at baseline and +2, +4, +8 and +12 weeks in each treatment arm. RESULTS Total body tissue fat (mean±SE) was 30.1±2.2% after GH compared with 31.9±2.2% after placebo, P<0.001 (ANOVA). There were no significant changes in BMI (kg/m2), 29.1±1.3 after placebo vs 28.8±1.2 after GH; or waist to hip ratio (WHR), 0.91±0.01 after both placebo and GH. Baseline plasma leptin showed a significant correlation with baseline BMI, r=0.67, P<0.005 and baseline percentage total body fat, R=0.89, P<0.001. Plasma leptin (adjusted by using baseline percentage total body fat as a covariate) showed a significant linear decrease with time on GH compared with placebo (P=0.03 ANOVA). CONCLUSIONS Plasma leptin and total body fat fall promptly in response to low-dose replacement of GH in GH-deficient subjects. Hormone-induced changes in leptin can occur in humans in the absence of change in body mass index.

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TL;DR: The roles of the Rb and the hereditary breast cancer susceptibility gene (BRCA2), which lie within 25 cM of each other on chromosome 13q12–14, in the multi‐step aetiology of endocrine tumours are investigated.
Abstract: OBJECTIVE Allelic deletion of the retinoblastoma (Rb) gene on chromosome 13 has been reported in both pituitary and parathyroid tumours. We have investigated the roles of the Rb and the hereditary breast cancer susceptibility gene (BRCA2), which lie within 25 cM of each other on chromosome 13q12–14, in the multi-step aetiology of endocrine tumours. PATIENTS AND MEASUREMENTS Seventy-seven endocrine tumours (43 anterior pituitary, 22 parathyroid, 7 carcinoid, and 5 pancreatic islet cell tumours) with paired leucocytes have been examined for loss of heterozygosity (LOH) at the Rb and BRCA2 loci by using specific oligonucleotide primers for the PCR amplification of microsatellite polymorphisms at three intragenic Rb markers, Rb1.20, Rbi4 and D13S153, and D13S260 which is linked to the BRCA2 locus. RESULTS Seventy-five of the 77 tumour–leucocyte pairs were informative and LOH was detected in 1 of 16 non-functioning pituitary tumours, 1 of 8 prolactinomas, 3 of 19 parathyroid adenomas and 1 of 1 parathyroid carcinoma. All the 3 parathyroid adenomas with LOH were associated with aggressive clinical and histopathological features. Allele loss was not detected in any of the 16 somatotrophinomas, 2 corticotrophinomas, 1 gonadotrophinoma, 7 carcinoid tumours (6 bronchial, 1 metastatic intestinal) or 5 pancreatic islet cell tumours that were informative. CONCLUSIONS These results demonstrate that allelic deletions of the 13q12-14 region occur in some pituitary adenomas and 16% of parathyroid adenomas. The extensive loss, which involves both the Rb gene and the BRCA2 locus, suggests that tumour suppressor genes in this region other than Rb or BRCA2 may be involved in the development and progression of some endocrine tumours.

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TL;DR: The prevalence of thyroid function abnormalities in a psychiatric population on admission (as compared to the prevalence in a normal population), and whether such thyroid function irregularities are associated with the occurrence or development of cognitive and affective disorders are sought.
Abstract: OBJECTIVE Cognitive and affective functioning is sensitive to changes in thyroid hormones. We have sought to determine: (1) the prevalence of thyroid function abnormalities in a psychiatric population on admission (as compared to the prevalence in a normal population), and (2) whether such thyroid function abnormalities are associated with the occurrence or development of cognitive and affective disorders. DESIGN Serum was collected 2–3 weeks after hospitalization in 3 major clinics from 3756 psychiatric patients in 1987–1990, stored, and assayed in 1993 for the presence of antibodies against the TSH-receptor and thyroperoxidase (TPO-Ab) and for TSH levels. The psychiatric cohort was matched with a control population of healthy individuals living in the same area (n = 1877). The prevalence study was followed by a case-control study involving patients from one clinic that had routinely assigned a DSM-IIIR classification to its patients. Cases were those admissions with thyroid abnormalities and three subgroups of cases were randomly formed demonstrating either TSH less than 0.4 mU/l (n = 44) or over 4.0 mU/l (n = 44), or TPO-Ab positivity (n = 50). Cases were compared to random controls from the same psychiatric population, viz patients without thyroid abnormalities (n = 83). Comparison was with respect to their psychiatric follow-up diagnosis (the investigator was blinded to the thyroid test results). RESULTS Prevalence study. The percentage of patients positive for TSH-receptor-Ab was 0.26 (9/3504), for TPO-Ab was 10.0 (331/3316) and outside the TSH range of 0.4–4.0 mU/l was 10.0 ((332/3316): 5.9% (198/3316) >4.0 mU/l and 4.1% (134/3316) <0.4 mU/l). Abnormal total thyroxine levels were found in only 9.8% of subjects with abnormal TSH, indicating the predominantly subclinical character of the thyroid alteration. In comparison, the healthy area controls over 55 years of age showed the same prevalence of positive TPO-antibodies and TSH under 0.4 mU/l, but a higher prevalence of TSH over 4.0 mU/l. Case-control study. In the case control analysis differences could not be noticed with regard to prevalences of dementia, schizophrenia or other psychiatric illnesses apart from the prevalence of affective disorders which were more prevalent in TPO-Ab positive patients and patients with a low serum TSH. Since prior use of lithium, carbamezapine, carbimazole and/or thyroxine could be a factor of importance in this association, analyses were also carried out excluding patients with such prior drug use. In these analyses affective disorders were still more prevalent in patients with a low serum TSH (particularly in males, 40% in cases vs 9% in controls, P 4.0 mU/l) and a subgroup of the affective disorders, viz with a rapid cycling of bipolar disorder (18% in cases vs 0% in controls, P < 0.001). CONCLUSION Thoug h causal relations cannot be determined from this cross-sectional study, this admission survey found early forms of autoimmune thyroid disease, sometimes characterized only by TPO-Abs, highly significantly associated with rapid cycles of a bipolar disorder. It also found a weak association between subclinical hyperthyroidism (low serum TSH without TPO-Ab positivity) and affective disorder.

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TL;DR: The impact of the menopause, as well as other factors such as age, body mass index (BMI) and cigarette smoking, on ovarian and adrenal androgen levels in women aged 40–60 years are investigated.
Abstract: Objective The impact of the menopause on androgen production is poorly understood. We have investigated the impact of the menopause, as well as other factors such as age, body mass index (BMI) and cigarette smoking, on ovarian and adrenal androgen levels in women aged 40-60 years. Design Cross-sectional study of blood hormones sampled weekly over one month in volunteer 40-60-year-old women. Subjects One hundred and forty-one women, aged between 40 and 60, recruited from community sources (non-clinical), not using hormone replacement or steroidal contraceptives, and with a current sexual partner. Fifty were categorized as premenopausal (ovulating), 37 as perimenopausal and 54 as post-menopausal. Measurements The following variables were assessed; menopausal status (based on menstrual history and pattern and plasma progesterone), age, BMI, smoking, oestradiol (E2), oestrone (E1), LH, FSH, total testosterone (TT), androstenedione (A), SHBG, free androgen index (FAI), dihydroepiandrosterone (DHEA), dihydroepiandrosterone sulphate (DHEAS) and cortisol. Results are based on multiple regression analysis. TT was positively related to A, BMI and LH. A was negatively related to age and FSH, and positively to DHEA, DHEAS and premenopausal status. SHBG was negatively related to BMI and positively to E1 and non-smoking. DHEA and DHEAS were negatively related to age and were higher in smokers. Both E1 and E2 were related to menopausal status and to FSH. Surprisingly, E2 was negatively related to BMI. Conclusions A variety of factors influence androgen production in this age group. Whereas it is difficult to predict the effect of menopause on androgen levels, LH stimulation of post-menopausal interstitial cells, modulated by a variety of factors including nutrition, and smoking, are likely to be relevant.

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TL;DR: The aim of this study was to investigate the role of the cytokine interleukin‐6 (IL‐6) in alterations of thyroid hormone metabolism seen in NTI.
Abstract: OBJECTIVES Non-thyroidal illness (NTI) is frequently accompanied by alterations in circulating thyroid hormone concentrations, despite patients remaining clinically euthyroid. The mechanisms accounting for these changes in circulating thyroid hormone concentrations remain unknown. Much attention has focussed on the role of inflammatory cytokines which are known to be important mediators of disease. The aim of this study was to investigate the role of the cytokine interleukin-6 (IL-6) in alterations of thyroid hormone metabolism seen in NTI. DESIGN Longitudinal study of hospital in-patients, correlating serum IL-6 concentrations with circulating thyroid hormone concentrations. PATIENTS Two hundred and seventy in-patients recruited consecutively, excluding those with known or suspected thyroid disorder. The patients were divided into 5 subgroups reflecting the nature of their NTI and comprised 41 patients with liver disease, 99 with renal disease, 19 intensive care (ITU) patients, 22 with cardiac disease and 89 patients with general medical, or surgical conditions. MEASUREMENTS Serum IL-6 concentrations were determined using a commercially obtained immunoassay (IL-6 Quantikine assay, R&D Systems, Abingdon, UK). Serum total T4 and total T3 were measured using chemiluminescent immunometric assays (Kodak Clinical Diagnostics Ltd, Amersham, UK) and serum TSH was measured using a third-generation chemiluminescent immunometric assay (Amerlite TSH 30, Kodak Clinical Diagnostics Ltd, Amersham, UK). RESULTS Ninety-three patients studied (35%) had a serum T3 below the normal range (<1.0 nmol/l), 89 patients (33%) had a serum T4 below the normal range (<65 nmol/l) and in 58 patients (21%) both serum T3 and T4 were below the normal range. There was a significant negative correlation between serum total T3 and IL-6 (r = −0.219; P<0.001) and total T4 and IL-6 (r = −0.132; P = 0.032), but not between TSH and IL-6 (r = −0.075; P = 0.22). The ITU patient subgroup had the highest IL-6 concentrations (229.3 ± 48.1 ng/l, mean ± standard error), whilst also having the lowest T3 (0.93 ± 0.08 nmol/l), TSH (0.79 ± 0.25 mU/l) and T4 concentrations (66.6 ± 7.3 nmol/l). The subgroup of patients under general medical or surgical care had least disturbance of their T3 (low in 19%) and T4 (low in 8%) concentrations, whilst also having the lowest mean IL-6 concentration (39.0 ± 5.3 ng/l). The renal patient subgroup, whilst including a high proportion of patients with low T3 (39%) and T4 (45%) concentration, demonstrated only modest elevation of IL-6 concentrations (mean 41.4 ± 8.5 ng/l). CONCLUSIONS Our data revealed a statistical relation between elevated serum IL-6 concentrations and alterations in circulating thyroid hormone concentrations seen in NTI; however, the findings in patients with renal disease suggest that circulating IL-6 is not the only factor responsible for alteration in thyroid hormone metabolism in NTI.

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TL;DR: Circulating IGF‐I and IGF binding protein‐3 (IGFBP‐3) levels both increase in puberty where growth velocity is high and the concentration of free IGF‐i and possible IGF BP‐3 proteolytic activity in puberty has not previously been studied.
Abstract: OBJECTIVE Circulating IGF-I and IGF binding protein-3 (IGFBP-3) levels both increase in puberty where growth velocity is high. The amount of free IGF-I is dependent on the IGF-I level and on the concentrations of the specific IGFBPs. Furthermore, IGFBP-3 proteolysis regulates the bioavailability of IGF-I. However, the concentration of free IGF-I and possible IGFBP-3 proteolytic activity in puberty has not previously been studied. SUBJECTS AND MEASUREMENTS We investigated serum levels of easily dissociable IGF-I concentrations and ultrafiltrated free IGF-I levels by specific assays in 60 healthy boys and in 5 boys with precocious puberty before and during GnRH agonist treatment. In addition, total serum IGF-I, IGFBP-1 and IGFBP-3 levels as well as IGFBP-3 protease activity were determined. RESULTS Free (dissociable and ultrafiltrated) IGF-I concentrations were significantly higher in pubertal boys than in prepubertal children and correlated significantly with the molar ratio between IGF-I and IGFBP-3 (r = 0.69, P < 0.0001 and r = 0.54, P = 0.0008, respectively) and inversely with IGFBP-1 (r = -0.47, P < 0.0001 and r = -0.43, P = 0.0003, respectively). Multiple regression analysis suggested that IGFBP-3 level, and not IGFBP-1, was the major determinant of the free IGF-I serum level in normal boys. Free IGF-I levels were elevated in boys with precocious puberty and decreased during GnRH treatment. IGFBP-3 proteolysis was constant throughout puberty (mean 20%). CONCLUSIONS We conclude that easily dissociable and ultrafiltrated free IGF-I serum levels are increased in boys with normal and precocious puberty and suggest that the increased free IGF-I serum concentration in puberty primarily reflects changes in total concentrations of IGF-I and IGFBPs secondary to increased GH secretion, but that it is not influenced by changes in IGFBP-3 proteolysis.

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TL;DR: This study evaluates the results of IPS sampling in patients with Cushing's disease, and compares them with both imaging findings and transsphenoidal examination.
Abstract: OBJECTIVE While inferior petrosal sinus (IPS) sampling correctly diagnoses pituitary-dependent Cushing's syndrome if a significant ratio of plasma ACTH between the IPS and the peripheral blood is demonstrated, little has been said about the significance of a negative ratio in Cushing's disease (e.g. a false-negative result). This study evaluates the results of IPS sampling in patients with Cushing's disease, and compares them with both imaging findings and transsphenoidal examination. DESIGN The results of IPS sampling were retrospectively compared with both imaging findings and transsphenoidal examination. IPS samples were obtained before and 2, 5 and 10 minutes after intravenous administration of 100 μg of CRH. PATIENTS Thirty-two patients with Cushing's disease were evaluated. All subsequently underwent transsphenoidal examination of the pituitary gland. MEASUREMENTS The ratio of the ACTH concentrations at the IPS and in the peripheral blood (IPS : P ratio), and the ratio of the ACTH concentrations between the IPSs (interpetrosal ratio) were calculated. Radiographic evaluation of the pituitary gland was performed with magnetic resonance imaging (MRI, 29 cases) or computed tomography imaging (CT, 3 cases). RESULTS Transsphenoidal examination of the pituitary gland revealed a microadenoma in 27 cases. Radiological imaging showed a signal compatible with a microadenoma in 22 cases (68.8%), and correctly located the tumour at the side found at surgery in 14 of the 22 cases with positive transsphenoidal findings (MRI 13 cases, CT 1 case, overall 63.6%). Successful bilateral catheterization was accomplished in 30 patients (93.8%). Samples before and after CRH stimulation were drawn in 24 cases. No major complications were observed with the technique. IPS catheterization correctly predicted Cushing's disease (by means of a significant IPS : P ACTH ratio) in 27 of the 30 patients (90%) with basal sampling, and in 23 of the 24 cases with samples drawn before and after CRH administration (95.8%). Taking into account the 12 patients with a lateral microadenoma shown at transsphenoidal examination, IP sinus ACTH ratio was in agreement with the side recorded by the neurosurgeon in 8/12 cases (66.7%). MRi correctly located the tumour in 8/12 patients (66.7%). One patient showed no significant IPS : P ACTH ratio in any set of samples. His MRI showed no sign of a microadenoma. Two years later, another pituitary MRI evaluation showed a midline hypodense signal. The transsphenoidal examination revealed a microadenoma and the post-operative plasma cortisol and urinary free cortisol fell to 293 nmol/l and 100 nmol/24 h, respectively. CONCLUSIONS Only when a significant IPS : P ACTH ratio is present can Cushing's disease be established by IPS sampling. The absence of a significant IPS : P ACTH ratio does not necessarily imply ectopic secretion of ACTH, nor does it exclude Cushing's disease. The results of lateralization by IPS sampling do not remove the need for a thorough transsphenoidal examination of the contents of the sella turcica.

Journal ArticleDOI
TL;DR: The long‐term cardiovascular effects of GH administration in adults are of major clinical importance, given the increasing use of such treatment, and recombinant human GH (rhGH) substitution in GH deficient men is evaluated.
Abstract: OBJECTIVE The long-term cardiovascular effects of GH administration in adults are of major clinical importance, given the increasing use of such treatment. We have evaluated long-term cardiovascular effects of recombinant human GH (rhGH) substitution in GH deficient men. DESIGN S.c. rhGH 0.5 U/kg/week or placebo was administered in a 6-month double-blind, cross-over study, followed (after a year without substitution) by a 42-month period of open GH substitution. PATIENTS We evaluated 7 GH-deficient men serially and compared the results with 21 men matched in terms of age and height. MEASUREMENTS Investigations included exercise tests and Doppler-echocardiography to determine exercise capacity and cardiovascular performance. RESULTS Heart rate and systolic blood pressure at rest increased with GH substitution to the level of the controls, as did diastolic blood pressure after an initial reduction. Age-adjusted exercise capacity increased during the study and we found no evidence of ischaemic heart disease on exercise ECG. Stroke volume increased with GH substitution, thereby normalizing the initially reduced cardiac index. There was no significant change in left atrial or ventricular internal dimensions, systolic function as measured by fractional shortening, or diastolic function as measured by isovolumic relaxation time and left ventricular filling (A/E ratio). However, a lower atrial emptying index than that seen among controls might indicate some diastolic disturbance and there was a definite increase in left ventricular wall thickness compared with controls (to 25.1±1.5 vs 19.7±0.4 mm, P<0.001). CONCLUSIONS We found that GH substitution in GH-deficient adults had a beneficial effect on physical performance and cardiac output. The concomitant increase in left ventricular mass index might be an effect of an excessive substitution dose.