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Vitamin D deficiency, which continues to be widespread amongst persons of Asian descent in the UK, is often detected from abnormal results on routine biochemistry. The aim of this study was to assess the frequency of abnormal results from routine baseline tests of serum calcium, phosphate, and alkaline phosphatase in patients who subsequently proved to have vitamin D deficiency and secondary hyperparathyroidism. A retrospective examination was undertaken to assess these baseline indices in a cohort of 84 such patients seen in Bradford-5 male; 80 of Asian descent; median age 46 years (range 16-82); serum 25-hydroxyvitamin D<10 microg/L; parathyroid hormone >54 ng/L. Calcium was normal in 55 patients (66%), phosphate in 68 (81%) and alkaline phosphatase in 24 (29%). In only 5 patients were all three indices outside the normal range. The median parathyroid hormone concentration was significantly greater in patients with abnormal routine biochemistry (145 [range 55-1662] ng/L) than in patients with normal routine biochemistry (88 [59-322] ng/L) but the median 25-hydroxyvitamin D levels did not differ (3.1 [1.3-9.9] and 3.0 [1.5-7.3] microg/L). Routine biochemistry was normal in 20% of cases. If routine biochemistry is relied upon to detect vitamin D deficiency and osteomalacia, a substantial minority of cases will be missed. [ABSTRACT FROM AUTHOR]

Aim: Epidemiological studies suggest that vitamin D deficiency is common in patients with primary hyperparathyroidism (PHPT). They have higher levels of serum parathyroid hormone (PTH) and markers of bone turnover and fractures are more frequent than vitamin D-replete patients. However, there are concerns that Vitamin D repletion might exacerbate pre-existent hypercalcaemia. Therefore, we aimed to determine if vitamin D replacement improved biochemical indices of calcium metabolism without worsening underlying hypercalcaemia., Subjects and Methods: This is a prospective, observational study based on routine clinical practice, set up in a secondary care centre. 45 consecutive patients with mild biochemical hypercalcaemia due to PHPT and hypovitaminosis D were enrolled. The mean age of the cohort was 61 years (range 25-85 years), predominately Asian (32 patients) and female (41 patients). They received 20,000 IU of oral cholecalciferol, once a week, for 3 months. Calcium, phosphate, alkaline phosphatase and PTH were measured at baseline, 4, 8 and 12 weeks following treatment. Vitamin D levels were obtained at baseline and at 12 weeks, after they completed their treatment., Results: Vitamin D levels normalised at week 12 (mean ± SD, 18.8 ± 9.4 versus 76 ± 20 nmol/L, p = 0.0001) and PTH levels improved following treatment completion (21.2 ± 10 versus 16.2 ± 6 pmol/L, p = 0.026). There was no significant increase in serum calcium levels during vitamin D supplementation., Conclusions: High doses of oral cholecalciferol normalised vitamin D levels without worsening underlying hypercalcaemia in individuals with PHPT.

Background: Hypopituitarism is associated with increased cardiovascular mortality, and it has been suggested that unphysiological glucocorticoid replacement regimens might contribute to this risk. Traditional glucocorticoid replacement regimens have often led to excessive serum cortisol levels. The hypercortisolaemia of Cushing's syndrome is associated with an increased risk of thromboembolism., Objective: To examine whether short-term higher-dose hydrocortisone replacement regimens adversely affect the fibrinolytic system., Design: Crossover study comparing tailored low-dose (LD) glucocorticoid regimen (mean, 17·5 mg hydrocortisone daily), with a traditional high-dose (HD, 30-mg hydrocortisone daily) regimen for 2 weeks., Patients: Ten patients with hypopituitarism and ACTH deficiency - median (range) age, 59 (41-75) years - and 10 age- and sex-matched controls. Nine patients had growth hormone deficiency (five replaced), nine patients had TSH deficiency (nine replaced), eight had gonadotrophin deficiency (five replaced). During the study, other pituitary hormone replacement therapy remained unchanged. Patients with acromegaly and Cushing's syndrome were excluded., Measurements: Hourly serum cortisol for 11 h, plasminogen activator inhibitor-1 (PAI-1), tissue plasminogen activator (tPA) and fibrinogen levels after 2 weeks of treatment with both LD and HD regimens., Results: No overall significant differences were found between the three groups using the Kruskal-Wallis test: PAI-1: [median (range)] HD, 25 (5-53) ng/ml; LD, 21 (4-56) ng/ml; controls, 27 (8-51); P = 0·3; tPA: HD, 10 (5-15) ng/ml; LD, 10 (4-13) ng/ml; controls 10 (3-13); P = 0·46; and fibrinogen: HD, 2·5 (1·8-3·5) g/l; LD, 3·0 (2·3-4·4) g/l; controls, 2·6 (1·6-3·2): P = 0·97 In addition, no significant differences between HD and LD using Wilcoxon's paired test; PAI-1 (P = 0·91), tPAag (P = 0·47) and fibrinogen (P = 0·09)., Conclusions: An increased dose of hydrocortisone for 2 weeks creates excessive glucocorticoid exposure, but does not significantly affect fibrinolytic-coagulation parameters., (© 2012 Blackwell Publishing Ltd.)

Background: There is a lack of data regarding the timing and particularly the severity of hypothyroidism post radioiodine (RI)., Aim: To investigate the timing and severity of hypothyroidism in RI-treated hyperthyroid patients., Methods: Retrospective examination of the records of 183 RI-treated hyperthyroid patients (79 autoimmune hyperthyroidism, 46 toxic multinodular goiter, and 58 hyperthyroidism of indeterminate etiology)., Results: One hundred and fifty-nine patients requiring a single dose of RI (435 MBq), 107 (67%) developed hypothyroidism. Hypothyroidism detected in: 16% of patients at <8 weeks, 46% at 8 to <16 weeks, 24% at 16 to <24 weeks, 9% at 24 to <36 weeks, 3% at 36 to <52 weeks, and 2% at >52 weeks. One hundred and eighty-three patients had follow-up after one or more doses of RI and 124 (68%) patients developed hypothyroidism; of these, 44 (36%) had TSH>50 mU/l and 34 (27%) had free T4<5 pmol/l when hypothyroidism was first detected. Of those patients with a delayed outpatient visit (no.=77) and those with an outpatient visit within the recommended target interval (no.=47), median TSH was 23 (0.05-152) mU/l and 32 (0.05-150) mU/l, respectively (p=0.75) and median free T4 was 7.1 (1.3-16.7) pmol/l and 6.6 (1.3-15.4) pmol/l, respectively (p=0.21) at first detection of hypothyroidism., Conclusions: The severity of hypothyroidism when first detected during follow-up is of concern and suggests that closer monitoring of thyroid function is required, particularly during the first 6 months post- RI therapy.

Context: Ten percent of serum total cortisol (TC) is unbound; the remainder is bound to cortisol-binding globulin (CBG) and, to a lesser extent, albumin. CBG concentrations can drop significantly, particularly in critical illness, resulting in a low TC although the free, active, cortisol may be normal or increased. In the context of a low CBG, the diagnosis of pituitary-adrenal insufficiency with measurements of TC is difficult., Objective: To remind clinicians of the difficulty in interpreting TC when the CBG is low, the circumstances when CBG concentrations may decrease and that measurement of CBG and calculation of the free cortisol index can help in the assessment of pituitary-adrenal reserve., Case: We present two patients at risk of primary and secondary adrenal insufficiency with a poor response to 250 microg Synacthen. In both cases we confirmed low CBG concentrations but a normal free cortisol index (FCI), confirming normal pituitary-adrenal reserve., Intervention: In case one, we have been able to avoid long-term steroid replacement therapy. We continue to reduce the steroid dose in case 2 but have been limited by the need for high-dose steroid treatment for exacerbations of the patient's airways disease., Conclusion: The use of TC in the assessment of the hypothalamic-pituitary-adrenal (HPA) axis may give rise to misleading results if the CBG concentration is low. The FCI may be a better marker of pituitary-adrenal reserve in these subjects. Clinicians should be cautious when interpreting abnormal cortisol results and we emphasize the importance of good clinical assessment.

Struma ovarii is a rare cause of hyperthyroidism and particularly rare in patients with coexisting Graves' disease. We describe a 28-year-old female who presented with symptoms and signs of hyperthyroidism (free thyroxine [FT(4)] 39 pmol/L, thyrotropin [TSH] < 0.05 mU/L) and associated ophthalmopathy, consistent with Graves' disease. The patient relapsed twice: once after initial successful management with carbimazole and subsequently after subtotal thyroidectomy. Radioisotope scanning showed focal uptake bilaterally in the neck and believing this was the source of thyroid hormone excess, carbimazole was restarted. A left ovarian mass was found on ultrasound during the investigation of unrelated nephrotic syndrome resulting from focal segmental glomerulosclerosis. A 555-g struma ovarii was removed surgically. Hypothyroidism developed postoperatively (FT(4) 9.7 pmol/L, TSH 36 mU/L). Circulating TSH receptor stimulating antibodies were positive and immunohistochemical studies confirm the presence of TSH receptors on the struma ovarii. The demonstration of TSH receptors on the struma ovarii increases previous speculation that struma ovarii growth and function may be augmented by the circulating TSH receptor stimulating antibodies of Graves' disease.

Objective: Vitamin D deficiency and osteomalacia remain commonplace within the Asian community in Bradford. The treatment of vitamin D deficiency and osteomalacia is cheap and effective, but there are few data on long-term outcomes. Studies have suggested that a minority of patients fail to normalize parathyroid hormone (PTH) levels during therapy with vitamin D. This study aimed to determine what proportion of Asian patients with vitamin D deficiency and secondary hyperparathyroidism normalize PTH levels following therapy with oral vitamin D and to examine reasons for failure to normalize PTH., Design: This study examined the impact of an oral regimen of vitamin D 800 i.u. (20 micrograms) and calcium 1000 mg daily, on PTH levels within an endocrinology outpatient clinic. patients 51 (4M:47F) Asian patients, median age 39 years (range 16-77 years) with vitamin D deficiency (25-hydroxyvitamin D < 25 nmol/l) and secondary hyperparathyroidism (PTH > 5.7 pmol/l)., Measurements: All patients had at least one follow-up measurement of PTH and calcium during treatment. A subgroup of patients gave consent for examination of GP-prescribing records to indirectly asses adherence to therapy., Results: PTH normalized in only 28/51 (55%) patients (group N) and failed to normalize in 23/51 (45%) patients (group F). Baseline patient characteristics including: age, basal serum 25-hydroxyvitamin D (25OHD), basal serum PTH, basal serum calcium and post treatment serum calcium, were similar in groups N and F. Mild hypercalcaemia occurred in only two (3.9%) patients. The proportion of prescriptions collected by patients in group N was 75 (17-100)% and in group F was 17 (0-100)%, P < 0.0001., Conclusions: This study has demonstrated that long-term oral treatment with vitamin D and calcium, fails to normalize PTH in a significant proportion of patients with vitamin D deficiency and osteomalacia. This is most likely related to lack of adherence to long-term treatment. Improved ways of treating this condition need to be explored.

Aim: Insulin lispro used in an intensive basal/bolus regimen produces equivalent glycaemic control to human-soluble insulin but reduces rates of hypoglycaemia. We tested the hypothesis that the use of rapid-acting analogues might prevent the development of defective hypoglycaemic counterregulation during intensive insulin therapy., Methods: Ten patients with type 1 diabetes (four female, mean age 33 +/- 3 years, diabetes duration 12 +/- 2 years) participated in an open, randomized cross-over study, with 2 months run-in and 4-month treatment periods using either lispro or human-soluble insulin before meals and human NPH insulin (NPH) at night. The total of reported hypoglycaemic episodes (lispro vs. soluble, 123 vs. 128) and HbA(1c) (6.1 +/- 0.2 vs. 6.6 +/- 0.2%) were similar during both treatments. At the end of each period, we measured symptomatic, counterregulatory and cognitive responses, and glycaemic thresholds during hypoglycaemia, induced with a hyperinsulinaemic clamp (blood glucose of 5, 4.5, 3.5 and 2.5 mmol/l)., Results: We found similar overall responses of adrenaline, cortisol, growth hormone and total symptom score. Glycaemic thresholds for rises in adrenaline (3.1 +/- 0.2 vs. 3.1 +/- 0.2 mmol/l, p = 0.76), cortisol (2.2 +/- 0.1 vs. 2.2 +/- 0.1 mmol/l, p = 0.16), growth hormone (3.3 +/- 0.15 vs. 2.9 +/- 0.2 mmol/l, p = 0.13), symptoms (3.2 +/- 0.2 vs. 3.3 +/- 0.1 mmol/l, p = 0.051) and impaired cognitive function (3.0 +/- 0.2 vs. 3.0 +/-0.2 mmol/l, p = 0.20) were also similar., Conclusion: Four months of intensive treatment, with insulin lispro used pre-prandially and isophane at night, produced relatively preserved but equivalent physiological responses to hypoglycaemia as those on soluble insulin. Longer periods of treatment or alternative regimens may be necessary to demonstrate beneficial effects on hypoglycaemic physiological responses.

This article discusses the characteristic features of growth hormone secretion and insulin-like growth factor I (IGF-1) concentrations both in patients with acromegaly and in normal subjects. The therapeutic options for the treatment of acromegaly are briefly discussed, as are the current definitions of successful therapy. The article focuses on the use of serum and urinary growth hormone measurements along with the current and potential use of serum IGF-1, both at diagnosis and during long-term follow-up.

Due to persistent qualitative abnormalities in GH secretion following treatment, and lack of a sensitive marker of GHD in mid-adult life it is extremely difficult to diagnose GHD in treated acromegalic patients. The diagnosis of GHD in patients with pituitary disease relies on provocative tests of GH reserve. Arginine releases GH by reducing somatostatin inhibition of GH release, whereas GH secretagogues (GHS) affect GH release by direct stimulation of the GHS receptor, though an intact GH releasing hormone (GHRH) axis is a prerequisite. The peak GH response to insulin-induced hypoglycaemia and arginine in acromegalic patients, in whom basal serum GH levels of less than 5 mU/l have been achieved, is greatly diminished in those treated by hypothalamo-pituitary irradiation. We aimed to study the response of successfully treated acromegalic patients to the growth hormone secretagogue hexarelin in view of its different putative mechanism of action, and in addition, to determine whether it has any value in the diagnosis of GH deficiency in this subset of patients. Nineteen acromegalic patients, in whom mean serum GH levels below 5 mU/l have been achieved through treatment, were recruited. Eight of the patients had been treated by surgery alone (Group A) and 11 had received primary or postoperative irradiation (Group B). All patients underwent 20 min blood sampling to provide a 24-h GH profile. Serum IGF-I was measured from a sample drawn between 0900 h and 1000 h. On a second visit arginine 20 g/m2 was infused over 30 min, blood samples were taken before commencing the infusion and at 30-min intervals thereafter for 180 min. At the final visit hexarelin 1.5 mcg/kg was administered as an intravenous bolus at t = 0. Blood was drawn at 15-min intervals from - 30 to 180 min. All patients in group A showed an increment in serum GH following hexarelin (DeltaGHHEX) > 20 mU/l, a normal response to arginine, and a mean 24-h GH > 0.5 mU/l. In group B only 4/11 achieved a DeltaGHHEX > 20 mU/l, 5/11 producing a response of < 2 mU/l. Four of the five patients with a DeltaGHHEX < 2 mU/l were also demonstrated to have a mean 24-h GH of < 0.5 mU/l and serum IGF-I SDS < + 0.5. All four patients in Group B who achieved a DeltaGHHEX > 20 mU/l, were observed to show an absent or minimal GH response to arginine. Despite loss of the GH response to arginine, the DeltaGHHEX is retained in a proportion of those patients in whom "safe" GH levels were achieved following irradiation. From the putative mechanisms of action of these provocative agents a plausible explanation would be that the GHRH axis is more resilient than endogenous somatostatin-secreting neurones to radiation-induced damage. Furthermore, GH secretagogues may have a role, in combination with serum IGF-I levels, in the diagnosis of GH deficiency in treated acromegaly.

In patients with treated acromegaly, improved survival is associated with serum GH concentrations below 2 microgram/L (5 mU/L). A principal aim of therapy in acromegaly is to achieve a GH level less than 2 microgram/L, as such levels are thought to be "safe." However, such GH levels do not always equate with normalization of plasma insulin-like growth factor I (IGF-I), although epidemiological data linking survival or morbidity to IGF-I levels are at present lacking. The aims of this study were 1) to further define the nature of GH release in those acromegalic patients who achieve mean GH concentrations below 2 microgram/L post therapy, 2) to examine the effect of different therapeutic interventions on the 24-h GH profile (surgery alone or radiotherapy), and 3) to determine the relationship between the various characteristics of the 24-h GH profile and IGF-I production in acromegalic subjects who have achieved GH below 2 microgram/L. Spontaneous 24-h GH secretion was measured using both a conventional immunoradiometric assay (limit of detection, 0.4 microgram/L) and an ultrasensitive assay (limit of detection, 0.002 microgram/L). The GH data have been analyzed by several methods: 1) the pulse detection algorithm Cluster, 2) a distribution method for detection of peak [the observed concentration 95%, i.e. the threshold at or below which GH concentrations are assessed to be 95% of the time, as calculated by probability analysis (OC 95%)] and trough (OC, 5%) GH activity, 3) deconvolution analysis, and 4) approximate entropy analysis. GH was sampled every 20 min for 24 h, along with basal IGF-I and IGF-binding protein-3, in 21 treated acromegalic patients with a mean GH below 2 microgram/L [ACR; 9 women and 12 men; median age (range), 49 (31-76) yr] and 16 healthy controls [C; 6 women and 10 men; age, 50 (30-75) yr]. Mean 24-h serum GH concentrations were [median (range)]: ACR, 1.1 (0.04-1.5) microgram/L; C, 0.4 (0.02-3.3) microgram/L (P = 0.28). GH pulse frequency was: ACR, 11 (1-14)/24 h; C, 10 (8-18)/24 h (P = 0.41). In the GH profiles the mean heights of the GH peaks were: ACR, 1.2 (0.05-2.8) microgram/L; C, 0.8 (0.02-5.1) microgram/L (P = 0.91), and the mean GH valley nadirs were: ACR, 0.65 (0.03-1.1) microgram/L; C, 0.09 (0.01-1.8) microgram/L (P < 0.02). The OC 95% was: ACR, 1.0 (0.04-3.8) microgram/L; C, 1.0 (0.02-10) microgram/L (P = 0.65), and the OC 5% was: ACR, 0.09 (0.01-0.6) microgram/L; C, 0.01 (0.001-0.4) microgram/L (P < 0.001). The median IGF-I was: ACR, 227 (100-853) microgram/L; C, 156 (89-342) microgram/L (P < 0.005). Approximate entrophy values were: ACR, 1.06 (0.35-1.45); and C, 0.57 (0.27-1.19); P < 0.05. In the acromegaly group a significant positive correlation was found between IGF-I and the calculated GH secretory burst amplitude in the radiotherapy subset (r = 0.85; P < 0.0005) as well as between IGF-I and both the mean GH valley nadir (r = 0.60; P < 0.004) and the trough (OC 5%) GH activity for the acromegalic patients as a whole (r = 0.55; P < 0.02). We conclude that in treated acromegaly (GH, <2 microgram/L), 1) IGF-I (by approximately 50%) and basal GH secretion (by 5-fold) remain significantly elevated compared with control values despite similar mean 24-h GH concentrations; 2) the calculated GH secretory pulse amplitude, mean GH valley nadir, and OC 5% correlate positively with IGF-I; 3) the greater mean GH valley nadir and OC 5% in acromegalic patients compared with controls may account for the raised IGF-I; and 4) radiotherapy is unlikely to normalize the GH secretory pattern, which underlies the persisting elevated IGF-I levels.

Radiotherapy continues to have an important role in the treatment of acromegaly and is particularly effective at halting tumour growth, causing tumour shrinkage and reducing growth hormone (GH) concentrations in the long term. The major disadvantages of radiotherapy include the slow reduction in GH levels and damage to the other hypothalamic-pituitary axes. The 24 hour GH profile in active acromegaly compared with normals, characteristically shows an increased frequency of GH pulses, increased disorderliness (approximate entropy) of GH release, increased mean GH valley nadir, increased non-pulsatile fraction of GH and either similar or increased GH pulse amplitude. Complete surgical excision of a GH secreting adenoma may reverse these abnormalities and reduce circulating insulin-like growth factor-1 (IGF-1) concentrations to normal. However, very few data are available regarding the effects of radiotherapy on GH pulsatility in patients with acromegaly. Radiotherapy rarely leads to normalisation of the pattern of spontaneous GH release and may therefore be associated with an elevated IGF-1 even when 24 hour GH concentrations are comparable to healthy controls. The impact of such a biochemical state on morbidity and mortality in acromegaly is unknown. The continuing effects of radiotherapy may potentially transform an individual from a state of GH excess, to a state of GH deficiency, with as yet undetermined effects. In addition, radiotherapy leads to significant hypothalamic dysfunction, with the possible loss of endogenous somatostatin (SMS) production. This may potentially alter somatostatin (SMS) receptor expression on somatotroph adenomas and alter their responsiveness to subsequent SMS analogue therapy.

Objective: Acromegaly is associated with reduced life expectancy, while therapeutic 'cure' (defined by achievement of GH levels < 5 mU/l) is associated with normalization of life expectancy. Surgery remains the treatment of choice but in those in whom operative 'cure' is not achieved, radiotherapy and/or medical treatment are valuable treatment modalities. The chance of subsequent 'cure' with radiotherapy or somatostatin analogue therapy is increased if the post-operative GH level is reduced below 30 mU/l. Using strict criteria for cure and a single dedicated pituitary surgeon, two large European studies reported 'cure' rates of 42% and 56%. In the Manchester region, surgery for these patients has been performed by a number of neurosurgeons, with no specific designated pituitary surgeon dominating the picture. We wished to examine the impact of this surgical strategy on cure rates and the incidence of a post-operative GH level below 30 mU/l., Design: We reviewed the GH results between 1974 and 1997 for every acromegalic who had been referred to the endocrine departments of the two Manchester hospitals responsible for the majority of pituitary disease referrals in Manchester and who had been subsequently referred for pituitary surgery., Patients and Measurements: Seventy-three (33 male) patients had had GH status assessed before and after surgery by an OGTT or GH profile. The patients were aged between 19 and 70 (mean 43) years at surgery. Seventy-one underwent transsphenoidal and 2 transfrontal surgery. Nine surgeons performed operations., Results: Eighteen (24.7%) had microadenomas and 51 (69.9%) macroadenomas. In 4 patients (5.5%) insufficient data were available to size the adenoma. 17.8% of patients were cured by surgery, 38.8% with microadenomas and 11.8% with macroadenomas. In addition, of 52 patients whose GH levels were > 30 mU/l before surgery, only 27 (51.9%) had GH levels below 30 mU/l post-operatively (81.8% of microadenomas, 43.2% of macroadenomas)., Conclusion: In comparison with other series, the cure rate in this study is significantly lower. The success in reducing GH levels below 30 mU/l post-operatively is difficult to compare with previously published studies, as few groups have analysed their data in this manner. Nonetheless, of our acromegalic patients with a pretreatment GH level in excess of 30 mU/l, nearly 50% have similar GH status postoperatively, thereby rendering them less amenable to cure by alternative therapeutic modalities. This highlights the importance of a specialist pituitary surgeon, not only for GH secreting microadenomas but also for GH secreting macroadenomas. If these patients are not 'cured', the cost of continuing therapy becomes a significant burden on health-care costs. In addition, if the postoperative GH levels remain above 30 mU/l the chances of achieving adequate control of GH levels are greatly reduced, thereby increasing mortality rates as well as morbidity in these patients.

The current definition of cure after treatment for acromegaly stipulates a reduction in GH levels to less than 2 ng/mL (< 5 mU/L), as such GH concentrations are believed to be associated with normalization of long term survival. We sought to further define the nature of the cure in such patients, when cure has been achieved by alternative therapeutic modalities, in the expectation that hypothalamic neuroregulatory control of GH secretion might be affected differently by radiotherapy or surgery. In particular we wished to determine the effect of therapy modality on endogenous somatostatin (SMS) tone, using the GH response to i.v. arginine as a paradigm. We studied 20 patients with cured acromegaly (mean 24-h GH concentration, < 2 ng/mL). Eight patients had been cured by surgery only (S; 4 women and 4 men; mean +/- SEM age, 52 +/- 5 yr), and 12 patients had been cured by radiotherapy (R; 4 women and 8 men; age, 52 +/- 3 yr). Sixteen healthy subjects were studied as a control group (C; 6 women and 10 men; age 53 +/- 3]. The median (range) GH during 24-h profiles was similar in each group: S, 1.3 (0.7-1.8) ng/mL; R, 0.6 (0.4-1.8) ng/mL; and C, 0.7 (0.4-3.2) ng/mL (P = 0.57). The median incremental GH responses to arginine were significantly lower in the R group compared with those in the S and C groups: S, 6.4 (2.1-16.6) ng/mL; R, 0.1 (0-1.7) ng/mL; and C, 9.2 (0-16.1) ng/mL (P = 0.0002; S vs. R, P < 0.01; S vs. C, P > 0.05; R vs. C, P < 0.001). We conclude that in acromegalic patients deemed to be cured (GH, < 2 ng/mL), the mode of therapy has considerable influence on the remaining hypothalamic-somatotroph function. In view of the putative mechanism by which arginine releases GH, we suggest that radiotherapy leads to a reduction or complete loss of endogenous SMS tone. This may have implications for the treatment of those acromegalic patients who are not cured (GH, > 2 ng/mL) and who require SMS analog therapy.

Tolbutamide is used increasingly as an investigative tool in in vivo studies of the physiology of glucose tolerance. Its hypoglycemic effect in nondiabetic subjects is widely variable, reflecting possible variability in its pharmacokinetics, an insulinergic response, an extrapancreatic effect of the drug, or the hypoglycemic effect of insulin itself. Using population-based modeling, we have investigated the kinetics and dynamics of tolbutamide and assessed covariates in two groups of healthy subjects. The results indicate a high variability in insulinergic effect, measured by the area under of the curve of insulin (0-60 min), in response to tolbutamide injection (coefficient of variation = 29-96%). However, it appears that impaired insulin sensitivity is compensated by higher insulin secretion in response to tolbutamide. Thus the hypoglycemic effect of high insulin secretion is minimal in insulin-resistant subjects. Application of the model indicated that tolbutamide has appreciable extrapancreatic effects mediated by prolongation of the residence time of insulin in a remote effect and by enhancement of glucose effectiveness. An effect in increasing the insulin sensitivity index is also possible but could not be confirmed statistically for all groups of subjects studied. These observations may explain inconsistencies between the results of tolbutamide and insulin injection in the frequently sampled intravenous glucose tolerance test and call for further study of insulin- vs. tolbutamide-modified frequently sampled intravenous glucose tolerance tests in the assessment of the insulin sensitivity and glucose effectiveness indexes.

There is circumstantial evidence implicating hypoglycaemia in the sudden overnight death of young patients with insulin-dependent (Type 1) diabetes mellitus (IDDM), the mechanism of which is unknown. We have investigated the effects of hypoglycaemia on the electrocardiogram in 15 patients with diabetes (8 with IDDM and 7 with NIDDM) using a high resolution computer-based system. Patients were randomized to either 2 h of euglycaemia or hypoglycaemia (at around 3 mmol l(-1)) during the afternoon, using hyperinsulinaemic glucose clamps, the two visits separated by a period of at least 4 weeks. Corrected QT interval (QTc), plasma potassium, and adrenaline were measured at baseline and at 0, 60, and 120 min. The degree of QTc lengthening (from baseline) during clamped hypoglycaemia was greater compared to the euglycaemic control period in patients with IDDM (median[range] at 60 min, 156[8 to 258] vs 6[-3 to 28] ms, p <0.02) and NIDDM (120 min, 128[16 to 166] vs 4[-3 to 169] ms, p <0.05). The fall in plasma potassium was greater during clamped hypoglycaemia compared to euglycaemia in those with NIDDM (p <0.03) but not in those with IDDM (p> 0.06). The rise in plasma adrenaline was greater during clamped hypoglycaemia in both groups (IDDM p <0.02, NIDDM p <0.02) and there was a strong relationship between the rise in adrenaline and increase in QTc (r = 0.73, p <0.0001). These data demonstrate alteration of ventricular repolarization with lengthening of the QT interval during hypoglycaemia and suggest a possible mechanism by which hypoglycaemia could cause ventricular arrhythmias.

We tested the hypothesis that transfer from porcine to human insulin causes a fall in nocturnal blood glucose and an increase in the frequency of hypoglycaemic episodes. Twenty IDDM patients (age 19-55, duration 3-36 years) used Velosulin and Insulatard twice daily for 12 weeks, double-blinded to species (human (H) or porcine (P)) in a randomized crossover study. Species was changed after 4 weeks' run-in and 4 weeks later, with insulin doses unchanged on transfer. Ten patients underwent each sequence (H/P/H or P/H/P) and were admitted on the first and eighth night after transfer for hourly blood glucose measurement (22.00-07.00). Biochemical hypoglycaemia (<3.5 mmol l(-1)) was observed on 39 of the 80 patient-nights studied (48.75%). The number of episodes were similar during each night (H1 8, H8 10, P1 10, P8 11, p = 0.83). Total reported symptomatic episodes (H 51 vs P 73, p = 0.85), total HbA1 (H 9.8 +/- 0.3%, P 10.0 +/- 0.3%, p = 0.32) and daily insulin doses (H 0.63 +/- 0.04 units kg(-1) day(-1) vs P 0.63 +/- 0.05 units kg(-1) day(-1), p = 0.54) were not different. Despite an apparent fall in blood glucose levels from night 1 to 8 on transfer to human (AUC 82.3 +/- 7.8 vs 61.4 +/- 5.3 mmol.h l(-1), p < 0.05) but not porcine insulin (AUC 70.7 +/- 7.2 vs 70.1 +/- 7.5 mmol.h l(-1), p = 0.74), there was no difference when all 4 nights were considered together (p = 0.30). We conclude that dose for dose transfer to human insulin does not increase numbers of episodes of nocturnal or reported hypoglycaemia.

Disruption of intraislet mechanisms could account for the impaired glucagon response to hypoglycemia in type 1 diabetes. However, in contrast to animals, there is conflicting evidence that such mechanisms operate in humans. We have used i.v. tolbutamide (T) (1.7 g bolus + 130 mg/h infusion) to create high portal insulin concentrations and compared this with equivalent hypoglycemia using an i.v. insulin infusion (I) (30 mU/m2 x min). Ten normal subjects underwent two hypoglycemic clamps; mean glucose; I (53 +/- 1 mg/dL); and T (53 +/- 1 mg/dL) (2.9 +/- 0.04 mmol/L vs. 2.9 +/- 0.05 mmol/L), held for 30 min. During hypoglycemia, mean peripheral insulin levels were greater with I (59 +/- 4 mU/L) than T (18 +/- 3 mU/L), P < 0.001. Calculated peak portal insulin concentrations were greater during T (282 +/- 28 mU/L) than I (78 +/- 4 mU/L), P < 0.00005. The demonstration of a reduced glucagon response during T-induced hypoglycemia (111 +/- 8 ng/L vs. 135 +/- 12 ng/L, P < 0.05) with higher portal insulin concentrations suggests that intraislet mechanisms may contribute to the release of glucagon during hypoglycemia in man.

Background and Objectives: Adequate assessment of patients on glucocorticoid replacement therapy is of great importance to avoid the consequences of under or over treatment, but no simple test is available for this. The aims of this study were (1) to assess adequacy of glucocorticoid replacement in hypoadrenal patients, (2) to correlate serum cortisol levels (cortisol day curve) with 24-hour urine free cortisol excretion and (3) to assess the impact of glucocorticoid dose optimization on markers of bone formation and bone resorption., Design: Cross-sectional study of current replacement therapy and a prospective study of the effect of dose alteration on bone turnover markers., Patients: Thirty-two consecutive patients on replacement glucocorticoid therapy (12 Addison's disease, 20 hypopituitarism) from a University teaching hospital out-patient department., Measurements: Serum and urinary cortisol, osteocalcin, N-telopeptide of type I collagen (NTX) and bone mineral density., Results: 28/32 (88%) patients required a change of therapy; 24/32 (75%) a total reduction in dose, 18/32 (56%) a change in replacement therapy regimen or drug and 14/32 (44%) both changes. The mean daily dose of hydrocortisone was reduced from 29.5 +/- 1.2 to 20.8 +/- 1.0 mg. A significant correlation was found between peak cortisol and 24-hour urine free cortisol/ creatinine (Spearman correlation r = 0.60, P < 0.0001; n = 51). Following hydrocortisone dose reduction, median osteocalcin increased from 16.7 micrograms/l (range 8.2-65.7) to 19.9 micrograms/l (8.2-56.3); P < 0.01, with no change in the NTX/creatinine ratio., Conclusions: A high proportion of patients on conventional corticosteroid replacement therapy are over treated or on inappropriate replacement regimens. To reduce the long term risk of osteoporosis, corticosteroid replacement therapy should be individually assessed and over replacement avoided.

Objectives: We wished to compare peak and incremental rise in plasma cortisol in response to insulin induced hypoglycaemia (IIH) stress test, i.m. glucagon stimulation test (IMGST) and short Synacthen test (SST) in patients with pituitary disease, using a modern radioimmunoassay for cortisol. We compared the three stimulants using receiver operator characteristic (ROC) plots, assuming a cortisol threshold of 500 nmol/l or 580 nmol/l for the IIH stress test which we used as the standard from which to evaluate the SST and the IMGST., Patients and Design: We prospectively studied 16 patients (8F, 8M mean age 43.69 +/- 3.72 years) admitted to the investigation ward for IIH stress test and who were asked to undergo two additional tests (IMGST and SST) on consecutive days., Measurements: We measured serum cortisol at baseline, 30, 45, 60, 90 and 120 minutes during the IIH stress test; baseline, 150 and 180 minutes during GST, and baseline and 30 minutes during the SST., Results: There was a significant rise in cortisol from baseline in all tests (P < 0.001). There was no significant difference among the peak plasma cortisol responses or the incremental rises in plasma cortisol following IMGST, SST and IIH stress test (repeated measures ANOVA F = 0.704, P = 0.503; F = 0.238, P = 0.79). The ROC plots clearly showed that the SST has poor diagnostic utility at both IIH thresholds, compared with the IMGST., Conclusion: The peaks and incremental rises in cortisol following all three tests are comparable. Using the insulin induced hypoglycaemia stress test as a reference and peak cortisol thresholds of 500 and 580 nmol/l as discriminating variables, the short Synacthen displayed poor diagnostic utility when compared to the i.m. glucagon stimulation test. The short Synacthen may be misleading if used as a screening test as advocated by a number of authors.

There is little information concerning the physiological response to hypoglycaemia induced by sulphonylureas. We compared the physiological and symptomatic responses to insulin and tolbutamide induced hypoglycaemia in 8 normal subjects. While infusing either insulin or tolbutamide, we used a glucose clamp to maintain blood glucose at 4.5 mmol l-1 for 30 min and lowered it to 2.9 mmol l-1 for a further 30 min. Mean peripheral insulin levels during the insulin infusion arm in comparison with the tolbutamide infusion were not significantly different during the euglycaemic plateau: 106 +/- 4 vs 77 +/- 15 mU l-1 (mean +/- SEM) (mean difference 29 mU l-1, 95% CI -22 to 80; p = NS) but were greater during the hypoglycaemic plateau: 106 +/- 3.5 vs 21.0 +/- 4.0 mU l-1 (mean difference 85 mU l-1, 95% CI 72 to 98; p < 0.0001). Portal insulin concentrations, calculated from C-peptide data were not significantly different during the euglycaemic plateau with insulin as compared to tolbutamide. However, during hypoglycaemia portal insulin concentrations were significantly higher 15 min from the start of the plateau, during insulin infusion. During hypoglycaemia induced by either insulin or tolbutamide there were similar peak responses of glucagon: 124 +/- 14 vs 128 +/- 7 ng l-1 (mean difference -4, 95% CI -39 to 31; p = NS) and adrenaline: 2.9 +/- 0.4 vs 2.8 +/- 0.3 nmol l-1, (mean difference 0.1, 95% CI -0.9 to 1.0; p = NS). Increases in tremor and sweating and deterioration in reaction time were similar during both periods of hypoglycaemia as were increases in total: 18.5 +/- 1.4 vs 19.6 +/- 2.2 (mean difference -1.0, 95% CI -3.8 to 1.8; p = NS) and autonomic: 8.9 +/- 0.9 vs. 9.9 +/- 1.3 (mean difference -1.1, 95% CI -5.9 to 3.6; p = NS) symptom scores. We conclude that there is no difference in the glucagon, sympathoadrenal, cognitive or symptomatic response during hypoglycaemia induced by either insulin or tolbutamide. This suggests that the different insulin concentrations produced by these contrasting models of hypoglycaemia had no effect on the physiological response and patients taking sulphonylureas can be expected to develop similar warning symptoms to those on insulin.

The pathogenesis of the extrathyroidal manifestations of Graves' disease-ophthalmopathy and pretibial myxedema (Graves' dermopathy)-involves fibroblast activation and increased mucin (glycosaminoglycan) production. It is nuclear why fibroblasts are activated at these sites and evidence for site-specific and generalized fibroblast activation is conflicting. One previous report has demonstrated an increase in glycosaminoglycan deposition in the forearm skin of patients with Graves' disease but without pretibial myxedema. We have sought to confirm the existence of subclinical dermopathy in the forearm tissue from patients with untreated (UG) and treated (TG) Graves' disease and compared the histological changes with normal controls (C), treated toxic nodular goiter (MNG) and Graves' dermopathy specimens (PTM), using stains for mucin, elastin, glycosaminoglycans (GAGs), and HLA-DR molecules. Four of 4 PTM specimens stained positive for mucin, with varying sparse, fragmented, or dense elastin fibers. Four of 5 PTM specimens stained heavily for GAGs using colloidal iron and 2 of 5 stained heavily using colloidal gold. None of the patients in groups UG, TG, MNG, or the controls, showed mucin deposition or elastin changes. Mild staining with colloidal gold for GAGs was seen in 1 each of the UG, the TG, and MNG groups, and 4 of 8 controls. Heavy staining with colloidal iron for GAGs was seen in 1 TG patient and 1 control, while moderate staining was found in several TG, UG, and controls. In 2 of 4 PTM specimens the monoclonal antibody CR3/43 (against HLA-DR) stained frequent dermal fibroblast-like cells and in 2 a lymphocytic infiltrate was seen. Only 1 of 8 UG patients had multiple CR3/43 staining cells present in the dermis: 3 of 8 TG and 1 of 8 controls had a few CR3/43 stained cells. Overall we found no evidence of dermal mucin deposition in the forearms of 16 patients with Graves' disease and a similar GAG distribution to normal controls. HLA-DR expression by fibroblast-like cells in the dermis suggests activation of these cells in the dermis of the PTM specimens, but no evidence of widespread fibroblast activation was found in the forearms of patients with Graves' disease.

Isolated TSH deficiency is rare. The diagnosis is based on (i) symptoms and signs of thyroid hormone deficiency, (ii) demonstration of an absent or impaired TSH response to TRH and (iii) other pituitary hormones remaining intact. We report a 60-year-old female in whom isolated TSH deficiency was found, with a free thyroxine - 7.0 pmol/L (11-20), total triiodothyronine level - 1.5 nmol/L (1.1-2.6) and thyroid stimulating hormone - 0.87 mU/L (0.38-4.3). A TRH test on two separate occasions demonstrated an inappropriately low TSH response. Computed assisted tomography revealed a partially empty sella and other pituitary hormones were demonstrated to be intact. We were unable to detect pituitary antibodies using indirect immunofluorescence on sections of monkey pituitary. Treatment with thyroxine improved this patient's symptoms and suppressed the TSH further.

In patients receiving long-term therapeutic or replacement corticosteroids, delayed or inappropriate adjustment of steroid dosage during intercurrent illness may be fatal. We used a questionnaire to assess current levels of patient knowledge, awareness of the need for action during intercurrent illness and the frequency with which steroid warning cards and Medic Alert pendants were carried, in 61 patients on long-term replacement corticosteroids and in 40 patients receiving long-term therapeutic corticosteroids. Only 67 of the 101 patients taking corticosteroids were carrying a steroid warning card. Eleven of the 21 Medic Alert owners wore their pendants. Only 18 of the 41 patients in the therapeutic group and 41 of the 60 patients in the replacement group would take appropriate action during an intercurrent illness (P < 0.001). Lack of patient knowledge in this important area emphasizes the need for continuing and effective education of these groups of patients during follow-up. An information sheet detailing the exact changes to be made during intercurrent illness may help reinforce verbal advice.

We report a case of steatorrhoea and sub-total villous atrophy, occurring during therapy with mefenamic acid. The patient recovered on cessation of the drug while continuing a normal diet.