bluuebunny/crossref_metadata_2025 huggingface dataset:
Intravenous aminobisphosphonate in Paget's disease: clinical, biochemical, histomorphometric and radiological responses
Authors: Fenton Anna J. , Gutteridge Donald H. , Kent G. Nell , Price Roger I. , Retallack Robert W. , Bhagat Chotoo I. , Worth Graeme K. , Thompson Richard I. , Watson Ian G. , Barry‐Walsh Caltriona , Matz Leonard R.
Published: March 2008

Intravenous 3‐amino‐l‐hydroxypropylidene‐1, 1‐blsphosphonic acid (APD) was used to treat 26 patients with Paget's disease. Three daily dosages were studied; 20–30 mg/day in 20 patients, 45 mg/day in three patients and 60 mg/day in three patients, by daily 4‐hour Infusions for 2–10 days. The fasting urinary hydroxyprollne excretion (Hype) declined exponentially, reaching 50% of pretreatment values at 1·92±0·16 (mean±SEM) days. This initial rapid decline was complete by 4 days following treatment to a mean of 28·0±3·4% of pretreatment values. Thereafter, there was no significant decline in Hype. The Initial rate of decline of Hype was unchanged by Increasing the daily dose of APD. Transient non‐symptomatic hypocalcaemia with secondary hyperparathyroidism occurred In all patients. No adverse changes In the renal handling of calcium or phosphate, as seen with high‐dose 1‐hydroxyethylldene‐1,1‐bisphosphonate (EHDP), were seen in any patient on any daily dose. Fever occurred In 73% of patients in the first 2 days of treatment. Overall, there was a significant fall In the lymphocyte count (P> 0·005 febrile group, n=19; P> 0·02 non‐febrile group, n=7) and a fever‐dependent rise in the neutrophil count (P> 0·005 febrile group only). The occurrence of fever was associated with a more rapid decline in Hype, compared to the non‐febrile group, so that Hype was significantly lower in the febrile group by day 5 (P > 0·025). Seventy‐two per cent of patients with bone and/or joint pain reported a reduction in pain. APD therapy resulted in repair or arrest of progression of Pagetic lytlc bone lesions in those seven patients with measurable lesions. Quantitative histomorphometry was performed in eight patients. Significant Improvement was seen in all Indices. In the six patients for whom a post‐treatment calcification rate could be deter‐mined, there was no evidence of a mineralization defect. All patients with mild‐moderate disease (Hype > 10 μmol/IGF) achieved normal Hype and alkaline phosphatase values following a single course of APD. Provided that pretreatment Hype was · 10 μmol/IGF, an upper limit for the total dose of APD required to achieve normalization of Hype could be estimated. For those patients with ‘severe’ disease (defined as Hype > 10 μmot/1 GF), a reduction of > 50% In Hype could be achieved readily, but biochemical normalization was not possible with a single course of up to 315 mg of APD.
Abnormalities in fasting circulating proinsulin concentration in mild gestational diabetes
Authors: Dornhorst A. , Davies M. , Anyaoku V. , Hampton S. M. , Elkeles R. S. , Beard R. W. , Johnston D. G.
Published: March 2008

Fasting plasma proinsulln, Insulin and glucose concentrations were measured In ten women with mild gestational diabetes and ten controls matched for race, age (32·6 vs 31 ±6 years), body mass index (28·8 vs 27·6) and gestational week (24·4 vs 25 ± 4 weeks). There was no significant difference in fasting plasma glucose between these gestational diabetics and their controls (median 4·7, range 3·7–6·0 mmol/l vs 4·5, range 3·4–5·3 mmol/l). The fasting proinsulin levels were significantly higher in the gestational diabetics compared with the controls (median 12·2, range > 4–14·8 pmol/l vs 5·8, range > 4–12·8 pmol/l, P ± 0·02, Wilcoxon Summed Rank Test), while the calculated intact insulin levels (immunoreactive insulin minus proinsulin) were significantly lower (median 14·5, range 6·3–81·8 pmol/l vs 51·6, range 11·7–312 pmol/l, P± 0·01). The ratio of proinsulin to calculated Intact insulin was significantly higher in the gestational diabetics than the controls (median 0·66, range 0·16–2·04 vs 0·12, range 0·03–0·62), P± 0·01). These results demonstrate that gestational diabetics, with normal fasting plasma glucose values, have abnormalities In pancreatic β‐cell secretion, which are likely to be Important both in the aetiology of gestational diabetes and non‐Insulin dependent diabetes.
Episodic ACTH and cortisol secretion in normal children
Authors: Wallace W. H. B. , Crowne E. C. , Shalet S. M. , Moore C. , Gibson S. , Utley M. D. , White A.
Published: March 2008

The aim of this study was to determine the normal relationship between ACTH and cortisol secretion in children. Fourteen children (nine male, five female; median age 11·3 years) were hospitalized and blood samples were taken every 20 min for 24 h. A circadian rhythm was observed with median 0900 h and midnight ACTH values of 1·80 and > 0·97 pmol/l, and for cortisol 296 and 62 nmol/l respectively. The median (range) areas under the curve for ACTH and cortisol were 29·7 (9·0–53·8) pmol/l/h and 5114 (3562–8630) nmol/l/h respectively. There were no significant differences detected for ACTH and cortisol secretion between males and females, or between prepubertal (n= 9) and pubertal subjects (n= 5). Using a novel form of time series analysis we have shown that both ACTH and cortisol are secreted with a dominant periodicity of 0·7–1·0 h, representing 24–34 secretory episodes of ACTH and cortisol In 24 h. For cortisol, but not ACTH, there is a significant secondary periodicity of 2–3·2 h. To look for shared periodicities we have used the technique of coherency. This reveals that for six of the children ACTH and cortisol are secreted with a significant shared periodicity of 0·8–1·0 h, and for a further five children a similar secondary shared periodicity Is present. Therefore in normal children ACTH and cortisol secretion are Interdependent and episodic but are not influenced by either pubertal status or gender.
The impact of ovarian laser surgery on the gonadotrophin secretion in women with polycystic ovarian disease
Authors: Rossmanith Winfried G. , Keckstein Jörg , Spatzler Kristine , Lauritzen Christian
Published: March 2008

To evaluate the effects of ovarian surgery on the deranged episodic gonadotrophin release of women with the poly‐cystic ovarian disease (PCOD), we studied 11 patients with the clinical and endocrinological features of PCOD before and after Iaparoscopic laser coagulations of ovarian surfaces and cysts. During both occasions, blood was collected at 15‐min intervals for 8 h to determine LH and FSH secretory profiles and additionally for 3 h during GnRH Injections (25 pg twice within 2 h) to assess pituitary responsiveness. Serum testosterone, androstendione and oestrogen (oestrone, oestradlol) levels were markedly reduced (P > 0·05 or less) after surgery. Mean LH concentrations declined (P > 0·001), while FSH levels Increased (P > 0·01) following laser treatments. The LH pulse frequencies (by Cluster analysis) did not change after ovarian surgery, but the LH pulse amplitudes were markedly reduced (P > 0·01). Lower (P > 0·05 or less) LH concentrations were attained in response to GnRH challenges, and the stimulated FSH release also tended to decrease after laser treatments. Thus, ovarian surgery In PCOD women resulted in reduced serum sex steroid concentrations and In divergent effects on serum LH and FSH levels. The attenuated pituitary LH responsiveness after ovarian surgery suggests action of sex steroids primarily at the pituitary site, while the Increase In FSH concentrations may be attributed to other factors selectively modulating FSH release.
Phorbol ester, not growth hormone releasing factor, consistently stimulates growth hormone release from somatotroph adenomas in culture
Authors: Emoto Naoya , Ohmura Eiji , Isozaki Osamu , Tsushima Toshio , Shizume Kazuo , Demure Hiroshi
Published: March 2008

In order to study the mechanism of GH secretion from somatotroph adenoma cells, we have compared the effect of 12–O‐tetradecanoyl phorboi‐13‐acetate (TPA) with that of growth hormone releasing factor (GRF) on GH secretion from human somatotroph adenoma cells cultured in monolayer. Pituitary adenoma cells were obtained from 13 patients with acromegaly undergoing surgery. On the 7th day of culture, the cells were exposed for 2 h to secretagogues. All 13 adenoma cell cultures (100%) responded to TPA (1·6–16·0 nmol/I) with a two‐ to six‐fold increase in GH release (240·37% Increase of control: mean±SE). The response was detectable within 10 min, and was maximal at 2 h. Phosphollpase C (7·7 mmol/I) also stimulated a two‐to ten‐fold Increase In GH release in all four adenomas examined (100%). GH release was stimulated by GRF (2·0 nmol/I) in eight out of 12 adenoma cells (67%), but the magnitude of the responses to GRF (60·18% Increase of control: mean ± SE) were much smaller than that of TPA. Five out of 13 adenomas secreted detectable amount of PRL Into the medium and these five adenomas (100%) responded to TPA (16·0 nmol/I) with a two‐ to six‐fold Increase. These observations indicate that the activation of protein kinase C is the consistent stimulator in GH and PRL secretion In human somatotroph adenoma cells. However, It is not determined whether the protein kinase C
Pyridostigmine fails to increase either spontaneous or GHRH‐stimulated GH secretion during day or night in growth hormone‐insufficient children
Authors: Kirk J. M. W. , Ross R. J. M. , Trainer P. J. , Froud A. L. J. , Davies S. C. , Savage M. O. , Besser G. M.
Published: March 2008

objective The aim of the study was to Investigate whether pyridostigmine, a cholinesterase Inhibitor which is thought to act at the hypothalamus to Inhibit somatostatin secretion, would augment spontaneous or GHRH‐stimulated serum GH levels In patients with GH‐insufficiency. DESIGN Oral pyridostigmine 60 mg or placebo was administered at the start of a 9‐h subcutaneous infusion of either GHRH (1–29)NH2 10 μg/kg/h or saline control. Studies were performed during the daytime (0900–1800 h) in five patients, and the night‐time (2100–0600 h) In a further five.

patients Ten short, pre‐pubertal children (aged 6–11 years; eight boys) with growth hormone Insufficiency were studied.

measures Blood for serum GH was sampled every 20 min, and analysed using the PULSAR program.

results The subcutaneous infusion of GHRH 10 μg/kg/h Increased mean serum GH levels (± SEM): by day 17.7(±6.8) vs placebo 2.2(±0.4) mU/I (p>0.01), and by night 26.9(± 3.3) vs 5.5(± 1.3) mU/I (p > 0.05). There was a significant rise In mean ‘baseline’ GH concentration: by day 5.5(±1.7) vs 1.0(±0.0) mU/I (p>0.05); and night 8.2(±2.7) vs 1.3(±0.3) mU/I (p>0.05). Pyridostigmine failed to produce a significant overall increase In either spontaneous or GHRH‐stimulated GH secretion by day or night, although there was a significant rise In mean GH levels during the 3 h following pyridostigmine administration In the morning: 4.4(±1.1) vs 2.4(±0.5) mU/I (p>0.001). GHRH or pyridostigmine given singly or in combination had no significant effect on the number of pulses. Side‐effects attributable to pyridostigmine occurred in seven children.

conclusions Pyridostigmine, either on Its own or as an adjuvant therapy In combination with GHRH, acts for only a brief time and does not offer any potential benefit In the management of children with short stature.
Effect of ritanserin, specific 5HT–2 antagonist, on PRL secretion in normal subjects and in different hyperprolactinaemic conditions*
Authors: Falaschi P. , Rosa M. , Rocco A. , D'Urso R. , Proletti A. , Melts G. B.
Published: March 2008

The availability of a new specific anti 5HT–2 compound, ritanserin (RTS), led us to further investigate the role of serotonin in controlling PRL secretion. The drug was administered to normoprolactinaemic subjects and to patients with differing hyperprolactinaemic conditions. While RTS failed to modify PRL levels in normoprolactinaemic subjects and in patients with PRL‐secreting pituitary adenomas, a marked decrease in the hormone was obtained in patients with functional and puerperal hyperprolactinaemia. The lack of effect of RTS in PRL‐secreting pituitary adenomas suggests that the reported suppression of PRL by other antiserotoninergic drugs, such as metergoline, is probably due to their concomitant dopamlnergic activity
The presence of cation‐dependent proteases for insulin‐like growth factor binding proteins does not alter the size distribution of insulin‐like growth factors in pregnancy
Authors: Davies S. C. , Holly J. M. P. , Coulson V. J. , Cotterill A. M. , Abdulla A. F. , Whlttakert P. G. , Chard T. , Wass J. A. H.
Published: March 2008

objective The aim was to Investigate the sera of pregnant women for the presence of specific proteases for insulin‐like growth factor binding proteins (IGFBPs) and to determine the effect of these on the distribution of IGFs in the circulation

design The method used was the chromatographic and electrophoretic analysis of patients’ serum

patients Sera were examined from normal women during pregnancy: first trimester (n=4), second trimester (n= 4) and third trimester (n= 10). Eight women with Type I diabetes in the third trimester were also studied along with sera from ten normal adult volunteers.

measurements Circulating IGF‐I and IGF‐II levels were measured by RIA and their distribution examined by gel filtration. The pattern and stability of the IGFBPs was Investigated by Western Iigand blotting

results A marked reduction in the serum levels of IGFBP‐2, IGFBP‐3 and IGFBP‐4 on Western Iigand blotting, which was associated with the presence of three Independent, cation‐dependent proteases that were specific for different IGFBPs, was found in late pregnancy. Gel filtration of third trimester serum revealed most of the IGF‐I to be present in a complex larger than 130 kDa, with a similar distribution to that found in serum of non‐pregnant women. The enzymatic modification of the binding proteins made apparent by the decrease in binding protein bands on Western Iigand blotting of preincubated samples had no effect on the distribution of IGF‐I following size ractionation

conclusions There appear to be at least three Independent enzymes that are Induced or activated during pregnancy to modify IGFBP‐2, IGFBP‐3 and IGFBP‐4 sufficiently to prevent their detection by Iigand blotting. However, this enzymatic processing does not alter the distribution of IGFs, suggesting that the altered binding proteins are still able to carry IGFs but with reduced affinity. Such an alteration in the carrying mechanism of IGFs may have profound effects upon the bioavailability of the IGFs to the maternal tissues and contribute to the altered metabolic demands of pregnancy
The effect of growth hormone (GH) therapy on urinary pyridinoline cross‐links in GH‐deficient adults
Authors: Schlemmer Annette , Johansen Julia S. , Pedersen Saren A. , Jargensen Jens O. L. , Hassager Christian , Christiansen Glaus
Published: March 2008

objective The aim was to study the effect of growth hormone (GH) on new markers of bone resorption (fasting urinary excretion of pyridinium cross‐links (pyridinoline and deoxypyrWlnoline)) in GH‐deficient adults

design Randomized, double‐blind, placebo‐controlled cross‐over study. The treatment periods (GH 2 IU/in2 subcutaneously, or placebo daity for 4 months) were separated by a 4‐month washout period.

patients Twenty GH‐deficient adults (aged 18–39)

measurements Blood and fasting urine samples were collected at the end of each 4‐month treatment period. Plasma bone Gla protein was measured by radioimmunoassay and urine pyridinoline and deoxypyrfdinoline were measured by spectrofluorometry after high performance liquid chromatography and corrected for urinary creatinine

results GH increased fasting urinary excretion of pyridinoline (287 ± 123%, P > 0·001) and deoxypyridinoline (313 ± 140%, P > 0·001). The GH‐induced Increment In these parameters correlated with the increase seen in plasma bone Gla protein (r= 0·83–0·86, P > 0·001).

conclusion Four months of GH substitution in GH‐deficient adults increases bone resorption as well as bone formation. The effect on bone mass has yet to be assessed
Insulin secretion, insulin sensitivity and glucose‐mediated glucose disposal in Cushing's disease: a minimal model analysis
Authors: Page Renee , Boolell Mltra , Kalfas Anna , Sawyer Steven , Pestell R. , Ward Glenn , Alford Frank
Published: March 2008

objective We wished to assess the contributions of Insulin secretion, insulin sensitivity and glucose‐mediated glucose disposal to glucose tolerance in subjects exposed to chronic glucocorticoid excess. DESIGN Patients with Cushing's disease were subjected to a frequently sampled intravenous glucose tolerance test before and at least 3 months after curative surgery and compared to a control group

patients Seven patients with clinical and biochemically proven pituitary dependent Cushing's disease and 10 healthy control subjects were studied

measurements Paired glucose and insulin plasma profiles were analysed by the Minimal Model method of Bergman, which provided simultaneous estimates of the glucose decay rate, Insulin secretion, insulin sensitivity and glucose‐mediated and non‐insulin‐mediated glucose disposal. Data were evaluated by non‐parametric statistical analysis and reported as median and interquartile ranges

results Basal glucose, insulin, C‐peptlde and glucagon levels were significantly raised preoperatively and fell towards normal post‐operatlvely. Glucose tolerance assessed as glucose decay rate was reduced significantly preoperatively (pre: 1·3 (0·8–2·0) vs post: 1·6 (1·5–2·6) per min x 102, p > 0·05). First phase insulin release was similar in the Cushing's disease and control subjects. In contrast, second phase insulin release was significantly greater preoperatively and remained high post‐operatlvely compared to control subjects (pre: 18·8 (16·7–23·6) vs post: 16·7 (8·5–18·8) vs control 11·1 (4·5–15·4) mU/g/min2 x 10‐2, P > 0·002). Median insulin sensitivity was reduced by 60% preoperatively in the Cushing's disease subjects compared to the post‐operative Cushing's disease and control subjects (pre: 2·1 (1·3–4·2) vs post: 5·0 (3·2–7·3) vs control 5·1 (2·2–7·2) per min/mU/l x 104). Median glucose‐mediated glucose disposal was reduced by 40% In the pre and post‐operative Cushing's disease subjects compared to the control group (pre: 1·1 (0·6–2·1) vs post: 1·1 (0·6–2·1) vs control 1·9 (1·4–2·6) per min x 102), but this was not statistically significant. However, non‐insulin‐mediated glucose disposal was significantly reduced In the preoper‐atlve Cushing's disease subjects (pre: 0·55 (0·08–1·59) vs control 1·43 (0·94–2·27) per min x 102, p > 0·05). In the Cushing's disease subjects, glucose tolerance correlated with both Insulin sensitivity (rs= 0·84, P > 0·01) and non‐insulin‐mediated glucose disposal (rs= 0·56, P > 0·05). The fractional clearance rate of insulin was unaltered by Cushing's disease.

conclusions Cushing's disease subjects are characterized by impaired glucose tolerance due to both reduced insulin sensitivity and non‐fnsulln‐mediated glucose disposal, In the presence of enhanced Insulin secretion
Serum thyroglobulin measurements in thyroid cancer: evaluation of‘false’ positive results
Authors: Black E. G. , Sheppard M. C.
Published: March 2008

objective Serum thyroglobulin (Tg) should be undetectable in patients successfully treated for thyroid carcinoma. We have examined the course of disease in 19 patients with raised serum Tg (< 5 μ g/l) on initial measurement but no other evidence of residual, recurrent or metastatic cancer.

design 416 patients from several centres were followed for periods between 1 and 9 years. Serum Tg was measured at 6–12‐month intervals

patients All had differentiated thyroid cancer, treated by partial or total thyroldectomy and/or 131I ablation, and were receiving suppressive thyroxine therapy.

measurement Serum Tg was measured and clinical, X‐ray and scan assessment made of presence or absence of residual, recurrent or metastatlc cancer

results Of 416 patients initially assessed, only 19 had Tg < 5 μ g/l but no clinical or radiological evidence of disease. At follow‐up, 11 patients had developed overt signs of malignancy; one had been treated with 131I with a subsequent fall in Tg; five had Tg between 5 and 20 μ g/l with incompletely suppressed TSH levels; two subjects remained with slightly elevated Tg and undetectable TSH.

conclusion Patients with elevated Tg require careful follow‐up even in the apparent absence of disease. Moderate elevation of serum Tg may be due to inadequate thyroxine suppression therapy, assessed by detectable TSH values measured in a sensitive assay
Androgen dependent stimulation of aromatase activity in genital skin fibroblasts from normals and patients with androgen insensitivity
Authors: Stlllman S. C. , Evans B. A. J. , Hughes I. A.
Published: March 2008

objective To measure the effect of androgens or aromatase activity as an index of androgen responsiveness in patients with androgen insensitivity

design Genital skin fibroblasts were established in culture using primary skin explants obtained from normal males at the time of circumcision and from androgen insensitive patients who had surgery either for gonadectomy (complete androgen insensitivity syndrome) or for reconstruction of the external genitalia (partial androgen insensitivity syndrome)

patients Foreskin samples were obtained at the time of circumcision in 27 normal males. Scrotal or labla majora skin was obtained at the time of surgery from 14 patients with the complete and 22 with the partial forms of the androgen insensitivity syndrome

measurements Basal and stimulated levels of aromatase activity were measured in genital skin fibroblasts following preincubation with natural and synthetic, non‐metabolizable androgens

results Following a 48‐hour preincubation with testosterone or dihydrotestosterone, there was a five to six‐fold stimulation of aromatase activity in normal fibroblasts. Mibolerone, a synthetic androgen, produced similar results. The stimulatory effect was blocked by anti‐androgens. Seven patients with partial androgen insensitivity, of whom four were either receptor deficient or showed a qualitative defect in androgen binding, had reduced mibolerone induced stimulation of aromatase activity. All ten patients with receptor negative complete androgen insensitivity had an absent response. There was no aromatase induction in a further three patients with complete androgen insensitivity who were receptor positive. Two siblings in the latter group had an exon deletion encoding for part of the DNA binding domain of the androgen receptor

conclusions Androgens stimulate aromatase activity in genital skin fibroblasts from normals. The response is mediated via the androgen receptor and can be decreased or absent in patients with the androgen insensitivity syndrome. This may be a useful in‐vitro marker of androgen responsiveness in such patients
The relationship between growth hormone (GH) messenger ribonucleic acid levels and hormone release from individual cells derived from human GH‐secreting pituitary adenomas
Authors: Hofland L. J. , Velkeniers B. , van Koetsveld P. M. , Hooghe‐Peters E. L. , Lamberts S. W. J.
Published: March 2008

GH mRNA expression and GH release by Individual cells derived from four GH‐secreting pituitary adenomas were studied by in‐situ hybridization and the reverse haemolytic plaque assay, respectively. In addition the percentage of PRL mRNA‐containing cells was determined in these cell suspensions. The percentages of GH mRNA‐containing cells varied between 52 and 89 while the percentages of GH plaque forming cells varied between 25 and 77. Frequency distributions of GH mRNA levels in individual cells and of individual GH plaque areas showed a majority of the cells having low GH mRNA levels and secreting low amounts of GH respectively, while there is a low proportion of cells expressing high GH mRNA levels and forming large GH plaques. There was a significant correlation between the GH mRNA levels and the GH plaque areas of individual cells from the four adenomas (P > 0.001). The percentages of PRL mRNA‐containing cells in the four different adenomas amounted to > 1, 5, 2 and 18. Cultured cells from the adenomas consisting of 5 and 18|X% PRL mRNA‐containing cells also contained and released measurable amounts of PRL. Our data show that Individual cells from GH‐secreting pituitary adenomas are heterogeneous with respect to GH mRNA expression, a small proportion of the cells expressing a high amount of GH mRNA. The heterogeneity in GH mRNA expression is correlated with the heterogeneity In GH release. These observations suggest that a considerable part of GH secreted from a GH‐secreting pituitary adenoma is produced by a minority of the GH‐secreting tumour cell population. This might be a basis for the disappointing degree of tumour shrinkage which is observed in most acromegalic patients treated with the somatostatin analogue SMS 201–995.
The relationship between sex steroids and bone mineral content in women soon after the menopause
Authors: Spector T. D. , Thompson P. W. , Perry L. A. , McGarrigle H. H. , Edwards A. C.
Published: March 2008

Prevention of postmenopausal osteoporosis is now possible with current therapy, if initiated soon after the menopause and continued for at least 10 years. Simple ways of detecting those at risk of subsequent osteoporosis are urgently needed. This study investigated the hypothesis that certain serum sex hormones could predict bone mineral content (BMC) as measured by dual photon densitometry, soon after the menopause. The subjects included 136 healthy white females within 30 months of their last menstrual period with a mean age of 52 years. Of the sex hormones, the adrenal androgen dehydroeplan‐drosterone sulphate (DHEAS) correlated best with spinal BMC, a relationship which was significant using multiple regression (P = 0.02), although the correlation was weak (r =+0.19). A direct physiological role for DHEAS has yet to be found, despite being present in large quantities in serum, although it may act as a marker for other processes. No association was seen between testosterone, sex hormone binding globulin, oestradiol, oestrone and oestrone sulphate and spinal BMC. No significant correlations with any hormones were seen with femoral BMC. The data suggest that serum sex hormones are not useful markers of current bone mineral status soon after the menopause, although further work is needed to explore the relationship with DHEAS
Corticotrophin releasing hormone (CRH1–41) stimulates the secretion of adrenocorticotrophin, vasopressin and oxytocin but not adrenocorticotrophin precursors: evidence from petrosal sinus sampling in man
Authors: Nussey S. S. , Page S. R. , Peterson D. B. , Byrne J. , Crosby S. R. , White A. , Ang V. T. Y. , Jackson R. , Jenkins J. S.
Published: March 2008

To examine the relationship between corticotrophin releasing hormone (CRH), arginine vasopressin (AVP) and oxytocin (OXT) we have studied the responses of adenohypophyseal and neurohypophyseal hormones to CRH in eight patients (age 26–64 years, six female) with suspected pituitary‐dependent Cushing's syndrome during bilateral, simultaneous inferior petrosal sinus catheterization. Blood samples were taken from both petrosal sinuses and a peripheral vein before, and at 5‐min intervals for 15 min after, an intravenous injection of 100 μg human CRH1–41. CRH increased sinus AVP concentrations in all eight patients and OXT concentrations in four of five patients studied. Although AVP concentrations often increased in both sinuses, the side of maximal AVP rise was termed sidemax‐AVP. CRH did not affect peripheral or petrosal sinus mean concentrations of LH, FSH, GH or TSH. While there was no change in mean peripheral concentrations of AVP, OXT, ACTH, ACTH precursors or prolactin after CRH, sinus concentrations of OXT, ACTH and prolactin on sidemax‐AVP were markedly elevated over contralateral values. CRH did not increase mean sinus concentrations of ACTH precursors. In seven patients with either no radiological abnormality of the pituitary fossa or a small adenoma the mean ACTH precursor/ACTH ratio in blood sampled from all sites was 2.1 |Mp 0.16 (mean |Mp SEM, n = 50). In a patient with a large, locally invasive tumour the mean ACTH precursor/ACTH molar ratio was 32.1 |Mp 1.3 (n = 12; P > 0.001), suggesting that alterations in this molar ratio may reflect the biological properties of the tumour. The source of CRH‐stimulatable AVP and OXT remains uncertain. While it is recognized that the data were accumulated in patients with pathology of the hypothalamo—hypophyseal—adrenal axis, these observations suggest a novel relationship between AVP, OXT and CRH in the regulation of ACTH secretion in man. We suggest that the relation between plasma AVP and corticosteroids seen in clinical hypoadrenal states could be explained by chronic stimulation of AVP secretion by CRH.
Genetic differences shown by HLA typing among Japanese patients with euthyroid Graves' ophthalmopathy, Graves' disease and Hashimoto's thyroiditis: genetic characteristics of euthyroid Graves' ophthalmopathy
Authors: Inoue Daisuke , Sato Kaoru , Maeda Masahiro , Inoko Hidetoshi , Tsuji Kimiyoshi , Mori Toru , Imura Hiroo
Published: March 2008

Euthyroid Graves' ophthalmopathy (EO) is an ophthalmic disorder without persistent hyperthyroidism. To elucidate genetic differences among EO, Graves' disease (Gr) and Hashimoto's thyroiditis (H), we analysed HLA‐A, B, C, DR, DO, D and DP types in 23 Japanese EO patients, 88 Gr patients, 46 H patients and 186 control subjects utilizing assays of lymphocyte cytotoxicity and restriction fragment length polymorphism (RFLP). When compared with the control subjects, EO patients showed significant associations with HLA B40 (w61), DR9, DQw3, and Dw15 (P > 0.01) and with HLA B12 and Cw1 (P > 0.05). When allowance was made for the number of antigens tested, only DQw3 was significant. Significant differences were found between EO and Gr (DPw2), and between EO and H (Cw1) even after correction of P values. Comparisons between EO and related subgroups of Gr confirmed the heterogeneity of EO again. It is concluded from these results that EO is associated with different HLA types from Gr and H.
Prevalence and follow‐up of abnormal thyrotrophin (TSH) concentrations in the elderly in the United Kingdom
Authors: Fade J. V. , Franklyn J. A. , Cross K. W. , Jones S. C. , Sheppard M. C.
Published: March 2008

Increasing use of assays for TSH with improved sensitivity as a first‐line test of thyroid function has raised questions regarding prevalence and clinical significance of abnormal results, especially values below normal. We have assessed the thyroid status of 1210 patients aged over 60 registered with a single general practice by measurement of serum TSH using a sensitive assay. High TSH values were more common in females (11.6|X%) than males (2.9|X%). TSH values below normal were present in 6.3|X% of females and 5.5|X% of males, with values below the limit of detection of the assay present in 1.5|X% of females and 1.4|X% of males. Anti‐thyroid antibodies were found in 60|X% of those with high TSH but only 5.6|X% of those with subnormal TSH. Eighteen patients were hypothyroid (high TSH, low free thyroxine) and one thyrotoxic (low TSH, raised free thyroxine) at initial testing. Seventy‐three patients with elevated TSH but normal free T4 were followed for 12 months; 13 (17.8|X%) developed low free T4 levels and commenced thyroxine, TSH returned to normal in four (5.5|X%) and 56 (76.7|X%) continued to have high TSH values. Sixty‐six patients with TSH results below normal were followed. Of the 50 subjects with low but detectable TSH at initial testing, 38 (76|X%) returned to normal at 12 months; of those 16 with undetectable TSH followed, 14 (87.5|X%) remained low at 12 months. Only one subject (who had an undetectable TSH) developed thyrotoxicosis. In view of the marked prevalence of thyroid dysfunction in the elderly, we suggest that screening of all patients over 60 should be considered. It is important that those with high TSH are followed in view of the risk of progression to overt hypothyroidism, but the risk of thyrotoxicosis in those with TSH values below normal appears small.
Human plasma melatonin and urinary 6‐sulphatoxy melatonin:studies in natural annual photoperiod and in extended darkness
Authors: Matthews C. D. , Guerin M. V. , Wang X.
Published: March 2008

Summary. Objectives The alms of the study were (1) to examine the human plasma melatonin rhythm at the equinoxes and the solstices in the natural photoperlod (35.S); (2) to examine melatonin rhythms in the same subjects under extended darkness conditions to expose any suppressive (gating) effects of light at any time of the year; (3) to undertake a rigorous examination of the relationship between plasma melatonin and the urinary metabolite 6‐suiphatoxy melatonin at varying times of the year.

Design At the equinoxes and solstices, unrestricted subjects had hourly urine collections followed by venous blood sampling taken under natural light conditions for 24 hours. Following a 24 hour Interval, a similar collection regime was performed with subjects held under conditions of extended darkness (5 hours darkness prior to natural sunset and following natural sunrise) for a further 24 hours.

Subjects Groups of four (minimum) to six female volunteers (age range 18–35 years) were studied, who had a normal lifestyle, no history of depression, and were not taking any medication or recently engaged in shiftwork.

measurements The plasma was assayed for melatonin and the urine samples for 6‐suiphatoxy melatonin by radioimmunoassay.

results The onset of natural melatonin secretion was delayed until after sunset at all seasons but was earlier In summer, and not different from the time of sunset in extended darkness. The offset of melatonin secretion under natural conditions occurred at sunrise in autumn and winter but was delayed until after sunrise during spring and summer, particularly in extended darkness.

No significant changes in the duration of melatonin secretion were observed between seasons nor between the duration of melatonin secretion under natural photoperiod or extended darkness.

The measurement of 6‐suiphatoxy melatonin proved to be a close Indicator of the phase and amplitude of secretion of plasma melatonin. Both onset and offset times of 6‐sulphatoxy melatonin were delayed compared to the times when plasma melatonin was detectable/undetectable. A good correlation exists between the total plasma melatonin secretion and that of 6‐sulphatoxy melatonin.

conclusions The results suggest evidence for a suppressive

(gating) effect of light at dawn only during summer which was associated with a phase advance of the onset of melatonin secretion at this time of year. The lack of a major gating effect of environment light on melatonin secretion, and the unchanging duration of secretion through the year In the normally entrained human, highlight differences between the human and those photoperiodic animal species which breed seasonally.

Urinary 6‐suiphatoxy melatonin proved to be a good Indicator of plasma melatonin levels under rigorous examination and Is confirmed as a useful clinical measure.
The use of venous catheterization in the diagnosis and localization of bilateral phaeochromocytomas
Authors: Newbould E. C. , Ross G. A. , Dacle J. E. , Bouloux P. M. G. , Besser G. M. , Grossman A.
Published: March 2008

Summary. objective The purpose was to assess the value of venous catheter sampling as a method for the location of phaeochromocytomas, particularly when imaging techniques have been equivocal or ambiguous.

design Venous catheter sampling was carried out in cases of suspected phaeochromocytoma, and compared with samples obtained from other patients without phaeochromocytomas undergoing adrenal venous catheterization.

patients Three patients had phaeochromocytomas (subsequently confirmed by histology); five patients had no clinical or biochemical evidence of phaeochromocytoma but were being Investigated for other conditions. MEASUREMENTS Catecholamlne and cortisol assays were performed on plasma samples from the adrenal veins and elsewhere, and the noradrenallne to adrenaline (NA:AD) ratio was calculated.

results In patients without phaeochromocytomas the NA:AD ratio was < 1 In nine adrenal vein samples; In four adrenal vein samples with NA:AD ratio of > 1, the presence of a phaeochromocytoma was subsequently confirmed. An extra‐adrenal tumour was also located by comparison of central and peripheral venous catecholamine concentrations.

conclusions Venous catheterization with measurements of catecholamines, and determination of NA:AD ratios, allows for the rapid and confident diagnosis and localization of unllateral, bilateral, and extra‐adrenal phaeochromocytomas.
Nocturnal melatonin secretion in thyroid disease and in obesity
Authors: Röjdmark S. , Berg A. , Rössner S. , Wetterberg L.
Published: March 2008

Summary. objective The purpose was to Investigate whether the function of the pinealocytes is changed in patients with disturbed metabolic rate or In subjects with marked obesity.

design Venous blood was sampled every second hour between 1800 and 0800 h, and urine collected between 2200 and 0700 h.

patients Eight patients with thyrotoxicosis, six with primary hypothyroidism, eight with maturity‐onset obesity, and 12 healthy controls were Included In the study. MEASUREMENTS Peak serum melatonin values during the night, total nocturnal melatonin secretion (estimated by melatonin incremental areas), and urinary excretion of melatonin were determined in each participant.

results Patients with hypothyroidism were found to have higher peak serum melatonin values, total nocturnal melatonin secretion, and urinary excretion of melatonin than normal individuals (Peak melatonin values: 0.55 × 0.13 vs 0.27 × 0.04 nmol/l, respectively; P < 0.05. Melatonin incremental areas: 3.38 × 0.80 vs 1.45 × 0.26 nmol/1 h; P < 0.05. Melatonin excretion: 0.140 × 0.023 vs 0.081 × 0.013 nmol/9 h; P < 0.05). Neither of these values differed significantly from the normal In patients with thyrotoxicosis or obesity. Although thyrotoxic patients thus released a normal amount of melatonin during the night, their melatonin secretion peak was phase advanced (melatonin secretion peak appearing at 1.1 × 0.5 h In thyrotoxic, and at 3.4 × 0.5 h in normal participants; P < 0.01). No such phase shifts were seen in patients with obesity or hypothyroidism.

conclusions These findings imply that both hypothyroid and thyrotoxic patients have disturbed pineal function, which is not the case in patients with obesity. The mechanism underlying these observations remains to be elucidated.
Control of immunoactive inhibin production by human granulosa cells
Authors: Hillier S. G. , Wickings E. J. , Illingworth P. I. , Yong E. L. , Reichert Jr L. E. , Baird D. T. , McNeilly A. S.
Published: March 2008

Summary. objective The aim was to determine the relation between stage of antral follicular development and granulosa cell production of immunoactive inhibin.

design Primary granulosa cell cultures In serum‐free Medium 199 were Incubated at 37°C for 96 hours with a change of medium at 48 hours. Inhibin and steroid levels in culture medium were determined by radlolmmunoassay. The Inhibin assay was based on the N‐terminal 1–26 amino acid sequence of the α‐chain of porcine 32 kDa inhibin using plα1–26‐GLY27‐TYR28 as the immunogen, tracer and standard.

patients

Granulosa cells were obtained from the ovaries of women with regular menstrual cycles undergoing hysterectomy with unilateral or bilateral oophorectomy to treat non‐malignant gynaecological disease.

results Basal production of immunoactive Inhibin by granulosa cells from presumptive preovulatory follicles (> 15 mm diameter) was 5–13 times higher than that by granulosa cells from immature (< 10 mm diameter) or intermediately mature (10–15 mm diameter) follicles. Basal production of progesterone and oestradlol followed a qualitatively similar pattern, establishing a positive relation between functional granulosa cell maturity and inhibin production. Treatment of granulosa cell cultures from Immature follicles with follicle‐stimulating hormone (FSH), but not luteinizing hormone (LH), increased inhibin production, time and dose dependently. FSH, but not LH, also brought about similar Increases in steroid hormone synthesis by granulosa cells from immature follicles. The stimulatory effect of FSH on granulosa cell inhibin production was augmented at least twofold by the presence of testosterone or 5α‐dihydrotestosterone (1.0 μmol/I) but was unaffected by oestradiol. Granulosa cells from intermediately mature follicles undertook variable degrees of both FSH and LH‐responsive inhibin production which generally corresponded with gonadotrophin‐responsive steroid production. Granulosa cells from presumptive preovulatory follicles showed inconsistent inhibin responses to FSH. However, LH caused marked (at least twofold) Increases in inhibin production, paralleling LH‐responsive steroid production.

conclusion These results show that for human beings, granulosa cell capacity to produce immunoactive inhibin in vitro increases with follicular maturity. FSH, but not LH, stimulates inhibin production by immature granulosa cells and this response to FSH Is subject to modulation by androgen. During preovulatory follicular development, production of inhibin, like steroids, becomes increasingly responsive to LH. Such a development‐related pattern of granulosa cell inhibin production helps explain how, post‐ovulation, the corpus luteum is able to secrete inhibin as well as steroids. It is also compatible with the concept that locally produced inhibin could participate In the paracrine control of follicular development during the human menstrual cycle.
Cholinergic blockade with pirenzepine induces dose‐related reduction in glucose and insulin responses to a mixed meal in normal subjects and non‐insulin dependent diabetics
Authors: Bevan J. S. , Ara Jamal , Page M. D. , Scanlon M. F. , Peters J. R.
Published: March 2008

Summary. objective The aim of the study was to assess the effects of chollnerglc blockade with pirenzepine on glucose and Insulin responses to a mixed meal In normal subjects and patients with non‐insulin dependent diabetes (NIDDM). Further, to assess In normal subjects the relative Importance of nocturnal GH suppression by plrenzepine.

design Placebo, 100 or 200 mg pirenzepine were given to the normal subjects 1 hour before a standard mixed meal. The effects of placebo or 200 mg pirenzepine at night on nocturnal GH secretion and subsequent breakfast carbohydrate tolerance were also studied. NIDDMs were given placebo or 200 mg pirenzepine before the meal.

subjects We studied six healthy male volunteers (ages 20–22, body mass Indices 20.3–23.3) and ten NIDDMs (eight men, ages 42–74); five obese (BMI 25.5–31.8) and five non‐obese (BMI 21.2–24.8).

measurements Serial plasma glucose and Insulin concentrations were measured for 3 hours after a standard mixed meal.

results Acute pretreatment of normal male volunteers with plrenzepine produced a dose‐related Improvement in carbohydrate tolerance. Peak post‐prandial plasma glucose levels were delayed and significantly reduced following 200 mg orally (6.5±0.1 mmol/l), but not following 100 mg (7.3±0.3), compared with placebo (7.6±0.3). Peak insulin levels were similarly delayed and reduced by the 200 mg dose only (36.5±6.1 mU/l, compared with 49.8±8.7).

Suppression of nocturnal GH by 200 mg pirenzepine at night produced a small reduction In fasting plasma glucose (5.0±0.1 mmol/l, compared with 5.3±0.1, p< 0.02) but did not Improve subsequent breakfast carbohydrate tolerance.

Peak plasma glucose in NIDDMs was reduced following plrenzepine (12.4±0.9 mmol/l) compared with placebo (14.3±1.0, p<0.01). This reduction was equally significant in obese and non‐obese groups. Peak plasma insulin was also reduced by pirenzepine (22.4±3.9 mU/l) compared with placebo (42.4±5.3, p<0.01). Insulin suppression was quantitatively greater in obese than in non‐obese patients,

conclusions Improvement in carbohydrate tolerance after plrenzepine in normal subjects is dose related and largely independent of GH suppression. Cholinergic blockade can also improve meal carbohydrate tolerance with simultaneous reduction in plasma Insulin concentrations In non‐insulin dependent diabetics, particularly those with obesity.
An association between hypothalamic‐pituitary dysfunction and peripheral endocrine function in extreme obesity
Authors: Weaver J. U. , Noonan K. , Kopelman P. G.
Published: March 2008

Summary. objective The aim was to Investigate a possible relation‐ship between measures of Insulin secretion and glucose disposal and hypothalamic–pituitary function In extreme obesity.

design A cross‐sectional analysis of obese subjects attending the Obesity Clinic at the Royal London Hospital and normal weight volunteers was undertaken. Investigations were performed on separate occasions and in random order.

patients The subjects were 34 extremely obese women, menstruating and with normal glucose tolerance (mean Body Mass Index, BM1= 42) and 15 normal weight female controls (mean BMI = 22)

measurements The following were measured: fasting insulin, relative Insulin resistance calculated using fasting Insulin and plasma glucose by the homoeostatic model of assessment, Insulin release during a 75‐g oral glucose tolerance test (insulin area under the curve), steady‐state plasma glucose level achieved during a simultaneous Intravenous Infusion of dextrose, insulin and somatostatin, and the prolactin and growth hormone (GH) responses to Insulin‐Induced hypoglycaemia.

results In the obese group an Impaired prolactin response to hypoglycaemia (mean area under the curve obese 54 U/l min, controls 155 U/1 min; p=0.0001) was Inversely correlated to fasting insulin, r2=0.142, p=0.03; relative insulin resistance, r2=0.134, p=0.03 and steady‐state plasma glucose level, r2=0.345, p=0.0004 whereas the Impaired GH response (mean GH area under the curve obese 1.9 U/1 min, controls 65.7 U/1 min; p=0.0001) was Inversely correlated to steady‐state plasma glucose level, r2=0.196, p=0.01. Backward procedure for stepwise regression analysis confirmed the steady‐state plasma glucose level to be the most Important variable associated with the prolactin and growth hormone response among the remaining Indices of Insulin secretion/resistance.

conclusion We conclude from these findings that hyperinsullnaemia In obesity Is an Important association with altered hypothalamic–pituitary function indicated by Impaired prolactin and growth hormone secretion to Insulin‐Induced hypoglycaemia.