bluuebunny/crossref_metadata_2025 huggingface dataset:
Outpatient assessment of residual growth hormone secretion in treated acromegaly with overnight urinary growth hormone excretion, random serum growth hormone and insulin like growth factor‐1
Authors: Parfitt Vernon J. , Flanagan Daniel , Wood Peter , Leatherdale Brian A.
Published: March 2003

OBJECTIVE

To assess the outpatient investigations, overnight urinary growth hormone (uGH) excretion, random serum GH and insulin like growth factor 1 (IGF‐1), and GH indices from the oral glucose tolerance test (OGTT) (fasting, nadir and mean GH), as measures of mean GH secretion in treated acromegaly, in comparison with a GH day series, which served as a gold standard.

DESIGN

Prospective cross‐sectional study, with patients admitted to a metabolic ward for the following investigations: random GH, IGF‐1, 6 point GH day series (day 1), 9 h timed overnight uGH excretion, OGTT with GH response (day 2). Agreements between the mean GH during the day series and the other outcome measures, and the diagnostic performance of the latter, for the presence or absence of active acromegaly (mean GH during day series  5 or < 5 mU/l, respectively) were determined.

PATIENTS

26 patients with treated acromegaly (11 with inactive acromegaly off drug therapy).

MEASUREMENTS

Serum GH and uGH were measured by immunoradiometric assays and IGF‐1 by radioimmunoassay.

RESULTS

Agreements with the mean GH during the day series were perfect for the nadir GH during the OGTT with a 2 mU/l cutoff (Cohen's kappa (κ) = 1, P < 0.00001), almost perfect for the fasting and mean GH throughout the OGTT (both κ = 0.92, P < 0.0001) and random GH (κ = 0.85, P < 0.0001), and substantial for the nadir GH with a 5 mU/l cutoff (κ = 0.77, P < 0.0001), IGF‐1 (κ = 0.62, P < 0.001) and overnight uGH excretion (κ = 0.61, P = 0.002). Nadir GH with a 2 mU/l cutoff was completely accurate for diagnosing the presence or absence of active acromegaly (positive and negative predictive values (% ± standard error percentage) 100 ± 8% and 100 ± 10%). None of the outpatient tests used alone was an adequate diagnostic test (positive and negative predictive values: overnight uGH excretion − 86 ± 10% and 75 ± 13%; random GH −100 ± 11% and 85 ± 11%; IGF‐1 − 92 ± 10% and 71 ± 13%) and so combinations of tests were assessed. The best was overnight uGH excretion plus random GH (positive and negative predictive values 88 ± 9% and 100 ± 12%). Using all three outpatient investigations, the positive predictive value of three raised results was 100 ± 13%.

CONCLUSIONS

In treated acromegaly, residual GH secretion can be reliably assessed with the OGTT, using standard diagnostic criteria. It can also be assessed on an outpatient basis with overnight uGH excretion and random GH, as direct measures, and IGF‐1. If these are all normal, active acromegaly is excluded. Three raised results denote active acromegaly, and one or two raised results would need further investigation with a GH day series.
Comparative evaluation of conventional and dynamic magnetic resonance imaging of the pituitary gland for the diagnosis of Cushing's disease
Authors: Tabarin Antoine , Laurent François , Catargi Bogdan , Olivier‐Puel Fréderique , Lescene Robin , Berge Jerôme , San Galli François , Drouillard Jacques , Roger Patrick , Guerin Jean
Published: March 2003

OBJECTIVES

The ability of MRI to detect pituitary ACTH‐secreting adenomas in patients with Cushing's disease is limited. Owing to different dynamics of contrast enhancement between adenomas and normal pituitary tissue, it has been suggested that obtaining images within seconds after gadolinium (Gad) injection using dynamic procedures increases the sensitivity of MRI in the detection of pituitary microadenomas. The objective of this study was to compare the ability of conventional magnetic resonance imaging (CMRI) and dynamic MRI (DMRI) to detect ACTH‐secreting pituitary adenomas.

DESIGN

Twenty‐six consecutive patients with ACTH–dependent Cushing's syndrome and 10 normal subjects were investigated. According to the results of inferior petrosal sinus sampling, 21 patients had Cushing's disease and five had ectopic ACTH syndrome. Patients with Cushing's disease were operated regardless of the results of imaging studies. All underwent identical MRI and DMRI procedures using a 1.0 T magnet. Image sampling time during DMRI was 19 sec. Scans were randomly mixed and analysed blind, retrospectively and independently by two experienced radiologists. The clarity of the images was assessed by the analysis of agreement among radiologists. MRI findings were compared to surgical and histopathological findings.

RESULTS

Surgical exploration identified three macrodenomas and 14 microadenomas. One microadenoma was found at pathological examination after subtotal hypophysectomy and no tumour was found in three cases. According to the combined opinion of radiologists, the three macroadenomas were identified equally well with CMRI and DMRI. Eight ACTH‐secreting microadenomas were detected with CMRI and 11 with DMRI. The three microadenomas detected with DMRI only were visualized within 60 sec following Gad injection. No false positives occurred with CMRI. Three false positives were obtained with DMRI: one in a patient with ectopic ACTH syndrome while a silent microprolactinoma and normal tissue were found at the site of the radiological abnormality in two patients with Cushing's disease. In our study, the sensitivity of DMRI is greater than that of CMRI (0.67 vs. 0.52) but is associated with a loss in specificity (0.80 vs. 1.00). False positives may result from the increased sensitivity of DMRI which detects incidental pituitary lesions, technical artefacts or lowest clarity of images, as suggested by a lower observer agreement of DMRI (Kappa statistic 0.66 vs. 0.83). Overall, the two MR procedures had equivalent diagnostic power (0.72).

CONCLUSIONS

In our hands, dynamic procedures did not improve the usefulness of MRI in Cushing's syndrome.
Cognitive dysfunction in patients with pituitary tumour who have been treated with transfrontal or transsphenoidal surgery or medication
Authors: Peace  , Orme  , Padayatty  , Godfrey  , Belchetz
Published: March 2003

OBJECTIVE

This study was carried out to examine the neuropsychological status of patients treated for pituitary tumour by transfrontal surgery, transsphenoidal surgery or medical treatment only, with or without radiotherapy.

DESIGN AND MEASUREMENTS

Three groups of 23 patients who had been treated for pituitary tumour were compared with 23 healthy controls on a range of neuropsychological measures. The surgical patients were also subdivided into two groups and compared. The neuropsychological measures were standardized psychological tests designed to assess aspects of attention, memory and executive function.

PATIENTS

The patients were those who had been treated with transfrontal surgery (n = 23), transsphenoidal surgery (n = 23) and medication only (n = 23). The groups did not differ with respect to age, education or premorbid ability level as assessed by the National Adult Reading Test. All participants were free of known sources of cognitive impairment other than pituitary tumour.

RESULTS

Comparison of the four groups revealed that nearly half of the transfrontal, one‐third of the transsphenoidal and one‐quarter of the non‐surgical group had three or more neuropsychological tests scores below the 10th percentile compared to less than 5% of the controls. Impairments in memory and executive function were found in both surgical groups. The non‐surgical patients appeared to have problems only on tasks requiring high levels of cognitive processing. Differences were found between the two surgical groups with respect to the severity of the cognitive impairment, the transfrontal patients having more severe impairment than the transsphenoidal. No significant negative effects on cognitive functioning were associated with radiotherapy; however, transfrontal surgery patients who had not been treated with radiotherapy were found to be more impaired than other patients. This was thought to be related to radical surgery.

CONCLUSIONS

Many patients with treated pituitary tumour suffer significant cognitive impairment. The severity and nature of impairment differs between treatment groups, although the cause of this could not be addressed by this study. Recommendations are made for future research and clinical practice.
Bone mineral density in women with cytotoxic‐induced ovarian failure
Authors: Howell  , Berger  , Adams  , Shalet
Published: March 2003

OBJECTIVE

Premature ovarian failure is associated with a reduction in bone mineral density. As survival rates following treatment for haematological malignancies improve, chemotherapy‐induced ovarian failure is becoming more common. However, there are few data concerning the impact of this on bone mineral density (BMD). We have therefore measured the BMD in 33 women with ovarian failure following treatment with cytotoxic chemotherapy.

PATIENTS AND DESIGN

We studied 33 women who received combination chemotherapy for Hodgkin's disease (n = 27), non‐Hodgkin's lymphoma (n= 4), sarcoma (n = 1) and acute myeloid leukaemia (n= 1). The mean (range) age of the subjects at the time of BMD measurement was 37.5 (24–50) years and the mean (median: range) duration of amenorrhoea was 49 (24: 5–277) months. Eleven women had received hormone replacement therapy (HRT) for a mean (range) duration of 25 (1–62) months. BMD was measured by single photon absorptiometry or single X‐ray absorptiometry, and dual energy X‐ray absorptiometry at the distal and proximal radius, the femoral neck and the lumbar spine, respectively. BMD was expressed as Z‐scores and statistical analysis was performed using the Wilcoxon matched‐pairs signed‐rank test.

RESULTS

There was no significant reduction in BMD at the hip, spine or forearm in the cohort as a whole, although there was a trend to reduce bone density at all sites. When patients who had received HRT were excluded from the analysis there were small reductions in mean BMD at all sites, but this was only statistically significant at the proximal forearm (Z‐score = −0.65; P = 0.03). Mean BMD of the HRT‐treated patients was normal at all sites. Only seven patients (21%) had a BMD Z‐score < −2 at any site.

CONCLUSION

It is inappropriate to assume that ovarian failure from different aetiologies has a similar deleterious impact on the skeleton. Untreated premature ovarian failure following cytotoxic chemotherapy results in some reduction in bone mineral density, but this is of a minor degree and is less than that observed in other hypo‐oestrogenic states. The reason for this is unclear but studies of residual hormone production in the cytotoxic‐damaged ovary may provide an answer.
The systemic stress response to thermal injury in children
Authors: Sedowofia Kofi , Barclay Cameron , Quaba Awf , Smith Alberto , Stephen Rhona , Thomson Margaret , Watson Anthony , McIntosh Neil
Published: March 2003

OBJECTIVE

Thermal injury is extremely stressful, but data characterizing the endocrine stress response to this injury in children are sparse. The objective of this study was to measure the effects of thermal injury on the levels of stress hormones in children and to assess the temporal changes associated with them.

PATIENTS

Twenty‐three children, 13 girls and 10 boys aged between 5 months and 12 years 3 months (mean, 2 years 11 months), with burns covering 10–61% of their body surface (mean, 20.5%) were studied during the first 5 days following injury.

MEASUREMENTS

The levels of arginine vasopressin, angiotensin II, cortisol, adrenaline, noradrenaline and dopamine were measured in sequential blood samples obtained from thermally injured children on admission and at specified time intervals during the 5 days of the investigation.

RESULTS

At admission the concentrations of all the hormones were high, and varied widely between individual patients. The geometric mean and 95% confidence intervals of admission hormone levels were as follows: arginine vasopressin 18.3 (8.3–40.7) pmol/l; angiotensin II 122.0 (56.0–266.2) pmol/l; cortisol 650.6 (473.0–895.0) nmol/l; dopamine 1.0 (0.1–8.0) nmol/l; adrenaline 6.4 (3.2–12.5) nmol/l and noradrenaline 2.3 (1.3–4.3) nmol/l. Although the concentrations of arginine vasopressin and cortisol returned to normal 24 to 36 h after admission, the levels of angiotensin II, adrenaline and dopamine fluctuated and remained higher than normal throughout the study (108 h).

CONCLUSIONS

Thermal injury results in the release of abnormally high levels of stress hormones in children. Although there are similarities between some of the data reported here and those reported in adults, higher levels of adrenaline and lower levels of noradrenaline than reported in adults suggest important differences too. These differences may need to be taken into account in the management of burn‐injured children.
Life expectancy following surgery for pituitary tumours
Authors: Bates A. S. , Bullivant B. , Sheppard M. C. , Stewart P. M.
Published: March 2003

OBJECTIVE

Hypopituitarism, predominantly al‐though not exclusively due to nonfunctioning pituitary tumours, has been associated with reduced life expectancy. Mortality from vascular diseases contributed significantly to the overall increase in mortality in some, but not all of the studies published to date. The aim of this study was to contribute further data to the debate regarding the putative association of vascular mortality with hypopituitarism.

DESIGN AND PATIENTS

A retrospective case note review of patients undergoing pituitary surgery in Birmingham, between 1/1/70 and 1/1/92. Subjects were identified from neurosurgical and neuropathology records. 348 patients were identified of which 197 were male (median age at surgery 48.4, range 11–79 years) and 151 female (median age at surgery 47.8, range 9–78 years). All cause mortality and mortality from vascular disease was compared to the general population of the UK using the Person Years computer programme.

RESULTS

There was a small increase in all cause mortality (SMR 1.2; 95% CI 0.95–1.55), but this was not statistically significant in this study (P = 0.06). Mortality from vascular disease was reduced (SMR 0.7; 95% CI 0.5–1.1; P = 0.03) particularly in the female cohort (SMR 0.5; 95% CI 0.2–1.0; P < 0.01) with the male subjects having similar mortality to that expected in an age and sex matched control population (SMR 0.9; 95% CI 0.5–1.4; P = 0.26).

CONCLUSION

Although patients with pituitary deficiency may be subject to a small increase in all cause mortality, the results of this study do not support the view that hypopituitarism is associated with a significant increase in vascular disease. There is a pressing need for a large prospective study with comprehensive data collection, including both endocrine data and information regarding clinical outcome, to clarify this issue. In the interim it would seem prudent to base the need for GH replacement therapy on quality of life issues rather than any potential for increased longevity.
Discrepancy between serum leptin values and total body fat in response to the oral growth hormone secretagogue MK‐677
Authors: Svensson  , Carlsson  , Carlsson  , Jansson  , ‐Å. Bengtsson
Published: March 2003

OBJECTIVE

Growth hormone (GH) treatment decreases total body fat while this effect has not yet been documented for the oral GH secretagogue MK‐677. In the present study, the effects of MK‐677 treatment on serum levels of leptin, thyroid hormones and testosterone were determined.

DESIGN

This was a randomized, double‐blind, and parallel study. Twenty‐four healthy obese males, 19–49 years of age, with body mass index (BMI) > 30 kg/m2 and a waist:hip ratio > 0.95, were treated with MK‐677 (25 mg/day; n = 12) or placebo (n = 12) for 8 weeks.

RESULTS

MK‐677 treatment increased serum leptin levels and leptin/body fat ratio at 2 weeks of treatment (P < 0.05 vs. placebo) but no significant change was observed at 8 weeks. An increase in serum free 3, 5, 3′‐triiodothyronine (free T3) was not detected until 8 weeks of MK‐677 treatment (P < 0.05 vs. placebo). Peak serum thyroid stimulating hormone (TSH) concentration after MK‐677 administration was similar to that after placebo administration at initiation of treatment and at 2 weeks. At 8 weeks of MK‐677 treatment, mean peak serum TSH concentration was increased (P < 0.05 vs. placebo) although it remained within the normal range. Serum peak values of luteinizing hormone (LH) and follicle stimulating hormone (FSH) were similar after MK‐677 and placebo administration. MK‐677 treatment reduced serum total testosterone (P < 0.05 vs. placebo) although total testosterone/sex hormone‐binding globulin (SHBG) ratio (an index of free testosterone) was not changed.

CONCLUSION

Treatment with the oral GH secretagogue MK‐677 transiently increased serum leptin levels and leptin/body fat ratio at 2 weeks of treatment, and increased serum free T3 after 8 weeks. These results indicate that MK‐677 treatment is able to affect circulating factors of importance for adipose tissue mass and fuel metabolism.
Expression of the androgen metabolizing enzyme UGT2B15 in adipose tissue and relative expression measurement using a competitive RT–PCR method
Authors: Tchernof André , Lévesque Éric , Beaulieu Martin , Couture Patrick , Després Jean‐Pierre , Hum Dean W. , Bélanger Alain
Published: March 2003

OBJECTIVES

We have demonstrated previously that obesity in men was significantly associated with low plasma testosterone levels and higher concentrations of the androgen metabolite androstane‐3α,17β‐diol glucuronide, suggesting that androgen metabolism and elimination is increased in this condition. The objective of the present study was to investigate whether adipose tissue was a site of expression of the androgen metabolizing enzymes UDP‐glucuronosyltransferases (UGT) 2B15 and 2B17.

DESIGN AND PATIENTS

Subcutaneous and visceral adipose tissue was obtained from male patients subjected to various abdominal surgeries.

MEASUREMENTS AND RESULTS

By performing reverse transcriptase–PCR (RT–PCR) amplification of mRNA extracted from adipose tissue samples, UGT2B15 transcript was detected in both subcutaneous and omental adipose tissue while UGT2B17 transcript expression was very low, or undetectable. A quantitative, competitive RT–PCR method was established and used to quantify UGT2B15 messenger RNA. The level of UGT2B15 expression was also measured in other human tissues. Although the major sites of expression were the liver and the lung, expression in adipose tissue was similar to levels found in the prostate, testis and mammary gland.

CONCLUSIONS

These results demonstrate for the first time that both subcutaneous and visceral adipose tissue express androgen metabolizing enzyme UGT2B15 mRNA and further support the role of adipose tissue as a site of steroid metabolism.
Cushing's syndrome secondary to ectopic ACTH secretion from metastatic breast carcinoma
Authors: Wigg Susan J. , Ehrlich Allison R. , Fuller Peter J.
Published: March 2003

Breast carcinoma is a rare cause of ectopic ACTH syndrome. There are only two previously reported cases in which ACTH secretion is documented. We describe the case of a 56‐year‐old woman who presented with clinical and biochemical features of ectopic ACTH syndrome in the setting of metastatic breast carcinoma. Despite aggressive management of her ectopic ACTH syndrome, her course was complicated by opportunistic infection, respiratory failure and death. Immunostaining of the breast metastases for ACTH was positive and in situ hybridization revealed proopiomelanocortin gene expression. This is the first reported case of ectopic ACTH syndrome associated with metastatic breast cancer in which the technique of in situ hybridization has been used to confirm the breast cancer metastases as the source of ectopic ACTH secretion.
Increased MEN1 mRNA expression in sporadic pituitary tumours
Authors: McCabe  , Gittoes  , Sheppard  , Franklyn
Published: March 2003

BACKGROUND

The MEN1 gene on chromosome 11q13 encodes a tumour suppressor gene, mutations in which cause multiple endocrine neoplasia (MEN) type 1 syndrome. Loss of heterozygosity (LOH) at this locus is a common finding amongst sporadic pituitary tumours. We have therefore screened the MEN1 gene for mutations in sporadic pituitary tumours and, as the gene is a putative tumour suppressor, have quantified mRNA expression in tumorous and normal pituitaries to assess the role of MEN1 in pituitary tumorigenesis.

SUBJECTS AND DESIGN

Thirty‐one nonfunctioning pituitary tumours, 8 GH secreting, 2 TSH‐secreting tumours and 1 corticotrophinoma have been assessed for the presence of MEN1 mutations, to examine the hypothesis that MEN1 mutations may contribute to the pathogenesis of sporadic pituitary neoplasms. In addition, quantitative changes in the pretranslational expression of the tumour suppressor gene MEN1 have been determined in 42 pituitary tumours and 6 normal pituitaries using semiquantitative reverse transcriptase PCR.

RESULTS

No novel or previously published mutations were apparent in the MEN1 coding regions of any tumours studied, although several polymorphisms were identified. Transcriptional changes of the gene, assessed by semiquantitative RT‐PCR, indicated that nonfunctioning and GH‐secreting pituitary tumours are associated with significantly increased pretranslational expression of the MEN1 gene. In addition, the single corticotrophinoma showed increased expression compared to normal, as did one of the two TSH‐omas.

CONCLUSION

Coding mutations of the putative tumour suppressor gene MEN1 are unlikely to contribute to pituitary tumorigenesis in sporadic nonfunctioning, GH‐secreting and TSH‐secreting adenomas. Changes in pretranslational expression of MEN1 were observed in pituitary tumours, suggesting that changes in the level of MEN1 expression, rather than coding changes, may be of functional importance in influencing sporadic pituitary tumorigenesis.
Serum IGF‐I and IGFBP‐3 concentrations do not accurately predict growth hormone deficiency in children with brain tumours
Authors: Weinzimer Stuart A. , Homan Sarah A. , Ferry Robert J. , Moshang Thomas
Published: March 2003

OBJECTIVE

The growth hormone (GH)‐dependent growth factors insulin‐like growth factor‐I (IGF‐I) and IGF‐binding protein‐3 (IGFBP‐3) may be superior to provocative GH testing in diagnosing GH deficiency (GHD) in children. In adults with brain tumours (BT) and GHD, however, provocative GH testing more accurately reflects GHD than either IGF‐I or IGFBP‐3. We assessed growth factor levels in children with GHD due to BT with respect to brain tumour type, pubertal stage, growth velocity, bone age delay, and body mass index (BMI).

DESIGN

Retrospective case review of all patients followed at our centre with GHD following treatment of BT.

PATIENTS

72 children (51 M, 21 F) with BT diagnosed with GHD by clinical and auxological criteria, including provocative GH testing, in whom pre‐GH treatment IGF‐I and IGFBP‐3 levels were obtained.

MEASUREMENTS

Auxological data, including height, weight, growth velocity, and pubertal stage; and biochemical data, including GH response to provocative GH testing and pre‐GH treatment serum IGF‐I and IGFBP‐3 concentrations.

RESULTS

IGF‐I levels were normal (above −2 SD) in 19 of 70 children (27%), and IGFBP‐3 levels were normal in 21 of 42 (50%). In children with GHD, pubertal stage correlated significantly with both IGF‐I (r = 0.328, p < 0.006) and IGFBP‐3 (r = 0.364, P < 0.02). Normal IGF‐1 levels were found in 1/15 children with craniopharyngioma (Cranio) (7%), 10/30 with primitive neuroectodermal tumours (PNET) (33%), and 5/12 children with hypothalamic/chiasmatic glioma (HCG) (42%) (P < 0.05). IGFBP‐3 levels were normal in 4/13 Cranio patients (31%), 8/15 PNET patients (53%), and 6/8 HCG patients (75%) (P = ns). Tanner staging varied significantly among tumour types: mode = 1 for Cranio and PNET vs. mode = 3 for HCG (P < 0.03). BMI did not differ between patients with low vs. normal growth factor levels.

CONCLUSIONS

Low IGF‐I levels were more predictive of growth hormone deficiency than low IGFBP‐3 levels in our brain tumour patients, but both were poor predictors of growth hormone deficiency in children with hypothalamic‐chiasmatic glioma and in pubertal children. Serum IGF‐I and IGFBP‐3 levels, therefore, do not always reflect growth hormone deficiency in children with brain tumours, particularly in those with hypothalamic‐chiasmatic glioma or those already in puberty.
The course of Graves' ophthalmopathy is not influenced by near total thyroidectomy: a case‐control study
Authors: Marcocci  , Bruno‐Bossio  , Manetti  , Tanda  , Miccoli°  , Iacconi  , Bartolomei  , Nardi  , Pinchera  , Bartalena
Published: March 2003

OBJECTIVE

The relationship between the method of treatment of hyperthyroidism due to Graves' disease and the course of Graves' ophthalmopathy is debated. Antithyroid drug therapy is associated with no change, or even amelioration, of ophthalmopathy. Although controversial, radioiodine may be followed by progression of eye disease, preventable by glucocorticoid administration. Whether thyroidectomy affects the course of ophthalmopathy is uncertain.

DESIGN

In a case control study, the course of non‐severe Graves' ophthalmopathy after thyroidectomy was investigated and the results compared with those observed in patients treated with methimazole.

PATIENTS

Thirty patients with Graves' hyperthyroidism and non‐severe/absent ophthalmopathy were treated with near‐total thyroidectomy (Group 1, Tx), after achievement of euthyroidism with methimazole. After surgery, all patients started levothyroxine replacement therapy. Sixty patients treated with methimazole, matched for age, sex, duration of hyperthyroidism, degree of ocular involvement and smoking habits, were used as controls (Group 2, MMI).

MEASUREMENTS

Patients were seen every 1–2 months for 12 months for thyroid tests and ocular evaluation.

RESULTS

In Group 1, ocular parameters did not change in 17 of 18 patients with pre‐existing ophthalmopathy, and in 12 patients without ophthalmopathy. Eye manifestations worsened only in one (3.3%) patient with pre‐existing ophthalmopathy. In Group 2, ocular parameters did not change in 58 patients (33 with, and 25 without ophthalmopathy), while new ophthalmopathy occurred in two without pre‐existing eye disease. One of the 30 patients treated by surgery (3.3%) had permanent hypoparathyroidism.

CONCLUSIONS

Treatment of Graves' hyperthyroidism with near‐total thyroidectomy in patients with non‐severe or absent pre‐existing ophthalmopathy is not associated in the short term with significant effects on the course of ophthalmopathy.
Serum levels of growth hormone binding protein in children with normal and precocious puberty: relation to age, gender, body composition and gonadal steroids
Authors: Juul Anders , Fisker Sanne , Scheike Thomas , Hertel Thomas , Müller Jørn , Ørskov Hans , Skakkebæk Niels E.
Published: March 2003

AIM

To study the regulation of GHBP serum levels by gonadal steroids in normal and precocious puberty.

STUDY PROTOCOL

We studied GHBP levels in relation to age, sex, pubertal maturation, body composition as well as to circulating IGF‐I and gonadal steroid levels in 320 healthy children. Furthermore, we studied the regulation of circulating GHBP in 33 girls with central precocious puberty before and during gonadal suppression with GnRH agonist.

METHODS

GHBP was determined by a time‐resolved fluoroimmunoassay (GHBP TR‐FIA) based on a commercially available immunoassay for GH, the DELFIA GH assay.

RESULTS

In healthy children GHBP levels were significantly higher in normal girls compared with boys, and there was no significant increase in GHBP in puberty in both sexes. GHBP levels did not correlate with height (SDS), age, pubertal stage, IGF‐I or testosterone/oestradiol levels in boys and girls, respectively. There were significant correlations between BMI and GHBP in boys and girls (R 2 = 0.14 and R 2 = 0.12, both P < 0.0001). Furthermore, GHBP correlated highly significantly with the percentage body fat, determined by BIA in 43 healthy girls (R 2 = 0.40, P < 0.0001). GHBP levels were significantly higher in girls with central precocious puberty (CPP) (1.31 SDS (1.26), mean (SD)) compared to prepubertal controls (P < 0.0001), and above + 2 SD in 10 out of 33 patients. In girls with CPP, GHBP correlated inversely with oestradiol before treatment (R 2 = 0.26, P < 0.01) and there was a tendency towards a positive correlation with BMI (R 2 = 0.13, P = 0.078). By contrast, there were no signficant correlations between GHBP and IGF‐I or height SDS. Gonadal suppression with GnRH agonist treatment caused a transient significant increase of 0.57 SD after 2 months of treatment (P < 0.001), but decreased to baseline levels hereafter.

CONCLUSION

We conclude that in children, as in adults, body fat is the primary determinant for the circulating level of GHBP, and that the difference in body fat is probably the main factor for the higher levels of serum GHBP in girls compared with boys, as well as for the negative influence of testosterone levels in boys and of oestrogen levels in girls. The elevation in GHBP levels observed in girls with central precocious puberty is probably due their higher body fat content.
Treatment of pituitary‐dependent Cushing's syndrome: long‐term results of unilateral adrenalectomy followed by external pituitary irradiation compared to transsphenoidal pituitary surgery
Authors: Nagesser S. K. , van Seters A. P. , Kievit J. , Hermans J. , van Dulken H. , Krans H. M. J. , van de Velde C. J. H.
Published: March 2003

BACKGROUND The preferred treatment of Cushing's disease (CD) nowadays is transsphenoidal pituitary surgery (TPS). Prior to TPS, patients at the Leiden University Medical Centre were treated by unilateral adrenalectomy followed by external pituitary irradiation (UAPI). We report on long‐term results of both UAPl and TPS and compare remission, relapse rates, and complications.

PATIENTS AND METHODS A retrospective Study was carried out on 130 patients with CD. Patients with pituitary macroadenoma were excluded. Eighty‐six and 44 patients underwent UAPl and TPS, respectively. Of these patients, 85 and 41 were evaluable for long‐term results.

RESULTS Remission following UAPl and TPS was identical at 64% (54/85 and 27/41). Cumulative relapse was also comparable ‐ 17% (9/54) and 22% (6/27), respectively, ‐ for UAPl and TPS, although the mean follow‐up periods were different ‐ 21.4 years and 8.5 years, respectively. Cumulative disease‐free survival curves after UAPl and TPS are identical until 5 years of follow‐up, but diverge thereafter indicating more sustained remissions following UAPl (P=0.17, Wilcoxon statistic). Pituitary dysfunction following UAPl (36%) and pituitary surgery (55%) likewise did not dlffer significantly. However, pituitary dysfunction was an immediate event after TPS, whereas it developed after a mean interval of 17.8 years following UAPI.

Low‐dose dexamethasone testing during follow‐up had no value in predicting therapeutic outcome.

CONCLUSIONS The results of unilateral adrenalectomy followed by external pituitary irradiation do not Justify that this therapy is totally abandoned in favour of transsphenoidal pituitary surgery. Unilateral adrenalectorny followed by external pituitary irradiation is a valid therapeutic modality for the treatment of Cushing's disease, and could be considered as alternative to bilateral adrenalectomy and under some circumstances to transsphenoidal pituitary surgery.
Association of thyrotrophin receptor antibodies with the clinical features of Graves' ophthalmopathy
Authors: Gerding Martin N. , van der Meer Jolanda W. C. , Broenink Margreet , Bakker Onno , Wiersinga Wilmar M. , Prummel Mark F.
Published: March 2003

OBJECTIVE

Graves' ophthalmopathy (GO) and Graves' hyperthyroidism are closely associated diseases and thought to be caused by the same autoimmune process. An obvious explanation for this would be the presence of autoantibodies reacting with an autoantigen present in the orbit and the thyroid gland. The TSH‐Receptor (TSH‐R) antibodies are a likely candidate, because they cause Graves' hyperthyroidism and the TSH‐R appears to be present also in orbital tissues. If TSH‐R antibodies are responsible for the ophthalmopathy one would expect their titres to correlate with clinical characteristics of the eye disease. The aim of the present study is to see whether TSH‐R antibodies are related to the activity and severity of the thyroid‐associated ophthalmopathy.

DESIGN AND PATIENTS

TSH‐R antibody levels were measured as TBII (TRAK assay), and TSI (cAMP response of a TSH‐R transfected cell line) in serum of 63 patients with untreated moderately severe GO, accompanying Graves' thyroid disease; all patients had been euthyroid for > 2 months.

RESULTS

TBII and TSI titres were strongly related to each other. TBII or TSI titres did not correlate with thyroidal or orbital disease duration, nor with TPO antibody levels. In contrast, we found a striking and highly significant correlation between the Clinical Activity Score (CAS) of the eye disease, and both TBII (r = 0.54; P < 0.0001) and TSI (r = 0.50; P < 0.0001). In addition, a weaker but significant relation was found between proptosis (in mm) and TBII (r = 0.36; P = 0.004) and TSI (r = 0.49; P = 0.0001). No correlation was found with eye muscle motility.

CONCLUSION

TSH‐R antibody levels correlate directly with clinical features of Graves' ophthalmopathy. The results support the hypothesis of a pathogenetic role of TSH‐R antibodies and the TSH‐R in the orbit of Graves' ophthalmopathy patients.
Ablation of the thyroid remnant and 131I dose in differentiated thyroid cancer
Authors: Doi Suhail A.R. , Woodhouse Nicholas J.Y.
Published: March 2003

AIMS

To compare the efficacy of remnant ablation following a single low dose (specific activity of 131I administered, 1074–1110 MBq) vs. a single high dose (mostly 2775–3700 MBq) of 131I in patients with differentiated thyroid cancer and to determine whether or not the extent of surgery influences outcome.

METHODS

Nineteen studies have reported the results of low dose 131I ablation. Of these, 11 met our criteria for a comparative analysis. Two additional cohorts of ours were added and these were analysed in two groups based on the extent of surgery (near‐total [NT; Woodhouse1] vs. sub‐total [ST; Woodhouse2]). There were 518 low dose and 449 high dose patients in all.

RESULTS

The average failure of a single low dose was 46 ± 28% (SD). Meta‐analysis revealed a statistically significant advantage for a single high over a single low dose and a pooled reduction in relative risk of failure of the high dose of about 27% (P < 0.01). From this we estimate that for every seven patients treated one more would be ablated given a high rather than a low dose (assuming a low dose failure risk of 50%). Also, a significantly greater proportion of patients are ablated after a single high or low dose, if they underwent near‐total as opposed to sub‐total thyroidectomy (summary relative risk (RR) 1.4; P < 0.05).

CONCLUSION

High dose 131I is more efficient than low dose for remnant ablation particularly after less than total thyroidectomy. Results suggest that patients with differentiated thyroid cancer should routinely have a total thyroidectomy followed by high dose 131I (2775–3700MBq) for ablation of the remnant.
Corpus luteum response to exogenous HCG during the mid‐luteal phase of the menstrual cycle
Authors: Tay  , Lenton
Published: March 2003

OBJECTIVE

To assess a range of exogenous HCG regimes designed to simulate the endocrine environment occurring in biochemical, single and multiple pregnancies and to study the response of the corpus luteum to those regimes.

DESIGN

Prospective clinical study.

PATIENTS

Twenty‐five normally cycling women aged 24–35 years were given one of four regimes of HCG injections designed to mimic the HCG concentrations found following spontaneous implantation. Regimes A, B, C and D were designed with starting HCG doses of 60, 140, 250 and 1000 iu, respectively. The daily HCG injections were then increased to give a doubling concentration every 30 h for regime A, every 27 h for regime B, every 24 h for regimes C and D. HCG administration was started on either days 7 or 8 after the LH peak.

MEASUREMENTS

Plasma HCG and progesterone concentrations.

RESULTS

Subjects given regime A failed to demonstrate any rescue of the corpus luteum despite low‐detectable amounts of HCG in the circulation equivalent to those seen in some biochemical pregnancies. In contrast, subjects given regimes B and C demonstrated prompt increases in progesterone secretion immediately after the first HCG injection achieving HCG and progesterone concentrations in plasma similar to those seen in normal singleton pregnancies. Subjects given regime D also showed rapid rescue of the corpus luteum but this time achieved plasma HCG concentrations in the range normally seen in multiple pregnancies. All subjects in regimes B, C and D secreted significantly higher amounts of progesterone than those in regime A (P < 0.001). However, despite the greater amounts of HCG used in regime D, the amount of progesterone produced was not significantly different from regimes B or C.

CONCLUSIONS

The exogenous HCG regimes used in this study successfully mimicked the hormonal environment found in biochemical, single and multiple pregnancies and elicited appropriate corpus luteum responses.
The insulin hypoglycaemia and overnight metyrapone tests in the assessment of the hypothalamic–pituitary–adrenal axis following pituitary surgery
Authors: Courtney  , McAllister  , McCance  , Hadden  , Leslie  , Sheridan  , Atkinson
Published: March 2003

OBJECTIVE

To compare the insulin hypoglycaemia test with the short overnight metyrapone test in the assessment of the hypothalamic–pituitary–adrenal (HPA) axis posthypophysectomy.

DESIGN

Prospective comparative study of the insulin hypoglycaemia test and the overnight metyrapone test in 32 patients 4–6 weeks after pituitary surgery.

SUBJECTS

Thirty‐two patients with known pituitary disease. None with present or previous Cushing's syndrome.

OUTCOME MEASUREMENTS

Maximum serum cortisol achieved during insulin induced hypoglycaemia compared with 0900 hours serum 11‐deoxycortisol level following a weight related oral dose of metyrapone at 0000 h.

RESULTS

One of the 32 patients required further surgery and was studied twice after each operation. Thirty‐three results are therefore compared. Twenty‐six of these had a normal cortisol response of 550 nmol/l or above leading to the cessation of replacement hydrocortisone. Six of these 26 patients however, failed the metyrapone test (11‐deoxycortisol level less than 200 nmol/l). After 3–40 months (median 20 months) of follow‐up off steroid therapy, no patient to date has displayed any clinical evidence of steroid deficiency. Of the seven patients who failed the insulin hypoglycaemia test, six also failed the metyrapone test.

CONCLUSIONS

The overnight metyrapone test identified more patients with possible ACTH deficiency than the insulin hypoglycaemia test. Further follow‐up of these patients is required before a final judgement can be made as to whether more subtle but clinically relevant ACTH deficiency can be detected by the metyrapone test. Our clinical follow‐up to date would not support this.
Salivary, but not serum or urinary levels of progesterone are elevated after topical application of progesterone cream to pre‐and postmenopausal women
Authors: O'leary Peter , Feddema Peter , Chan Katherine , Taranto Mario , Smith Margaret , Evans Sharon
Published: March 2003

OBJECTIVE

The use of topically applied micronised (‘natural’) progesterone as a substitute for synthetic oestrogens and progestogen preparations is controversial. The aim of this study was to examine the changes in blood and salivary concentrations of progesterone following a single topical application of a progesterone cream.

PATIENTS AND MEASUREMENTS

We investigated six premenopausal women in the luteal phase and six postmenopausal women to determine the short‐term changes in serum, urinary and salivary progesterone concentrations following a single 64 mg topical application of micronised progesterone.

RESULTS

Serum progesterone concentrations did not increase during the first 3 hours after application of progesterone cream, however, salivary values rose significantly in both premenopausal and postmenopausal women, consistent with the view that progesterone is absorbed and transported through the body. Salivary progesterone concentrations were significantly elevated above basal levels by 30–60 minutes and reached peak levels at 1–4 h, with mean levels approximately fivefold higher in premenopausal, than in menopausal women.

CONCLUSIONS

Salivary progesterone measurements confirm that topically applied progesterone is absorbed, despite the lack of change in serum progesterone concentrations. However, at the dose administered, serum progesterone levels do not reach those observed after oral or vaginally delivered progesterone preparations. Higher doses may be required to induce biological responses within the endometrium.
Relationship between blood pressure and glucose tolerance in acromegaly
Authors: Jaffrain‐Rea M.‐L. , Moroni C. , Baldelli R. , Battista C. , Maffei P. , Terzolo M. , Correra M. , Ghiggi M. R. , Ferretti E. , Angeli A. , Sicolo N. , Trischitta V. , Liuzzi A. , Cassone R. , Tamburrano G.
Published: March 2003

BACKGROUND

Hypertension represents a well‐known risk factor for cardiovascular diseases. The pathogenesis of hypertension in acromegaly is commonly viewed as multifactorial, but the possible influence of metabolic disorders on blood pressure (BP) in affected patients is largely unknown.

OBJECTIVE

The aim of the present study was to evaluate the impact of glucose metabolism abnormalities on BP values in a series of patients with active acromegaly.

DESIGN

An open multicentre prospective study.

PATIENTS

Sixty‐eight patients with active disease, aged 47·5 ± 11·7 years, have been studied. Thirty‐nine had normal glucose tolerance (NGT), 16 impaired glucose tolerance (IGT) and 13 suffered from diabetes mellitus (DM).

MEASUREMENTS

Mean clinical BP values were calculated as the mean of BP values obtained by sphygmomanometric measurement in three separate occasions and mean 24‐h, diurnal and nocturnal systolic (SBP) and diastolic (DBP) values were obtained by 24‐h ambulatory blood pressure monitoring (ABPM).

RESULTS

Patient's age and the degree of glucose tolerance abnormalities were found to significantly and independently influence BP values. All clinical and ABPM SBP and DBP values significantly increased with age by linear regression (P < 0·02 for all BP values, 0·30 ≤ R ≤ 0·43), and the independent influence of this parameter on BP values was confirmed by mutivariate analysis. Similarly, the independent influence of glucose tolerance abnormalities on BP values was confirmed when introducing age as a covariable in a multivariate analysis, and patients with DM presented significantly higher clinical SBP and 24‐h, diurnal and nocturnal SBP and DBP than patients with NGT (P < 0·02 for clinical SBP, P < 0·015 for all ABPM values, respectively). In addition, patients with DM showed significantly higher 24‐h, diurnal and nocturnal DBP than those with IGT (P < 0·05 in all cases). In contrast, no significant difference was found between NGT and IGT patients. No significant influence of disease duration, BMI, GH, IGF‐I, or fasting and 2‐h post glucose load insulinaemia on BP values was observed.

CONCLUSIONS

Abnormalities of glucose metabolism significantly contribute to increase systolic blood pressure and especially diastolic blood pressure in acromegalic patients. Careful control of blood pressure and of risk factors for developing systemic hypertension, with special reference to glucose tolerance, is mandatory to decrease cardiovascular morbidity and mortality in such patients.
Screening for an AIRE‐1 mutation in patients with Addison's disease, type 1 diabetes, Graves' disease and Hashimoto's thyroiditis as well as in APECED syndrome
Authors: Meyer G. , Donner H. , Herwig J. , Böhles H. , Usadel K. H. , Badenhoop K.
Published: March 2003

Autoimmune polyendocrinopathy‐candidiasis‐ectodermal dystrophy (APECED) is a rare systemic autoimmune disorder of monogenic and autosomal‐recessive inheritance. To date, 29 APECED causing mutations have been identified in the responsible gene AIRE‐1, coding for a regulator of transcription. The aim of this study was to examine whether mutations in AIRE‐1, in their heterozygous form, predispose to the more common isolated autoimmune endocrinopathies Addison's disease, type 1 diabetes mellitus, Graves' disease and Hashimoto's thyroiditis.

Patients with isolated autoimmune endocrine disorders as well as healthy controls were analysed for two of the most common AIRE‐1 mutations, mutation R257X in exon 6 and a 13‐bp deletion in exon 8. Mutations were detected by polymerase chain reaction based techniques.

In total, 726 individuals were investigated for mutation R257X. Subjects comprised patients with Addison's disease, IDDM, Graves' disease and Hashimoto's thyroiditis. With regard to the 13 bp deletion we could screen 91 patients with Addison's disease. In addition, six patients with the APECED syndrome including one family were analysed for both mutations.

Out of the 12 alleles in APECED patients six contained either mutation R257X or the 13 bp deletion, confirming that these mutations prevail in Europe. R257X was found in one subject with Hashimoto's thyroiditis in its heterozygous form. The 13 bp deletion was not detected in any subject with Addison's disease.

The two studied AIRE‐1 mutations are so rare in the general population that they can not contribute to susceptibility for the more common isolated autoimmune disorders.
Prevalence of diabetes and impaired glucose tolerance in adult hypopituitarism on low dose oral hydrocortisone replacement therapy
Authors: McConnell E. M. , Bell P. M. , Hadden D. R. , McCance D. R. , Sheridan B. , Atkinson A. B.
Published: March 2003

OBJECTIVE The conventional dosage of hydrocortisone, used for many years in the management of hypopituitarism (30 mg per day), has now been shown to be more than is physiologically necessary. On this conventional corticosteroid therapy studies have demonstrated an increased prevalence of diabetes and impaired glucose tolerance, which may contribute to the increased vascular morbidity and mortality reported in the condition. In these studies no information is available on oral glucose tolerance test (OGTT) timing in relation to administration of oral steroid and variable hydrocortisone doses were employed.

PATIENTS In order to assess glucose tolerance in patients treated with lower, more physiological doses, we performed a 75‐g OGTT at least 1 month after hydrocortisone therapy was adjusted to 15 mg at 0800 h and 5 mg at 1700 h in 45 adult onset hypopituitary patients (30 M, 15 F). Mean (± SD) duration of hypopituitarism was 12 ± 10 years, mean age 52 ± 14 years and BMI 29·3 ± 5·1 kg/m2. All were on hydrocortisone, 43 on thyroxine, 31 on sex steroids, 9 on desmopressin and 33 had documented growth hormone deficiency. Hydrocortisone 15 mg was taken at 0800 and the OGTT commenced at 0900.

RESULTS Using standard WHO criteria 36 patients (80%) had normal glucose tolerance, 1 (2%) had newly diagnosed diabetes and 8 (18%) had impaired glucose tolerance. Using the recently announced American Diabetes Association criteria for diagnosis 96% had normal glucose tolerance, 2% had diabetes and 2% impaired fasting glucose.

CONCLUSION The markedly reduced prevalence of diabetes and impaired glucose tolerance on lower hydrocortisone replacement doses in our series of patients with hypopituitarism, not previously known to be diabetic, is of great interest. This lower prevalence may eventually result in reduced vascular complication rates.