bluuebunny/crossref_metadata_2025 huggingface dataset:
The thyroid gland in acromegaly: an ultrasonographic study
Authors: Cheung N. W. , Boyages S. C.
Published: November 2003

OBJECTIVEAn association between acromegaly and goitre is well recognized. We have studied the incidence and morphology of goitre in acromegaly, and examined the role of IGF‐I and TSH in goitre pathogenesis.

DESIGN AND SUBJECTSThirty‐seven subjects with acromegaly, active or in remission, were assessed by ultrasound to determine thyroid volume (TV) and morphology, and compared with normal controls. Nine subjects with acromegaly were also studied again following treatment with octreotide for 1 year.

RESULTSCompared with controls, TV was greater (28.7±18.3 ml vs 5.4±2.6 ml, P<0.001) and IGF‐I levels were higher (62.0±34.8 nmvs 28.9±10.9 nmP<0.001) in subjects with acromegaly. Those with active disease tended to have larger glands (30.0±17.2 ml vs 22.2±16.7 ml, P=0.18). The overall incidence of goitre was 92%. Twenty‐seven subjects (73%) had nodules or heterogeneous thyroid echotexture. Subjects with nodular goitre had a longer duration of acromegaly than those with homogeneous glands (12.1±5.7 vs 7.6±4.0 years, P=0.032). Those with nodular glands also had larger goitres than those with homogeneous glands (35.2±18.8 ml vs 19.5±11.9 ml, P=0.032). Thyroid volume correlated with IGF‐I levels (r2=0.38, P=0.002) and body mass index (r2=0.24, P<0.001), and there was an inverse relationship with TSH levels (r2=0.46, P=0.032). Patients studied again after treatment with octreotide for 1 year had a reduction in TV from 32.6±16.1 to 27.6±17.0 ml (P=0.041).

CONCLUSIONSThis study confirms that goitre is a common finding in acromegaly. Our findings suggest that early in the course of the disease, diffuse goitre occurs. Subsequently, thyroid autonomy and nodule formation develop, and further growth may occur independent of TSH. With control of GH hypersecretion, a reduction in thyroid size occurs, but this may be limited by the extent of thyroid nodularity.
A CTLA‐4 gene polymorphism is associated with both Graves' disease and autoimmune hypothyroidism
Authors: Kotsa K. , Watson P. F. , Weetman A. P.
Published: November 2003

OBJECTIVEThe autoimmune thyroid diseases, Graves' disease and autoimmune hypothyroidism, result from a complex interaction between genetic, environmental and endogenous factors. The genetic loci conferring susceptibility remain unclear. A recent report has demonstrated an association between a microsatellite polymorphism of the CTLA‐4 gene (allele 106) on chromosome 2q33 and Graves' disease in Caucasian patients in the USA. The aim of the present study was to confirm this association in UK patients and to determine whether this polymorphism is also associated with autoimmune hypothyroidism.

DESIGNAnalysis of Caucasian patients with autoimmune thyroid disease from a single clinic, compared to local Caucasian controls.

PATIENTSWe studied 112 patients with Graves' disease, 44 with autoimmune hypothyroidism and 91 controls.

MEASUREMENTSCTLA‐4 microsatellite gene polymorphisms were determined by polymerase chain reaction amplification of genomic DNA and resolution of the products on sequencing gels.

RESULTSAs in previous studies, 21 alleles of the CTLA‐4 microsatellite region were detected. Allele 106 was significantly increased in patients with Graves' disease (P=0.006) and in those with autoimmune hypothyroidism (P=0.02) when compared to controls. There was no significant difference between the groups in the distribution of the other alleles and no association between allele 106 and sex, HLA‐DR or ‐DQ specificities or the presence of ophthalmopathy in the Graves' patients.

CONCLUSIONSThese results confirm that the CTLA‐4 gene, or one closely associated with it, confers susceptibility to Grave's disease but is not specific as the CTLA‐4 106 allele is also associated with autoimmune hypothyroidism. This association seems to be with autoimmune thyroid disease in general.
Combined βFSH and βLH response to TRH in patients with clinically non‐functioning pituitary adenomas
Authors: Somjen D. , Tordjman K. , Kohen F. , Baz M. , Razon N. , Ouaknine G. , Stern N.
Published: November 2003

OBJECTIVE‘Paradoxical’ responses of LH, FSH, α‐subunits and βLH to TRH have previously been reported in individuals with clinically non‐functioning pituitary tumours (NFT). The present study was designed to assess the in vivoin vitro responses of βFSH to TRH in NFT. We further examined the possibility that a TRH challenge with combined measurement of βFSH and βLH will identify a common anomalous secretory pattern in patients with NFT.

DESIGN, PATIENTS AND MEASUREMENTSForty patients with NFT underwent a standard TRH test (400 μg intravenously). Blood samples for the determination of βFSH, βLH, FSH and LH were collected prior to TRH as well as 15, 30, 45, 60 and 90 minutes following injection. Additionally, cultured adenomatous cells from eight of these patients were exposed to TRH in the absence and presence of octreotide and gonadotropin subunits were determined.

RESULTSTRH elicited a marked rise in circulating βFSH in 29 of 40 individuals and in βLH in 28 of 36 patients with NFT. In a subgroup of eight individuals whose tumours were harvested during surgery and cultured for 7–21 days, TRH increased βFSH or βLH and α‐subunit release in cultured adenomatous cells in all cases, including tumours from subjects not responding to TRH in vivo. In this subgroup of patients octreotide inhibited basal βFSH secretion but not basal βLH secretion both in vivo and in primary cultures of NFT cells. Both the in vivoin vitroβFSH, βLH and α‐subunit responses to TRH were entirely inhibited by octreotide. In all, 38 of the 40 subjects could be identified by either elevated basal βFSH or βLH levels and/or an abnormal rise in either βFSH or βLH in response to TRH.

CONCLUSIONThe measurement of basal and TRH‐stimulated β‐FSH and β‐LH levels identifies an abnormal hormonal secretory pattern in the vast majority (>90%) of patients with clinically nonfunctioning pituitary tumours.
Thyroid volume and function after 131I treatment of diffuse non‐toxic goitre
Authors: Nygaard B. , Faber J. , Veje A. , Hansen J. E. M.
Published: November 2003

OBJECTIVE Traditional treatment modalities of diffuse non‐toxic goitre are thyroid hormone suppression or surgery. When treating nodular non‐toxic goitre with 131I treatment a reduction in thyroid volume to about 50% has been observed. In the present study we evaluated the effect of 131I treatment of diffuse non‐toxic goitre.

DESIGN Retrospective study of patients treated for a diffuse non‐toxic goitre and followed by evaluation of thyroid volume measured by ultrasound.

PATIENTS Ten selected patients from our out‐patient clinic with diffuse non‐toxic goitre.

MEASUREMENTS Thyroid volume was measured by ultrasound and thyroid function by serum values of T4, T3, T3 uptake ratio, TSH, TSH receptor antibodies and thyroid peroxidase antibodies (anti‐TPO). Measurements were performed before and 1, 3, 6 and 12 months (and 18 months (n=7), thyroid volume measured in six patients)) after 131I treatment.

RESULTS Thyroid volume declined in all patients from median 41 (range 27–160) ml to 20 (range 9–108) ml over 1 year, a reduction of 47%. One patient developed transient and one persistent hypothyroidism in the follow‐up period. Both had elevated anti‐TPO levels before treatment (331 and 9185 U/ml) and demonstrated titre increases of 2.5 and 30 times after 3 and 6 months, respectively. Pretreatment values were reached after 1 year. The other eight patients had normal anti‐TPO levels and free T4 and T3 indices did not change during follow‐up, whereas serum TSH levels demonstrated upward trends within the normal range (P<0.05). TSH receptor antibodies were normal and remained so in all patients.

CONCLUSION S131I treatment of diffuse non‐toxic goitre reduces thyroid volume by approximately 50% within 12–18 months. Hypothyroidism, during a limited follow‐up period, developed only in patients with positive anti‐TPO levels before treatment.
Treatment of radiation‐induced growth hormone deficiency with growth hormone‐releasing hormone
Authors: Ogilvy‐Stuart A. L. , Stirling H. F. , Kelnar C. J. H. , Savage M. O. , Dunger D. B. , Buckler J. M. H. , Shalet S. M.
Published: November 2003

In children with hypothalamic causes for GH deficiency there are theoretical reasons why a GHRH analogue might be better than conventional GH therapy in promoting growth.

OBJECTIVEWe have aimed to determine the efficacy and safety of growth hormone‐releasing hormone (GHRH) (1–29)‐NH2 given as a twice daily subcutaneous injection in the treatment of growth failure in children with radiation‐induced GH deficiency.

DESIGNA multicentre study comparing growth before and after 1 year of treatment with GHRH (1–29)‐NH2, 15 μg/kg twice daily, by subcutaneous injection in children with radiation‐induced GH deficiency. On completion of the study year all children were treated with GH (05 U/kg/week) and growth parameters were documented over the next year.

PATIENTSNine children (six boys) with radiation‐induced GH deficiency following cranial (n = 4) or craniospinal (n = 5) irradiation for a brain tumour distant from the hypothalamic–pituitary axis (n = 8) or prophylaxis against central nervous system leukaemia (n = 1) were studied. All were prepubertal when the study commenced, which was at least 2 years from radiotherapy.

MEASUREMENTSAnthropometry and pubertal staging were carried out at 3‐monthly intervals and bone age estimations at 6‐monthly intervals (TW2 method). Pretreatment standing height velocities were compared with values during the year of GHRH treatment and then after the first year of GH therapy. In those that had received craniospinal irradiation, a change in leg‐length Standard deviation score (SDS) was noted before and after GHRH therapy. Changes in skin‐fold thickness and bone age during the GHRH study year were documented. Adverse events and 3‐monthly measurements of clinical chemistry, haematology, lipid profile and thyroid function were recorded.

RESULTSThere was a significant increase in height velocity from 33 (SD 11) cm/year before treatment, to 60 (SDS 15) cm/year after 1 year of GHRH treatment (P = 0004). GHRH maintained or improved the leg length SDS in children who had received craniospinal irradiation. Bone age increased by a mean of 11 years/chronological year during treatment with GHRH. Subsequent height velocity during 1 year of GH therapy was 75 (SD 15) cm/year. No adverse changes in biochemical or hormonal analyses were noted or adverse events that could be attributed to GHRH therapy. One child went into puberty during the GHRH study year and three were pubertal during the first year of GH therapy.

CONCLUSIONIn cranially irradiated children, GHRH was effective in increasing growth velocity but this was less than that seen in response to GH therapy, although it matched that in children with isolated idiopathic GH deficiency treated with the same dose and schedule of GHRH administration.
Thyroid dysfunction in patients with amyloid goitre
Authors: Kimura Hironori , Yamashita Shunichi , Ashizawa Kiyoto , Yokoyama Naokata , Nagataki Shigenobu
Published: November 2003

OBJECTIVES

Widespread amyloid deposition in the thyroid gland causes diffuse, clinically apparent enlargement of the thyroid (amyloid goitre: AG). The aim of this study was to clarify the abnormalities of thyroid function in patients with AG.

DESIGN

Thirty patients with secondary amyloidosis were retrospectively analysed. Their thyroid status was evaluated using the results of routine thyroid function tests and measurement of thyroid autoantibodies. Thyroid needle biopsy was carried out to identify amyloid deposition in the thyroid gland.

RESULTS

Thyroid enlargement was observed in 19 (63%) of 30 patients with amyloidosis. Eleven of these 19 patients had a thyroid biopsy and/or autopsy and amyloid deposition was histologically revealed in 10 (defined as AG) of these 11 patients. Nine of 10 patients (90%) with AG had abnormalities of thyroid function, including five patients with hypothyroidism, one with hyperthyroidism, one with transient hypothyroidism, and two with low T3 syndrome. Five had thyroid autoantibodies. The patient with hyperthyroidism had positive thyroid stimulating antibody (TSAb) and high 131I thyroidal uptake, suggesting the coexistence of Graves’ disease. Another patient suffered from thyroidal pain and showed transient hypothyroidism, high level of serum thyroglobulin and low thyroidal uptake of 123I, the clinical course being compatible with subacute thyroiditis.

CONCLUSIONS

The incidence of thyroid abnormalities accompanied by AG, although asymptomatic, is unexpectedly high. Thyroid function should therefore be regularly assessed during follow‐up of patients with systemic amyloidosis.
Insulin‐like growth factor‐I in growth hormone‐deficient adults: relationship to population‐based normal values, body composition and insulin tolerance test
Authors: Svensson Johan , Johannsson Gudmundur , Bengtsson Bengt‐Åke
Published: November 2003

BACKGROUNDAlthough an insulin tolerance test (ITT) is the most commonly used method for detecting growth hormone (GH) deficiency (GHD) in adults, measurements of serum insulin‐like growth factor‐I (IGF‐I) may also be of value.

OBJECTIVETo validate the use of serum IGF‐I concentration in the diagnosis of GHD in adults.

DESIGNA cross‐sectional study.

PATIENTSOne hundred and four patients, 60 men and 44 women, with known pituitary disease and verified GHD based on ITT.

MEASUREMENTSSerum IGF‐I was determined by radioimmunoassay after acid–ethanol extraction. Body composition was estimated with total body potassium combined with total body water assessments.

RESULTSAccording to age‐ and sex‐adjusted population‐based reference values, 51 patients had serum IGF‐I concentrations below −2 SD of the predicted values and 53 had concentrations within 2 SD. Fifty‐seven per cent of the patients aged 41 years (25th percentile) or below and 39% of the patients aged 57 years (75th percentile) or above had serum IGF‐I concentrations below −2 SD. Women had lower mean IGF‐I SD scores than men (P < 0.01). Serum IGF‐I was correlated with peak GH response during ITT (r = 0.40; P < 0.001), age (r = −0.27; P < 0.01), duration of hypopituitarism (r = −0.52; P < 0.001), number of pituitary hormonal deficiencies (r = −0.35; P < 0.001), body cell mass (r = 0.30; P < 0.01) and serum insulin (r = 0.21; P < 0.05). The peak GH response during ITT correlated with spontaneous GH secretion, duration (P = −0.48; P < 0.001) and number of deficiencies (r = −0.50; P  0.001).

CONCLUSIONThe measurement of serum IGF‐I concentrations is not suitable as a single diagnostic test for growth hormone deficiency in adults. Even as a screening test, its use appears to be limited, especially in elderly subjects. The serum level of IGF‐I was influenced by several factors in addition to GH, such as age, gender, anthropodometry and serum insulin level. The peak GH response during the insulin tolerance test appears to be influenced to a lesser degree by these factors.
Acromegaly, colonic polyps and carcinoma
Authors: Jenkins Paul J. , Fairclough Peter D. , Richards Toby , Lowe David G. , Monson John , Grossman Ashley , Wass John A. H. , Besser Michael
Published: November 2003

OBJECTIVE

It has been suggested that patients with acromegaly may be at risk of developing colorectal carcinoma. In order to clarify this issue, we have evaluated the prevalence of carcinoma, premalignant tubulovillous adenomas and hyperplastic colonic polyps in a large cohort of patients with acromegaly.

DESIGN

Prospective colonoscopic examination by a single operator.

PATIENTS

One hundred and twenty‐nine patients with biochemically proven acromegaly.

RESULTS

At least one lesion was visualized in 63 patients. Adenocarcinoma was present in six patients (5%), but only two had symptoms; all lesions were endoscopically obvious. Compared with a normal group, the odds ratio of colorectal cancer is increased at 13.5 (95% confidence intervals (c.i.) 3.1–75). One or more tubulovillous adenoma was found in 34 patients (26%) and this prevalence was age‐dependent, occurring in 39% of patients aged 70 years or over. Comparing the prevalence of left‐sided colonic adenomas with that in a normal group, there is a higher prevalence among patients over 49 years with an odds ratio of 4.2 (95% c.i. 2.5–6.8). Patients with acromegaly who had an adenoma were significantly older than unaffected patients (61.9 vs 54.1 years; P < 0.001) but had similar GH and IGF‐1 levels and duration of disease.

CONCLUSIONS

Patients with acromegaly have an increased risk of developing colorectal cancer and a significantly higher prevalence of tubulovillous adenomas compared with normal subjects. Routine surveillance colonoscopy is indicated in this group of patients.
Extracervical fibrosclerosis causing obstruction of a ventriculo‐peritoneal shunt in a patient with hydrocephalus and invasive fibrous thyroiditis (Riedel's struma)
Authors: Natt Neena , Heufelder Armin E. , Hay Ian D. , Grant Clive S. , Goellner John R.
Published: November 2003

The association of invasive fibrous thyroiditis (IFT) with foci of extracervical fibrosclerosis is well recognized. Affected sites include the retroperitoneum, the mediastinum, the biliary tract, and the orbit. The development of subcutaneous fibrosclerosis, however, is extremely rare. We report a patient with known invasive fibrous thyroiditis and hypoparathyroidism who presented with localized subcutaneous fibrosclerosis of the anterior chest wall resulting in compression of his ventriculoperitoneal shunt. The aetiology of IFT has remained unclear. Several histological and serological features, including the presence of mononuclear cells within the fibrosclerotic process, the occurrence of microscopic vasculitis, and the detection of autoantibodies directed against thyroid‐specific antigens in a large proportion of patients with IFT, currently support the notion of autoimmune mechanisms playing a role in the pathogenesis of this rare disease.
Altered bioavailability due to changes in the formulation of a commercial preparation of levothyroxine in patients with differentiated thyroid carcinoma
Authors: Olveira G. , Almaraz M. C. , Soriguer F. , Garriga M. J. , Gonzalez‐Romero S. , Tinahones F. , Ruiz de Adana M. S.
Published: November 2003

OBJECTIVES

In July 1995 we began noticing an unusually high rate of elevated TSH levels in patients with differentiated thyroid cancer treated with levothyroxine — specifically the brand Levothroid®— becoming more obvious from September 1995. Faced with the possibility that these findings had some relationship to the drug taken, we carried out a prospective study, changing this brand of levothyroxine for another.

DESIGN AND PATIENTS

We studied 58 patients with differentiated thyroid carcinoma (50 women and eight men; aged 22–75 years) who were being treated with levothyroxine and who had previously had adequate TSH suppression. Their Levothroid® tablets were changed to the same dose of Dexnon® tablets, and their clinical and analytical response was evaluated 2 months later. The patients were divided into two groups according to their TSH level at the start of the study: group 1, 42 patients with TSH > 0.2 mU/l (not suppressed) and group 2, 16 patients with TSH ≤ 0.2 mU/l (suppressed).

RESULTS

After 2 months with Dexnon® the TSH levels in group 1 fell significantly (P < 0.0001) also decreasing in group (P < 0.09). The free T4 and free T3 rose significantly in both groups. After the change to Dexnon®, 17 patients (40%) in group 1 had suppressed TSH and 26 (62%) had free T4 levels above the upper limit of normal vs none at baseline (P < 0.001). The group 2 patients maintained their inhibited TSH values after treatment with Dexnon®, and the free T4 was above the upper limit of normal in 15 (94%) vs 3 (19%) at baseline (P < 0.001). The Levothroid® tablets collected from the patients in both groups formed part of those which the manufacturer later withdrew from the market. These batches possessed the correct dosage, but they had been made from ‘non‐micronized’ raw materials from another supplier.

CONCLUSIONS

The most probable cause of the inadequate TSH suppression in our patients was the reduction in bioavailability in certain batches of Levothroid®, although we are unable to rule out the possibility that the results obtained after the changeover to Dexnon® were due to its greater bioavailability. Simple changes in the manufacture of levothyroxine tablets may produce important variations in their bioavailability, having an adverse effect on the clinical control of the patients, and causing extra expense by the need for repeated patient visits and thyroid function tests.
Different effects of growth hormone releasing peptide (GHRP‐6) and GH‐releasing hormone on GH release in endogenous and exogenous hypercortisolism
Authors: Borges Maria‐Helena S. , DiNinno Fernanda B. , Lengyel Ana‐Maria J.
Published: November 2003

OBJECTIVE

Chronic hypercortisolism is associated with decreased GH responsiveness to GHRH. GHRP‐6 is a synthetic hexapeptide that releases GH in several species, including man. As GHRH and GHRP‐6 apparently stimulate GH release by different mechanisms, we evaluated the GH responses to these peptides in patients with endogenous and exogenous glucocorticoid excess and also in control subjects.

DESIGN

Six patients with endogenous hypercortisolism, nine with exogenous glucocorticoid excess and 10 normal controls were submitted to three tests, in random order, with GHRH (100 μg), GHRP‐6 (1 μg/kg) or GHRP+GHRP‐6, in the same doses, i.v., on separate days.

MEASUREMENTS

GH was measured by immunofluorometric assay. IGF‐I was determined by radioimmunoassay. Plasma glucose was measured by the glucose‐oxidase technique.

RESULTS

Peak GH values (mean ± SE; μg/l) after GHRH were significantly blunted in endogenous (2.0 ± 0.7) and exogenous (3.6 ± 1.2) hypercortisolaemic patients compared to controls (24.9 ± 5.1). The endogenous group had lower peak GH values after GHRP‐6 alone (7.7 ± 1.9) or together with GHRH (18.8 ± 5.8) than those observed in controls (GHRP‐6: 22.1 ± 3.6; GHRH+GHRP‐6: 77.4 ± 15.0) and in exogenous hypercortisolism (27.4 ± 6.2 and 78.1 ± 19.9). There were no differences in the GH responses to GHRP‐6 alone or in combination with GHRH when controls were compared to the exogenous group. No changes in plasma IGF‐I and glucose levels were observed.

CONCLUSIONS

Our results suggest that hypercortisolism had a different effect on the GH‐releasing mechanisms stimulated by GHRH and GHRP‐6. Moreover, in endogenous hypercortisolism both GHRH and GHRP‐6 pathways are affected, while in the exogenous group GHRP‐6 releasing mechanisms are apparently preserved.
Corticotrophic macroadenoma of the pituitary associated with hypoadrenalism
Authors: Peacock I. , Jeffcoate W. J.
Published: November 2003

A 60‐year‐old man underwent transfrontal surgery for a macroadenoma of the pituitary which presented with chiasmal compression, and immunohistochemical examination of the resected specimen revealed a corticotrophic tumour. Despite subsequent external irradiation, he was left with a large tumour remnant, which continued to grow. There were no clinical signs of Cushing's syndrome either before or after surgery and 24 h urine excretion of cortisol was not elevated. Plasma ACTH concentrations were marginally raised. However, there was loss of circadian variation in serum cortisol concentrations and administration of high‐dose oral dexamethasone was followed by a marked and reproducible rise in both ACTH and cortisol. Two years later he developed symptoms and signs of hypoadrenalism and urine cortisol excretion was low, even though the paradoxical response to dexamethasone was preserved. Treatment with 0.5 mg dexamethasone each day was associated with partial resolution of his symptoms and urine cortisol concentration rose into the normal range. This treatment was maintained until his death in hospital in April 1988. The possible mechanism underlying the association between a corticotrophic tumour and hypoadrenalism are discussed.
Serum leptin through childhood and adolescence
Authors: Clayton Peter E. , Gill Matthew S. , Hall Catherine M. , Tillmann Vallo , Whatmore Andrew J. , Price David A.
Published: November 2003

OBJECTIVE

Leptin is the protein product of the recently cloned ob gene, that has been implicated in the control of body weight and thermogenesis, but also independently stimulates the reproductive axis. As major changes in body composition and gonadal function occur during human adolescence, we have assessed serum leptin concentration through childhood.

SUBJECTS AND MEASUREMENTS

Serum leptin was measured in a radioimmunoassay in samples from 235 healthy children from 5 to 18 years of age. Its relationship to body mass index (BMI) (expressed as standard deviation score (SDS)) and the changes in concentration both within and between sexes over the stages of puberty were analysed.

RESULTS

Serum leptin was present at similar concentrations in both sexes over the prepubertal years and increased in parallel into early puberty (breast stage (B) 2, genital stage (G) 2). Thereafter serum leptin in the boys declined to a nadir in G5. In contrast in girls, leptin remained constant in mid‐puberty rising to a peak at B5. Factors influencing leptin (BMI SDS, age and testicular volume) were assessed therefore in the pre‐ and peripubertal stages (B1–2, G1–2) compared to the later pubertal stages (B3–5, G3–5). In all groups, leptin was positively correlated to BMI SDS (r2=38–41% in girls, r2=31–35% in boys). However in B1–2 and G1–2, leptin was also positively related to age, which contributed a further 27% and 20% respectively to the variability. In B3–5, age only accounted for an additional 5% in leptin variability. In contrast in G3–5, leptin was related positively to BMI SDS (r2=35%) and negatively to testicular volume (r2=24%).

CONCLUSIONS

The influence of BMI on leptin is a significant factor throughout the prepubertal and pubertal years of both sexes. The additional negative effect of testicular volume in the boys contributes to the sexual dichotomy in leptin concentration at the completion of puberty. The similar rise in leptin over the prepubertal years into early puberty in both sexes, related not only to BMI SDS but also independently to age, would suggest that leptin may have a facilitatory role in human pubertal development.
Methionine potentiates both basal and GHRH‐induced GH secretion in children
Authors: Bellone J. , Farello G. , Bartolotta E. , Aimaretti G. , Bellone S. , Mucci M. , De Matteis F. , Ghigo E.
Published: November 2003

OBJECTIVE

It is widely accepted that arginine is a potent GH secretagogue in man, probably acting via inhibition of hypothalamic somatostatin release. Although many other amino acids are known to stimulate GH secretion, their effects and mechanisms of action have not been extensively studied in humans. The aim of the present study was to clarify the effect, if any, of methionine (MET) on GH secretion in children with normal short stature (normal height velocity and IGF‐1 >100 μg/l).

DESIGN

We studied the effect of MET (0.2 g/kg intravenously (i.v.) over 30 min) on both basal and GHRH (1 μg/kg i.v. at 0 min)‐induced GH secretion (group A) comparing its effect with that of arginine (ARG) at low and classical doses 0.2 and 0.5 g/kg i.v. over 30 min) (groups B and C). The effect of the combined administration of MET and ARG (0.5 g/kg i.v. over 30 min) (group D) on GH secretion was also studied.

PATIENTS

Thirty‐four children (20 male and 14 female, age 12.8–14.0 years), divided into four groups.

MEASUREMENTS

Serum GH was measured in duplicate by immunoradiometric assay.

RESULTS

In group A, MET increased basal GH levels (peak, mean ± SEM 14.6 ± 2.6 vs 2.6 ± 0.6 mU/l; P < 0.01) and potentiated the GH response to 1 μg/kg i.v. GHRH (78.0 ± 17.6 vs 41.6 ± 9.8 mU/l; P < 0.02). In group B, ARG (0.2 g/kg) increased basal GH levels (16.2 ± 5.2 vs 2.4 ± 0.6 mU/l; P < 0.03) and potentiated the GH response to GHRH (119.6 ± 20.4 vs 48.8 ± 14.2 mU/l; P < 0.01). In group C, ARG (0.5 g/kg) induced a clear GH rise (28.0 ± 3.8 vs 2.0 ± 0.6 mU/l; P < 0.001) and potentiated the GH response to GHRH (93.4 ± 10.0 vs 34.2 ± 4.6 mU/l; P < 0.001). The GH responses to MET and ARG alone in groups A and B were similar and lower than that to ARG in group C. The GH responses to MET or ARG combined with GHRH in groups A, B and C were similar. In group D MET failed to modify the GH response to 0.5 g/kg i.v. ARG (10.8 ± 6.4 vs 9.6 ± 6.0 mU/l).

CONCLUSION

Methionine potentiates both basal and GHRH‐induced GH secretion in children as effectively as arginine. As methionine has no interaction with arginine, our data suggest that these amino acids act via a common mechanism.
A novel mutation causing complete deficiency of thyroxine binding globulin
Authors: Ueta Yoshihiko , Mitani Yasuo , Yoshida Akio , Taniguchi Shinichi , Mori Atsumi , Hattori Kimihiko , Hisatome Ichiro , Manabe Ichiro , Takeda Kyoko , Sato Ryoichi , Ahmmed Gias U. , Tsuboi Mariko , Ohtahara Akira , Hiroe Koh , Tanaka Yasushi , Shigemasa Chiaki
Published: November 2003

OBJECTIVE

Thyroxine binding globulin (TBG) is a serum protein that transports thyroxine. Three naturally occurring mutations have been reported to produce complete deficiency of TBG (TBG‐CD). The first to be reported was TBG‐CD5 in caucasian families of French‐Canadian origin and consists of substitutions in exons 2 and 3. TBG‐CD of English ethnic origin (TBG‐CD6) is characterized by a thymine deletion in codon 165 (exon 1). In Japanese families with TBG‐CD (TBG‐CDJ), a variant has been characterized with a deletion of the first base of the codon for amino acid 352 (exon 4) in the common type TBG. In this communication we report a new type of TBG‐CD in a family of japanese ethnic origin that is characterized by a single nucleotide substitution in place of two nucleotides in exon 1. This is an uncommon mutation which we have been unable to find in other genes.

DESIGN

Exons of the TBG gene amplified by the polymerase chain reaction (PCR) were subcloned and sequenced. To examine for the presence of the same mutation in potentially affected individuals, we performed PCR using primer‐directed mutagenesis or allele‐specific amplification.

PATIENTS

The index case was of Japanese ethnic origin, and was diagnosed as having TBG deficiency on the basis of undetectable serum TBG. The patient consented to this evaluation and the protocol was in accordance with IRB standards.

MEASUREMENTS

Serum thyroid hormones, thyrotrophin binding inhibitory immunoglobulin and TBG concentrations were measured by conventional radioimmunoassay. Genomic DNA was extracted from white blood cells.

RESULTS

In the index case exons 2, 3 and 4 were normal, but nucleotides 144 (cytosine) and 145 (thymine) in exon 1 were substituted with a single base (adenine) which induced a frame shift in the reading frame, resulting in an early stop codon at codon 51. The patient and his daughters were confirmed as having this mutation using primer‐directed mutagenesis or allele‐specific amplification.

CONCLUSIONS

We have described a novel mutation in the TBG gene in a Japanese family. This results in a frame shift and premature stop codon, and was associated with undetectable serum TBG in the index case.
Glucoregulatory disorders in school refusal students
Authors: Iwatani Noritaka , Miike Teruhisa , Kai Yumiko , Kodama Mihoko , Mabe Hiroyo , Tomoda Akemi , Fukuda Keiko , Jyodoi Takako
Published: November 2003

OBJECTIVES

Our previous studies demonstrated autonomic nervous system disorders and cerebral blood hypoperfusion in school refusal students with underlying emotional distress due to fear or anxiety associated with school attendance. Because severe stress is known to affect glucoregulatory metabolism, this study used the oral glucose tolerance test (OGTT) to measure glucose metabolism in school refusal students.

DESIGN

A three‐hour OGTT was performed. In preparation for the test, students fasted overnight. After a fasting blood sample was drawn, students were given solutions containing a predetermined amount of glucose based on their body weight (1.75 g/kg to a maximum 75 g). After glucose ingestion, blood samples were drawn at 30, 60, 90, 120, 150, and 180 min to measure blood glucose (BG), immunoreactive insulin (IRI), pancreatic glucagon (IRG) and growth hormone (GH) levels. BG levels, IRI response, cumulative BG (ΣBG), cumulative IRI (ΣIRI), insulin/glucose ratio (ΔIRI/ΔBG), and insulinogenic index (ΣIRI/ΣBG) were then compared to previously reported normal control data. As an index of emotional difficulties, the self‐rating depressive scale (SDS) was carried out.

PATIENTS

Eighty‐one school refusal students (40 males and 41 females), 11–19 years of age (14.8 ± 2.1), were studied. Their school refusal periods ranged from one month to eight years. All students were within – 15 to + 20 %(‐0.04 ± 8.6) of ideal body weight.

MEASUREMENTS

BG levels were determined using a glucose oxidase reaction method. Serum hormones were measured by radioimmunoassay.

RESULTS

BG levels at all OGTT time intervals and ΣBG were significantly higher in school refusal students than the normal control data (ΣBG: 39.5 ± 4.4 vs 33.3 ± 3.4 mmol/l, P < 0.001). Although the insulin response was abnormally low relative to the prevailing hyperglycaemia (ΣIRI/ΣBG: subjects vs control = 232 ± 129 vs 375 ± 271, P < 0.01), normal beta cell secretory ability was speculated (ΣIRI: subjects vs controls = 2805 ± 1274 vs 2523 ± 1219 pmol/l). This suggests a relative suppression of insulin secretion. A paradoxical increase of GH was observed in 19 students after glucose ingestion.

CONCLUSIONS

Glucoregulatory disorders observed in school refusal students may be caused by emotional distress. Multiple factors including autonomic nervous system disorders, derangement of neuropeptides in the hypothalamus, and hormonal imbalances may also affect glucoregulatory metabolism, predisposing these students to hyperglycaemia. We speculate that the glucoregulatory system compensates for decreased blood flow to the brain by increasing blood glucose concentrations, thereby providing sufficient glucose as the primary energy source used during normal brain metabolism.
Postoperative tetany in patients with Graves' disease: a risk factor analysis
Authors: Yamashita Hiroyuki , Noguchi Shiro , Tahara Kazuki , Watanabe Shin , Uchino Shinya , Kawamoto Hitoshi , Toda Masakatsu , Murakami Nobuo
Published: November 2003

OBJECTIVE

There is little information regarding the clinical risk factors for postoperative tetany in patients with Graves' disease. We analysed the risk factors responsible for postoperative tetany by univariate and multivariate analysis in thyroidectomized patients with Graves' disease, and we discuss the mechanisms of hypocalcaemia and tetany after surgery.

PATIENTS

The subjects were 1742 consecutive patients with Graves' disease who underwent subtotal thyroidectomy between 1992 and 1994.

RESULTS

Univariate analysis of 15 possible risk factors demonstrated that 10 were significant: sex, required operation time, blood loss, preoperative serum calcium level, estimated weight of thyroid remnant, size of goitre, amount of excised thyroid tissue, serum alkaline phosphatase concentration, age at operation and TSH‐binding inhibitory immunoglobulin (TBII). In multivariate analysis in female patients, the risk factors were: preoperative lower serum calcium level, younger age, higher serum alkaline phosphatase concentration, larger size of goitre and higher value of TBII, in order of decreasing probability of significance.

CONCLUSION

These results, combined with previous observations in which a significant decline in serum parathyroid hormone level was found in patients with Graves' disease who suffered postoperative tetany, suggest that postoperative tetany may occur during the period of bone restoration due to antithyroid drug  therapy and be due to continuation of a calcium    flux into bone concomitant with transient hypoparathyroidism induced by surgery. Calcium supplements during the preoperative period and/or after surgery may be appropriate for patients who are anticipated to develop postoperative tetany based on these risk factors.
Evidence for a primary abnormality of thecal cell steroidogenesis in the polycystic ovary syndrome
Authors: Gilling‐Smith C. , Story H , Rogers V. , Franks S.
Published: November 2003

OBJECTIVE

Polycystic ovary syndrome (PCOS) is a common endocrinopathy of unknown aetiology. The aims of this study were to identify whether ovarian thecal cell steroidogenesis is abnormally regulated in PCOS by measuring steroid responses to a single dose of hCG before, and during, suppression of endogenous LH levels by a GnRH analogue (GnRHa).

DESIGN

Serum levels of LH, FSH, 17αhydroxyprogesterone (17OHP), androstenedione, testosterone and dehydroepiandrosterone sulphate were measured before, and 48 hours after, a single intramuscular injection of 10 000 IU hCG. The test was repeated 4 weeks after suppression of endogenous LH levels by GnRHa.

PATIENTS

The ovarian responses to hCG were compared in three groups of women. Eleven women had normal ovaries and regular cycles, eight had polycystic ovaries but no clinical features of the syndrome (PCO group) and eight had polycystic ovaries, anovulation and either severe hirsutism or alopecia (PCOS group).

RESULTS

Before GnRHa treatment, LH levels were significantly higher in the PCOS group but hCG stimulated a similar rise in 17OHP in all three groups. Following analogue, LH levels were suppressed in all three groups but the 17OHP responses to hCG were significantly higher in both the PCO and PCOS groups compared with normal controls.

CONCLUSIONS

These findings provide further evidence in favour of an intrinsic abnormality of thecal cell steroidogenesis in the polycystic ovary.
Increased thyrotrophin levels and loss of the nocturnal thyrotrophin surge in Sheehan's syndrome
Authors: Abucham Julio , Castro Vania , Maccagnan Paulo , Vieira Jose G. H.
Published: November 2003

OBJECTIVE

Since panhypopituitarism in patients with Sheehan's syndrome is due to massive pituitary necrosis with only minor hypothalamic involvement, we hypothesized that serum TSH levels would be low but its circadian rhythm preserved in these patients.

DESIGN AND PATIENTS

Basal and TRH‐stimulated mean afternoon (1500–1700 h) and nocturnal (0100–0300 h) TSH levels were determined in 10 patients with Sheehan's syndrome before and during T4/glucocorticoid replacement and in seven controls.

MEASUREMENTS

Serum concentrations of T3, T4, free T4 (fT4) and cortisol were measured by radioimmunoassay; TSH, GH, PRL and LH were determined by immunofluorimetric assay.

RESULTS

Afternoon TSH levels were markedly increased in Sheehan's syndrome patients compared with controls (3.3 ± 1.0 vs 0.5 ± 0.15 mU/l, respectively, P = 0.002). At night, TSH levels remained unchanged in Sheehan's syndrome patients (3.3 ± 1.1 mU/l) but rose significantly in controls (1.1 ± 0.34 mU/l, P = 0.016). The nocturnal TSH increment was significantly higher in controls than in patients (143 vs−4.9%, respectively, P = 0.0001). In eight patients with normal serum fT4 levels during treatment, basal TSH levels decreased to 0.16 ± 0.05 mU/l (P≤ 0.008), being barely detectable or undetectable in four patients. In the six patients with detectable TSH during treatment, nocturnal TSH increments were normal in four and blunted in two. There was a strong correlation between pre‐ and post‐treatment basal TSH (r = 0.82, P = 0.012) and between pre‐ and post‐treatment peak TSH after TRH (r = 0.91, P = 0.0017), but no significant correlation between TSH and thyroid hormone levels. The per cent ratio of peak TSH after TRH between treated patients and controls, an estimate of the relative size of the functional thyrotroph pool in Sheehan's syndrome patients, was 7%.

CONCLUSIONS

Loss of TSH rhythm in Sheehan's syndrome is usually secondary to hormonal deficiency and results from maximally increased secretory activity of a decreased pool of thyrotrophs. The paradox of increased TSH levels and decreased thyroid function in Sheehan's syndrome could result from decreased TSH bioactivity and/or from a critically reduced thyrotroph population that fails to sustain sufficient TSH secretion in the face of rising serum thyroid hormone levels.
Cabergoline treatment of acromegaly: a preliminary dose finding study
Authors: Jackson Stephen N. J. , Fowler Jane , Howlett Trevor A.
Published: November 2003

OBJECTIVES:

Studies of the dopamine agonist cabergoline in the treatment of hyperprolactinaemia have shown it to be a potent, long‐acting and well‐tolerated. The older dopamine agonist, bromocriptine, has traditionally had a place in the medical management of acromegaly, but poor patient tolerance of the high doses required, the need for multiple daily administration and incomplete biochemical responses have limited its role. We therefore sought to investigate the effect of cabergoline on growth hormone (GH) secretion in acromegaly and to define the most appropriate dose for suppression of GH

DESIGN AND MEASUREMENTS:

Patients with active acromegaly (defined as most recent random GH > 5mU/l) were identified from the departmental clinical information system. After informed consent was obtained, basal GH levels were estimated during a 5 point day curve at least 2 months after withdrawal of any existing medical therapy for acromegaly. The cabergoline dose was escalated on a monthly basis for 4 months with a repeat 5 point GH day curve at the highest dose, and 0900 and 0930 GH estimations at the intermediate dose increment stages. Serum IGF‐1 and prolactin were estimated on each occasion. Biochemical remission was defined as serum GH < 5mU/l.

PATIENTS:

Eleven acromegalics were investigated. Previous treatment included surgery (7), radiotherapy (5) and bromocriptine (5). Three patients had not received any previous treatment. All had random GH persistently > 5mU/l prior to the study.

RESULTS:

Ten patients completed the study. Of these, 7 showed a fall in the GH to ≤33% and IGF‐1 to ≤67% of the basal value but only 2 achieved biochemical remission. All subjects showed maximum GH response at a dose of 0.5 mg daily of cabergoline. Four patients were unable to tolerate the maximum dose of 1 mg daily (nausea in one and non‐specific symptoms in three). The patient excluded from the analysis discontinued cabergoline and underwent surgery after 1 month because of worsening visual field defects.

CONCLUSIONS:

Cabergoline may be a useful adjunct to the currently available treatment for acromegaly, but rarely achieves the goal of mean GH < 5mU/l. The maximum suppression of GH is achieved within the dose range 1 mg twice weekly to 0.5 mg daily.
Influence of residual C‐peptide secretion on nocturnal serum TSH peak in well‐controlled diabetic patients
Authors: Coiro V. , Volpi R. , Marchesi C. , Capretti L. , Speroni G. , Caffarri G. , Chiodera P.
Published: November 2003

OBJECTIVE

Several alterations in hypothalamo–pituitary–thyroid (HPT) function have been described in diabetes mellitus and have been attributed to metabolic decompensation. The present study was performed in order to establish whether residual endogenous insulin secretion in patients with insulin‐dependent diabetes mellitus (IDDM) may play a role in the control of HPT function.

DESIGN

The nocturnal (2230 h–0200 h) serum TSH surge, the TSH response to TRH (200 μg as an i.v. bolus) and serum free thyroid hormone levels were evaluated in C‐peptide positive (CpP) (subjects with residual detectable endogenous pancreatic beta‐cell activity) and C‐peptide negative (CpN) patients both before and after optimization of metabolic status by 3 days of treatment with continuous subcutaneous insulin infusion, and in normal controls. TSH response to TRH and serum free thyroid hormone levels were assessed in the morning.

SUBJECTS

Twenty male diabetic patients hospitalized to achieve a better control of hyperglycaemia were subdivided into 10 CpP (age: 33 ± 1.5 years (mean  ± SE); body mass index (BMI): 22.6 ± 0.3) and 10 CpN (age: 32 ± 1.7 years; BMI: 22.5 ± 0.4) patients. Nine normal men (age: 34.0 ± 1.2 years; BMI: 23.1 ± 0.4) served as controls.

MEASUREMENTS

The nocturnal serum TSH peak was measured by dividing the highest night‐time TSH value by the next morning TSH value and then multiplying by 100. Serum TSH levels were measured in samples taken just before (time 0) and 30 minutes after TRH administration. Serum free thyroid hormone levels were measured in samples taken at time 0 of the TRH test.

RESULTS

Before improvement of hyperglycaemia, CpP and CpN patients showed similar alterations in HPT function; i.e. serum free T3 levels and TSH responses to TRH were lower than normal; the nocturnal TSH surge was absent. Correction of hyperglycaemia normalized all examined HPT parameters in CpP diabetics, whereas normalization in serum free T3 levels and pituitary TSH responsiveness to TRH in CpN patients was not accompanied by restoration of the nocturnal TSH peak.

CONCLUSIONS

These data indicate that the absence of residual pancreatic beta‐cell function in patients with insulin‐dependent diabetes mellitus is associated with neuroendocrine dysfunction in the regulation of circadian TSH secretion, which is not reversible after restoration of good glycaemic control.
An analysis of testosterone implants for androgen replacement therapy
Authors: Handelsman David J. , Mackey Mary‐Anne , Howe Chris , Turner Leo , Conway Ann J.
Published: November 2003

OBJECTIVE

To review 13 years of experience using fused crystalline testosterone implants for androgen replacement therapy in order to identify pattern of usage (including continuation rates) and adverse events emerging during therapy and factors associated with adverse events including implant extrusions.

DESIGN

Retrospective review of prospectively collected data on characteristics of patients and implant procedures performed as well as adverse events reported during routine follow‐up.

PATIENTS

Over 13 years 973 implant procedures using fused crystalline testosterone implants were performed in 221 men.

MEASUREMENTS

Continuation rates and adverse events such as extrusions, bleeding, infection or others were recorded and analysed in relationship to characteristics of the patient and the implant procedure performed.

RESULTS

Overall rate of adverse events (108/973, 11.1%) was significantly related to increased numbers of implants (4.2 ± 0.1 vs 4.0 ± 0.03, P = 0.031) and higher levels of physical activity at work (P = 0.030). The most common adverse effect was extrusion (83/973, 8.5%) which was related to occupational classification (P = 0.033) and increasing work activity (P = 0.044) and occurred more frequently than by chance in multiple (16 vs 3.3 expected) rather than single (65 vs 76.1 expected) episodes. Bleeding (22/973, 2.3%) was significantly associated with an increased number of implants (4.5 ± 0.2 vs 4.0 ± 0.03, P = 0.020) but even in the worst cases (3/22) it was of minor clinical importance. Infection was rare (6/973, 0.6%) but occurred more among thinner men. The overall continuation rate was 92.7% increasing from 86% after the first implantation to >99% after the tenth implant.

CONCLUSIONS

This study demonstrates the very satisfactory clinical acceptability of testosterone pellet implants for androgen replacement therapy within a single unit with experienced operators. The only regular adverse effect is extrusion, which may be related to mechanical factors such as habitual work activity but also possibly procedural factors. Other adverse effects such as bleeding, infection and fibrosis were rare. An improved method of implant delivery would enhance this old but durable technology.