bluuebunny/crossref_metadata_2025 huggingface dataset:
MELAS syndrome associated with diabetes mellitus and hyperthyroidism: a case report from Taiwan
Authors: Yang Chwen‐Yi , Lam Hing‐Chung , Lee Hsin‐Chen , Wei Yau‐Huel , Lu Chlh‐Chen , Han Tlan‐Mu , Tsalt Jin‐Llan , Chuang Yen‐Hwang , Lee Jenn‐Kuen
Published: March 2008

MELAS syndrome Is a form of mitochondrial myopathy with manifestations of seizure, stroke‐like syndrome, lactic acidosis, ragged red muscle fibres and mitochondrial encephalopathy. The syndrome has been reported in association with a variety of endocrine and metabolic disorders Including diabetes mellitus (DM), hypothalamo‐pituitary hypofunction, hypothalamic growth hormone deficiency and delayed puberty. Mitochondrial DNA (mtDNA) point mutation may be the major pathological defect. However, association of MELAS syndrome with hyperthyroidism has not previously been reported. A case Is reported from Taiwan of a 32‐year‐old woman suffering from MELAS syndrome with associated DM and hyperthyroidism. When the latter was diagnosed In April 1988, the patient underwent subtotal thyroidectomy. There was no family history of thyroid disease. Because of repeated seizures, she had computed tomography (CT) and magnetic resonance Imaging (MRI) of the brain which showed focal, low‐density lesions over the cerebral hemispheres. Both serum and cerebral spinal fluid lactic acid levels were elevated. Mild elevations of serum T4 and T3 and a high titre of TSH receptor antibody were still present. Hyperglycaemla was noted during hospitalization and DM confirmed by oral glucose tolerance test. Muscle biopsy showed ragged red fibres. DNA analysis showed an A‐to‐G transition at the 3243rd nucleotide position of the tRNALeu(uur)gene of the mtDNA from the patient. Quantitative polymerase chain reaction (PCR) and restriction analysis revealed that about 60% of the blood mtDNA was of mutant type. The patient received antithyroid drugs for hyperthyroidism, diet control for DM and anti‐epileptic drugs for seizure.
Mineralocorticoid hypertension and congenital deficiency of 11β‐hydroxysteroid dehydrogenase in a family with the syndrome of‘apparent’mineralocorticoid excess
Authors: Mllford David V. , Shackleton Cedrlc H. L. , Stewart Paul M.
Published: March 2008

The so‐called syndrome of‘apparent mineralocorticoid excess’(AME) Is a rare cause of endocrine hypertension thought to result from a defect In the peripheral conversion of Cortisol to cortisone. Less than 30 cases have been described. From a consanguineous marriage we present a family comprising 2 and probably 3 affected cases of AME. The index case is a 4‐year‐old boy with mineralocorticoid hypertension, short stature, failure to thrive, hypokalemic nephropathy and osteopenia. The ratio of the urinary excretion of tetrahydrocortisone/tetrahydro‐cortisols was reduced at 0‐05 (reference range 1.77‐2.11), and the plasma half‐life of 3H‐11α‐cortisol elevated at 152 minutes (reference range 30‐50) indicative of severe 11β‐hydroxysterold dehydrogenase deficiency. Plasma Cortisol concentrations were normal and dally secretion rate reduced. Dexamethasone administration induced a natriuresis in keeping with the observation that Cortisol itself is the implicated mineralocorticoid. Treatment with amiloride lowered blood pressure, increased potassium levels, and resulted in an Increase In growth rate.

The boy's twin brother died at the age of 3‐5 years following a trivial diarrhoeal illness and was almost certainly affected. AME was also diagnosed in a younger brother (age 17 months), but both parents are normal.

Congenital deficiency of 11β‐hydroxysterold dehydrogenase should be considered in any child with mineralocorticoid hypertension and failure to thrive. As Cortisol is the‘offending’mineralocorticoid in this condition, the term‘apparent’mineralocorticoid excess Is perhaps obsolete. The cloning of renal isoforms of 11β‐HSD should facilitate the description of the molecular basis of this condition.
Menstrual disturbance and hypersecretion of progesterone in women with congenital adrenal hyperplasia due to 21‐hydroxylase deficiency
Authors: Hoimes‐Walker D. J. , Conway G. S. , Honour J. W. , Rumsby G. , Jacobs H. S.
Published: March 2008

OBJECTIVE While menstrual disturbance is often quoted as a feature of congenital adrenal hyperplasia (CAH), little is known about the mechanism of this symptom. We set out to determine the relationship between menstrual pattern and biochemical characteristics of women with CAH due to 21‐hydroxylase deficiency.

PATIENTS AND DESIGN All 21 female patients with classic CAH attending the adult endocrinology clinics at The Middlesex Hospital were reviewed. Their ages at menarche and menstrual pattern were recorded and blood samples were taken in the follicular phase of the menstrual cycle when on their usual maintenance therapy.

MEASUREMENTS Measurements Of serum LH, FSH, progesterone, 17α‐hydroxyprogesterone, testosterone, androstenedione and plasma renin activity were recorded. Urinary steroid profiles were obtained by gas chromatography and mass spectrometry. Molecular genetic analysis of the 21‐hydroxylase gene was performed on leucocyte DNA.

RESULTS In the 18 patients who had spontaneous menarche the degree of menstrual disturbance and progesterone excess was related to the effectiveness of adrenal suppressive therapy. Three out of 21 patients, however, failed to experience menarche on standard medical therapy. These patients with primary amenorrhoea were characterized by reduced endometrial thickening, by non‐suppressible serum progesterone concentrations despite suppression of 17α‐hydroxyprogesterone levels and by the presence of progesterone metabolites in urinary steroid profiles. Molecular genetic analysis did not differentiate between patients with raised progesterone concentrations and those without.

CONCLUSION A subgroup of women with congenital adrenal hyperplasia have the triad of non‐suppressible serum progesterone of adrenal origin, primary amenorrhoea and Infertility due to failure of endometrial thickening. The characteristic urinary steroid profile best distinguishes this subgroup of women from others with Congenital adrenal hyperplasia and menstrual disturbance due to inadequate adrenal suppression.
Prevalence of an immunological LH β‐subunit variant in a UK population of healthy women and women with polycystic ovary syndrome
Authors: Rajkhowa M. , Taibot J. A. , Jones P. W. , Pettersson K. , Haavisto A. M. , Huhtaniemi I. , Clayton R. N.
Published: March 2008

OBJECTIVE An Immunological LH β‐subunit variant has been described, which is undetectable using monoclonal antibodies directed to the intact LH molecule alone. Subjects have been found homozygous or heterozygous for nucleotide mutations within codons 8 and 15 in the LH β‐subunit gene. The prevalence of the variant LH β‐subunit has been estimated in a healthy UK population of women of reproductive age and in women with polycystic ovary syndrome (PCOS). The relationship of the variant molecule to the clinical and hormonal parameters of the subjects has been evaluated.

DESIGN The control and PCOS subjects were screened for the presence of the mutation by using a ratio of two immunofluorometric assays using monoclonal antibodies (Mab). One assay, not detecting the LH variant, uses a Mab directed to the intact LH molecule and a β‐specific Mab. The other assay, detecting both the variant and wildtype LH, uses two β‐subunit specific Mabs. The mutations in the LH β‐subunit gene were confirmed by restriction fragment length polymorphism. The relationship of the presence of the variant to the clinical and hormonal parameters was assessed by ANOVA.

PATIENTS Two hundred and twelve normal ovulatory women, of whom 86 (31%) were obese (body mass Index >25) and 146 (69%) non‐obese, and 153 women with PCOS, 115 (75%) obese and 38 (25%) non‐obese participated in the study.

RESULTS The variant LH was detected In 31 (15%) controls and 32 (21%) PCOS subjects (P=0.124) using specific Mab. Obese PCOS had a higher incidence of the heterozygous LH variant compared to obese controls (odds ratio 2.5, P=0.03), and compared to non‐obese PCOS (odds ratio 6.3, P= 0.01). The previously described two mutations in codon 8 and codon 15 were present in all subjects detected to be mutant hetero or homo‐zygous by RFLP. There was no relationship between the presence of the variant LH and the clinical and hormonal parameters In the PCOS subjects; however, in the controls the presence of the variant LH was associated with a higher serum total testosterone (P=0.046), oestradiol (P=0.03) and SHBG (P=0.002).

CONCLUSIONS The results of this study show that the variant LH β‐subunit is a common polymorphism occurring in 15% of a healthy UK population of women. The prevalence was not higher in women with PCOS, though it was over represented in obese women with PCOS. The presence of the variant did not alter the clinical or hormonal expression of the disorder in women with PCOS. Its presence in the controls was however associated with higher serum oestradiol and probably secondary elevation of SHBG and testosterone, suggesting that the variant form of LH may be associated with subtle changes in the function of the hypothalamic‐pituitary‐gonadal axis.
Nifedipine, but not verapamil, acutely elevates parathyroid hormone levels in premenopausal women
Authors: Wynne Alan O. , Romanskl Susan A. , Klee George G. , Ory Steven J. , O'Fallon William M. , Fitzpatrick Lorraine A.
Published: March 2008

BACKGROUND Calcium channel antagonist therapy in humans has been associated with changes In anterior pitultary, thyroid and adrenal hormone secretion. Human studies assessing effects of calcium channel antagonists on calclotropic hormones have been few and typically involved small numbers of subjects studied for short periods of time. Few of these previously published studies have included women. The endocrine effects of calcium channel antagonists in women have become increasingly important as more women are taking these agents for diseases such as hypertension, angina, Raynaud's phenomenon and migraine.

OBJECTIVE To assess both acute and chronic effects of calcium channel antagonists on calclotropic hormones in women.

DESIGN A four‐week prospective, randomized trial.

SUBJECTS Twenty‐nine premenopausal women, randomly assigned to receive either 240 mg of sustained release verapamil or 30 mg of sustained release nifedipine daily.

LABORATORY END‐POINTS Total and ionized serum calcium, phosphate, creatinine, parathyrold hormone (PTH), parathyroid hormone‐related protein (PTHrP) and calcitonin, measured at baseline, after 24 hours, and 28 days of treatment.

RESULTS Total and ionized calcium, phosphate, creatinine, PTHrP and calcitonin levels were not altered significantly after 24 hours or 28 days in any of the subjects, when compared to baseline. There were no significant differences in PTH levels after 24 hours or 28 days of verapamil treatment. There was a significant increase in serum PTH levels after 24 hours of nifedipine therapy; however, these differences were not evident after 28 days of therapy.

CONCLUSIONS The short‐term administration of nifedipine results in increased release of parathyroid hormone; however, long‐term administration has no significant effect on the concentrations of calclotropic hormones.
Absence of mutations in the MEN2A region of the ret proto‐oncogene in non‐MEN 2A phaeochromocytomas
Authors: Chew S. L. , Lavender P. , Jain A. , Weber A. , Ross R. J. M. , Wass J. A. H. , Besser O. M. , Clark A. J. L.
Published: March 2008

OBJECTIVE To determine the presence of abnormalities of the MENZA region of the ret proto‐oncogene in phaeochromocytomas/paragangllomas (PHAEO) of different aetiologies.

DESIGN Total RNA was extracted from tumours and used as templates for reverse transcriptase polymerase chain reactions. A ret primer pair, which encompasses the region which is mutated in the germ‐line of patients with MEN 2A, was used. The resulting 262‐bp product was sequenced.

PATIENTS Ten PHAEOs were examined. Four tumours were from von Hippel‐Lindau disease patients; five were sporadic, Isolated tumours; one from a patient with multiple endocrine neoplasia type 2A (MEN 2A). The medullary thyroid cancer from the single MEN 2A patient was also examined.

RESULTS A heterozygous TGC to CGC mutation of codon 634 (cysteine to arginine) was found In the PHAEO and medullary thyroid cancer from the MEN 2A patient. The 262‐bp ret fragment was not found in two tumours (one malignant PHAEO and one secretory paraganglloma), although the Intra‐cellular ret tyrosine kinaw domain was detected in these tumours. The cysteine codons were normal in all other non‐MEN 2A PHAEOs.

CONCLUSION Mutations of key cysteine codons of the ret proto‐oncogene may be specific to MEN 2A.
Natural history of thyroid associated ophthalmopathy
Authors: Perros Petros , Cromble Alex L. , Kendall‐Taylor Pat
Published: March 2008

BACKGROUND The natural history of thyroid associated ophthalmopathy is poorly documented, although It is widely thought that many cases Improve spontaneously with time. This has Important Implications in the management of patients and is also a critical factor when assessing the effects of different treatments.

OBJECTIVE To document the natural history of thyroid associated ophthalmopathy, 59 patients were studied longitudinally and the severity of eye disease documented at regular Intervals.

METHODS Fifty‐nine patients with thyroid associated ophthalmopathy who had not received Immunosuppressive or surgical treatment for their eye disease, were recruited from a combined thyroid‐eye clinic. They were assessed at presentation and at 3–6‐monthly Intervals for a median of 12 months. The eyes were assessed by separate and objective measurements relating to the status of the eyelids, cornea, extraocular muscles, proptosis and optic nerve function. In addition, a scoring system based on the above measurements was used to grade the overall severity of eye disease.

RESULTS Thirteen patients (22%) Improved substantially, 25 patients (42·4%) showed minor Improvement, 13 patients (22%) did not change, and 8 patients (13·5%) deteriorated progressively, to the extent that Immunosuppressive treatment was considered to be necessary.

CONCLUSIONS A significant proportion of patients with thyroid associated ophthalmopathy (64·4% in the present series) Improve spontaneously so serial assessment plays an Important part in deciding which patients require Immunosuppressive treatment. These findings also support the view that clinical trials designed to test the efficacy of new treatments in thyroid associated ophthalmopathy should be scrupulously controlled to allow for the natural tendency towards remission.
Psychopathology in patients with endogenous Cushing's syndrome: ‘atypical’ or melancholic features
Authors: Dorn Lorah D. , Burgess Ellen S. , Dubbert Billinda , Simpson Serge‐Emll , Friedman Theodore , Kllng Mitchell , Gold Philip W. , Chrousos George P.
Published: March 2008

OBJECTIVEProlonged elevations of glucocorticoids have been linked to the affective disturbances experienced by patients with Cushing's syndrome. Major depression has been most commonly reported In patients with endogenous Cushing's syndrome. The purpose of this study was to determine whether these patients experience melancholic or ‘atypical’ subtype depression and to determine relations between current psychological functioning and factors such as duration and severity of Cushing's syndrome.

DESIGN AND PATIENTSWe examined 33 adult patients with documented Cushing's syndrome and 17 hospitalized, matched controls, using standardized structured interviews and tests.

RESULTSDuring the active phase of Cushing's syndrome (prior to and/or on admission), 66.7% of all patients reported histories meeting criteria for a psychiatric diagnosis. Of those with a diagnosis during Cushing's syndrome, 50% reported major depression. Upon presentation to this institution, atypical depression was the most common diagnosis involving 51.5% (n= 17) of ail enrolled patients. Of the 17 with atypical depression, 8 reported a co‐morbid psychiatric disorder. The duration of Cushing's syndrome was an Important factor in predicting whether patients sought psychological Intervention or met criteria for psychiatric diagnosis.

CONCLUSIONPatients with active endogenous Cushing's syndrome exhibit significant psychopathology expressed primarily by atypical depression. Longer duration of Cushing's syndrome may place them at increased risk of such psychopathology.
Elevated serum lipoprotein(a) in subclinical hypothyroidism
Authors: Kung A. W. C. , Pang R. W. C. , Janus E. D.
Published: March 2008

OBJECTIVES Asymptomatic lymphocytic thyroiditis and subclinical hypothyroidism are associated with increased risk for coronary artery disease. The present study aimed at evaluating serum lipoprotein(a)(Lp(a), measured as apo(a), and other lipid parameters In 32 subjects with asymptomatic subclinical hypothyroidism.

SUBJECTS Thirty‐two Chinese subjects with asymptomatic subclinical hypothyroidism were compared to 96 age and sex‐matched healthy controls.

RESULTS Subclinical hypothyroid patients had higher (P < 0.005) apo(a), total triglyceride (TG), total cholesterol (TC) and low density lipoprotein cholesterol (LDL‐C) but lower (P < 0.05) high density lipoprotein cholesterol (HDL‐C) levels compared with sex and age‐matched controls (apo(a) 296 (48–1650) vs 182 (19–1952 U/I), geometric mean (range); TG 1.86 ± 0.94 vs 1.33±0.74mmol/l (mean ± SD); TC 6.10 ±1.17 vs 5.42 ±1.13 mmol/l; LDL‐C 410 ± 1.00 vs 3.49 ± 0.96 mmol/l; HDL‐C 1.15 ± 0.40 vs 1.34 ± 0.40 mmol/l, respectlvely). Apo A‐I and apo B were also higher than controls (1.96 ± 048 vs 1.48 ± 029 g/l and 1.44 ± 042 vs 1.05±029 g/l, respectively). Total cholesterol/HDL ratio and LDL/HDL ratio were also elevated in these subjects (577 ± 1.96 vs 428 ±1.19 and 389 ± 1.41 vs 2.79 ± 0.97, respectively, both P < 0.0005). Individual analysis revealed that 16 (50%) subjects had hyperlipoprotelnaemia (TC > 5.2 mmol/l in 10;TC > 52 mmol/l and TG > 2.3mmol in six) as compared to 21(208%) in the control group (P < 0.005). Subjects with TSH ± 11.0mlU/l had significantly higher TC/HDL and LDL/HDL ratios. A significant correlation was observed between TSH levels and TC/HDL ratios (r = 0.455, P < 001).

CONCLUSIONS Subclinical hypothyroidism Is associated not only with elevated LDL‐cholesterol levels and low HDL‐cholesterol levels but also with elevated lipoprotein (a). This may further Increase the risk development of atheroscierosis.
Childhood IQ measurements in infants with transient congenital hypothyroidism*
Authors: Calaciura Francesca , Mendorla Gluseppina , Distefano Marco , Castorina Salvatore , Fario Teresa , Motta Rosa Maria , Sava Lidia , Delange François , Vigneri Riccardo
Published: March 2008

OBJECTIVE In view of the fact that, during the first period of life, thyroid hormones are critical for brain development, we investigated whether even transient congenital hypothyroidism could affect the long‐term intellectual development of affected infants.

DESIGN A case‐control study of intellectual development, auxometric parameters and thyroid function performed in late infancy in children with documented transient congenital hypothyroidism or hyperthyrotrophinaemia at birth.

PATIENTS Nine children born in an endemic goitre area who had short‐term transient congenital hypothyroidism or hyperthyrotrophinaemia after birth (TCH) were studied and compared to nine matched children born in the same area at the same time but having normal thyroid function at birth (N).

MEASUREMENTS Global, verbal and performance IQs were evaluated on the Wechsler scale. Height, bone age, total and free thyroid hormones, thyroid volume, thyroglobulin, basal and TRH stimulated TSH were also measured.

RESULTS Height and bone age were similar in the two groups. Thyroid function tests were also similar in the two groups except for basal and TRH stimulated serum TSH and serum Tg which were higher in the TCH than in the control group. Global, verbal and performance IQs were systematically lower in the TCH than in the N group. (78.3 ± 11.1 vs 90.9 ± 14.2, P < 0.05; 84.4 ± 15.4 vs 96.2 ± 14.8, P NS; 75.0 ± 8.5 vs 89.2 ± 12.5, P < 0.01 respectively).

CONCLUSION Infants born and living in an endemic goitre area, who had biochemical signs of thyroid hypofunction at birth, had a lower intelligence quotient at the age of 7–8 years than matched controls living in the same environmental conditions but with normal thyroid function at birth. The present findings strongly suggest that abnormalities in thyroid function at birth, even when transient, can adversely affect long‐term intellectual development.
Phasic serum lipid excursions occur during cyclical oral conjugated oestrogens but not during transdermal oestradiol sequentially combined with oral medroxyprogesterone acetate
Authors: Lemay André , Oodin Sylvie , Cédrin Isabella , T‐Lemay Luclle
Published: March 2008

BACKGROUND AND OBJECTIVE Recent data Indicate that oral medroxyprogesterone acetate (MPA) has limited unfavourable, neutral or even favourable effects on serum lipid fractions when added to oestrogen replacement therapy. The purpose of this study was to evaluate the serum lipid fractions at the beginning and at the end of each phase of a sequentially combined resplacement cycle comparing the oral and the transdermal routes of oestrogen administration.

DESIGN Randomized study with a matched control group. Oral con|ugated oestrogens (OCE, 0‐625 mg) or transdermal oestradiol (TE 50 μg) was taken from day 1 to day 25 and MPA (5mg) added on days 14 to 25. Serum lipids were evaluated on days 1, 14 and 25 of monthly replacement cycles.

PATIENTS The early post‐menopausal women In the control group (n = 11) and in the treatment groups (OCE/MPA, n= 15; TE/MPA, n= 17) were evaluated every 3 months for 12 months and every 6 months for another 12 months.

MEASUREMENTS Serum levels of triglycerides (TG), cholesterol (C) fractions and apollpoprotelns (Apo) and their respective ratios were measured at months 1,3,6,9, 12,18,24. Menopausal symptoms and uterine bleedings were evaluated in parallel and an endometrial biopsy was performed at the end of the 12th and 24th months of treatment. RESULTS After 14 days of OCE, C, LDL‐C, and Apo B were decreased and TG, HDL‐C and Apo A1 were Increased. The sequential addition of MPA accentuated the reduction of LDL‐C and Apo B but attenuated the elevation of TG, HDL‐C and Apo A1. These changes tended to revert toward baseline during the period free of medication. By contrast, at the end of 14 days of TE there was a non‐significant reduction in TG and LDL components and a limited increase in HDL‐C and Apo A1. During the subsequent addition of MPA there was no significant decrease in TG, LDL‐C or Apo B but an elimination of the increase In HDL components. These combined changes resulted in a significant reduction in the LDL‐C/HDL‐C ratio and a significant elevation in the Apo A1/Apo B ratio only In the OCE/MPA group.

CONCLUSION Overall, oral conjugated oestrogens Induced favourable intragroup changes in cholesterol fractions whereas transdermal oestradiol maintained serum lipids at levels not different from baseline. The sequential addition of oral medroxyprogesterone acetate attenuated the beneficial elevation of HDL, did not affect the beneficial effect of oestrogens on ratios of cholesterol fractions and attenuated the unfavourable effect of oral conjugated oestrogens on triglycerides. The partial loss of beneficial effects on lipoproteins during cyclical interruption of hormone therapy would be an argument in favour of the evaluation of continuous regimens of oes‐trogen/progestagen replacement.
Growth hormone treatment of short Chinese children with β‐thalassaemia major without GH deficiency
Authors: Low L. C. K. , Kwan E. Y. W. , Lim Y. J. , Lee A. C. W. , Tarn C. F. , Lamf K. S. L.
Published: March 2008

OBJECTIVE Despite regular transfusion and desferoxamine treatment, growth failure Is commonly seen In adolescent children with β‐thalassaemla major. The growth failure has been thought to be due to GH resistance rather than GH deficiency. We Investigated the effect of GH on short non‐GH deficient children with β‐thalassaemia.

DESIGN Recombinant human GH was given In a dose of 0‐14IU/kg/day subcutaneously in an open study.

PATIENTS Fifteen prepubertal Chinese children with β‐thalassaemia major (ranging from 7.16 to 14.7 years In age) with height −1.5 SD or more below the population mean for age and a growth velocity of less than 5 cm/year were treated with growth hormone for one year. All children had peak GH response >15mlU/l to insulin Induced hypoglycaemia and normal thyroid function and adrenal reserve.

MEASUREMENTS Anthropometric measurements were performed every 3 months. Morning urine was tested twice weekly for glycosuria. Blood count, renal and liver function tests, fasting blood glucose, IGF‐I and fructosa‐mine levels were assessed at entry and every 3 months during treatment. Fasting Insulin was measured before and after 3 and 12 months of GH treatment. Skeletal maturity was assessed before and after one year of treatment.

RESULTS Treatment was stopped in two children after 6 months because of poor growth response and noncompliance with treatment and In one child at 9 months because of bone marrow transplantation. In the 13 children, the growth velocity increased from 3.6±0.7 cm/year to 8±1.2 cm/year after one year of GH treatment (P<0.001). IGF‐I was low before treatment (10.1±2.7nmol/l), rising significantly to 15.8±4.8, 18.4±4.6, 19.3±6.4 and 21.9±7.5nmol/l at 3, 6, 9 and 12 months of treatment (P<0.005). The mean pretreatment bone age in the 13 children was 9.58±1.41 years and increased to 10.53±1.43 years after one year of treatment (ΔBA/CA 0.95±0.3 years). None of the patients developed glycosuria or hypertension. There was no significant change in blood count, renal and liver function, thyroid function, fasting blood glucose or insulin concentrations during treatment.

CONCLUSION Growth failure In these children with normal GH reserve and low serum IGF‐I concentrations would suggest GH insensltlvity. Supraphyslologlcal doses of exogenous GH can cause a significant increase In serum IGF‐I levels and a significant Improvement in short‐term growth of short children with β‐thalassaemia major.
Long‐term results of growth hormone therapy in children with short stature, subnormal growth rate and normal growth hormone response to secretagogues
Authors: Wit Jan‐Maarten , Boersma Bart , de Muinck Keizer‐Schrama Sabine M. P. F. , Nienhuls Henrlët E. , Oostdijk Wilma , Otten Barto J. , Delemarre‐Van de Waal Henriëtte A. , Reeser Maarten , Waelkens Johan J. J. , Rikken Berthon , Massa Guy G. ,   Dutch Growth Hormone Working Group
Published: March 2008

BACKGROUND AND OBJECTIVE Growth hormone treatment In children with Idiopathic short stature (ISS) leads to growth acceleration in the first years, but the effect on final height is still poorly documented. We therefore studied the long‐term effect of GH therapy in children with Idiopathic short stature.

DESIGN We have treated 27 prepubertal children with ISS with recombinant human GH (rhGH) in an initial dosage of 2 IU/m2 body surface/day subcutaneously, which was doubled either after the first year if the height velocity increment was less than 2 cm/year, or thereafter if height velocity fell below the P50 for bone age. Growth and bone maturation of the treatment group (ISS group, n= 21) were compared to those of an untreated control group with ISS (ISS controls, n= 27) and of a group of rhGH treated children with isolated GH deficiency (GHD group, n= 7).

RESULTS In 9 patients of the ISS group still on treatment, height standard deviation score (HSDS) for chronological age increased from −3.8±0.7 to −2.3±0.9 (mean±standard deviation) over 6 years, while in matched ISS controls HSDS for age did not change. HSDS for age in the GHD group increased from −3.9±0.6 to −1.8±0.7 after 4 years, significantly more than the ISS group. Bone maturation was accelerated In the ISS and GHD groups. HSDS for bone age and predicted adult height did not change in either group. Final height in 12 children of the ISS group was −2.6±1.0 SDS. In the untreated controls final height was similar. A low integrated GH concentration over 24 hours, a low GH peak to provocative stimuli, and minimal initial BA delay predicted a favourable outcome.

CONCLUSION rhGH treatment In this group of children with Idiopathic short stature did not increase average final height. Part of the heterogeneity of the response can be attributed to the variation in endogenous GH secretion and initial bone age delay.
Thyroid cell survival in coculture with autologous peripheral or intrathyroidal lymphocytes
Authors: Massart C. , Glbassler J. , Le Gall F. , Raoul M. L. , Beurtin F. , Genetet N. , Genetet B. , Lucas C.
Published: March 2008

OBJECTIVE We have studied lymphocyte Induced cytotoxicity and the production of interferon gamma (IFN‐α) and tumour necrosis factor alpha (TNF‐α) during coculture of thyrocytes and autologous lymphocytes from patients with Graves' disease and from normal subjects.

PATIENTS Thyroid tissues and lymphocytes were obtained from 28 patients with Graves' disease and from 9 control subjects.

MEASUREMENTS Lymphocyte induced cytotoxicity was evaluated on autologous thyrocytes using 5 metabolic tests: the MTT assay, the neutral red uptake, lactate dehydrogenase measurement and glutathione assay. IFN‐γ and TNF‐α measurements were performed after 1, 5 or 7 days' coculture.

RESULTS The lymphocytes Isolated from peripheral blood (PB lymphocytes) altered the morphology and the metabolism of autologous thyrocytes. The Intrathyroidal lymphocytes Isolated after Dispase digestion were not toxic whereas mechanically Isolated lymphocytes exerted a little toxicity. No difference was seen between Graves' disease and normal cells.The supernatants from cocultures had higher IFN‐γ levels than those from lymphocyte cultures, in coculture, PB lymphocytes secreted more IFN‐γ and TNF‐α than Intrathyroidal lymphocytes. The PB lymphocyte Induced cytotoxicity was not due to IFN‐γ and TNF‐α alone.

CONCLUSION Peripheral blood lymphocytes are cytotoxic in vitro to autologous thyrocytes whereas Intrathyroidal lymphocytes exert little or no cytotoxicity according to their isolation method. The mechanisms of lymphocyte Induced toxicity remain to be explained.
Measurement of serum concentrations of inhibin‐A (α‐βA dimer) during human pregnancy
Authors: Muttukrlshna S. , George L. , Fowler P. A. , Groome N. P. , Knight P. G.
Published: March 2008

OBJECTIVE The alms were to measure concentrations of Inhibin‐A (α‐βA dimer) in peripheral serum during normal human pregnancy, to establish which molecular weight form(s) are present In pregnancy serum and to relate the concentrations of inhlbin‐A to those of oestradlol and progesterone.

DESIGN In a retrospective cross‐sectional study 211 serum samples collected at 2‐week Intervals from week 8 to 38 of gestation were analysed for inhlbln‐A by enzyme immunoassay and oestradlol and progesterone by radioimmunoassay. Pooled samples corresponding to first, second and third trimester were subsequently used for fast protein liquid chromatography chromatographic analysis of Inhibln forms present.

PATIENTS Blood samples were obtained from normal pregnant women attending the antenatal clinic.

RESULTS Concentrations of Inhibin‐A in peripheral serum gradually decreased from 1.76±0.15/μg/l in week 8 of gestation to 0.86±0.12μg/l in week 16 (P<0.01). Concentrations remained low during the second trimester but Increased markedly (P<0.01) during the third trimester reaching a maximal value of 5.68±0.89 μg/l In week 36. Chromatographic analysis of pooled serum samples from the first, second and third trimester showed that the fully processed 31‐kDa molecule is the predominant circulating form of inhlbln‐A throughout human gestation. Likewise, only the 31‐kDa form was Identified in extracts of term placenta which contained ∼20 μg inhibin‐A/kg tissue.

CONCLUSION Inhlbin‐A, principally the 31‐kDa form, is present in peripheral blood throughout human gestation at concentrations up to 50 times greater than maximum values found during the spontaneous menstrual cycle (∼100ng/l). The finding of highest serum values during the third trimester and of significant concentrations In term placenta firmly support a placental rather than luteal origin for this material.
Non‐islet cell tumour induced hypoglycaemia with acromegaloid facial and aral swelling
Authors: Trivedi Nltin , Mithal Abrlsh , Sharma Ajay K. , Mishra Saro Kant , Pandey Rakesh , Trivedi Bakula , Daughaday William H.
Published: March 2008

The syndrome of non‐islet cell tumour hypoglycaemia (NICTH) has been linked with the synthesis and secretion of ‘big’ IGF‐II. We report a patient with a large pelvic clear cell sarcoma who developed recurrent severe hypoglycaemia and In addition presented with severe soft tissue facial swelling, skin tags and nuchal hyperpigmentation. After resection of the tumour serum ‘big’ IGF‐II returned to normal and the acromegaloid skin changes remitted.
Prolactin receptors in human pituitary adenomas
Authors: Ciccarelli E. , Faccani G. , Longo A. , Ore G. Dalle , Papotti M. , Grottoll S. , Razzore P. , Ghè C. , Muccioli G.
Published: March 2008

OBJECTIVE In the rat, prolactin receptors (PRL‐R) have been identified In normal pituitary cells and In anterior pituitary tumours induced by oestradiol. No published data are available concerning PRL‐R in the human pituitary. The aim of our study was therefore to detect the presence of PRL‐R in the normal human pituitary gland and human pituitary adenomas.

DESIGN Evaluation of free and total PRL‐R In the normal pituitary gland and different pituitary tumours characterized by Immunocytochemical analysis.

PATIENTS Twenty‐six unselected patients (14 M, 12 F) who underwent surgery for pituitary adenoma (3 prolactinomas, 4 GH‐PRL adenomas, 5 GH adenomas, 1 ACTH adenoma, 9 glycoprotein and/or α‐subunlt adenomas, 4 null ceils adenomas) were studied. Nine pltultaries from subjects whose death was unrelated to brain and endocrine diseases, were also studied as a control group in the PRL binding studies.

MEASUREMENTS Free PRL‐R in microsomal membranes were determined by in‐vitro radioreceptor assay using 125l‐labelled human PRL as llgand. Total PRL‐R were also measured In the same membrane fractions by removing endogenous PRL bound to its receptors using 4 m MgCl2.

Serum PRL levels were also evaluated in all patients before surgery using an IRMA method.

RESULTS Specific binding values for PRL (free PRL‐R) were 0.39±0.03% (range 0–1.96%) In the pituitary adenomas. These binding values were Identical to those observed in normal pltultaries (0.38±0.07%, range 0.1–0.78%). Elevated PRL binding (1.25% and 1.96%) was found in two patients with PRL secreting adenomas and very high serum PRL levels (5768 and 11240 mU/l. No PRL binding was shown In 4 patients. Treatment of membranes with 4 M MgCl2 increased the specific binding (total PRL‐R) In both pituitary tumours (0.5±0.11%; P<0.001) and normal pituHarles (0.47±0.07%; P<0.02).

CONCLUSIONS Our data have demonstrated the presence of prolactin receptors in normal cadaveric pituitary and in most pituitary adenomas, Irrespective of histological classification. In particular, elevated prolactin receptor levels were shown In PRL‐secreting tumours from patients with markedly increased serum PRL levels. Our study may support several lines of experimental evidence for a specific functional role for PRL in the growth of some pituitary adenomas.
Age related changes in the pituitary‐testicular axis in normal men; lower serum testosterone results from decreased bioactive LH drive
Authors: Mitchell Robert , Hollls Sally , Rothwell Claire , Robertson William R.
Published: March 2008

OBJECTIVE The mechanism underlying the slight hypoandrogenism associated with normal ageing remains unclear. We have therefore examined age related changes in the activity of the pituitary‐testicular axis In healthy normal males.

DESIGN Random blood samples were obtained from 219 normal men whose ages ranged from 20 to 79 years. At the time of the study, none of the men had received treatment or had ever had any endocrine dysfunction diagnosed.

MEASUREMENTS Luteinizing hormone was measured In the subjects' plasma using a commercially available immunoradiometric assay (IRMA, Serono Malaclone) and a fully validated In‐vitro bioassay. Testosterone and FSH were measured using standard radioimmunoassays (RIA) whilst sex hormone binding globulin was assayed by an IRMA.

RESULTS Levels of total testosterone (total‐T) and bioactive LH fell with age (r=−0.231 and −0.189 respectively) by 5.9nmol/l and 2.3IU/I respectively between grouped patients aged 20‐39 years (Group A) and 60–79 years (Group C). In contrast, immunoreactlve LH remained unchanged. The LH B:I ratio also fell with age (P<0.0001) being 5.0±0.3 (group A) and 3.3±0.2 (group C), representing a fall of 33%. Since Immunoreactivlty remained constant, this fall primarily represented the decline in LH bioactivity. Bioactive, but not immunoreactlve LH correlated to total‐T (P=0.009, n=209) and the total‐T:LH ratios fell by over 30% between groups A and C using the IRMA, but remained unchanged by bioassay.

CONCLUSIONS There Is an underlying decline In both total‐testosterone and free‐testosterone index, and bioactive LH levels with advancing age, suggestive of a hypothalamo‐pituitary defect which leads to lower bioactive LH levels which in turn are responsible for the diminished gonadal steroidogenesis. Elucidation of the mechanism underlying this slight decline in hypothalamo‐pituitary testicular activity Is complicated by differences between the data obtained by immunoassay or bioassay.
The effect of a continuous infusion of a somatostatin analogue (octreotide) for two years on growth hormone secretion and height prediction in tall children
Authors: Hindmarsh P. C. , Pringle P. J. , Stanhope R. , Brook C. G. D.
Published: March 2008

OBJECTIVE Strategies to limit the final height of tall children have centred on the use of high doses of sex steroids to advance skeletal maturation. This limits therapy to the peripubertal years whereas the greatest gain In height is in the prepubertal years. Prepubertal growth Is largely GH dependent and previous work has documented modulation of GH secretion by once or twice daily subcutaneous Injection of the somatostatin analogue octreotide. In this study we have determined the effects of a nocturnal infusion of octreotide on height prediction, GH and TSH secretion in tall children.

DESIGN A patient controlled study in which height prediction and 24‐hour GH and TSH secretion were compared prior to and during the course of a 2‐year treatment programme with a nocturnal infusion of octreotide in a dose of 1–1.5 μg/kg body weight given subcutaneously.

PATIENTS Nine tall children (4M; 5F) aged 7–14 years with final height predictions of 179 cm or greater in the girls and between 183 and 202 cm in the boys were studied.

MEASUREMENTS Height prediction using the Tanner‐Whltehouse system prior to and at the end of 2 years of treatment. Twenty‐four‐hour serum GH and TSH concentration profiles, thyroxine, IGF‐I and GH responses to GHRH(1–29)NH2 were studied prior to and at the end of the first year of therapy.

RESULTS Treatment with octreotide led to a significant reduction in height prediction In 7 of the 8 children who completed treatment (median reduction 3.5 cm, range +2.8 to −11.5; Wilcoxon, P=0.05). Twenty‐four‐hour mean serum GH concentration decreased by 50% (MANOVA, P=0.03) during therapy and this was accompanied by an increase In the percentage of samples giving values less than 0.5mU/1 (MANOVA, P=0.02). There was no overall change in the serum GH response to GHRH(1‐29)NH2 or serum IGF‐I concentrations. Nocturnal serum TSH concentrations were reduced to levels observed during the daytime but these changes had no effect on serum thyroxine values. One patient developed gallstones during the course of therapy.

CONCLUSIONS A nocturnal infusion of octreotide reduces GH secretion and height prediction in tall children. Therapy with somatostatin analogues allows a reduction In growth rate to be Instigated in the prepubertal years reducing the actual height from which will commence the pubertal growth spurt.
Lymphocytic hypophysitis: unusual features of a rare disorder
Authors: Jenkins P. J. , Chew S. L. , Lowe D. G. , Afshar F. , Charlesworth M. , Besser G. M. , Wass J. A. H.
Published: March 2008

OBJECTIVE Lymphocytic hypophysitis is a rare disorder which usually affects women and Is often associated with pregnancy. We reviewed our experience of this disorder In order to see whether these features were universal amongst our patients.

DESIGN A retrospective review of case notes.

PATIENTS Four patients with histologically proven lymphocytic hypophysitis.

MEASUREMENTS Each patient had undergone full radiological and biochemical assessment of anterior and posterior pituitary function.

RESULTS Only one woman presented during pregnancy, one patient was a man with coexistent active acromegaly, and one progressed over 5 years to panhypopituitarism. In one further patient, histological analysis revealed normal anterior pituitary tissue adjacent to lymphocytic follicles.

CONCLUSIONS Lymphocytic hypophysitis should be considered in the differential diagnosis of any patient with a pituitary mass. We suggest that the entire removal of such a mass is warranted both for accurate diagnosis and definitive treatment.
Multicentre study on prevalence of endocrine complications in thalassaemia major
Authors:   Italian Working Group on Endocrine Complications In Non‐endocrine Diseases
Published: March 2008

OBJECTIVE Thalassaemia major Is a common and serious medical problem, worldwide. However, there are few data concerning the various endocrine disorders which occur in this condition. We have surveyed 25 Italian centres in order to establish the prevalences and times of onset of endocrine disorders In patients with β‐thalassaemia major.

PROJECT AND PATIENTS A questionnaire specifically designed to investigate the prevalences of endocrinopathles was sent to 25 paediatric and haematology departments. The following data were recorded in the questionnaire: sex, age, height and weight, pubertal status according to Tanner's classification, history of secondary amenorrhoea, type of endocrinopathy and hormone levels at diagnosis, associated complications, serum ferritin level, liver enzymes (ALT) and compliance with treatment.

RESULTS An analysis of data from 1861 patients showed that failure of puberty was the major clinical endocrine problem and was present in 51 % of boys and 47% of girls, all over the age of 15 years. Secondary amenorrhoea was recorded in 23% of patients (mean age 18.3 years), primary hypothyroidism in 6.2% (mean age 15.8 years), insulin dependent diabetes mellitus in 4.9% (mean age 18.1 years) and hypoparathyroidism In 3.6% of the patients (mean age 18.7 years). At present, the ma|orlty are in the second or third decades of life. The prevalences of hypothyroidism, insulin dependent diabetes mellitus and hypoparathyroidism differed in the various centres, whereas the frequency of pubertal disorders was very similar.

CONCLUSIONS Our study has demonstrated several points. Endocrine evaluation in thalassaemic patients must be carried out regularly, especially in those patients over the age of 10 years with Iron overload and poor compliance with chelation therapy.

The prevalences of some complications, such as insulin dependent diabetes and hypothyroidism, were lower than previously recorded. Hence, It is to be hoped endocrine complications will be less common In the future, for patients who have started chelation therapy during the first years of life.

Because of the improved survival of thalassaemic patients with insulin dependent diabetes, and the high Incidence of multiple endocrine complications, ft is important to carry out careful follow‐up studies for the early detection of any other associated complications to facilitate correct treatment.
Short stature in homozygous β‐thalassaemia is due to disproportionate truncal shortening
Authors: Rodda C. P. , Reld E. D. , Johnson S. , Doery J. , Matthews R. , Bowden D. K.
Published: March 2008

BACKGROUND and objective Growth failure In homozygous β‐thalassaemia has been recognized for many years, and has persisted despite major treatment advances. In this cross‐sectional study, sitting and standing height were measured to determine whether growth failure was disproportionate.

DESIGN Patient data were analysed In three age groups, 2‐10 years, 11‐18 years and 19 and over. Sitting height and sublschlal leg length were also determined In a cohort of parents (n= 19) and normal Greek adolescents (n= 32).

PATIENTS AND MEASUREMENTS Of the known 156 patients with homozygous β‐thalassaemla In the State of Victoria, 154 (98.7%) attend our Institution. Sitting and standing heights were measured, using Harpenden stadlometers, In 57 of 60 (95%) patients aged 2‐18 years and in a random selection of 51 of 89 patients aged 19 and over (57%). Measurements are expressed as mean ± SDS. Other data analysed Included serum concentrations of ferritin, zinc, copper, FSH, LH, oestradlol and testosterone, according to standard laboratory assays, together with pubertal status and bone age in patients aged less than 19 years.

RESULTS Standing height standard deviation scores in the 2–10 age group were −0.687 ± 0.861 (n= 9), in the 11–18 age group were −1.838 ± 1.413 (n= 48) and In the age group 19 and over were −1.175 ± 1.126. In Individuals aged 2–10 years, sitting height standard deviation scores (SDS) were −1.56 ± 1.02, In Individuals 11–18 years were −3.76 ± 1.51 (n= 48), and In individuals 19 years and over were −2.77 ± 1.20 (n= 51), compared with sublschlal leg length SDS which were, In Individuals aged 2–10 years 0.214 ± 0.91; In 11‐18 years, −0.063 ± 1.347, and In individuals 19 and over, 0.37 ± 1.18. These data show that the reduction in standing height was the result of truncal shortening. Mean sitting height SDS was significantly lower In children with homozygous β‐thalassaemla, compared with their parents (P < 0.001), and in a subgroup of Greek adolescents with homozygousβ‐thalassaemia compared with age and sex matched normal Greek adolescents (P < 0.001). No correlation was found between truncal shortening and other clinical and biochemical variables measured.

CONCLUSIONS Short stature In our patients with homozygous β‐thalassaemla is due to disproportionate truncal shortening. The aetiology of truncal shortening in this patient group is likely to be multifactorial, although hypogonadism and chelation therapy may be contributory factors.