bluuebunny/crossref_metadata_2025 huggingface dataset:
Demonstration of thyroid stimulating activity within H chain fragments of TSAb‐IgG by protease digestion and reduction
Authors: Kouki Tsuyoshi , Inui Takehiro , Hachiya Takashi , Okabe Hidetoshi , Ochi Yukio , Kajita Yoshihiro
Published: November 2003

OBJECTIVE Whether or not the distribution of biologically active fragments in TSAb‐IgG molecules parallels antigen‐binding activity in other anti‐thyroidal antibodies was examined.

DESIGN Both the thyroid stimulating (TS) activity (cAMP production in thyroid cells) and TSH binding inhibition (TBI) activity (determined by TSH receptor assay) were examined by measuring the reduction in TSAb‐IgG followed by gel‐filtration on Sephadex G‐100. Two forms of IgG were separated from TSAb‐IgG by column chromatography using Protein L‐Sepharose (specifically binds to κ chain). The IgG(κ) was reduced with dithiothreitol (DTT) and the unbound fraction (UF) (the free heavy (H) chain) and the bound fraction (BF) (the free κ chain and the non‐reduced IgG(κ)) were separated using Protein L‐Sepharose. The Fab fragment was separated by Protein A‐Sepharose after papain hydrolysis of TSAb‐IgG, then separated into two Fab(κ) and Fab(λ) forms by Protein L‐Sepharose. The Fd fragment (or fragment containing Fd) was prepared from Fab(κ) by DTT reduction followed by Protein L column.

RESULTS The free H chain fraction showed TS and TBI activity, but neither anti‐thyroglobulin (Tg) nor anti‐thyroid peroxidase (TPO) antibody activities. The free light (L) chain was not biologically active. Similar TS and TBI activities were found not only in IgG(κ) and IgG(λ) but also in the Fab(κ) and Fab(λ) fractions. Fd fragment that was not contaminated with free κ chain had TS and weak TBI activities.

CONCLUSIONS The thyroid stimulating activity in 5 TSAb‐IgG samples was found in IgG (κ), IgG (λ), Fab (κ), Fab (λ), H chain and Fd separated by papain digestion and reduction. These results showed that TSAb was polyclonal and that the Fd fragment was important as the biologically active site.
Effects of hyperthyroidism and radioactive iodine given to ablate the thyroid on the composition of whole stimulated saliva
Authors: Ford Henry , Johnson Lesley , Purdie Gordon , Feek Colin
Published: November 2003

OBJECTIVE For many years there has been speculation about possible damage to the salivary glands following administration of ablative doses of radioactive iodine for treatment of hyperthyroidism. We have investigated the changes that occur in the composition of saliva in hyperthyroidism and after the administration of an ablative dose of radioactive iodine to hyperthyroid subjects.

DESIGN The study consisted of two parts: first, a comparison of a group of hyperthyroid patients with a group of normal subjects with regard to the concentration or activity of 10 constituents of saliva; second, measurement of those constituents 3–42 weeks after administration of 370 MBq of radioactive iodine to a group of hyperthyroid subjects.

PATIENTS Saliva specimens from 38 untreated out‐patients with hyperthyroidism due to Graves' disease or toxic nodular goitre were studied to evaluate the effects of hyperthyroidism and the results were compared with a group of 93 normal subjects. Seventy‐one samples of saliva from 26 patients with persistent hyperthyroidism were collected and analysed 3–42 weeks after radioactive iodine administration.

MEASUREMENTS The flow rate; the concentrations of total protein, iodine, calcium, urate, phosphate, potassium and immunoglobulin A; and the activities of N‐acetylglucosaminidase, lysozyme and lactate dehydrogenase were measured.

RESULTS In hyperthyroidism the salivary flow rate and the concentrations of urate and potassium were significantly (P<0.05) increased and the concentrations of total protein, calcium and lactate dehydrogenase activity significantly decreased compared to the control group. After radioactive iodine was administered, significant positive trends were observed in the concentrations of total protein, N‐acetylglucosaminidase and immunoglobulin A. These trends were independent of the free T3 levels obtained from the same specimens.

CONCLUSIONS Hyperthyroidism leads to a number of changes in salivary composition. For most of the salivary components measured no significant changes were observed 3–42 weeks after administration of 370 MBq of radioactive iodine to patients with persistent hyperthyroidism. The relatively small positive trends in the concentrations of total protein, N‐acetylglucosamidase activity and immunoglobulin A may have been due either to changes in thyroid status or to the effects of radiation on the salivary glands, or both.
Interleukin‐6 secreting phaeochromocytoma associated with clinical markers of inflammation
Authors: Takagi Miki , Egawa Takeshi , Motomura Takashi , Sakuma‐Mochizuki Junko , Nishimoto Norihiro , Kasayama Soji , Hayashi Seiji , Koga Masafumi , Yoshizaki Kazuyuki , Yoshioka Toshiaki , Okuyama Akihiko , Kishimoto Tadamitsu
Published: November 2003

Phaeochromocytomas have been shown to produce not only catecholamines but other neuropeptides and hormones, with a variety of clinical manifestations. We report a 70‐year‐old female patient with phaeochromocytoma exhibiting sustained hypertension, low‐grade fever, thrombocytosis, and elevated levels of plasma fibrinogen and C‐reactive protein. Serum interleukin (IL)‐6 levels were significantly elevated, whereas serum IL‐1α and IL‐β were not detectable. After surgical removal of the tumour, hypertension and low‐grade fever disappeared, and the laboratory findings including serum IL‐6 concentrations became normal. Immunohistochemical study of the tumour showed positive staining for IL‐6. Culture of the resected tumour revealed the production of large amounts of IL‐6. It is suggested that IL‐6 secreted by the tumour was responsible for some of the clinical manifestations in this patient.
Circulating leptin concentrations in polycystic ovary syndrome: relation to anthropometric and metabolic parameters
Authors: Chapman Ian M. , Wittert Gary A. , Norman Robert J.
Published: November 2003

OBJECTIVE To determine the relation between metabolic and anthropometric parameters and circulating leptin concentrations in women with polycystic ovary syndrome (PCOS).

DESIGN AND PATIENTS Correlation of fasting serum leptin concentrations with anthropometric measures and multiple metabolic parameters including insulin and glucose responses to a 2‐hour 75‐g oral glucose tolerance test (OGTT) in 85 women with PCOS (17–36 years, body mass index (BMI) 29.9 ± 0.9 kg/m2, mean ± SD) and 18 control women (25–47 years, BMI 25 ± 1.7 kg/m2). Diagnostic criteria for PCOS: characteristic ovarian morphology on ultrasound plus at least two of (1) elevated serum testosterone; (2) elevated serum androstenedione; and (3) reduced serum SHBG concentrations.

MEASUREMENTS Concentrations of androgens, lipids, PRL, gonadotrophins, and leptin were measured in the baseline fasting blood sample from an OGTT. Insulin and glucose were measured throughout OGTT. Serum leptin concentrations were measured by radioimmunoassay.

RESULTS Log leptin levels in the PCOS group correlated significantly with BMI (r = 0.85, P < 0.0001) and with 8 other parameters including waist/hip ratio (r = 0.51, P = 0.0005). By stepwise regression analysis, only BMI (P < 0.0001) and plasma high density lipoprotein concentration (P = 0.02) were independently correlated with log leptin levels, both positively. There was no effect of fat distribution, as measured by waist/hip ratio, on leptin concentrations. Comparison of control subjects to a BMI‐matched subgroup of 55 PCOS subjects revealed significantly higher circulating concentrations of LH, testosterone, DHEAS, progesterone and androstenedione, and higher glucose and insulin responses to OGTT in the PCOS group. Leptin levels were not different between the PCOS subgroup and control group (14.8 ± 1.3 vs 12.1 ± 2.3 μg/l, mean ± SE, P = 0.26) and the relation of BMI to leptin levels determined by linear regression analysis also did not differ between the two groups.

CONCLUSIONS Our results indicate that circulating leptin concentrations in women with PCOS, a condition characterized by hyperandrogenaemia, increased LH concentrations and insulin resistance, are strongly related to BMI and not independently affected by circulating levels of insulin, gonadotrophins or sex hormones.
Fluctuating hyper‐hypocortisolaemia: a variant of Cushing's syndrome
Authors: Leibowitz Gil , White Anne , Hadani Moshe , Gross David J.
Published: November 2003

We present a patient with severe Cushing's syndrome secondary to an invasive pituitary tumour. Cortisol secretion fluctuated between severe hypercortisolaemia associated with features of Cushing's syndrome to recurrent symptomatic hypocortisolaemia. Normal ACTH precursors to ACTH ratio during the various stages of cortisol secretion indicated that periodic decreased prohormone processing did not contribute to the unique presentation in the patient. Thus, the the extreme fluctuations of plasma cortisol levels are most probably due to unexplained erratic changes of ACTH secretion.
Placental 11β‐hydroxysteroid dehydrogenase: a key regulator of fetal glucocorticoid exposure
Authors: Benediktsson Rafn , Calder Andrew A. , Edwards Christopher R. W. , Seckl Jonathan R.
Published: November 2003

OBJECTIVE Placental 11β‐hydroxysteroid dehydrogenase (11β‐HSD), which converts active cortisol to inactive cortisone, has been proposed to be the mechanism guarding the fetus from the growth retarding effects of maternal glucocorticoids; however, other placental enzymes have also been implicated. Placental 11β‐HSD is unstable in vitro, and enzyme activity thus detected may not be relevant to the proposed barrier role. We have therefore examined placental glucocorticoid metabolism in dually perfused freshly isolated intact human placentas.

DESIGN Placentas were obtained from randomly selected normal term deliveries. The maternal circuit was perfused with physiological concentration of cortisol, the fetal effluent collected and steroid metabolites separated and quantified using silica columns (Sep‐pak Plus) and HPLC.

RESULTS Most of the maternally administered cortisol was metabolized to cortisone, and no conversion of cortisone to cortisol was detected. Cortisone was the only product of cortisol metabolism. Inhibition of 11β‐HSD with glycyrrhetinic acid allowed cortisol to gain direct access to the fetal circulation.

CONCLUSION We conclude that human placental 11β‐HSD plays a crucial role in controlling glucocorticoid access to the fetus. Other enzymes are not significant contributors at physiologically relevant cortisol concentrations.
Acute administration of hexarelin stimulates GH secretion during day and night in normal men
Authors: Loche Sandro , Colao Annamaria , Cappa Marco , Ferone Diego , Merola Bartolomeo , Faedda Antonella , Imbimbo Bruno P. , Deghenghi Romano , Lombardi Gaetano
Published: November 2003

OBJECTIVE Hexarelin is a synthetic hexapeptide with potent GH‐releasing activity in both animals and men. The aim of this study was to investigate the effect of a bolus injection of hexarelin given in the morning during wakefulness and during nocturnal sleep in a group of normal adult men.

DESIGN AND SUBJECTS Eight normal men, aged 21–33 years, of normal height and within 10% of ideal body weight were studied. All subjects received in random order saline or hexarelin (2 μg/kg) in the morning between 0800 and 0900 h after they had fasted overnight. The same experiments were performed during nocturnal sleep in the same subjects. Saline or hexarelin were injected within 30 minutes after the onset of sleep between 2300 and 2400 h. Sleep was recorded by visual inspection.

MEASUREMENTS In all four test sessions blood samples were taken 30, 15 minutes and immediately before the injection of saline or hexarelin and then every 15 minutes for 2 hours. GH was measured by an immunoradiometric assay. All values are expressed as peak GH levels or as area under the curve (AUC) calculated by trapezoidal integration.

RESULTS Mean peak GH concentrations after hexarelin during the morning (58.2 ± 4.7 μg/l) (GH μg/l × 2 = mU/l) were not different from those observed during sleep (61.2 ±4.3 μg/l). The rate of disappearance of GH from plasma was slower during sleep (t1/2 =64.9 ±14.8 min) than during morning hours (t1/2 = 24.9 ±1.4 min, P <0.01). Mean AUC responses to hexarelin during sleep (1466 ± 145 μg.min/l) were significantly higher than during morning hours (903 ± 94 μg.min/l, P < 0.001).

CONCLUSIONS These results show that GH responsiveness to a growth hormone releasing peptide is preserved during the night. This could be exploited for diagnostic and/or therapeutic purposes.
Serum leptin concentrations in patients with anorexia nervosa, bulimia nervosa and non‐specific eating disorders correlate with the body mass index but are independent of the respective disease
Authors: Ferron Fernando , Considine Robert V. , Peino Roberto , Lado Isabel G. , Dieguez Carlos , Casanueva Felipe F.
Published: November 2003

OBJECTIVE Leptin, the product of the ob gene, is a recently discovered hormone secreted by adipocytes. Serum leptin concentrations increase in correlation with the percentage of body fat, but little else is known about the physiological actions of leptin in humans. The aim of this study was to determine the role of leptin in severe eating disorders, and whether its levels are correlated with the specific disease or exclusively with body weight.

TESTS Serum concentrations of human leptin were analysed by specific radioimmunoassay and compared with the individual body mass indexes (BMI). The correlations between serum leptin concentrations and BMI, age and height were analysed.

PATIENTS A total of 65 women were studied: 25 patients with anorexia nervosa, 20 women with bulimia nervosa, 6 women with a diagnosis of non‐specific eating disorder, and 14 normal‐weight women who acted as controls. At the time of the study, the patients were non‐cured, under treatment, and at different stages of therapeutic evolution.

MEASUREMENTS Plasma leptin levels were measured by specific radioimmunoassay.

RESULTS The mean serum leptin in the normal‐ weight women was 10.5 ±1.1 μg/l, compared with 7.6 ±1.1 μg/l in the anorexia nervosa patients (P <0.05). This reduction in leptin levels was paralleled by the differences in BMI (21.4 ±0.4 vs 18.8 ±0.2) P < 0.05. These differences between the controls and anorexia nervosa patients were not observed in patients with bulimia nervosa who had a mean serum leptin level of 9.9 ±1.4 μg/l and BMI of 21.3 ±0.6, neither significantly different from controls. On the contrary, patients with non‐specific eating disorders showed a large reduction in BMI (17.9 ±1.2, P <0.05 vs control), and a parallel reduction in serum leptin levels, 4.5 ±1.0 (P <0.05 vs controls). When individual values of leptin were plotted against BMI a wide range was observed in all groups; in the control subjects from 5.6 to 17.7 μg/l, in anorexia nervosa patients from 2.1 to 28.1 μg/l, in patients with bulimia nervosa between 2.6 and 25.9 μg/l, and in women with non‐specific eating disorder from 2.0 to 8.9. No correlation was observed with the specific disease but in each group a significant correlation was observed only with BMI.

CONCLUSIONS Serum leptin levels in three groups of patients affected by severe eating disorders are not related to the specific pathology but are correlated with the individual BMI. The analysis of leptin values may be a useful index of assessing the adipose tissue stores in the clinical setting, but will be of no help for diagnosis nor prognosis of severe eating disorders.
Longitudinal changes of bone mineral density and bone turnover in postmenopausal women on thyroxine
Authors: Guo Chun‐Yuan , Weetman Anthony P. , Eastell Richard
Published: November 2003

OBJECTIVE The skeletal risks of subclinical hyperthyroidism in postmenopausal women on replacement thyroxine remain controversial. The aims of this study were to determine (1) the relationship between bone turnover and TSH levels and (2) whether reduction of thyroxine (T4) dose in postmenopausal women who have suppressed TSH levels is beneficial to bone mineral density (BMD) and bone turnover.

DESIGN A prospective study over 2 years of postmenopausal women treated with T4 with an age‐ and sex‐matched healthy control group.

PATIENTS AND MEASUREMENTS Sixty‐four postmenopausal women, ages 47 to 74 (61 ±9, mean ± SD), on T4 for between 2 and 14 years. Patients were divided into three groups: group 1 (n =23) with normal serum TSH levels, group 2 (n = 18) with suppressed serum TSH levels and group 3 (n =23) with a history of thyroidectomy and suppressed TSH levels (patients with thyroid cancer). Thirty‐six age‐matched healthy postmenopausal women were recruited as a control group. Bone mineral density (BMD), measured by dual‐energy X‐ray absorptiometry and bone turnover, were evaluated at baseline and over 2 years in the four groups. Serum TSH levels were measured every 6 to 12 months. In group 2, the dose of T4 was reduced after the baseline measurement and serum TSH levels were remeasured 1 to 4 months later. Serum TSH levels returned to the reference range after the reduction of T4 dose in group 2.

RESULTS The serum TSH level, after log transformation, was negatively correlated with serum levels of osteocalcin (BGP), bone alkaline phosphatase (BAP) and urinary cross‐linked N‐telopeptides pyridinoline of type I collagen (NTx) (linear correlation, r = −0.41 P < 0.001, r = −0.29 P =0.01 and r = −0.26 P = 0.033), respectively. There was no significant difference in BMD and bone turnover between the four groups at either baseline or follow‐up (ANOVA, P >0.05). The levels of serum BGP, BAP and urinary NTx decreased whereas lumbar spine and femoral neck BMD increased significantly in group 2 over 2 years (one sample t‐test, P =0.0021, 0.034, 0.0017, 0.011 and >0.001, respectively). In group 2, the rates of change of lumbar spine and femoral BMD were increased significantly and the rates of change of serum BGP and urinary NTx were decreased significantly compared with other groups (Scheffe test, P <0.05).

CONCLUSIONS In postmenopausal women on T4, bone turnover is related to the serum TSH level and a reduction of T4 dose in those with suppressed serum TSH levels can result in a decrease in bone turnover and an increase in bone mineral density.
Effect of mifepristone on folliculogenesis in women treated with recombinant FSH
Authors: Messinis I. E. , Krishnan M. , Kazem R. , Khadilkar S. , Templeton A. A.
Published: November 2003

OBJECTIVE To study the mechanism through which mifepristone interrupts folliculogenesis.

DESIGN Normally ovulating women undergoing donor intrauterine insemination (IUI) treatment were investigated during two menstrual cycles treated with gonadotrophins. In the first cycle (FSH cycle), the women were given 150 IU recombinant FSH (rFSH) s.c. on days 2, 4, 6, 8 and daily thereafter until the administration of hCG. During the second cycle (FSH + mifepristone cycle), the women received rFSH as above plus mifepristone tablets at a dose of 50 mg/day from cycle day 2 until the hCG injection. IUI was performed only in the FSH cycles.

PATIENTS Eleven normally ovulating women were studied. The women were used as their own controls during the cycle treated with rFSH only.

RESULTS Two women became pregnant during the FSH cycle and, therefore, data for comparison between the two cycles were available in nine women. In both cycles, only one follicle reached the preovulatory stage. However, during treatment with FSH + mifepristone the growth of the dominant follicle was temporarily arrested after day 8 of the cycle and ovulation was postponed by 2 days on average. Serum FSH values increased significantly in both cycles only during the daily administration of rFSH, i.e. towards the end of the experimental period when a normal growth of the follicle was re‐established. On the day of hCG injection, an endogenous LH surge had already started in six of the nine cycles treated with FSH (67%) but in none of the FSH + mifepristone cycles despite the preovulatory oestradiol (E2) levels. Endometrial thickness during the follicular phase and serum E2 and progesterone concentrations during the luteal phase, although in the normal limits, were significantly lower in the FSH + mifepristone than in the FSH cycles.

CONCLUSIONS These results suggest that mifepristone arrests follicular development at a stage beyond the recruitment‐selection point by delaying the growth of the dominant follicle. This is probably achieved through an effect of mifepristone on the ovary where it reduces the sensitivity of the selected follicle to FSH. Mifepristone may have a potential application for the inhibition of the LH surge in superovulation induction programmes.
Iodine insufficiency and neonatal hyperthyrotropinaemia in Hong Kong
Authors: Kung Annie W. C. , Lao Terence T. , Low Louis C. K. , Pang Richard W. C. , Robinson J. D.
Published: November 2003

OBJECTIVES 23% of the neonatal hypothyroidism in Hong Kong is transient. The present study aims to evaluate iodine excretion in healthy pregnant women in Hong Kong and to determine whether iodine insufficiency may occur in the local population to account for the type of neonatal thyroid dysfunction seen in our screening programme.

SUBJECTS Pilot screening of urinary iodine excretion was determined in 253 healthy pregnant women between 32 and 36 weeks gestation. Fetal and maternal thyroid function in relation to urinary iodine excretion was evaluated in another 55 pregnant women who had given birth to infants with cord blood TSH ≥ 16 mIU/l (95th percentile of the cord blood TSH screening programme) and the results were compared to a control group of 160 healthy women whose infants had cord blood TSH < 16 mIU/l.

RESULTS Using a cut‐off value of 0.79 μmol/l, a level as defined by WHO as iodine deficiency, we found that 35.8% of the pregnant women had urinary iodine concentrations below this cut off value. We demonstrated that the existence of borderline iodine supply affected the maternal and fetal thyroid function as evidenced by (i) a negative correlation between maternal TSH and urinary iodine concentration, (ii) higher cord blood TSH in those infants whose mothers had a low urinary iodine concentration as compared to those in whose mothers it was normal, (iii) women who had given birth to infants with cord blood TSH ≥6 mIU/l had lower urinary iodine concentrations and serum fT4 levels as compared to mothers who had given birth to infants with normal cord TSH levels, and their offspring also had higher cord blood thyroglobulin levels.

CONCLUSION Although Hong Kong is not a goitrous area, borderline iodine deficiency exists. Iodization of salt in our community could obviate the necessity for iodine supplements in pregnant women and other at‐risk groups.
Type III hyperlipidaemia with primary hypothyroidism: a unique clinical course of hyperlipidaemia during replacement therapy of thyroid hormone
Authors: Kobayashi J. , Yamazaki K. , Tashiro J. , Murano S. , Saito Y. , Morisaki N.
Published: November 2003

A patient is described with type III hyperlipidaemia and primary hypothyroidism who had a unique clinical course of hyperlipidaemia. The patient was a 65‐year‐old man with primary hypothyroidism. His plasma total cholesterol, triglyceride and high density lipoprotein‐cholesterol concentrations 1 year after starting thyroid hormone replacement therapy were 7.98, 4.04 and 0.72 mmol/l, respectively. His plasma apolipoprotein (apo) E level was 0.29 g/l and its phenotype was E2/2. Remarkably, this patient had no hyperlipidaemia before starting thyroid hormone replacement therapy but it became overt only after the hypothyroidism had been treated. Although we have not confirmed the mechanism for this, we speculate that a decrease in enzyme activities responsible for cholesterol production may have been sufficient to surpass the effect of apolipoprotein E2/2 and the decrease in enzyme activities involved in degrading and excreting plasma cholesterol, resulting in normolipidaemia.
Urinary growth hormone following exercise to assess growth hormone production in adults
Authors: Flanagan D. E. H. , Taylor M. C. , Parfitt V. , Mardell R. , Wood P. J. , Leatherdale B. A.
Published: November 2003

OBJECTIVE The insulin stress test (IST) is the most commonly used test to assess the GH reserve in children and adults. It is a time‐consuming, expensive and potentially dangerous test. We investigated whether measurement of urinary growth hormone excretion following exercise would prove a reliable method to diagnose adult GH deficiency.

DESIGN Healthy volunteers underwent a standard IST to confirm normal GH secretion. Using a standardized exercise protocol on a treadmill, the urinary excretion of GH was measured. Three patients confirmed as GH deficient by an IST were exercised using the same exercise protocol and their urinary excretion of GH was measured.

PATIENTS Ten healthy volunteers and three patients with hypopituitarism were evaluated.

MEASUREMENTS A standard IST was performed on both healthy volunteers and patients, with measurements of plasma GH and plasma cortisol. Urinary growth hormone and urinary GH/creatinine (GH/CR) ratios were measured before and after IST. On a separate visit, healthy volunteers and patients were exercised on the treadmill with measurements of plasma GH and cortisol. Urinary GH and GH/CR ratios were measured before and after exercise.

RESULTS There was at least a two‐fold increase in urinary GH and GH/CR ratios following exercise in all healthy adults. By contrast, patients with GH deficiency showed no rise in urinary GH or urinary GH/CR ratios following exercise.

CONCLUSIONS Measurements of urinary GH following exercise can distinguish between GH‐deficient adults and healthy volunteers. Urinary GH excretion can be measured over a timed interval following exercise or can be expressed as the GH/CR ratio. This can be measured on a single sample following exercise and can be used to diagnose GH deficiency. The exercise test employed for this study is arduous. We are therefore performing further studies with a less strenuous exercise protocol with a view to designing a ‘patient‐friendly’ exercise test for GH deficiency in adults.
A comparison of different methods for diagnosing acromegaly
Authors: Stoffel‐Wagner B. , Springer W. , Bidlingmaier F. , Klingmüller D.
Published: November 2003

OBJECTIVEThe present study was designed to assess the diagnostic value of different single measurements in comparison to the classic time‐consuming method, the oral glucose tolerance test (OGTT), in acromegaly.

DESIGN, PATIENTS AND MEASUREMENTS IGF‐I, free IGF‐I, 24‐hour‐urinary GH (uGH), serum IGFBP‐3 and 24‐hour‐urinary IGFBP‐3 (uIGFBP‐3) were measured in 12 patients with untreated active acromegaly, in 29 patients who had been treated but were not cured, in 13 patients with cured acromegaly and in 14 healthy control subjects, and compared with the results of the OGTT.

RESULTSIn all patients with active acromegaly, whether they had been treated or not, nadir GH in OGTT was >3 mU/I, whereas nadir GH was <1.88 mU/I in the cured patients and the control subjects. In patients with untreated active acromegaly IGF‐I, free IGF‐I, uGH and IGFBP‐3, but not uIGFBP‐3, were significantly higher than in healthy individuals (P<0.0001). Only IGF‐I values did not overlap with the control group. In those patients with acromegaly who had been treated but not cured these parameters overlapped with the control group. In patients with acromegaly there was a significant correlation between nadir GH levels in OGTT and IGF‐I (r=0.71), free IGF‐I (r=0.76, IGFBP‐3 (t=0.73) and uGH (r=0.81) (P<0.0001), but no correlation with uIGFBP‐3.

CONCLUSIONSOnly be means of the OGTT could patients with active acromegaly be completely distinguished from the control subjects and from cured patients. IGF‐I, free IGF‐I, IGFBP‐3 and uGH were useful in the diagnosis of acromegaly, but of limited value in the follow‐up of acromegalic patients after treatment. The determination of free IGF‐I, which has yet not been investigated in acromegaly, offered no advantage over that of total IGF‐I and IGFBP‐3; uIGFBP‐3 was not useful in the diagnosis of acromegaly.
Intracardiac metastases from neuroendocrine tumours
Authors: Drake W. M. , Jenkins P. J. , Phillips R. R. , Lowe D. G. , Grossman A. B. , Besser G. M. , Wass J. A. H.
Published: November 2003

We report three cases of intra‐cardiac metastases from neuroendocrine tumours of the carcinoid type. One presented in a manner identical to a left atrial myxoma; in one patient a left atrial mass was noted during investigations for weight loss and a lung mass; and in the third, two right ventricular deposits were detected on echocardiography when a patient with a disseminated GHRH‐secreting tumour was investigated for dyspnoea. Although to our knowledge this is only the third report of these lesions, we believe that this represents a form of carcinoid heart disease that is distinct from the valvular abnormalities seen in some patients with carcinoid syndrome. Neuroendocrine metastases should be considered in the differential diagnosis of intra‐cardiac tumours.
Galactorrhoea and amenorrhoea due to an intradural neurinoma originating from a thoracic intercostal nerve radicle
Authors: Katsuren Eiyu , Ishikawa San‐e , Honda Kazufumi , Saito Toshikazu
Published: November 2003

A 42‐year‐old woman had galactorrhoea and amenorrhoea. Four years previously she complained of sensory disturbance of her legs, with gait disturbance. Serum PRL level was 1408 mU/l. Magnetic resonance imaging showed a spindle‐shaped mass in the spinal canal at the level of the ninth thoracic vertebra. The tumour was removed and histologically was found to be a neurinoma originating from the right ninth intercostal nerve radicle. Soon after the operation, galactorrhoea, amenorrhoea and neurological symptoms disappeared. Prolactin levels normalized at 346 mU/l. These findings indicate that hyperprolactinaemia occurred as a result of the stimulation of afferent fibres from an intercostal nerve in a patient with intradural neurinoma of the intercostal nerve radicle.
Diminished adrenal androgen secretion in familial glucocorticoid deficiency implicates a significant role for ACTH in the induction of adrenarche
Authors: Weber A. , Clark A. J. L. , Perry L. A. , Honour J. W. , Savage M. O.
Published: November 2003

OBJECTIVE The mechanism of adrenarche is controversial, and there have been competing claims that its origin is in the hypothalamo‐pituitary axis or in the adrenal gland itself. ACTH is a proposed inducer of adrenarche so patients with ACTH resistance due to the familial glucocorticoid deficiency syndrome provide a model to clarify the degree to which ACTH is involved in the regulation of adrenal androgen secretion during adrenarche.

DESIGN Random analysis of plasma adrenal androgens and urinary adrenal androgen output in treated patients with familial glucocorticoid deficiency.

PATIENTS Eleven patients (6 males and 5 females, aged 6.5–21.6 years, 4 prepubertal, minimum bone age 9 years) with familial glucocorticoid deficiency were studied. In 6, mutations in the coding region of the ACTH receptor are the cause of their ACTH resistance. In the remaining 5 the receptor was normal.

MEASUREMENTS Physical examination, basal serum cortisol, basal plasma ACTH, serum cortisol after stimulation with 250 μg ACTH(1–24), plasma dehydroepiandrosterone‐sulphate (DHEAS) and plasma androstenedione (A4), total urinary androgen excretion and single‐stranded sequencing of the coding region of the ACTH receptor.

RESULTS DHEAS was undetectable in 8, and detectable but below the age‐matched reference values in 3 patients. A4 was measured in 10 patients, and in 3 patients (2 in late puberty) was found to be subnormal whereas in the remaining 7 patients A4 was normal for age and pubertal stage consistent with the gonadal contribution to peripheral A4 levels. Significantly diminished output of urinary adrenal androgen metabolites in 3 patients confirmed the results found in serum. The lack of adrenarche was independent of the presence of a mutation within the ACTH receptor and of the severity of glucocorticoid deficiency. Despite adequate glucocorticoid replacement therapy ACTH levels remained elevated in 10 of the 11 patients.

CONCLUSIONS Although reduced adrenocortical inner zone cell number may contribute to the lack of adrenarche, in some patients there appears to be a discrepancy between partial glucocorticoid deficiency and significantly diminished adrenal androgen secretion. These data imply a significant contribution of ACTH to the regulation of adrenarche in normal children either by having a priming effect on the adrenal gland or by acting in concert with other adrenal androgen stimulating factors.
The effect of treatment variables on mood and social adjustment in adult patients with pituitary disease
Authors: Peace K. A. , Orme S. M. , Sebastian J. P. , Thompson A. R. , Barnes S. , Ellis A. , Belchetz P. E.
Published: November 2003

OBJECTIVE Studies of mood in hypopituitary adults have yielded inconsistent results. This investigation was carried out to investigate whether treatment characteristics may be responsible for the inconsistent results.

DESIGN AND MEASUREMENTS We compared three groups of patients with a group of matched healthy controls on self‐report measures of mood and social adjustment (Beck depression inventory, State‐trait anxiety inventory, Social adjustment scale (modified)) and a measure of quality of life (Nottingham health profile, NHP).

PATIENTS The patient groups were those treated with transfrontal surgery (n=23), transsphenoidal surgery (n=23) or medication only (n=23). In addition, a close informant of each subject was asked to complete a social adjustment measure about the subject’s level of adjustment.

RESULTS On the self‐report mood and social adjustment measures and the emotion sub‐scale of the NHP, the transsphenoidal and medication patient groups rated themselves as being more depressed, anxious and having poorer social adjustment than the transfrontal or control groups. The close informants, however, rated all three patient groups as having poorer social adjustment than the controls. Patients treated with surgery and without radiotherapy reported fewer symptoms of depression than those treated with radiotherapy. Realistic self‐appraisal of social adjustment in surgical patients was found only in those treated with transsphenoidal surgery without radiotherapy.

CONCLUSIONS Patients treated for pituitary tumour, excepting those treated with transfrontal surgery and to a lesser extent those treated with radiotherapy, suffer from mild mood disturbance and self‐perceived decreased social adjustment. All patient groups are seen by others as having decreased social adjustment, raising the possibility that the transfrontal patients and possibly those who have had radiotherapy, lack insight. This may explain some of the discrepancies in the previous literature and needs to be taken into account when using self‐report measures with these patients.
Growth response and levels of growth factors after two years growth hormone treatment are similar for a once and twice daily injection regimen in girls with Turner syndrome
Authors: Van Teunenbroek A. , De Muinck Keizer‐Schrama S. , Stijnen T. , Waelkens J. , Wit J. M. , Vulsma T. , Gerver W. J. , Reeser H. , Delemarre‐van de Waal H. , Jansen M. , Drop S.
Published: November 2003

GH is known to improve height velocity in girls with Turner syndrome (TS) but the optimal dosage regimen has yet to be defined.

OBJECTIVE We attempted to improve the growth response by trying to mimic normal pulsatile GH secretion more closely.

DESIGN In a 2‐year study the effect of fractionated twice daily (BID) was compared with once daily (OD) s.c. injections of a total GH dose of 6 IU/m2/day. BID injections were administered as two‐thirds at bedtime and one‐third in the morning. The subjects concurrently received low dose ethinyl oestradiol (0.05 mg/kg/day, orally).

SUBJECTS Nineteen girls with TS aged 11 years or over, who were previously involved in a 10‐week GH cross‐over study.

MEASUREMENTS Height and bone age were evaluated in relation to untreated Turner reference data. Final height (FH) was predicted using the Bayley and Pinneau (BP) method, the modified Index of Potential Height (mIPHRUS), and a recently developed Turner‐specific method (PTSRUS) based on regression coefficients for height (H), chronological age (CA) and bone age (BA). Plasma levels of GH, GHBP, IGF‐I, and IGFBP‐3 were determined by RIA.

RESULTS After 2 years treatment the growth response expressed as HV, HVSDS, the change in HSDSCA, the gain in height over estimated untreated values and in FH prediction all showed significant improvements. Although mean values tended to be higher with OD injections, significant differences between groups were not found. Bone maturation was similar between groups and compared with untreated estimated values. Independent of treatment group, the change in HSDSCA after 2 years of GH treatment was related negatively to the baseline CA and HSDSCA, and positively to BA delay at baseline. After 18 months of GH treatment the significant decrease in GHBP plasma levels observed after 6 months was no longer significant. In contrast, IGF‐I and IGFBP‐3 plasma levels and the IGF‐I to IGFBP‐3 ratio increased significantly during 18 months GH therapy. None of these growth related factors showed a difference between groups in their 18 months change. Relevant side‐effects were not observed during the first 2 years of GH treatment.

CONCLUSIONS The present growth data are in conformity with the data of the earlier 24‐hour GH profiles. The growth response and plasma levels of growth related factors after 2 years GH on a total dose of 6 IU/m2/day in combination with low‐dose oestrogens were not significantly different between the once daily and the twice daily GH injection regimen.
Hypothalamic‐pituitary‐adrenal axis in abdominal obesity: effects of dexfenfluramine
Authors: Boushaki F. Z. , Rasio E. , Serri O.
Published: November 2003

OBJECTIVE Hyperactivity of the HPA axis is a possible mechanism underlying abdominal obesity. We aimed to evaluate in premenopausal women with abdominal obesity, (i) the hypothalamic‐pituitary‐adrenal (HPA) axis responses to direct pituitary stimulation with corticotrophin releasing hormone (CRH) and to opioid blockade with naloxone, and (ii) the interaction between short‐term serotoninergic activation with dexfenfluramine (dF), a serotonin‐release agonist, and these responses.

DESIGN AND SUBJECTS Eight obese women (mean BMI, 35 kg/m2) with waist to hip ratio (WHR) > 0.85 were tested with CRH (1 μg/kg i.v.) and naloxone (125 μg/kg i.v.) before and at the end of two treatment periods with dF (15 mg twice daily for 7 days) and placebo (washout 7 days) in a cross‐over design. Eight normal weight control women were tested with CRH and naloxone.

RESULTS Prior to treatment, ACTH and cortisol responses to naloxone (areas under the curve) were significantly higher in obese women then in control women (P=0.027 and P=0.035 respectively). dF treatment resulted in significant (P<0.05) reduction of ACTH and cortisol increments. In contrast, ACTH and cortisol responses to CRH were not significantly different in obese and control subjects and were unaffected by dF treatment.

CONCLUSION We conclude that women with abdominal obesity have hyperreactivity of the HPA axis to opiod blockage and that dexfenfluramine treatment reduces this hyperreactivity.
High Incidence of Positive Autoantibodies against Thyroid Peroxidase and Thyroglobulin in Patients with Sarcoidosis
Authors: Nakamura Hirotoshi , Genma Rieko , Mikami Tomoko , Kitahara Akira , Natsume Hiroko , Andoh Shinichiro , Nagasawa Shinsuke , Nishiyama Kozo , Chida Kingo , Sato Atsuhiko , Yoshimi Teruya
Published: November 2003

OBJECTIVE Although abnormalities of the humoral immune system, such as increased immunoglobulin production, are known in sarcoidosis, the relationship between sarcoidosis and autoimmune disorders is uncertain. We studied the incidence of thyroid autoantibodies and the prevalence of Hashimoto’s thyroiditis in patients with sarcoidosis.

PATIENTS AND MEASUREMENTS Sixty‐two patients with pulmonary sarcoidosis, diagnosed by a combination of clinical, radiographic and histological findings, were studied. As controls, three groups of subjects aged 40 and over without a known history of thyroid disease (60 patients with pulmonary diseases other than sarcoidosis, 88 hospital employees and 82 company workers), were also analysed. Antibodies against thyroid peroxidase (TPO‐Ab) and purified thyroglobulin (Tg‐Ab) were measured by radioimmunoassay and antibodies against microsomal antigen (MCHA) and thyroglobulin (TGHA), by haemagglutination.

RESULTS Seventeen of 62 patients (27.4%) had either positive TPO‐Ab or Tg‐Ab or both. All the patients with positive thyroid autoantibodies were of middle or advanced age, and the incidence of positive TPO‐Ab/Tg‐Ab in patients with sarcoidosis aged 40 and over was 54.5% in males, 32.4% in females and 37.8% overall. The prevalence was significantly higher in males compared to age‐matched control males (0–7.7% in the controls), and in female patients was twice that found in controls (11.8–16.3%). Seven patients had Hashimoto's thyroiditis, indicating that the prevalence was 11.3%, and much higher than that previously reported.

CONCLUSIONS The data show a remarkably high incidence of thyroid autoantibodies in patients of middle or advanced age with sarcoidosis, especially in males, and a higher prevalence of Hashimoto's thyroiditis than in previous reports.
Absence of desensitization by hexarelin to subsequent GH releasing hormone‐mediated GH secretion in patients with anorexia nervosa
Authors: Popovic V. , Micic D. , Djurovic M. , Obradovic S. , Casanueva F. F. , Dieguez C.
Published: November 2003

OBJECTIVEBoth the basal levels and the neuroregulation of GH secretion are perturbed in patients with anorexia nervosa. It is unknown if these alterations are due to severe undernutrition or if they reflect basic neurotransmitter alterations of the patient’s neural pathways. On the other hand, prior administration of the GH secretagogue hexarelin in normal subjects blocks the GH‐releasing capability of GH releasing hormone (GHRH) administered 2 hours later. In the present work a sequential test was performed using the administration of hexarelin as first stimulus followed 120 minutes later by GHRH. The two aims of the study were: (a) to evaluate the interaction of GHRH and hexarelin, and (b) to further understand the alterations in GH neuroregulation in patients with anorexia nervosa.

DESIGNThe GH stimuli used were hexarelin (1 μg/kg i.v.), a GH stimulus whose main action is hypothalamic, followed 120 minutes later by GHRH (1 μg/kg i.v.) as a pituitary stimulus. Each woman was tested once.

PATIENTSThirty‐two women matched for age participated in the study: six normal‐weight women as controls, 14 women with anorexia nervosa, seven women with secondary amenorrhoea due to voluntary weight loss for aesthetic reasons, and five normal‐weight women after 72 hours of a controlled hypocaloric diet (800 cal/day).

MEASUREMENTSPlasma GH levels were measured by time‐resolved fluoroimmunosasay, each value shown is the mean±SE in mU/l.

RESULTSThe administration of hexarelin to the normal‐weight women induced a clear‐cut GH secretion (expressed as mean±SE of GH peak in mU/l of 77.5±21.8, but blocked the GH‐releasing capability of GHRH administered 120 minutes later (6.6±2.8, P<0.05). In contrast, the women with anorexia nervosa showed a normal GH response after the two stimuli: hexarelin 64.8±9.2. GHRH 71.1±14.2. The absence of heterologous desensitization was specific to anorexia nervosa, because the women with amenorrhoea due to voluntary weight loss but with a normal energy intake showed a pattern similar to the controls (GH after hexarelin 60.3±9.5 and to GHRH 120 minutes later 6.2±1.0 (P<0.05)). Similarly, the women after the short‐term hypocaloric diet showed a hexarelin‐mediated GH secretion of 99.6±17.8, which blunted the subsequent administration of GHRH (GH mean peak of 9.9±2.9, P<0.05 vs hexarelin).

CONCLUSIONSIn the normal subjects, the administration of hexarelin induced clear‐cut GH secretion, but inhibited the action of GHRH when administered 120 min later, while this heterologous desensitization was not observed in the patients with anorexia nervosa. This sequentially delayed test may be of some value in the clinical setting for assessing the status of patients with anorexia nervosa.
The safety profile of GH replacement therapy in adults
Authors: Chipman J. J. , Attanasio A. F. , Birkett M. A. , Bates P. C. , Webb S. , Lamberts S. W. J.
Published: November 2003

OBJECTIVE The benefits of GH replacement in GH‐deficient adult patients are becoming accepted but the safety profile continues to be defined. The GH deficiency in adults may have arisen in either childhood or during adult life and these two groups differ with regard to history of disease. The aim of the present report was to study differences in safety profile between these two groups during long‐term replacement therapy with recombinant human GH (hGH). Possible factors which placed a patient at risk of experiencing an adverse event were also examined.

PATIENTS AND DESIGN GH‐deficient adult patients were randomized into two study protocols, differing only in age of onset of the GH deficiency syndrome. There were 98 patients with adult‐onset and 67 patients with childhood‐onset GH deficiency. Each study consisted of a 6‐month double‐blind placebo‐controlled phase followed by an open‐label hGH treatment phase. Glucose tolerance, incidence of treatment‐emergent adverse events and relationship to IGF status were studied throughout the 36 months of treatment.

RESULTS Human growth hormone‐related adverse events were reported less commonly in childhood‐onset patients compared with adult‐onset patients. Adult‐onset patients who continued into the open‐label therapy phase reported an increased incidence of arthralgia, myalgia and paraesthesia. There were significant increases in fasting glucose with hGH therapy but values remained within the normal range. Hypertension was reported in 7.7% of adult‐onset patients at 18 months of hGH, which was within the expected prevalence for the number of patients, but was not reported for any childhood‐onset patients. Only in adult‐onset patients were sufficient adverse events reported to enable analysis of risk factors. Patients reporting hGH‐related adverse events were significantly heavier and, therefore, received more hGH. There was a significantly greater increase in IGF‐I and IGFBP‐3 in the first month in patients who experienced hGH‐related adverse events compared with those who did not.

CONCLUSION The risks of replacement therapy with hGH in GH‐deficient adults varied with pathogenesis of disease; hGH‐related adverse events occurred more frequently in patients with adult‐onset compared with those with childhood‐onset GH deficiency. In the adult‐onset patients there was an increased risk of adverse events in heavier patients and those who had the greatest increases in IGF‐I and IGFBP‐3 at 1 month of therapy.