bluuebunny/crossref_metadata_2025 huggingface dataset:
Ovarian function in women with non‐insulin dependent diabetes mellitus
Authors: Stamataki K. E. , Spina J. , Rangou D. B. , Chlouverakis C. S. , Piaditis G. P.
Published: November 2003

OBJECTIVE Although insulin has been shown to stimulate ovarian steroidogenesis and hyperinsulinaemia has been implicated in the raised androgen levels found in diseases associated with significant insulin resistance, ovarian function has not been studied so far in women with NIDDM. We have assessed ovarian function in women with NIDDM at the early (hyperinsulinaemic) and late (relative insulinopaenic) stages of evolution of the disease after strong stimulation with buserelin, a long‐acting GnRH analogue. Significant differences in ovarian function would be expected, depending on the stage of evolution of NIDDM.

DESIGN Following an overnight fast, a standard OGTT (75 g, orally) was performed (0830 h) in all diabetic and control women. Blood samples were obtained for blood glucose, insulin and C‐peptide measurements before and at 30‐minute intervals for 2 hours. On the termination of the OGTT, a buserelin test (100 μg, s.c.) was performed (1030 h) and blood samples were obtained for FSH, LH, Δ4‐androstenedione, total testosterone, free testosterone and oestradiol measurements before and then at 4‐hour intervals for 20 hours.

SUBJECTS Thirty‐one women with NIDDM (13 hyperinsulinaemic and 18 with relative insulinopaenia), 12 obese and 11 normally menstruating non‐obese, non‐diabetic women, aged 29–39 years, were studied.

RESULTS The integrated response (AUC) of oestradiol to buserelin was found to be normal in hyperinsulinaemic NIDDM and obese non‐diabetic women in the face of an increased free testosterone response, while in relatively insulinopaenic NIDDM women the oestradiol response was significantly reduced in the face of a normal free testosterone response.

CONCLUSIONS The results suggest that in women with NIDDM the ovaries have a reduced ability to convert androgen to oestrogen, probably due to a reduction of ovarian aromatase activity. As oestrogens protect against atherogenesis, it is speculated that the relative inability of the ovaries to produce oestradiol in NIDDM women with relative insulinopaenia might be involved in the development of the macroangiopathy, which often complicates this disease.
Bioavailability and bioactivity of intravenous vs subcutaneous infusion of growth hormone in GH‐deficient patients
Authors: Laursen Torben , Møller Jens , Jørgensen Jens O. L. , Ørskov Hans , Christiansen Jens S.
Published: November 2003

OBJECTIVE The bioavailability of GH immunoreactive serum concentrations is reduced following subcutaneous (s.c.) as compared with intravenous (i.v.) administration. Whether this difference also translates into a different biological activity remains to be investigated. The aim of the present study was to evaluate the short‐term metabolic effects of GH following i.v. and s.c. delivery.

DESIGN AND MEASUREMENTS In a cross‐over design 10 GH‐deficient patients were randomized to receive GH (0.03 μg (0.1 mU)/kg/min) as a continuous i.v. or s.c. infusion for 39 hours on two different occasions. Preceding each study GH therapy was discontinued for 5 days. Serum profiles of GH, IGF‐I, IGF‐II, IGF binding protein 3 (IGFBP‐3), insulin, glucose and non‐esterified fatty acids (NEFA) were recorded during the studies. Serum GH was measured by a polyclonal radio‐immunoassay (RIA) and by a double monoclonal immunofluorimetric assay (DELFIA).

RESULTS Higher mean integrated values (AUC) of serum GH (mU/l) were obtained with i.v. GH delivery [47.4±5.1 (i.v.), 33.3±3.0 (s.c.), P<0.05]. The two GH assays showed qualitatively similar results, but higher mean GH concentrations were measured by RIA following both s.c. (P<0.001) and i.v. infusion (P<0.001). Serum IGF‐I levels displayed different patterns following i.v. and s.c. GH infusion (P<0.05 by ANOVA) and mean IGF‐I levels (μg/l) were lower following s.c. GH infusion [159.5±21.8 (s.c.), 185.2±27.7 (i.v.), P=0.002]. Serum IGF‐II levels were unaffected by short‐term GH treatment and by the route of GH administration. Serum IGFBP‐3 levels increased in response to GH administration (P<0.001), irrespective of route (P=0.76). The IGF‐I/IGFBP‐3 molar ratio increased significantly following GH administration (P<0.001), and a higher ratio was obtained following i.v. infusion (P<0.005). Subcutaneous GH infusion resulted in significantly lower mean levels of serum NEFA (P<0.02), whereas similar mean levels of serum insulin (P=0.54), blood glucose (P=0.24), energy expenditure (P=0.13), and respiratory exchange ratio (P=0.09) were observed on the two occasions.

CONCLUSIONS A reduced bioavailability of s.c. as compared with i.v. administered GH has been recorded with two independent GH assays, and this was also accompanied by a significant, albeit modest, reduction in biological activity.
Ethnicity affects IGFBP‐3 and IGF‐II in normal healthy young adult subjects
Authors: Hopkins K. D. , Lehmann E. D. , Jones R. L. , Holly J. M. P. , Cwyfan‐Hughes S. C. , Turay R. C. , Teale J. D. , Gosling R. G.
Published: November 2003

OBJECTIVE While the effects of age on the growth hormone/insulin‐like growth factor (IGF) axis are well documented, the influence of ethnic background is unknown. The differences in IGF and IGF binding proteins (IGFBPs) were investigated in two ethnic groups.

DESIGN A cross‐sectional study of an age‐selected cohort of healthy, normoglycaemic, non‐obese Caucasian (C) and Asian (A) subjects.

PATIENTS Fifty‐three (27 C, 26 A) subjects with a mean age (±SD) of 20.6±0.8 years were studied.

MEASUREMENTS Fasting measurements of glucose, insulin, IGF‐I, IGF‐II, IGFBP‐1 and IGFBP‐3. Western ligand blotting and immunoblotting with IGFBP‐2 and IGFBP‐3 of serum samples.

RESULTS There were no significant differences in IGF‐I levels between Caucasian and Asian subjects (C 218±55 vs A 229±40μg/l; P=0.44). IGF‐II (C 707±110 vs A 583±75μg/l; P<0.0001) and IGFBP‐3 (C 5.9±1.2 vs A 5.12±1.17 mg/l; P=0.01) levels were significantly higher in Caucasian subjects. Immunoblotting of ligand blots revealed no protease activity on either IGFBP‐3 or IGFBP‐2 to account for these ethnic differences.

CONCLUSIONS Ethnic differences in IGFBP‐3 and associated IGF‐II levels may affect the inter‐relationships of IGFs and their binding proteins and need to be considered when interpreting IGF data on growth and metabolism.
Long‐term cardiovascular effects of growth hormone treatment in GH‐deficient adults Preliminary data in a small group of patients
Authors: Johannsson Gudmundur , Bengtsson Bengt‐Åke , Andersson Bert , Isgaard Jörgen , Caidahl Kenneth
Published: November 2003

OBJECTIVE The long‐term cardiovascular effects of GH administration in adults are of major clinical importance, given the increasing use of such treatment. We have evaluated long‐term cardiovascular effects of recombinant human GH (rhGH) substitution in GH deficient men.

DESIGN S.c. rhGH 0.5 U/kg/week or placebo was administered in a 6‐month double‐blind, cross‐over study, followed (after a year without substitution) by a 42‐month period of open GH substitution.

PATIENTS We evaluated 7 GH‐deficient men serially and compared the results with 21 men matched in terms of age and height.

MEASUREMENTS Investigations included exercise tests and Doppler‐echocardiography to determine exercise capacity and cardiovascular performance.

RESULTS Heart rate and systolic blood pressure at rest increased with GH substitution to the level of the controls, as did diastolic blood pressure after an initial reduction. Age‐adjusted exercise capacity increased during the study and we found no evidence of ischaemic heart disease on exercise ECG. Stroke volume increased with GH substitution, thereby normalizing the initially reduced cardiac index. There was no significant change in left atrial or ventricular internal dimensions, systolic function as measured by fractional shortening, or diastolic function as measured by isovolumic relaxation time and left ventricular filling (A/E ratio). However, a lower atrial emptying index than that seen among controls might indicate some diastolic disturbance and there was a definite increase in left ventricular wall thickness compared with controls (to 25.1±1.5 vs 19.7±0.4 mm, P<0.001).

CONCLUSIONS We found that GH substitution in GH‐deficient adults had a beneficial effect on physical performance and cardiac output. The concomitant increase in left ventricular mass index might be an effect of an excessive substitution dose.
Immunological and chemical types of reversible hypothyroidism; clinical characteristics and long‐term prognosis
Authors: Sato Kaori , Okamura Ken , Hirata Tsuneo , Yamasaki Kouji , Ikenoue Hiroshi , Kuroda Takeo , Mizokami Tetsuya , Inokuchi Kaeko , Fujishima Masatoshi
Published: November 2003

OBJECTIVE Spontaneous improvement occurs in about one‐half of patients with primary hypothyroidism who reside in an iodine‐sufficient area of Japan, but the pathogenetic factors related to reversible hypothyroidism are still not fully understood. We therefore investigated the clinical features and prognosis of patients with reversible hypothyroidism with or without iodine excess and antithyroid antibodies.

DESIGN Amelioration of hypothyroidism was diagnosed when the elevated serum TSH concentrations (serum TSH concentration ≥ 40 mU/l) decreased by 50% or more during an iodine restriction period of 2–15 weeks without replacement therapy. Reversible hypothyroidism occurred in a post‐partum group (n = 20) and a non‐post‐partum group (n = 91).

The latter was then further classified into chemical (n = 28), immunological (n = 20), and mixed (n = 43) groups, according to the presence of iodine excess (serum non‐hormonal iodine level > 50 μg/l or a history of excess iodine ingestion), antithyroid autoantibody, or both, respectively.

MEASUREMENTS Clinical characteristics and long‐term prognosis were compared among the four groups. The rate at which hypothyroidism recovered was expressed as the number of days required for a 50% decrease in the serum TSH concentration. The level of thyroid echogenicity was measured by 10‐MHz ultrasonography.

RESULTS In the chemical group, the mean age, male : female ratio, and serum non‐hormonal iodine concentrations were all higher than those in the immunological group. The estimated rate at which hypothyroidism recovered was rapid (6.1 ± 3.1 (mean ± SD) days), the levels of thyroid echogenicity were near normal, and a histological examination (n = 7) revealed either colloid goitre or a normal thyroid in the chemical group. In the immunological and post‐partum groups, the recovery rate was slow (16.8 ± 9.6 days and 16.2 ± 5.8 days, respectively). The levels of thyroid echogenicity were markedly reduced but increased after the spontaneous recovery of the thyroid function in both groups. Aspiration cytology suggested lymphocytic infiltration in all patients examined in the immunological (n = 6) and post‐partum groups (n = 4). Relapse to overt hypothyroidism was observed more frequently in the immunological (38%) and mixed groups (35%) than in the chemical group (5%).

CONCLUSION Thyroid damage was more severe, recovery slower and the rate of relapse higher in the immunological than in the chemical type of reversible hypothyroidism.
Hyperprolactinaemia and verapamil: prevalence and potential association with hypogonadism in men
Authors: Romeo June H. , Dombrowski Robert , Kwak Yun S. , Fuehrer Susan , Aron David C.
Published: November 2003

OBJECTIVE Verapamil has been associated with hyperprolactinaemia, but there have been no population‐based studies. Our objective was to determine the prevalence and degree of hyperprolactinaemia associated with verapamil in the clinical setting.

DESIGN Observation with cross‐sectional and longitudinal components in the setting of an urban teaching hospital and its satellite out‐patient clinics.

PATIENTS Male out‐patients excluding those taking other drugs known to raise PRL, renal failure and known primary hypothyroidism (1265 eligible subjects). Control subjects were drawn from eligible out‐patients not taking verapamil.

MEASUREMENTS Serum PRL levels, frequency of persistent hyperprolactinaemia and total testosterone levels.

RESULTS Prolactin levels were obtained in 449 subjects on verapamil (35.5% response rate) and 166 controls. The proportions of individuals with hyperprolactinaemia (PRL > 460 mU/l) were 0.085 and 0.030 in the verapamil and control groups, respectively (P = 0.012, χ2‐test). The mean (±SD) serum PRL levels were 267 ± 205 and 203 ±118 mU/l in the verapamil and control groups, respectively (P < 0.001, independent t‐test). Of the 38 patients with previously determined elevated PRL levels, follow‐up data were obtained in 25 (65.8%); one was found to have a pituitary adenoma and was excluded from the analysis. Fifteen of the 24 were still on verapamil (Group 1) and 14 (93.3%) continued to be hyperprolactinaemic. In 9 patients verapamil had been discontinued (Group 2) and all had normal PRL levels. Continued verapamil use was associated with persistent hyperprolactinaemia (odds ratio > 120, P < 0.00001). The ± SD serum testosterone levels at follow‐up were significantly lower in Group 1 (6.16 ± 2.52 nmol/l) than in Group 2 (9.42 ± 3.92 nmol/l, P = 0.029, independent t‐test).

CONCLUSIONS The prevalence of hyperprolactinaemia associated with verapamil use in this study of male out‐patients was .5% (95% Cl 5.9–11.1%). The persistence of hyperprolactinaemia when verapamil was continued (Group 1) and the return to normal PRL levels when verapamil was discontinued (Group 2) confirm verapamil’s causal role in the development of hyperprolactinaemia. While low testosterone levels were common in both groups, testosterone levels were lower in patients on verapamil. Our data suggest that screening for hyperprolactinaemia should be considered in male patients taking verapamil.
Failure of the short ACTH test to unequivocally diagnose long‐standing symptomatic secondary hypoadrenalism
Authors: Soule Steven G. , Fahie‐Wilson Michael , Tomlinson Sophie
Published: November 2003

Recent guidelines propose that secondary hypoadrenalism can be reliably diagnosed, in the absence of acute ACTH deficiency or glucocorticoid use, by means of the short ACTH test (Synacthen). We report a patient who maintained a normal response to exogenous ACTH stimulation despite symptomatic chronic ACTH deficiency proven by the insulin tolerance and overnight metyrapone tests. It is suggested that partial ACTH deficiency may prevent involution of the adrenal cortex and preserve the cortisol response to ACTH stimulation. A normal cortisol response in the short ACTH test does not therefore exclude the possibility of clinically relevant ACTH deficiency.
Effect of follicle stimulating hormone or human chorionic gonadotrophin treatment on the production of gonadotrophin surge attenuating factor (GnSAF) during the luteal phase of the human menstrual cycle
Authors: Messinis I. E. , Lolis D. , Zikopoulos K. , Milingos S. , Kollios G. , Seferiadis K. , Templeton A. A.
Published: November 2003

OBJECTIVE Although there is much in‐vivo evidence for the existence of a gonadotrophin surge attenuating factor (GnSAF), its source and identity remain unknown. We have studied the control of GnSAF production by FSH and hCG during the luteal phase of the cycle.

DESIGN Normally cycling women were investigated in three cycle. Starting on day 5 after the midcycle LH peak, the women received i.m. injections of placebo (1st cycle control), hCG at a dose of 750 IU per day (2nd cycle) and FSH at a dose of 225 IU per day (3rd cycle) for five consecutive days. The response of LH to a single i.v. dose of 10 μg GnRH (GnSAF bioactivity) was investigated several times during the experimental period.

PATIENTS Six normally ovulating women with long‐standing unexplained infertility were studied. The women were used as their own controls during the cycle treated with placebo.

MEASUREMENTS Pituitary response to GnRH was calculated as the net increase in LH at 30 minutes (ΔLH) above the basal value.

RESULTS Serum concentrations of FSH and hCG increased significantly during the second and 3rd cycles respectively. Compared with the control cycles, ΔLH was significantly attenuated as early as 12 hours from the onset of FSH injections. In contrast, basal concentrations of oestradiol (E2) and immunoreactive inhibin started to increase 48 hours after the first injection of FSH, while progesterone values remained similar to those in the controls. During treatment with hCG, no attenuation was seen in ΔLH values, while those of E2, progesterone and inhibin showed a significant increase.

CONCLUSIONS These results demonstrate that during the luteal phase of the human menstrual cycle, FSH, but not LH, stimulates the production of gonadotrophin surge attenuating factor. It is suggested that the source of gonadotrophin surge attenuating factor at that stage of the cycle is a cohort of small follicles rather than the corpus luteum.
A low dose ACTH test to assess the function of the hypothalamic–pituitary–adrenal axis
Authors: Rasmuson S. , Olsson T. , Hägg E.
Published: November 2003

OBJECTIVE The insulin tolerance test (ITT) has long been used to assess the hypothalamic–pituitary–adrenal axis, but may be hazardous. The standard synthetic ACTH (Synacthen) test has been advocated as a substitute but is sometimes insensitive. In this study the ITT has been compared to a low dose ACTH stimulation test (1 μg) and the standard ACTH stimulation test (250 μg).

SUBJECTS Twenty‐seven subjects were studied, 24 with verified or suspected hypothalamic–pituitary disorders and three on long‐term glucocorticoid therapy.

DESIGN Insulin tolerance, low dose ACTH and standard ACTH tests were performed in all patients. The ITT was performed less than 48 hours after the ACTH tests. Synacthen was administered as an intravenous bolus.

MEASUREMENTS Serum cortisol values were determined by radioimmunoassay. The peak cortisol value during ITT was compared to the cortisol levels during the ACTH tests.

RESULTS There was a highly significant correlation between peak cortisol values during ITT and cortisol levels after 20–60 minutes in the low dose ACTH test (rs = 0.91–0.93; P< 0.0001) and after 30 and 60 minutes in the standard ACTH test (rs= 0.85 and 0.89 respectively; P< 0.0001). Four patients showed discrepancies between the three tests.

CONCLUSIONS The 1‐μg ACTH test follows the ITT more closely and may be more sensitive than the standard ACTH test in detecting more subtle insufficiency of the hypothalamic–pituitary–adrenal axis. The standard ACTH test and the insulin tolerance test may thus be replaced by the 1‐μg ACTH test in screening for secondary cortisol insufficiency. We recommend that serum cortisol is measured before and 30 and 40 minutes after the ACTH injection.
Flow cytometric analysis does not reliably differentiate benign from malignant phaeochromocytoma
Authors: Heaney A. P. , O'Rourke D. , Arthur K. , Beatty O. L. , Russell C. F. J. , Sloan J. M. , Hamilton P. , Atkinson A. B.
Published: November 2003

BACKGROUND AND OBJECTIVE The differentiation of benign from malignant phaeochromocytoma is difficult. We have examined whether the use of flow cytometric determination of nuclear DNA content would be useful as a predictor of malignant behaviour in patients with phaeochromocytoma as some previous studies had suggested that a diploid cytometric DNA pattern indicated benign disease.

DESIGN AND PATIENTS  DNA flow cytometry was performed on phaeochromocytoma tissue from 36 patients (19 female, 17 male; mean age at presentation 39.5 years). The results were correlated with clinical outcome after prolonged follow‐up.

MEASUREMENTS DNA histograms were constructed following nuclear suspension analysis.

RESULTS Of 26 patients followed up for more than 5 years after initial removal of primary phaeochromocytoma, three have died from malignant recurrence. In these patients a diploid DNA cytometric pattern was observed in two and an aneuploid pattern in one. Twenty‐one patients are still alive. DNA cytometry showed a diploid pattern in the one patient who developed recurrent phaeochromocytoma 4 years after removal of a primary tumour.

CONCLUSION In this study, three of nine patients with an apparently benign diploid cytometric pattern subsequently developed recurrent disease. Routine use of DNA flow cytometry did not reliably differentiate benign from malignant phaeochromocytoma. Prolonged clinical and biochemical follow‐up is still necessary for all patients with this condition.
FSH isoforms: bio and immuno‐activities in post‐menopausal and normal menstruating women
Authors: Creus Silvina , Pellizzari Eliana , Cigorraga Selva B. , Campo Stella
Published: November 2003

OBJECTIVE The full expression of gonadotrophin biological activity depends on the gonadotrophin carbohydrate component. Our aim was to study serum FSH isoforms present in the follicular phase (FPS) and in the menopause (PMS) since the endocrine status may influence the structure of incorporated oligosaccharides.

SUBJECTS Ten healthy post‐menopausal women (age range 53–68) not receiving any hormonal treatment and 10 healthy women (age range 20–28) in the follicular phase of their menstrual cycle were studied.

MEASUREMENTS Bio and immuno FSH‐activities (Sertoli cell aromatase induction assay and RIA, respectively) were determined in separated isoforms after concanavalin A chromatography. Isolated isoforms were: UB, unbound; WB, weakly bound and FB, firmly bound to the lectin.

RESULTS PMS showed two groups of immuno and bio‐active FSH isoforms: WB, bearing biantennary galactosylated type and FB, bearing high mannose or hybrid type oligosaccharides. Immuno and bio‐active FSH were not detected in the UB fractions. WB isoforms represented 82 ± 6% of the total bioactivity recovered in samples analysed individually; their B/I ratio was 0.85 ± 0.20. FB isoforms were 18 ± 6%; their B/I ratio was 3.27 ± 0.60. Whole serum B/I ratio was 1.20 ± 0.30. Similar results were obtained when pooled sera was analysed: WB: 77%, B/I: 0.82; FB: 23%, B/I: 3.75. Whole serum B/I in pooled samples was 1.10. FPS showed a different pattern. UB isoforms, bearing triantennary or bisecting oligosaccharides, were 41 ±3% of the total bioactivity recovered in samples analysed individually. Their B/I ratio was 0.61 ± 0.23. WB isoforms were 59 ± 3% and their B/I 0.76 ± 0.14. FB FSH isoforms were not detected. The whole serum B/I ratio was 0.60 ± 0.30. Similar results were obtained when pooled sera was analysed: WB 43%, B/I 0.42; FB 57%, B/I 0.62. Whole serum B/I in pooled samples was 0.70.

CONCLUSIONS These results show that, in normal women, circulating FSH bioactivity is associated with isoforms with different oligosacharide structures according to hormonal status. FSH in the follicular phase has a higher degree of branching and a more complete carbohydrate chain than the FSH secreted during the menopause.
Genetic analysis of seven Mediterranean families with multiple endocrine neoplasia type 2A
Authors: Oriola Josep , Hernandez Cristina , Simo Rafael , Barceló Anna , Casamitjana Roser , Vilardell Enric , Rivera‐Fillat Francisca
Published: November 2003

OBJECTIVE  Genetic analysis is now essential for the accurate screening of families with multiple endocrine neoplasia type 2 (MEN2). We present the genetic analyses by both haplotype and direct RET proto‐oncogene mutation analysis in seven Mediterranean MEN 2A families and have compared these results with biochemical screening tests and pathological examinations.

DESIGN Total DNA was extracted from leucocytes. Linkage analysis was performed using five RFLP systems from three loci that flank the MEN2A locus (FNRB, RBP3, D10S15). RET proto‐oncogene analysis was carried out by automatic DNA sequencing and adequate digestion of PCR amplified products for exons 10 and 11. Screening for medullary thyroid carcinoma or C‐cell hyperplasia was performed by the pentagastrin provocation test. Adrenal medullary function was assessed by measurements of 24‐hour urinary excretion of catecholamines and their metabolites. Serum calcium and phosphate measurements were the initial screen for hyperparathyroidism. Serum PTH was determined only if hyperparathyroidism was suggested by the former determinations.

PATIENT  Genetic study was performed in 59 individuals (39 at risk) from seven kindreds of Mediterranean origin with MEN 2A.

RESULTS  Diagnosis by linkage analysis was not possible in 30% of individuals at risk, but RET proto‐oncogene analysis identified all these individuals. Mutations of the RET proto‐oncogene were detected in exon 10 (codon 618) in one MEN 2A kindred and in exon 11 (codon 634) in the others. The results of direct analysis were concordant with linkage studies in each case. Three individuals from different MEN 2A kindreds, who were subsequently shown not to be gene carriers, had false positive pentagastrin stimulation tests.

CONCLUSION  Biochemical tests can be replaced by direct DNA mutation analysis as the first line screening test in order to identify gene carriers of MEN 2A.
Non‐islet cell tumour‐associated hypoglycaemia: 111In‐octreotide imaging and efficacy of octreotide, growth hormone and glucocorticosteroids
Authors: Perros Petros , Simpson John , Innes J. Alistair , Teale J. Derrick , McKnight John A.
Published: November 2003

A patient presented with frequent episodes of spontaneous hypoglycaemia due to a solitary fibrous tumour of pleural origin, secreting incompletely processed pro‐insulin‐like growth factor II (big IGF‐II). Somatostatin receptors were demonstrated in the tumour by 111In‐labelled octreotide scintigraphy, but despite maximal doses of octreotide, there was no suppression of big IGF‐II secretion and the hypoglycaemia persisted. The combination of GH and glucocorticoid therapy abolished the hypoglycaemia.
Hypogonadotrophic hypogonadism and primary amenorrhoea associated with increased melatonin secretion from a cystic pineal lesion
Authors: Walker A. B. , English J. , Arendt J. , MacFarlane I. A.
Published: November 2003

A 17‐year‐old girl presented with primary amenorrhoea and failure to develop secondary sexual characteristics, although her height was above the 90th centile. Endocrine investigations revealed hypogonadotrophic hypogonadism (basal LH and FSH levels <0.5 U/l; FSH rose to 2.0 U/l and LH to 1.0 U/l after GnRH). ACTH, GH, TSH and PRL secretion were normal. A magnetic resonance scan revealed no abnormality in the pituitary, pituitary stalk or hypothalamus but demonstrated a partly cystic enhancing lesion in the pineal region. Melatonin production (assessed as urinary 6‐sulphatoxymelatonin: aMT6s) at baseline was markedly increased: 459–530 ng/kg/24 h compared with aged‐matched controls: 136±69 (P=0.01). However, melatonin production retained a largely normal rhythm with increased production during the night. Treatment with ethinyloestradiol 100 μg daily had no apparent effect on the production of melatonin. Treatment with atenolol, 100 mg daily at 1600 h, was associated with suppression of nocturnal melatonin secretion but a brisk rebound in the morning and a considerably delayed peak excretion time (10.2 h) compared with controls (3.9 h). It is likely the pineal lesion, which may be hyperplasia or possibly even tumour, was responsible for the increased melatonin secretion. These data support the hypothesis that melatonin may have a causal role in hypogonadotrophic hypogonadism.
Effect of thyroid substitution on hypercholesterolaemia in patients with subclinical hypothyroidism: a reanalysis of intervention studies
Authors: Tanis Bea C. , Westendorp Rudi G. J. , Smelt Augustinus H. M.
Published: November 2003

OBJECTIVE The significance of mild hypercholesterolaemia in subclinical hypothyroidism and whether there is beneficial reduction after thyroxine replacement, remain controversial. We aimed to describe the association between hypercholesterolaemia and subclinical hypothyroidism, and to quantify the effect of thyroid substitution therapy by an analysis of previously published intervention studies.

DATA SOURCES Intervention studies cited in the Medline database from January 1976 until January 1995, with index terms cholesterol, hypercholesterolaemia, hyperlipidaemia, thyrotrophin (TSH), hypothyroidism, thyroid and human. A total of 148 studies were reviewed.

DATA EXTRACTION We recorded the year of publication, study design, number of patients enrolled, mean age, duration of thyroid substitution, normal range of TSH levels, TSH levels pre and post‐substitution treatment and total cholesterol in plasma before and after treatment.

DATA ANALYSIS (1) Qualitative description of studies on the relationship between hypercholesterolaemia and hypothyroidism, both subclinical and clinical. (2) Precision weighted pooled estimates of the effect of thyroid substitution therapy on the plasma levels of total cholesterol, in patients with subclinical and overt hypothyroidism.

RESULTS Subclinical hypothyroidism was two to three times more frequent in people with an elevated total plasma cholesterol. In addition, the total plasma cholesterol levels were slightly elevated in patients with subclinical dysfunction of the thyroid. Thyroid substitution therapy in patients with subclinical hypothyroidism, restoring the TSH levels to normal, decreased total cholesterol by 0.4 mmol/l (95% confidence interval (CI) 0.2–0.6 mmol/l) independently of the initial plasma level. The effect of thyroid substitution therapy on HDL‐cholesterol in patients with subclinical hypothyroidism was not consistent.

The effect of thyroid substitution in patients with overt hypothyroidism was highly dependent on the pretreatment levels of total cholesterol. In these patients substitution therapy decreased total cholesterol by 1.2 mmol/l (95% CI 0.9–1.5 mmol/l) when the plasma levels were elevated up to 8 mmol/l, and by 3.4 mmol/l (95% CI 3.0–3.7) when plasma levels were higher than 8 mmol/l. The high density lipoprotein (HDL)‐cholesterol level decreased and amounted to 0.16 mmol/l (95% CI 0.07–0.24).

CONCLUSIONS Thyroid substitution treatment in patients with hypercholesterolaemia and subclinical hypothyroidism decreases total plasma cholesterol by 0.4 mmol/l, but plasma levels remain elevated in most patients. Further treatment with dietary restriction and cholesterol synthesis inhibitors should then be considered.
Calcium‐sensing receptor mutations in familial hypocalciuric hypercalcaemia with recurrent pancreatitis
Authors: Pearce S. H. S. , Wooding C. , Davies M. , Tollefsen S. E. , Whyte M. P. , Thakker R. V.
Published: November 2003

OBJECTIVE Pancreatitis is an unusual complication of the benign disorder familial hypocalciuric hypercalcaemia (FHH) such that it could represent a distinct subgroup of FHH. In order to study this, we investigated three FHH kindreds with recurrent pancreatitis for mutations of the extracellular calcium‐sensing receptor (CaR) to identify a possible common genetic aetiology for typical FHH and that associated with pancreatitis.

PATIENTS AND METHODS Three FHH kindreds (18 affected, 14 unaffected members) in which the proband had presented with recurrent pancreatitis were identified. The entire 3234bp coding region of the CaR gene was examined by direct DNA sequencing using fluorochrome labelled dideoxy‐terminators. Mutations were confirmed and demonstrated to co‐segregate with FHH by restriction enzyme analysis.

RESULTS Three novel heterozygous missense mutations (Asn178Asp, Arg220Gln and Pro221Ser) in the extracellular domain of the CaR were identified in each of the probands. These mutations, which co‐segregated with the hypercalcaemia, were not detected as common polymorphisms in 55 unrelated normocalcaemic controls.

CONCLUSIONS Familial hypocalciuric hypercalcaemia with recurrent pancreatitis is associated with calcium‐sensing receptor mutations, and thus this variant has the same genetic aetiology as typical familial hypocalciuric hypercalcaemia.
Thyroid autoimmune disorders in patients with chronic hepatitis C before and during interferon‐α therapy
Authors: Marazuela M. , García‐Buey L. , González‐Fernández B. , García‐Monzón C. , Arranz A. , Borque M. J. , Moreno‐Otero R.
Published: November 2003

BACKGROUND AND AIMS Hepatitis C virus is involved in the induction of autoimmunity and interferon can also induce hepatic and non‐hepatic autoimmune reactions. This study assessed the prevalence of thyroid autoantibodies and autoimmune thyroid disorders in patients with chronic hepatitis C before and during interferon therapy.

PATIENTS AND METHODS We studied prospectively 207 patients positive for anti‐HCV and viral RNA. One hundred and forty‐four of them received a therapeutic trial of one year with interferon‐α. Free thyroxine, TSH and autoantibodies to thyroglobulin and thyroid microsomes were systematically tested at entry and at weeks 12 and 24 in both untreated and treated patients.

RESULTS Sixteen of the 207 patients (7.7%) had thyroid dysfunction, including positive antithyroid antibodies in 14 (6.7%) and hypothyroidism in 10 (4.8%) prior to interferon therapy. In addition, during pretreatment evaluation one patient developed clinical hyperthyroidism after transient subclinical hypothyroidism and another had subclinical hyperthyroidism. Prevalences of positive antithyroid antibodies and hypothyroidism were significantly higher in women (14.7 and 10.5%, respectively, vs 0% in men, P < 0.01) and were directly associated with increasing age (P < 0.01). The incidence of thyroid dysfunction was also significantly higher in patients with other autoantibodies such as anti‐nuclear (ANA) (P < 0.01). A trial with interferon was initiated in 144 patients and 8 of 142 (5.6%) without previous thyroid abnormalities developed thyroid dysfunction, including positive antithyroid antibodies in 7 (4.9%) and hypothyroidism in 4 (2.8%) with a prevalence again significantly higher in women (12.7 and 8.3%, respectively, vs 1% in men, P < 0.01) and also directly related to increasing age (P < 0.01). An association was found between the development of thyroid dysfunction during interferon therapy and the presence of other autoantibodies, including ANA, anti‐DNA and anti‐Sjögren’s antibodies (P < 0.01), as well as with the induction of autoimmune hepatitis and Sjögren's syndrome (P < 0.01 and < 0.05 respectively). Thyroid abnormalities were reversed in all patients when interferon therapy was discontinued.

CONCLUSIONS No significant association was found between chronic hepatitis C and the presence of thyroid autoimmunity in female patients. On the contrary, interferon therapy induced antithyroid autoantibodies and thyroid dysfunction de novo in patients with chronic hepatitis C without pre‐existing thyroid abnormalities. Thyroid dysfunction secondary to interferon was reversible after discontinuation of therapy.
Thyroid involvement by malignant histiocytosis of Langerhans' cell type
Authors: Kitahama Shinji , Iitaka Makoto , Shimizu Tadashi , Serizawa Naoki , Fukasawa Nobuhiko , Miura Shiro , Kawasaki Satomi , Yamanaka Kayo , Kawakami Yoshito , Murakami Saburo , Ishii Jun , Katayama Shigehiro
Published: November 2003

Involvement of the thyroid gland by Langerhans' cell histiocytosis is quite rare. We describe the case of a 58‐year‐old man referred for treatment of a progressively enlarging goitre. The trachea was severely stenotic and adjacent structures such as the left carotid vein and the thyroid cartilage were also involved. Central diabetes insipidus and severe combined immunodeficiency were associated. Although fine needle aspiration biopsy of the thyroid was initially interpreted as papillary carcinoma, anaplastic thyroid cancer was suspected. Treatment with prednisolone, doxorubicin and irradiation controlled the tracheal compression. A diagnosis of thyroid Langerhans' cell histiocytosis was finally made on the basis of the presence of Birbeck granules and CD1a and CD4 antigen in the thyroid tumour cells. Furthermore, positive staining for CD68 and lysozyme suggested that the tumour cells may have had the character of phagocytic cells in addition to their dendritic cell nature. This is the first case of thyroid involvement by malignant histicytosis of Langerhans' cell type with unusual phagocytic markers.
Hormone replacement therapy is associated with improved arterial physiology in healthy post‐menopausal women
Authors: McCrohon Jane A. , Adams Mark R. , McCredie Robyn J. , Robinson Jacqui , Pike Anne , Abbey Mavis , Keech Anthony C. , Celermajer David S.
Published: November 2003

OBJECTIVE Oestrogen replacement therapy is associated with a marked reduction in coronary event rates in post‐menopausal women. As older age is associated with progressive arterial endothelial damage, a key event in atherosclerosis, we assessed whether hormone replacement therapy (HRT) with oestrogen alone, or oestrogen and progesterone combined, is associated with improved endothelial function in healthy women after the menopause.

DESIGN Using high resolution external vascular ultrasound, brachial artery diameter was measured at rest and in response to reactive hyperaemia, with increased flow causing endothelium‐dependent dilatation (flow‐mediated dilatation).

PATIENTS  We investigated 135 healthy women; 40 were pre‐menopausal (mean±SD age/26±6 years, group 1), 40 were post‐menopausal and had never taken HRT (aged 58±3 years; group 2) and 55 were age‐matched post‐menopausal women who had taken HRT for >2 years, from within 2 years of the menopause (aged 57±4 years; group 3). In group 3, 40 women were on combined oestrogen and progesterone and 15 on oestrogen‐only HRT.

RESULTS In group 2, flow‐mediated dilatation was significantly reduced compared with group 1 (4.4±3.4 vs 9.6±3.6%, P<0.001), consistent with a decline in arterial endothelial function after the menopause. In group 3, however, flow‐mediated dilatation was significantly better than group 2 (6.2±3.3 vs 4.4±3.4%, P=0.01), suggesting a protective effect of HRT. Flow‐mediated dilatation was similar in women taking oestrogen alone and in those on combined HRT (5.5±2.8 vs 6.5±3.4%, P=0.40).

CONCLUSIONS Long‐term HRT is associated with improved arterial endothelial function in healthy post‐menopausal women. This benefit was observed in both the combined hormone replacement and unopposed oestrogen therapy groups. This may explain some of the apparent cardioprotective effect of HRT after the menopause.
Retrospective analysis of long‐term surgical results in acromegaly: preoperative and postoperative factors predicting outcome
Authors: Yamada Shozo , Aiba Tadashi , Takada Kouji , Ozawa Yasunori , Shimizu Taeko , Sawano Shinji , Shishiba Yoshimasa , Sano Toshiaki
Published: November 2003

OBJECTIVE Sixty‐one of 83 patients with acromegaly treated between 1969 and 1993 were analysed retrospectively to clarify which early postoperative factors were significant predictors of a successful long‐term outcome and which preoperative factors significantly influenced the early postoperative results.

PATIENTS Of the 61 patients, 30 were operated on before 1987 and 31 afterwards. A successful long‐term surgical outcome was defined as a long‐term mean basal GH level <6 mU/l (comparable to <3 μg/l), a normal IGF‐I level, and normal GH dynamics.

RESULTS Overall, 59% of patients (37% before 1987 and 81% after) had an early postoperative mean basal GH level <6 mU/l, and 56% (29% before 1987 and 77% after) met all three of the specified criteria for a successful long‐term surgical outcome. Statistical analysis confirmed that GH dynamics and postoperative mean basal GH level <6 mU/l were significant predictors of the long‐term surgical outcome, whereas the postoperative IGF‐I level alone was not. On the other hand, abnormal preoperative GH dynamics were normalized in all patients with a postoperative mean basal level <6 mU/l. In addition, there were no patients showing an unsuccessful long‐term outcome in those associated with both the early postoperative mean basal GH level <6 mU/l and normalization of the IGF‐I level. Therefore, measurement of the early postoperative mean basal GH level and the IGF‐I level may be an economical and simple guide to predict the long‐term surgical outcome. Moreover, multivariate analysis indicated that cavernous sinus invasion was an independent significant factor influencing the early postoperative outcome.

CONCLUSIONS Successful long‐term surgical outcome may be predicted if early postoperative mean basal GH level is reduced to <6 mU/l (<3 μg/l) and IGF‐I level becomes normal. This study also confirms that early diagnosis and treatment by an experienced endocrinologist and neurosurgeon can improve the operative results in patients with acromegaly.
Smoking and endocrine ophthalmopathy: impact of smoking severity and current vs lifetime cigarette consumption
Authors: Pfeilschifter Johannes , Ziegler Reinhard
Published: November 2003

OBJECTIVE Smoking has been associated with an increased incidence of endocrine ophthalmopathy (EO). In this study we examined the relation between smoking severity and the incidence of EO symptoms in patients with Graves’ hyperthyroidism.

DESIGN Patients were prospectively followed for at least one year after the onset of hyperthyroidism. Smoking and EO status were evaluated at 3−6‐ months intervals.

PATIENTS Two hundred and fifty‐three ambulatory patients with recent onset of Graves’ hyperthyroidism were studied.

MEASUREMENTS The incidence of total EO symptoms, proptosis, and diplopia at any time point before and after the occurrence of Graves’ hyperthyroidism was assessed by interview and physical examination.

RESULTS Smoking was associated with a 1.3‐fold increase in the overall incidence of symptomatic EO, and a 2.6 and 3.1‐fold increase in the incidence of proptosis and diplopia, respectively. The relative risk increased in parallel with the current number of cigarettes smoked per day. In contrast, lifetime tobacco use was not an independent risk factor for the development of EO symptoms. Former smokers had a significantly lower risk for the occurrence of proptosis and diplopia than active smokers with a comparable lifetime cigarette consumption.

CONCLUSIONS Our data suggest that current, but not lifetime, tobacco consumption constitutes a risk for the incidence of proptosis and diplopia in patients with Graves’ hyperthyroidism, and that this risk increases with smoking severity.
Thyroid function in idiopathic oedema
Authors: Czapla K. , Farish E. , Haynes E. C. M. , Henderson J. B. , Pelosi A. J. , Dunnigan M. G.
Published: November 2003

BACKGROUND The role of abnormal thyroid function in the aetiology of idiopathic oedema is unclear. Previous studies of small samples of patients have suggested a high prevalence of latent hypothyroidism and a possible deiodination defect in the conversion of T4 to T3 in this condition. There is a need to clarify the possible significance of abnormal thyroid function in a larger sample of idiopathic oedema patients.

OBJECTIVE The study was undertaken to compare basal thyroid function in idiopathic oedema patients and in an age and sex‐matched control group.

PATIENTS AND DESIGN After excluding one idiopathic oedema patient and three control subjects with abnormal thyroid function, basal thyroid function was compared in 44 idiopathic oedema patients and in 44 age and sex‐matched controls.

MEASUREMENTS Basal thyroid function was assessed in patient and control groups by measuring serum T4, fT4, T3, fT3 and TSH by standard methods.

RESULTS There were no significant differences in basal thyroid function between patient and control groups except for an elevated mean fT4 concentration in the idiopathic oedema group (P = 0.03). Exclusion of patients and controls taking oestrogen abolished this difference. T4 : T3 ratios were similar in patient and control groups.

CONCLUSION Abnormalities of basal thyroid function are uncommon in patients with idiopathic oedema and appear unrelated to the pathogenesis of this disorder. Similar T4 : T3 ratios between patient and control groups exclude a deiodination defect in idiopathic oedema.
Low‐dose growth hormone replacement lowers plasma leptin and fat stores without affecting body mass index in adults with growth hormone deficiency
Authors: Florkowski C. M. , Collier G. R. , Zimmet P. Z. , Livesey J. H. , Espiner E. A. , Donald R. A.
Published: November 2003

OBJECTIVE The ob gene product, leptin, is considered to be a marker of adipose tissue mass and a possible homeostatic regulator of body mass. Our objective was to examine the effect of GH replacement on adipose tissue stores and leptin in adult hypopituitarism.

SUBJECTS Twenty adults, mean age 47 years (range 20–69) with proven GH deficiency were randomly allocated to either GH (up to 0.25 U/kg/week in daily doses) or placebo for 3 months before cross‐over to the opposite treatment.

MEASUREMENTS Body composition was measured by dual‐energy X‐ray absorptiometry (DEXA) in the whole body, trunk and limbs. Plasma leptin was measured by radioimmunoassay at baseline and +2, +4, +8 and +12 weeks in each treatment arm.

RESULTS Total body tissue fat (mean±SE) was 30.1±2.2% after GH compared with 31.9±2.2% after placebo, P<0.001 (ANOVA). There were no significant changes in BMI (kg/m2), 29.1±1.3 after placebo vs 28.8±1.2 after GH; or waist to hip ratio (WHR), 0.91±0.01 after both placebo and GH. Baseline plasma leptin showed a significant correlation with baseline BMI, r=0.67, P<0.005 and baseline percentage total body fat, R=0.89, P<0.001. Plasma leptin (adjusted by using baseline percentage total body fat as a covariate) showed a significant linear decrease with time on GH compared with placebo (P=0.03 ANOVA).

CONCLUSIONS Plasma leptin and total body fat fall promptly in response to low‐dose replacement of GH in GH‐deficient subjects. Hormone‐induced changes in leptin can occur in humans in the absence of change in body mass index.