bluuebunny/crossref_metadata_2025 huggingface dataset:
Elevated inferior petrosal sinus levels of PTHrP in a patient with Cushing's disease
Authors: Höfle G. , Gasser R. W. , Buchfelder M. , Fahlbusch R. , Waldenberger P. , Finkenstedt G.
Published: March 2003

PTHrP has been found in various tissues, including prolactinomas and growth hormone producing adenomas. The function and clinical importance of PTHrP are poorly understood.

We report the case of a 25‐year‐old female patient with hirsutism. Autonomous ACTH‐dependent hypercortisolism was documented by endocrine testing. Magnetic resonance imaging (MRI) revealed a 3‐mm intrasellar hypointense lesion in the left side of the pituitary gland. The inferior petrosal sinus sampling disclosed a gradient of ACTH left central/peripheral of 30·5 and right central/peripheral of 2·0 and suggested the diagnosis of a left‐sided pituitary ACTH secreting microadenoma.

Interestingly, we found elevated PTHrP levels in the left inferior petrosal sinus with a gradient of 4·7 compared to peripheral venous blood and of 3·6 compared to the right sinus.

Our results fit very well to the concept of a para‐/autocrine secretion of PTHrP which has been proposed recently and suggest a role in the regulation of cell growth of pituitary adenomas.
Smaller LDL particle size in women with polycystic ovary syndrome compared to controls
Authors: Dejager S. , Pichard C. , Giral P. , Bruckert E. , Federspield M.C. , Beucler I. , Turpin G.
Published: March 2003

OBJECTIVE Women with polycystic ovary syndrome (PCOS) have an increased risk of cardiovascular disease. The contribution of lipid abnormalities to this higher risk, in particular atherogenic modifications of low density lipoprotein (LDL) such as a shift towards smaller LDL, has not been properly explored. We aimed to examine LDL size variation in relation to androgens and other risk factors in women with PCOS.

DESIGN Comparison of clinical and biochemical measurements in women with PCOS and women with normal ovarian function, of similar age and body mass index (BMI).

PATIENTS Thirty‐one women with PCOS and 27 controls were studied. Patients were recruited from the outpatient endocrine clinic.

MEASUREMENTS Fasting total cholesterol, triglycerides (TG), high density lipoprotein (HDL), LDL, glucose, insulin, gonadotrophins, androgens, oestradiol, 17 OH progesterone and SHBG were measured. LDL particle diameter was calculated based on distance travelled in polyacrylamide native gels. Recumbent blood pressure was measured automatically.

RESULTS LDL particle size appeared to be significantly smaller in hyperandrogenic PCOS as compared to regularly cycling women (P = 0006), independent of variations in lipid levels. SHBG was the only independent predictor of LDL size in this population, with a strong correlation, which persisted after adjustment for all confounding variables.

CONCLUSIONS Our results suggest that androgen excess and mild insulin‐resistance (both responsible for lower SHBG) may have an early modifying effect on low density lipoprotein size in polycystic ovary syndrome women. The denser pattern observed in polycystic ovary syndrome women could by itself constitute a higher cardiovascular risk, even in the absence of overt dyslipidaemia, and contribute to the excess risk of cardiovascular disease reported in this syndrome.
Effect of acute pharmacological modulation of plasma free fatty acids on GH secretion in acromegalic patients
Authors: Cordido Fernando , Peñalva Angela , Martinez Teresa , Casanueva Felipe F. , Dieguez Carlos
Published: March 2003

OBJECTIVES In acromegaly GH secretion is markedly increased due in most cases to a GH secreting pituitary adenoma. GH secretion is modulated by variations in the levels of free fatty acids (FFA). Recent studies in different clinical situations, have shown that reduction in FFA with acipimox (A) modifies somatotroph cell responsiveness. The aim of the present study was to evaluate the effect of acute pharmacological reduction of plasma FFA on both basal GH levels and GHRH‐mediated GH secretion in acromegalic patients.

PATIENTS Six acromegalic patients (four female, two male) aged 57 ± 4 years., with active disease due to pituitary adenomas were studied. Four of the patients had been treated previously by surgery and/or radiotherapy. The diagnosis of active acromegaly was established by clinical assessment, increased serum IGF‐I and impaired GH supression after oral glucose.

MEASUREMENTS Four tests were performed: placebo, A (250 mg, orally, − 210 minutes and − 60 minutes), GHRH (100 µg, iv, 0 minutes) and GHRH plus A. The different tests on each subject were performed in random order one week apart, each subject served as their own control. Serum GH was measured by RIA at appropriate intervals. The area under the curve (AUC) was calculated by the trapezoidal method. Statistical analysis was performed by Wilcoxon test. P < 0·05 was considered significant.

RESULTS The administration of A induced a FFA reduction during the entire test both when administered with placebo and with GHRH: AUC (mmol/l × 90 minutes): placebo plus placebo: 88·2 ± 7·3. Placebo plus A: 23·2 ± 4·6 (P < 0·05). Placebo plus GHRH: 85·4 ± 6·9. A plus GHRH: 21·8 ± 3·8 (P < 0·05). Mean peak GH level (µg/l) after placebo plus placebo was 5·0 ± 1·8 not significantly different than after placebo plus A with a mean peak of 6·2 ± 2 (P = ns). Mean peak GHRH‐induced GH secretion was 26·0 ± 15·4 and was not modified by previous A administration with mean peak of 24·4 ± 11·8 (P = ns).

CONCLUSIONS In acromegalic patients acute pharmacological reduction of FFA with acipimox did not modify basal GH levels or GHRH‐induced GH secretion, suggesting that the adenomatous somatotroph cell is unresponsive to physiological signals such as FFA which act at a pituitary level. These data support the hypothesis of an intrinsic neoplastic pituitary defect for the pathogenesis of acromegaly.
Urate and arteriosclerosis in primary hyperparathyroidism
Authors: Westerdahl J. , Valdemarsson S. , Lindblom P. , Bergenfelz A.
Published: March 2003

OBJECTIVEAn increased mortality due to cardiovascular disease has been reported in patients with primary hyperparathyroidism (pHPT). An association between urate and cardiovascular disease has been suggested. Metabolic abnormalities in pHPT may include urate. We therefore evaluated the metabolic arteriosclerotic risk profile in pHPT with special focus on the role of urate.

DESIGNRetrospective analysis of data before and 1 year after surgery for pHPT.

PATIENTS130 consecutive patients, over the age of 44 years, who underwent surgery for pHPT.

MEASUREMENTSBiochemical variables known to reflect risk of arteriosclerotic disease (AD) and renal function tests including measurement of glomerular filtration rate (GFR) were investigated before and 1 year after surgery.

RESULTSpHPT patients with AD (n = 40) were older and had higher serum levels of urate and triglyceride, and more impaired renal function in comparison with patients without AD. PTH and calcium values did not differ. Multiple logistic regression analysis indicated that urate was an independent risk factor for AD in pHPT (P < 0·01). Three variables were shown to be positively associated with urate; male gender (P < 0·01), fasting blood glucose (P < 0·05) and serum level of triglyceride (P < 0·05).

CONCLUSIONSUrate was found to be an independent risk factor for arteriosclerotic disease in primary hyperparathyroidism. Serum level of urate could (in addition to gender) be associated with a metabolic disorder comprising increased glucose and triglyceride levels.
The influence of growth hormone replacement on heart rate variability in adults with growth hormone deficiency
Authors: Leong King S. , Mann Paul , Wallymahmed Maureen , MacFarlane Ian A. , Wilding John P.H.
Published: March 2003

OBJECTIVE Growth hormone (GH) deficiency is associated with increased cardiovascular morbidity and mortality. Abnormalities in heart rate variability (HRV), a surrogate marker of cardiac autonomic tone, have also been found in untreated growth hormone deficient (GHD) patients. Similar abnormalities have been found in patients with complications postmyocardial infarction.

DESIGN AND MEASUREMENTS This study was designed to investigate whether GH treatment leads to normalization of cardiac autonomic tone.

HRV measurements were obtained from 15 minute resting ECG recordings in 11 untreated adult GHD patients (7 females; mean age 39·2 years), 10 GHD patients (6 females; mean age 46·2 years) reCENving GH replacement (mean duration, 52·7 months) and 12 healthy controls (7 females; mean age 44·6 ± 2·9 years) who were all of similar age, weight and BMI. The untreated GHD patients were then commenced on GH and HRV measurements repeated after 3 and 6 months of treatment.

RESULTS In accord with our previous findings, HRV analysis using Fast Fourier Transform (FFT) showed a distinct pattern of abnormality in GHD patients compared with controls. Specifically, there was an increase in nHF power (P = 0·04) and a reduction in nLF power (P = 0·04) (representing parasympathetic and sympathetic activity, respectively), a reduction in nVLF power (P = 0·03) and a 50% reduction in LF/HF ratio (P = 0·02) (a measure of sympathovagal balance) in GHD patients when compared with controls. HRV results in patients who have been on long‐term GH replacement were indistinguishable from controls. After 3 months GH replacement in the untreated GHD patient group, nVLF power had increased by 28% (P = 0·03) at 3 months and this was sustained at 6 months. However, no significant changes in LF and HF power were seen.

CONCLUSIONS These results suggest that abnormalities of the cardiac autonomic system in GHD patients may be correctable. Longer duration of prospective follow‐up will be required to determine at what time point improvements in the other frequency bands occur.
Differential diagnosis of polyuric/polydipsic syndromes with the aid of urinary vasopressin measurement in adults
Authors: Diederich S. , Eckmanns T. , Exner P. , Al‐Saadi N. , Bähr V. , Oelkers W.
Published: March 2003

OBJECTIVE A water deprivation test or a hypertonic saline infusion test with the measurement of plasma osmolality and plasma vasopressin are the gold standard tests in the differential diagnosis of polyuric syndromes. Because commercially available vasopressin kits are too insensitive for this approach, and the concentration of vasopressin in urine is much higher than in plasma, urinary vasopressin measurements may be an alternative to the more difficult plasma vasopressin measurement.

DESIGN The diagnostic value of the measurement of urinary vasopressin with a rather insensitive commercially available vasopressin kit was compared with plasma vasopressin measurement by a highly sensitive radioimmunoassay (RIA).

PATIENTS AND METHODS Thirteen normal subjects and 27 patients with polyuria/polydipsia were examined by an 8‐h fluid deprivation test. In all blood samples (0800 h, 1200 h, 1400 h and 1600 h) and in all urine collections (2‐hourly fractions), osmolality as well as vasopressin were measured.

RESULTS Using plasma vasopressin measurement with a highly sensitive RIA as gold standard test, nine patients were classified as having primary polydipsia, whereas 18 had partial or complete cranial diabetes insipidus. Whereas the substitution of plasma vasopressin measurement by urinary vasopressin measurement alone did not provide 100% separation between both groups, the product of urinary vasopressin and urinary osmolality related to plasma osmolality completely separated the patients with primary polydipsia from those with diabetes insipidus. Urinary measurement of vasopressin and osmolality alone, which was recommended as a noninvasive diagnostic procedure in children, was too insensitive for exact differential diagnosis in our adult patients.

CONCLUSIONS The simultaneous measurement of plasma vasopressin and plasma osmolality in a dehydration test is the most powerful diagnostic tool in the differential diagnosis of polyuria/polydipsia. However, if highly sensitive assays for plasma vasopressin measurements are not available, the measurement of urinary vasopressin with commercially available, less sensitive RIAs may be a diagnostic alternative, which showed nearly the same sensitivity as plasma vasopressin measurement in our study population.
Isolated growth hormone (GH) deficiency due to compound heterozygosity for two new mutations in the GH‐releasing hormone receptor gene
Authors: Salvatori Roberto , Fan Xiaoguang , Phillips John A. , Prince Melissa , Levine Michael A.
Published: March 2003

OBJECTIVE Mutations in the GH releasing hormone receptor (GHRH‐R) have recently been shown to cause autosomal recessive isolated GH deficiency (IGHD). Patients who are homozygous for GHRH‐R mutations have a subnormal GH response to pharmacological agents that stimulate GH secretion and an appropriate response to exogenous GH therapy. We searched for mutations in the GHRH‐R gene in a family in which two of three siblings were affected by IGHD.

DESIGN We sequenced the 13 coding exons, the intron‐exon boundaries and 327 bases of the promoter of the GHRH‐R gene from peripheral blood cell genomic DNA of an index patient.

RESULTS Both affected individuals were compound heterozygotes for two previously undescribed GHRH‐R mutations: a change in codon 137 that replaces histidine with leucine (H137L), and a 5 bp deletion in exon 11 (Del 1140–1144). The patients' father was heterozygous for the H137L mutation, and the mother was heterozygous for the exon 11 deletion. We used site‐directed mutagenesis to create the mutants in wild‐type GHRH‐R cDNA. Transient transfection of GHRH‐R cDNAs in Chinese hamster ovary cells showed that cells transfected with both mutant receptors failed to increase cyclic AMP after treatment with GHRH.

CONCLUSIONS We describe a family in which two siblings with IGHD were compound heterozygotes for two new mutations in the GHRH‐R gene. These results suggest that mutant alleles for GHRH‐R gene may be more common than previously suspected.
A novel chromosomal translocation t(3;5)(q12;p15.3) and loss of heterozygosity on chromosome 22 in a multifocal follicular variant of papillary thyroid carcinoma presenting with skin metastases
Authors: Smit Jan W. A. , Van Zelderen‐Bhola Shama , Merx Renee , De Leeuw Wiljo , Wessels Hans , Vink Robert , Morreau Hans
Published: March 2003

Classic genetic rearrangements in papillary carcinoma of the thyroid involve the RET‐ or TRK proto‐oncogenes. We report a novel chromosomal translocation t(3;5)(q12;p15.3), confirmed by fluorescence in situ hybridization, in a multifocal follicular variant of a papillary carcinoma of the thyroid in a 79‐year‐old woman, with skin metastases as a presenting symptom. Three years earlier, another cutaneous metastasis on her scalp was misdiagnosed as hidradenoma. Four tumour foci were recognized in the thyroid, two with a follicular variant of papillary carcinoma. To detect loss of heterozygosity, 14 chromosomes were investigated with 59 microsatellite markers. A clonal relationship was detected between the two foci of tumour in the thyroid gland containing follicular variant of papillary carcinoma and one of the skin lesions tested, all demonstrating loss of heterozygosity (LOH) in the same region of chromosome 22. Based on earlier reports, the low rate of LOH detected is in agreement with the diagnosis papillary carcinoma of the thyroid. Whole body scintigraphy performed after ablative therapy with radioiodine revealed multiple metastases in the lungs and skeleton. After repeated radioiodine therapy, thyroglobulin under thyroxine suppression became undetectable and post‐therapeutic scintigraphy revealed important regression of metastases.
Occurrence of ventricular late potentials in patients with active acromegaly
Authors: Herrmann B. L. , Bruch C. , Saller B. , Ferdin S. , Dagres N. , Ose C. , Erbel R. , Mann K.
Published: March 2003

OBJECTIVE Patients with acromegaly have an increased risk of ventricular dysrhythmias and sudden death. Late potentials in a signal‐averaged electrocardiogram (SAECG), a predictor of ventricular dysrhythmias, are frequently seen in patients after previous myocardial infarction, but little is known about the prevalence of late potentials in acromegaly. The aim of our study was to investigate the prevalence of late potentials in patients with acromegaly and their relation to the activity of the disease and to myocardial hypertrophy.

PATIENTS The study included 48 patients with acromegaly [27 males, 21 females, mean age 52·3 ± 14·2 years, 16 active disease, 32 cured or ‘well controlled’, under treatment with sandostatin analogues (12/32)] and 38 healthy volunteers as a control group.

RESULTS Late potentials were detected in 9/16 (56%) patients with active acromegaly vs. 2/32 (6%) with cured/well controlled acromegaly (P = 0·001), defined as normal age‐related IGF‐1 levels and GH levels suppressible below 1 µg/l after an oral glucose load (75 g). Late potentials were not related to muscle mass index (127 ± 35 active vs. 123 ± 34 g/m2 cured/well controlled). The association of disease activity with the detection of late potentials was independent of age, gender, duration of the disease and body mass index. In comparison to the control group, the prevalence of late potentials was significantly higher in patients with acromegaly (23%) than in the control group (0%; P < 0·001).

CONCLUSIONS Late potentials in the SAECG are frequently seen in active acromegaly and may represent an early and sensitive parameter to detect myocardial injury in acromegaly.
Urinary excretion of the aquaporin‐2 water channel exaggerated in pathological states of impaired water excretion
Authors: Saito Takako , Higashiyama Minori , Nakamura Tomoatsu , Kusaka Ikuyo , Nagasaka Shoichiro , Saito Toshikazu , Ishikawa San‐e
Published: March 2003

OBJECTIVE The present study was undertaken to determine whether the hydro‐osmotic action of arginine vasopressin (AVP) is exaggerated in pathological states of impaired water excretion by measuring urinary excretion of the aquaporin‐2 (AQP‐2) water channel.

PATIENTS AND MEASUREMENTS Eighteen hyponatraemic patients with impaired water excretion and 12 control subjects were studied during an acute oral water load (20 ml/kg body weight).

RESULTS In the patient group plasma AVP levels were 1·6 pmol/l, relatively high compared to plasma osmolality of 279·8 mmol/kg. Urinary excretion of AQP‐2 under ad libitum water drinking was 41·1 fmol/umol creatinine in the patient group, a value significantly greater than that of 21·7 fmol/μmol creatinine in the control subjects. The acute water load verified the impairment in water excretion in the patient group, as the excretion of the water load was only 28·2% (control, 77·3%, P < 0·001) and the minimum urinary osmolality was as high as 437·3 mmol/kg (control, 122·9 mmol/kg, P < 0·001). Also, the minimum urinary excretion of AQP‐2 was significantly greater in the patient group than that in the control. There was a positive correlation between plasma AVP levels and urinary excretion of AQP‐2 in the control subjects (r = 0·56, P < 0·01). In contrast, the urinary excretion of AQP‐2 was exaggerated compared to the respective plasma AVP levels in the patient group, and thus the positive correlation disappeared.

CONCLUSION These results indicate that hydroosmotic action of AVP is exaggerated more than that expected from plasma AVP levels in pathological states of impaired water excretion, with non‐suppressible, but normal, arginine vasopressin levels in spite of the hypo‐osmotic condition.
Elevated plasma non‐esterified fatty acid levels and insulin secretion in non‐diabetic relatives of type 2 diabetic patients
Authors: Butler T. J. , Barriocanal L. A. , Walker M.
Published: March 2003

OBJECTIVE High non‐esterified fatty acid (NEFA) levels impair glucose‐stimulated insulin secretion from islets derived from non‐diabetic Zucker rats that are genetically predisposed to diabetes. We therefore examined the effect of elevated plasma NEFA levels on insulin secretion in non‐diabetic first‐degree relatives of type 2 diabetic patients who are at increased risk of developing diabetes.

SUBJECTS AND STUDY DESIGN Normal glucose tolerant relatives (n = 9) and control subjects with no family history of diabetes were pair‐matched for age, sex, body mass index (BMI), insulin sensitivity and early insulin response during an oral glucose tolerance test (OGTT). Plasma NEFA levels were raised from 0 to 340 minutes by the infusion of 20% Intralipid and heparin. From 180 minutes, insulin secretion rates (IRSs) were assessed by stepped low‐dose glucose infusion.

RESULTS The mean (geometric mean ± 95% CI) NEFA levels were comparable between relatives and control subjects (2·7 [2·1–3·6] and 2·1 [1·7–2·7] mmol/l, paired analysis, NS). Similarly, plasma glucose levels achieved at each glucose infusion step were comparable between the groups. However, there were no significant differences between the groups for ISR throughout the study.

CONCLUSIONS Sustained elevation of plasma non‐esterified fatty acid levels does not decrease insulin secretion in non‐diabetic relatives of type 2 diabetic patients, and is therefore unlikely to be important in the development of the impaired pancreatic beta‐cell function in type 2 diabetes mellitus.
Plasma homocysteine is not a major risk factor for vascular disease in growth hormone deficient adults
Authors: Abdu T. A. M. , Elhadd T. A. , Akber M. , Hartland A. , Neary R. , Clayton R. N.
Published: March 2003

OBJECTIVE Several cardiovascular risk factors have been investigated in patients with adult growth hormone deficiency (GHD) to explain the observed increase in vascular mortality. Plasma homocysteine concentration has been identified recently as an independent risk factor for atherosclerosis. We wished to determine whether plasma homocysteine contributes to cardiovascular risk in adult GHD.

METHOD Plasma homocysteine was measured by fluorescence polarization immunoassay in 45 GH‐deficient adults on stable conventional hormone replacement (25M, 20F), age range 23–76 years, and compared with 55 matched controls (30M, 25F), age range 21–77 years. All subjects were free from clinical hypertension, diabetes, ischaemic heart disease and peripheral vascular disease. Blood pressure, body mass index and waist hip ratio were recorded. Serum creatinine and fasting lipids were measured. Serum vitamin B12 and folate levels, important cofactors in the homocysteine metabolic pathways, were also measured.

RESULTS Homocysteine levels were not different in patients and controls (9·75 [7·8–11·6]μmol/l vs. 9·65 [8·3–11·5]μmol/l, respectively, P = 0·88). Serum vitamin B12 was also not different (320·5 [262·0–427·5] pmol/l vs. 313·5 [277·0–460·5] pmol/l, respectively, P = 0·77). Serum folate levels were significantly lower in the patient group (7·05 [5·12–8·27] ng/ml vs. 7·80 [6·52–10·60] ng/ml, respectively, P = 0·03). When separated by gender, in males folate was not significantly different between patients and controls 7·05 [5·17–9·19]vs. 7·65 [6·15–10·22], P = 0·264, whereas in females, folate was significantly lower in patients at 7·05 [4·57–7·75] compared to controls at 8·4 [6·60–12·20], P = 0·01.

CONCLUSION Plasma homocysteine levels are not significantly elevated in GH‐deficient adults and are unlikely to be a major risk factor for vascular disease in these individuals.
Serum lipoprotein changes following IGF‐I normalization using a growth hormone receptor antagonist in acromegaly
Authors: Parkinson C. , Drake W. M. , Wieringa G. , Yates A. P. , Besser G. M. , Trainer P. J.
Published: March 2003

objectiveActive acromegaly is associated with altered lipid metabolism. The purpose of this study was to investigate the effect of serum IGF‐I normalization on serum lipoproteins and insulin, in patients with acromegaly receiving the GH receptor antagonist pegvisomant.

patientsTwenty patients (9 male, mean age 58·7 years, range 28–79) with active acromegaly (baseline serum IGF‐I > 130% the age‐related upper limit of normal) received pegvisomant and achieved a normal serum IGF‐I [585·2 ± 54·3 (mean ± SEM) to 169·2 ± 13·9 ng/ml,P < 0·0001].

measurementsTotal cholesterol (TC), high‐density lipoprotein (HDL) cholesterol, triglyceride (TG), apolipoprotein B (apo B), apolipoprotein A1 (apo A1), lipoprotein a [Lp(a)] and insulin were measured in a single batch analysis on samples obtained at baseline and the first occasion of serum IGF‐I normalization. Low‐density lipoprotein (LDL) was calculated using the Friedewald formula. Paired analysis was performed using Student’s pairedt‐test and the Wilcoxon signed rank test.

resultsNormalization of serum IGF‐I resulted in an increase in TC (5·0 ± 0·3 to 5·7 ± 0·4 mmol/l,P = 0·0068), an increase in LDL (3·0 ± 0·25 to 3·7 ± 0·31 mmol/l,P = 0·0093) and an increase in apo B (110·6 ± 7·76 to 127·1 ± 8·86 mg/l,P = 0·0014). TC and LDL increased in all but four patients. Despite a significant fall in fasting insulin levels (9·9 to 8·3 mU/l, range 8·85–19·8 to 6·33–11·6,P < 0·001) and insulin resistance (2·7 to 1·9, range 1·2–10·4 to 1–6·2,P < 0·001), mean serum TG and HDL levels were unaffected by IGF‐I normalization. The protein component of HDL, apo A1, increased (153 ± 4 to 166·4 ± 5·43 mg/l,P = 0·026) and Lp(a) declined (median 342 to 235 mg/l, range 60–1013 to 74–671),P = 0·0035). Baseline serum TC and LDL were below the age‐ and sex‐matched mean population value but after normalization of serum IGF‐I the distribution of serum TC and LDL values was similar to that of the general population.

conclusionsActive acromegaly is associated with lowered mean serum TC and LDL. Successful management using pegvisomant increases lowered baseline serum TC and LDL levels, restoring the distribution of values to that of the general population, and improves insulin resistance. These findings are consistent with the reported lipoprotein changes following GH administration to normal and GH‐deficient individuals.
Relationships of urinary phyto‐oestrogen excretion to BMD in postmenopausal women
Authors: Kim M. K. , Chung B. C. , Yu V. Y. , Nam J. H. , Lee H. C. , Huh K. B. , Lim S. K.
Published: March 2003

objective  Phyto‐oestrogens are plant compounds with both oestrogenic and anti‐oestrogenic properties. However, it is not known whether natural phyto‐oestrogens are beneficial or harmful in human osteoporosis. This study was performed to investigate the relationships between urinary phyto‐oestrogens and bone mineral density (BMD) in Korean postmenopausal women.

design  The subjects were classified into osteoporotic, osteopenic and normal groups according to their BMD as defined by WHO criteria. We compared the urinary phyto‐oestrogens of each group and studied whether urinary phyto‐oestrogens correlate with BMD.

patients  The subjects were 75 Korean postmenopausal women with ages ranging from 52 to 65 years (mean 58 ± 1·1 years). Mean number of years after menopause was 7·3 ± 1·3.

measurements  Twenty‐four‐hour urinary phyto‐oestrogens were measured by gas chromatography–mass spectrometry (GCMS) and BMD by dual‐energy X‐ray absorptiometry (DXA, Lunar Expert‐XL, Lunar Co., WI, USA).

results  In Korean postmenopausal women, urinary enterolactone (1·46 ± 1·11 µmol/day) was lower and daidzein (2·59 ± 3·25 µmol/day) was higher than in western women, and both levels were comparable to those in Japanese women. Daily urinary excretion of genistein and apigenin were 1·09 ± 0·912 and 0·48 ± 0·40 µmol/day, respectively. In subjects with osteoporosis, urinary enterolactone was lower (P < 0·05) but apigenin was significantly higher (P < 0·05) than in the controls. BMD of L2–L4 correlated positively with urinary enterolactone (r = 0·388, P < 0·01), and BMD of the femoral neck and Ward’s triangle correlated positively with urinary enterolactone (r = 0·271, P < 0·05 and r = 0·322, P < 0·05) but negatively with apigenin (r =−0·412, P < 0·01 and r = −0·395, P < 0·01). By multiple stepwise regression, the variables associated with spinal BMD were age, the amount of urinary apigenin and body mass index (BMI). The variables associated with femoral neck BMD were age and urinary apigenin.

conclusions  From these results, we conclude that urinary phyto‐oestrogens, especially enterolactone and apigenin, are related to BMD in Korean postmenopausal women. Our results also suggest the pos‐sibility that phyto‐oestrogens have differential effects on bone density. Further studies are needed to clarify the exact biological roles of phyto‐oestrogenic components on bone metabolism.
Interpersonal testosterone transfer after topical application of a newly developed testosterone gel preparation
Authors: Rolf C. , Knie U. , Lemmnitz G. , Nieschlag E.
Published: March 2003

objective Transdermal testosterone gel treatment is an effective androgen substitution therapy with several advantages over conventional substitution therapies. Whereas side‐effects due to overdosing of hypogonadal patients are unlikely, testosterone gel application without protection may cause severe side‐effects in other subjects (partners, family members) by contamination. Therefore, the risk of testosterone transfer of a newly developed 2·5% testosterone gel preparation was evaluated.

design In two clinical randomized open single‐centre studies on healthy male volunteers the percentage of testosterone remaining on the skin after gel application over time (n = 12) and the possibility of a transfer of testosterone to another person (n = 28) was evaluated. In the second study the endogenous testosterone production in the receiving subjects was suppressed by injecting 400 mg norethisterone enanthate (NETE).

results After 8 h approximately 60% of testosterone applied to the skin could be recovered. When the skin had been previously washed with water, only about 14% of applied testosterone could be recovered. After intense skin contact with a volunteer who had applied testosterone before on his forearm, no increase in testosterone serum levels could be found in NETE‐suppressed men.

conclusion Although considerable amounts of testosterone remain on the intact skin for several hours after evaporation of the alcohol vehicle, contamination of a second, especially female or prepubertal, subject causing side‐effects seems very unlikely.
Ectopic growth hormone‐releasing hormone secretion by thymic carcinoid tumour
Authors: Boix E. , Picó A. , Pinedo R. , Aranda I. , Kovacs K.
Published: March 2003

The case of a 33‐year‐old‐woman with Multiple Endocrine Neoplasia Type 1 (MEN1) syndrome and acromegaly due to ectopic growth hormone‐releasing hormone (GHRH) secretion by a thymic carcinoid tumour is reported. Immunohistochemistry revealed positive immunoreactivity for GHRH, vasoactive intestinal polypeptide, somatostatin and alpha‐subunit in the tumour cells. A previously undescribed new germ line mutation of the MEN1 protein gene was revealed.
99mTechnetium pentavalent dimercaptosuccinic acid scintigraphy in the follow‐up of clinically nonfunctioning pituitary adenomas after radiotherapy
Authors: Colao Annamaria , Ferone Diego , Lombardi Gaetano , Lastoria Secondo
Published: March 2003

BACKGROUND It is still difficult to differentiate pituitary adenoma remnants from postradiotherapy fibrosis by computed tomography (CT) or magnetic resonance imaging (MRI), especially in patients with clinically nonfunctioning pituitary adenomas (NFA), lacking circulating markers to follow disease progression or cure.

OBJECTIVE We investigated the usefulness of scintigraphy with technetium‐99m pentavalent dimercaptosuccinic acid [99mTc(V)DMSA], shown previously to detect most pituitary GH‐ and PRL‐secreting adenomas and NFA, with tumour‐to‐background ratios (T/B) as high as 25‐fold.

PATIENTS Eighteen patients with NFA (study group), 10 patients with GH‐ and three patients with PRL‐secreting adenomas (control group), all of whom had undergone previous surgery.

DESIGN The study was an open longitudinal design. Pituitary CT/MRI and 99mTc(V)DMSA scintigraphy was performed before and 1, 3 and 5 years after conventional radiotherapy. Tumour size was measured as maximal diameter of the residual lesion, while uptake of 99mTc(V)DMSA was measured as a T/B ratio.

RESULTS At study entry, pituitary 99mTc(V)DMSA uptake was found in 13 NFA (72·2%), seven GH‐secreting (70%) and all PRL‐secreting adenomas; remnant tumour was documented by CT/MRI in all 31 patients. Maximal remnant diameter was significantly higher in patients with positive (13·3 ± 0·9 mm) than in those with negative scintigraphy (7·0 ± 0·3 mm, P < 0·001). During the 5‐year follow‐up postradiotherapy, a significant decrease in 99mTc(V)DMSA uptake (9·7 ± 0·8 vs. 3·2 ± 0·5, P < 0·0001) occurred in all but three patients. Two NFA patients died of tumour invasion 19 and 36 months after radiotherapy and one acromegalic patient had no change in his hormone levels. In the eight negative patients (five NFA and three GH), scintigraphy remained negative throughout follow‐up. A remarkable shrinkage of the remnant tumour was observed in both the patients with negative (from 7·0 ± 0·3 to 1·9 ± 0·6 mm, P < 0·001) and in those with positive scintigraphy (from 13·3 ± 0·9 to 7·3 ± 0·6 mm, P < 0·001). At the end of the study, CT/MRI showed evident remnant tumour in 13 of 16 NFA (81·2%), nine GH‐secreting (90%) and all three prolactinomas (100%), while the scintigraphy was negative (T/B < 1) or faintly positive (T/B 1–2) in eight of 16 NFA (50%), five GH‐secreting (50%) and one prolactinoma (33·3%).

CONCLUSIONS Functional imaging of pituitary remnant adenomas (> 10 mm in size) by 99mTc(V)DMSA depicts viable pituitary adenoma remnants. This approach may be of clinical value in patients with clinically nonfunctioning adenomas to monitor the effects of radiotherapy.
Oestrogen supplementation attenuates responses to psychological stress in elderly men rendered hypogonadal after treatment for prostate cancer
Authors: Komesaroff Paul A. , Fullerton Meryl , Esler Murray D. , Jennings Garry , Sudhir Krishnankutty
Published: March 2003

background We have shown previously that oestrogens attenuate cardiovascular and hormonal responses to stress in perimenopausal women. The cardiovascular role of oestrogens in men is uncertain, despite preliminary evidence that endogenous oestrogens produced by aromatization of androgenic precursors are of physiological importance; hypogonadal men have very low levels of circulating oestrogen.

methods We therefore studied the haemodynamic and hormonal responses to a standardized laboratory mental stress test in 12 men (mean age 68·9 ± 2·6 SEM years) rendered hypogonadal as a result of treatment for prostatic cancer, before and after 8 weeks of oestrogen supplementation (oestradiol valerate 1 mg daily, n
= 7) or placebo (n = 5). The stress was administered as a standard mental arithmetic test of 10 minutes’ duration. Blood pressure, cortisol and ACTH were measured at baseline, and following 5 minutes and 10 minutes of stress, and ACTH again at 25 minutes on both days. Noradrenaline and adrenaline responses to mental stress, as well as changes in total body and forearm spillover of noradrenaline and noradrenaline clearance, were also measured.

results Oestrogen supplementation was well tolerated, with minimal adverse effects. Mean oestradiol levels increased from < 30 pmol/l to 308 ± 65 pmol/l after oestrogen treatment. Oestradiol significantly attenuated the mental stress‐induced increase in both systolic and diastolic blood pressures. Oestradiol also attenuated mental stress‐induced increases in ACTH, cortisol and adrenaline, but did not influence either total body or forearm spillover of noradrenaline. Responses to stress were unchanged after administration of placebo.

conclusions We conclude that oestrogen supplementation in men rendered hypogonadal as a result of treatment for prostate cancer is well tolerated and significantly attenuates blood pressure and hormonal responses to psychological stress. These findings suggest the need for further studies to examine a possible clinical role for oestrogen treatment in hypogonadal men.
Serum leptin concentrations of patients with sequential thyroid function changes
Authors: Hsieh Ching‐Jung , Wang Pei‐Wen , Wang Shan‐Tair , Liu Rue‐Tsuan , Tung Shih‐Chen , Chien Wen‐Yen , Lu Yung‐Chuang , Chen Jung‐Fu , Chen Chen‐Hsiong , Kuo Ming‐Chun
Published: March 2003

background Leptin, a recently discovered protein produced in adipocytes, regulates body weight by suppressing food intake and/or increasing energy expenditure. Thyroid hormones, which increase the basal metabolic rate and thermogenesis, have been reported to be one of leptin's regulating factors because alternations in thyroid status might lead to compensatory changes in circulating leptin.

objective The aim of this study was to assess the influence of sequential changes in thyroid function on serum leptin levels.

patients and methods The thyroid function status of 65 patients (55 women and 10 men, aged 40·6 ± 15·2 years, mean ± SD) with differentiated thyroid cancer who had received near‐total thyroidectomy was studied before I‐131 ablation therapy and after 2–4 and 6 months of levo‐thyroxine suppressive therapy. Thirty‐three (26 women, seven men; aged 41·0 ± 10·4 years, mean ± SD) of them were found to have become hypothyroid, then euthyroid and subsequently subclinically hyperthyroid. Their body mass index (BMI), body fat (%BF) by electrical bioimpedance, thyroid function and fasting serum leptin in these states were assessed and compared to those of 38 controls (30 women, eight men, aged 40·2 ± 11·3 years, mean ± SD). The controls had no past history or family history of thyroid diseases, and had the same range of BMI, between 20 and 30 kg/m2, as the patients.

results No difference in serum leptin levels was found between patients and controls with comparable age, sex, and BMI distribution in the euthyroid state. Using a repeated measures anova, tests of TSH, free T4 (FT4), BMI,%BF and leptin were performed on the 33 patients with sex as a grouping factor and thyroid state as a time factor. The sex difference for %BF and leptin proved to be statistically significant (P < 0·0001, and P = 0·0003, respectively). Serum leptin levels increased significantly from the hypothyroid to the subclinical hyperthyroid state (P < 0·0001) with a more pronounced increase found in females than in males (P = 0·03). Change of BMI during sequential thyroid function alterations was significant (P = 0·04) while change in %BF was not significant (P = 0·09). Pearson correlation analysis showed that serum leptin levels significantly correlated with BMI, %BF, FT4, and TSH (all P < 0·05). Using the generalized estimating equations, multivariate regression analysis revealed that FT4 was a statistically independent predictor for serum leptin (P < 0·0001). While other parameters were held constant, the mean serum leptin level increased by 1·47 units when serum FT4 was increased by one unit.

conclusion In conclusion, our data indicate that circulating thyroid hormone plays a relevant role in regulating leptin metabolism independent of BMI and body fat.
Detection of low titre TBII in patients with Graves’ disease using recombinant human TSH receptor
Authors: Morgenthaler Nils G. , Nagata Atsuo , Katayama Shigehiro , Bergmann Andreas , Iitaka Makoto
Published: March 2003

objectives We evaluated thyrotropin‐binding inhibitor immunoglobulin (TBII) in sera from patients with Graves’ disease (GD) by using the new human recombinant TSH receptor (TSH‐R) assay to determine if it is useful for the diagnosis and follow‐up of GD.

patients Serum samples from 25 patients with untreated GD, 24 with relapsing GD, 15 with GD in remission and 197 treated GD patients were examined. TBII was also measured in sera from healthy individuals (n = 69).

design and measurements TBII was retrospectively measured by using the conventional porcine TBII assay (pTBII) and the human recombinant TBII assay (hTBII). Specificity was adjusted at 97·5% for both assays by receiver‐operating characteristic (ROC) plot analysis, resulting in cut‐offs at 10·5% inhibition (hTBII) and 9·9% (pTBII). Sensitivity was 87% for hTBII compared to 52% for pTBII (P < 0·0001).

results Even in pTBII‐positive patients, hTBII values (57·6 ± 26·1%) were significantly (P < 0·0001) higher than pTBII values (34·2 ± 27·6%). When 139 pTBII‐negative serum samples from patients with treated GD were examined, 97 samples (69·8%) were positive for hTBII. hTBII values (23·9 ± 17·0%) were significantly (P < 0·0001) higher than pTBII values (4·1 ± 3·3%). hTBII was positive in 13 of 13 patients who were taking antithyroid drugs but had normal serum TSH levels. When 19 serum samples from pTBII‐negative untreated patients with GD were examined, 15 out of 19 (79%) were positive for hTBII. We also examined 24 patients with relapsing GD. hTBII was positive in 16 (64%) patients, whereas seven (16%) were positive for pTBII (P < 0·01). Positivity of hTBII in these untreated or relapsing GD patients was significantly higher than that of thyroid stimulating antibodies. We then examined TBII levels in 15 patients with GD in remission who had normal serum TSH values. hTBII was positive in seven patients at the time of blood withdrawal, and GD subsequently relapsed in three hTBII‐positive patients in 6 months.

conclusions Low TBII titres can now be followed more accurately during the course of treatment, which will also allow better longitudinal studies on the importance of TBII for the diagnosis as well as the prognosis of GD with respect to remission or relapse.
The management of primary hyperparathyroidism
Authors: Davies M. , Fraser W. D. , Hosking D. J.
Published: March 2003

Recent improvements in parathyroid imaging have led to renewed interest in the criteria for, and the surgical approach to, parathyroidectomy. It therefore seemed appropriate to review current evidence relating to the evaluation and management of primary hyperparathyroidism for those working within a general endocrine service. The recommendations are based on an electronic search spanning the past decade using the search terms hyperparathyroidism, management and parathyroidectomy/surgery, but we have also included key publications outside this period. The findings have been graded systematically (Appendix), according to the quality of the information available, to indicate the level of evidence on which they are based.
Relationship between plasma free fatty acids and uncoupling protein‐3 gene expression in skeletal muscle of obese subjects: in vitro evidence of a causal link
Authors: Sbraccia Paolo , D’Adamo Monica , Leonetti Frida , Buongiorno Angela , Silecchia Gianfranco , Basso Maria Sole , Tamburrano Guido , Lauro Davide , Federici Massimo , Di Daniele Nicola , Lauro Renato
Published: March 2003

objective To investigate whether skeletal muscle uncoupling protein‐2 (UCP2) and uncoupling protein‐3 (UCP3) gene expression is altered in massive obesity and whether it correlates with in vivo insulin sensitivity and with metabolic and hormonal status.

design Quantification of UCP2 and UCP3 gene expression in skeletal muscle of obese and lean subjects displaying different degrees of insulin sensitivity.

patients Fourteen obese and 10 age‐ and sex‐matched healthy control subjects with a mean body mass index (BMI) of 43·6 ± 1·4 and 22·8 ± 1·8 (± SEM), respectively.

measurements Insulin sensitivity by glucose clamp, body composition by bio‐impedance, fasting plasma glucose, insulin, leptin and free fatty acids (FFA). Skeletal muscle UCP2 and UCP3 mRNA levels by quantitative reverse transcription polymerase chain reaction (RT–PCR).

results No significant differences in UCP2 or UCP3 mRNA levels were found between obese and control subjects. No significant correlation was observed, in both groups, between UCP2 or UCP3 mRNA levels and both anthropometrical and metabolic parameters. In contrast, a highly significant correlation was observed between skeletal muscle UCP3, but not UCP2, mRNA levels and plasma FFA in the obese, but not in the lean, group. Furthermore, exposure of human myocytes to FFA for 24 h strongly induced both UCP3 and peroxisome proliferator‐activated receptor‐γ (PPARγ) but not UCP2 gene expression.

conclusions FFA levels correlate strongly with skeletal muscle UCP3 mRNA levels in obese, but not in lean, subjects; in addition, in human myocytes, high FFA concentrations promote UCP3 expression. Our studies therefore provide evidence that supports a role for increased plasma FFA concentrations in the regulation of human skeletal muscle UCP3 gene expression.
A single growth hormone (GH) determination is sufficient for the diagnosis of GH‐deficiency in adult patients using the growth hormone releasing hormone plus growth hormone releasing peptide‐6 test
Authors: Leal A. , Lage M. , Popovic V. , Torres E. , Koppeschaar H. P. F. , Paramo C. , Micic D. , Garcia‐Mayor R. V. , Dieguez C. , Casanueva F. F.
Published: March 2003

background The diagnosis of GH deficiency in adults is based on the provocative testing of GH secretion. When testing a patient with suspected GH deficiency, clinicians assess the whole secretory curve and select the GH peak as an index of secretory capability. This procedure is time consuming and the determination of GH in several samples is necessary. The combined administration of growth hormone releasing hormone (GHRH) plus growth hormone releasing peptide‐6 (GHRP‐6) is an effective test of GH secretion, and it has been unambiguously demonstrated that the elicited GH peak is capable of segregating normal GH secretion subjects from GH deficient patients on an individual basis. The GHRH + GHRP‐6 test biochemically classifies patients into three groups; those with a stimulated GH peak ≥ 20 µg/l are considered normal and those with peaks at ≤ 10 µg/l as GH deficient. The group comprising individuals between these parameters is considered uncertain, and the results are further interpreted according to clinical information, or by other tests.

objective  As the GHRH + GHRP‐6 test induces GH peaks consistently in the first 30 minutes, the working hypothesis assessed in this study was whether a single determination of GH 30 minutes after stimulus could provide the same clinical classification as the whole secretory curve.

patients and methods  Three hundred and forty‐nine adult subjects (146 patients with organic pituitary disease and 203 healthy subjects) were studied. All were administered GHRH 1 µg/kg i.v. plus GHRP‐6 1 µg/kg i.v. at 0 minutes, and blood samples were obtained at regular intervals. GH was determined in all samples.

results  GHRH + GHRP‐6‐evoked GH peaks in controls and patients were not correlated with GH basal values, making this determination useless for test validation. In contrast, an excellent correlation was observed between GH values at 30 minutes and the GH peaks (r = 0·994, P < 0·0001). When comparing the 30‐minute GH values against the peaks, the biochemical classification changed from normal toward uncertain in only five out of 203 control subjects, which is without clinical relevance according to Bayes theorem. Similarly, when the 30‐minute value was used instead of the peak in GH deficient patients, only two out of 146 patients moved from the uncertain area toward the GH deficient one. Thus, better diagnostic classification was provided for patients.

conclusions The GHRH + GHRP‐6 test is a convenient, safe and reliable, provocative test of GH reserve in adults, which can be reduced to a single fixed GH determination 30 minutes after stimulus.