bluuebunny/crossref_metadata_2025 huggingface dataset:
Fat distribution in obese women is associated with subtle alterations of the hypothalamic–pituitary–adrenal axis activity and sensitivity to glucocorticoids
Authors: Duclos M. , Gatta B. , Corcuff J.‐B. , Rashedi M. , Pehourcq F. , Roger P.
Published: March 2003

OBJECTIVES Obesity with abdominal body fat distribution (A‐BFD) and hypothalamic‐pituitary‐adrenal (HPA) axis activity are somehow linked, but the exact interactions still need clarification. Obese subjects display normal circulating plasma cortisol concentrations with normal circadian rhythms. However, when the HPA axis is pharmacologically challenged, body fat distribution matters and then A‐BFD obese women differ from those with subcutaneous body fat distribution (P‐BFD). We hypothesized that lower dose provocative and suppressive tests than those used to diagnose hypercortisolism of tumour origin or adrenal insufficiency would shed some light on the characteristics of the HPA axis activity in relation with body fat distribution.

PATIENTS AND METHODS Fifty premenopausal obese women were grouped according to their body fat mass distribution. Their plasma cortisol responses to (i) two low doses of dexamethasone (0·25 and 0·5 mg) with (ii) low dose of the ACTH analogue tetracosactrin (1 µg) were assessed. Salivary cortisol was also determined during the ACTH test.

RESULTS A‐BFD differed from P‐BFD women in terms of HPA axis responsiveness. They had comparatively: (i) increased nocturnal cortisol excretion (9·38 ± 2·2 vs. 6·82 ± 0·91 nmol/µmol creatinine, A‐BFD vs. P‐BFD, respectively, P = 0·03); (ii) increased salivary cortisol response to ACTH stimulation (1 µg) [salivary cortisol peak: 33·4 (14·1–129) vs. 28·5 (13·2–42·8) nmol/l; salivary AUC: 825 (235–44738) vs. 537 (69–1420) nmol/min/l; A‐BFD vs. P‐BFD, P = 0·04 for both]; and (iii) increased pituitary sensitivity to dexamethasone testing [postdexamethasone (0·25 mg) plasma cortisol levels: 163 (26–472) vs. 318 (26–652) nmol/l and postdexamethasone (0·5 mg) plasma cortisol levels: 26 (26–79) vs. 33 (26–402) nmol/l; A‐BFD vs. P‐BFD, P = 0·01 for both).

CONCLUSIONS These data demonstrate differences in the HPA axis activity and sensitivity to glucocorticoids between obese women differing in their body fat distribution, with both enhanced negative and positive feedback in those with abdominal obesity. Several mechanisms may explain these differences: central vs. peripheral hypotheses. Thus, abdominal obesity does not appear to be linked solely to one pathophysiological hypothesis.
Ventilation threshold as a measure of impaired physical performance in adults with growth hormone excess
Authors: Thomas Scott G. , Woodhouse Linda J. , Pagura Sonia M. , Ezzat Shereen
Published: March 2003

objective Fatigue is a prominent symptom among patients with GH excess and acromegaly. Identifying the physiological basis of such complaints and obtaining objective measures to quantify their severity remains an ongoing challenge. We investigated whether submaximal measures of aerobic performance can be used to assess GH excess‐associated fatigue objectively.

design and patients To investigate this possibility we examined the relation between physical function and physical capacity in 12 patients with active acromegaly and persistent fatigue before and after 3 and 6 months of treatment with the long‐acting somatostatin analogue octreotide (LAR®).

measurements Heart rate (HR) and rating of perceived exertion (RPE using Borg’s 10‐point scale) were measured during a 160‐metre self‐paced walk test (SPW). Maximum oxygen uptake (VO2max) and ventilation threshold (VeT: a measure of work rate when breathlessness develops) were measured during a progressive treadmill test to fatigue or symptom‐limited maximum. The Profile Of Mood States questionnaire (POMS) was used to quantify subjective feelings of fatigue and vigour. Morning fasting levels of GH and IGF‐I were measured using immunoassay of serum samples.

results SPW speed at a fast pace of 1·69 ± 0·18 m/s was achieved with higher than normal HR (112 ± 15/min; normal = 102) and RPE (2·4 ± 1·2). Similar to GH‐deficient adults, VO2max (22·6 ± 6·4 ml.kg−1.min−1; normal ~30 ml.kg−1.min−1) and VeT (13·1 ± 2·9 ml.kg−1.min−1; predicted normal ~16 ml.kg−1(min−1) were low. However, VeT occurred at a normal fraction of VO2max (VeT/VO2max = 0·58). VeT was significantly increased and plasma IGF‐I levels reduced following 3 and 6 months of octreotide LAR® treatment. Reduction in circulating IGF‐I levels was correlated with improvement in reported vigour (r = 0·85) and VeT (r = 0·65) (P < 0·05).

conclusions Our findings demonstrate impairment in physical function and physical capacity consistent with the perception of increased fatigue among acromegalic patients. These objective measures of compromised physical function are similar to the changes that we have reported previously in adults with GH deficiency. Taken together, these data suggest that a narrow window for GH/IGF‐I levels is required to maintain optimal physical function.
Isoflavone supplementation and endothelial function in menopausal women
Authors: Hale Georgina , Paul‐Labrador Maura , Dwyer James H. , Merz C. Noel Bairey
Published: March 2003

objective Despite strong observational evidence for a beneficial role of oestrogen in cardiovascular disease, recent trial results suggest that hormone replacement therapy (HRT) may have adverse effects in menopausal women with established coronary heart disease. Isoflavones are oestrogen analogues found in plants with oestrogen‐like properties and, because of a favourable side‐effect profile, may be ideal alternatives to HRT with respect to cardiovascular benefits. Endothelial function is a marker of cardiovascular health. We aimed to determine the effect of isoflavones on endothelial function using the brachial artery reactivity test.

design and measurements Twenty‐nine healthy menopausal women underwent entry and exit brachial artery reactivity testing following randomization to 2 weeks of an oral soy isoflavone concentrate containing 80 mg of soy isoflavones (Archer Daniel Midland Inc., IL, USA) or placebo.

results At study exit, there was no difference between placebo and isoflavone groups with respect to flow‐mediated dilation (%FMDmax), change (entry to exit) in %FMDmax or response to nitroglycerine (%TNG). Subgroup analyses assessing lipid and oestrogen effects did not produce any significant results.

conclusions These results suggest that short‐term oral isoflavone supplements do not improve endothelial function in healthy menopausal women.
Thyrotoxicosis induced by alpha‐interferon therapy in chronic viral hepatitis
Authors: Wong Vincent , Fu Angela Xi‐Li , George Jacob , Cheung N. Wah
Published: March 2003

background and objective It has been well documented that treatment of chronic hepatitis B and C infection with interferon alpha (IFN‐α) can lead to the induction of thyroid autoantibodies and hypothyroidism. Thyrotoxicosis, however, is less frequently observed and less well characterized.

patients and methods We reviewed the medical records of patients who developed thyrotoxicosis while receiving IFN‐α for either chronic hepatitis B or C infection at Westmead Hospital between 1996 and March 2001.

results Ten patients (four males and six females) were found to have biochemical thyrotoxicosis. The patients could be divided into two groups with different characteristics. The first group consisted of six patients who had clinical manifestations consistent with Graves’ disease, with either diffuse uptake in thyroid scintigraphy and/or positive thyroid‐stimulating antibodies. They all required prolonged treatment with antithyroid medications. The second group included three patients who had transient thyrotoxicosis, with progression to hypothyroidism after resolution of thyrotoxicosis.

conclusion Our study suggests that IFN therapy may provoke two different forms of thyrotoxicosis: a Graves’ disease picture or a biphasic thyroiditis pattern. The two entities should be differentiated, as they have different implications for treatment.
Gender and age influence the relationship between serum GH and IGF‐I in patients with acromegaly
Authors: Parkinson C. , Renehan A. G. , Ryder W. D. J. , O'Dwyer S. T. , Shalet S. M. , Trainer P. J.
Published: March 2003

background In patients with acromegaly serum IGF‐I is increasingly used as a marker of disease activity. As a result, the relationship between serum GH and IGF‐I is of profound interest. Healthy females secrete three times more GH than males but have broadly similar serum IGF‐I levels, and women with GH deficiency require 30–50% more exogenous GH to maintain the same serum IGF‐I as GH‐deficient men. In a selected cohort of patients with active acromegaly, studied off medical therapy using a single fasting serum GH and IGF‐I measurement, we have reported previously that, for a given GH level, women have significantly lower circulating IGF‐I.

objective To evaluate the influence of age and gender on the relationship between serum GH and IGF‐I in an unselected cohort of patients with acromegaly independent of disease control and medical therapy.

methods Sixty (34 male) unselected patients with acromegaly (median age 51 years (range 24–81 years) attending a colonoscopy screening programme were studied. Forty‐five had previously received pituitary radiotherapy. Patients had varying degrees of disease control and received medical therapy where appropriate. Mean serum GH was calculated from an eight‐point day profile (n = 45) and values obtained during a 75‐g oral glucose tolerance test (n = 15). Serum IGF‐I, IGFBP‐3 and acid‐labile subunit were measured and the dependency of these factors on covariates such as log10 mean serum GH, sex, age and prior radiotherapy was assessed using regression techniques.

results The median calculated GH value was 4·7 mU/l (range 1–104). A significant linear association was observed between serum IGF‐I and log10 mean serum GH for the cohort (R = 0·5, P < 0·0001). After simultaneous adjustment of the above covariates a significant difference in the relationship between mean serum GH and IGF‐I was observed for males and females. On average, women had serum IGF‐I levels 11·44 nmol/l lower than men with the same mean serum GH (P = 0·03, 95% CI 1·33–21·4 nmol/l). Age significantly influenced the relationship and for a given serum GH, IGF‐I was estimated to fall by 0·37 nmol/l per year (P = 0·04, 95% CI 0·015–0·72).

conclusions In keeping with previous observations of relative GH resistance in normal and GH‐deficient females we have observed lower serum IGF‐I levels for equivalent mean serum GH levels in females patients with acromegaly. This gender‐dependent difference is independent of disease activity and the use of concomitant medical therapy. Additionally, we have demonstrated that for a given serum GH level, age significantly influences IGF‐I concentrations in patients with acromegaly. These data have important implications for the use of serum IGF‐I and GH as markers of disease activity in acromegaly.
Bone metabolism markers and bone mass in healthy pubertal boys and girls
Authors: Van Coeverden S. C. C. M. , Netelenbos J. C. , De Ridder C. M. , Roos J. C. , Popp‐Snijders C. , Delemarre‐van de Waal H. A.
Published: March 2003

objective During puberty, bone growth and mineralization as well as bone turnover increase dramatically. The relation between height velocity and bone turnover is already known, but there are few studies in which both bone metabolism markers and bone mass throughout puberty have been measured.

design Semi‐longitudinal study. In 155 healthy boys (12·0 ± 1·5 years; range 8·8–15·7 years) and 151 healthy girls (11·2 ± 1·6 years; range 8·2–14·0 years) markers of bone formation and bone resorption were measured as well as sex steroids, IGF‐1 and IGF‐BP3, together with bone mineral content (BMC) and bone mineral density (BMD) of the lumbar spine, femur and total body during puberty. All bone measurements were repeated after 1 year.

results BMC and BMD increased throughout puberty in both sexes. Bone turnover markers increased significantly until maximum values were reached at stage G4 in boys and stage B3 in girls. Height velocity (HV) had a similar changing pattern. Sex steroids and IGF‐1 increased and reached adult values at pubertal stage 4. The correlations between bone metabolism markers and BMC were highly significant in boys, while correlations between bone metabolism markers and the increase in BMC over 1 year were significant in both sexes, as was observed for the correlations with HV.

conclusions Our data suggest that bone metabolism markers are good predictors of bone mass in boys and of bone mass increase in both sexes. In early puberty, sex steroids stimulate the pubertal growth spurt in conjunction with GH and IGF‐1. The fast increase in height gives rise to an increase in bone turnover and bone mineral apposition. It is known that at the end of puberty high levels of oestradiol inhibit chondrocyte proliferation. This leads to a decline in height velocity and bone turnover. Bone mass still increases under the influence of sex steroids and IGF‐1. The data in our study confirm previous reports that markers of bone turnover relate positively to height velocity.
Bone remodelling markers and serum cytokines in patients with hyperthyroidism
Authors: Akalin Aysen , Colak Ömer , Alatas Özkan , Efe Belgin
Published: March 2003

objective This study was designed in order to evaluate bone turnover with bone formation and resorption markers in hyperthyroidism and its possible relationship with serum cytokines interleukin 6 (IL‐6) and tumour necrosis‐α (TNF‐α), levels of thyroid hormones and thyroid autoantibodies.

design and patients Twenty‐six hyperthyroid patients including nine with Graves’ disease, 14 with toxic multi‐nodular disease and three toxic adenoma were studied. Twenty normal subjects served as the control group.

measurements Serum calcium, phosphorus, total and bone‐specific alkaline phosphatase, procollagen type 1‐C peptide (PICP), osteocalcin, IL‐6 and TNF‐α measurements were performed and deoxypyridinoline (free DPD), calcium, phosphorus and creatinine levels were measured in fasting morning urine specimens of all hyperthyroid patients and all controls. Also, serum total and free T3 and T4 and TSH were analysed and thyroid antiperoxidase and antithyroglobulin antibodies were determined in sera of hyperthyroid patients. Patients with hyperthyroidism received propylthiouracil treatment until the achivement of euthyroidism and then serum cytokine levels were remeasured.

results Mean serum values of osteocalcin, total and bone‐specific alkaline phosphatase were all significantly higher in hyperthyroid patients than in normal controls. PICP levels were not significantly different between these two groups. Urinary deoxypyridinoline levels were markedly elevated in hyperthyroid patients compared to the control group. There was a significant positive correlation between urinary free DPD levels and serum free T3, free T4 and T4 levels. Serum free T4 levels also correlated with urinary calcium levels. Serum IL‐6 values were significantly higher in hyperthyroid patients compared to control group. TNF‐α levels were slightly lower in patients with hyperthyroidism. No significant correlation was found between bone remodelling markers and serum cytokines. Serum Il‐6 levels were correlated positively with age. After the treatment period both IL‐6 and TNF‐α returned to levels comparable with euthyroid controls.

conclusion Bone turnover is increased in favour of resorption and the rate of resorption is associated with the levels of thyroid hormones in hyperthyroidism. The increase in the levels of serum IL‐6 in hyperthyroidism is not related directly with bone resorption seen in hyperthyroidism.
Dynamics of the plasma concentrations of TSH, FT4 and T3 following thyroxine supplementation in congenital hypothyroidism
Authors: Bakker Bert , Kempers Marlies J. E. , De Vijlder Jan J. M. , Van Tijn David A. , Wiedijk Brenda M. , Van Bruggen Michael , Vulsma Thomas
Published: March 2003

objective The dynamics of the plasma concentrations of various diagnostic determinants of thyroid function were analysed in children with congenital hypothyroidism (CH) after the start of T4 supplementation. The description of the biochemical dynamics of TSH and free T4 (FT4) during the first period of thyroxine treatment is important to depict the practical outlines of the initial dosage of T4 and dosage adjustments for newborns with variable forms of CH.

design A retrospective analysis was performed of frequent plasma TSH, total T4 (T4), FT4 and total T3 (T3) measurements in 30 CH neonates during the first weeks of treatment, treated with initial daily T4 dosages ranging from 4·8 to 11·1 µg/kg.

results A 50% reduction in the initial plasma TSH concentration was achieved after 3–4 days of treatment, independent of CH severity. At a median of 32 days after the start of T4 supplementation, plasma TSH ranged between 0·4 and 4·0 mU/l. The mean interval needed for FT4 to reach the age‐related normal values (12–29 pmol/l) was 3 days. The increase in plasma T3 concentrations levelled off within a few days, when T4 reached concentrations of around 100 nmol/l.

conclusions Plasma T3 and FT4 concentrations reach the normal range a few days after thyroxine treatment is started. By contrast, normalization of plasma TSH concentration takes several weeks. At the time that plasma TSH is normalized, CH neonates show a higher range of plasma FT4 concentrations than the normal range. When TSH normalization is the goal of treatment in CH, the target range for plasma FT4 during treatment in the first months needs to be adapted.

 During the first month of treatment the plasma TSH concentration is not helpful in assessing the proper T4 supplementation dosage. Once plasma TSH has reached normal values, it becomes a reliable determinant in addition to plasma FT4.
Ghrelin immunoreactivity in human plasma is suppressed by somatostatin
Authors: Nørrelund Helene , Hansen Troels K. , Ørskov Hans , Hosoda Hiroshi , Kojima Masayasu , Kangawa Kenji , Weeke Jørgen , Møller Niels , Christiansen Jens S. , Jørgensen Jens Otto L.
Published: March 2003

objective Ghrelin was recently identified as a specific endogenous ligand for the growth hormone secretagogue receptor (GHS‐R). This new hormone was isolated from rat and human stomach and was reported to circulate in human plasma, but the regulation and physiological significance of ghrelin in humans have not been clarified. The present study was undertaken to test the following hypotheses: (1) prolonged fasting, which is known to stimulate GH secretion, is associated with changes in ghrelin immunoreactivity; (2) somatostatin in the systemic circulation regulates ghrelin secretion; and (3) GH affects ghrelin levels.

design and patients The study population included normal subjects investigated on three occasions (fasting alone, fasting and somatostatin infusion ± GH); GH‐deficient adults investigated after 12 and 36 h of fasting ± GH, as well as patients with active acromegaly before and after somatostatin analogue treatment.

results Somatostatin infusion lowered ghrelin levels 70–80% (P < 0·0001), whereas continued fasting ± GH did not significantly affect ghrelin levels. In active acromegaly, suppression of plasma ghrelin levels was recorded after a single subcutaneous octreotide injection as well as during prolonged administration of slow‐release octreotide.

conclusions (1) Amplification of GH release during prolonged fasting is not caused by an increase in ghrelin immunoreactivity, (2) systemic somatostatin suppresses plasma ghrelin levels independently of GH status, and (3) the feasibility of measuring ghrelin in the circulation provides an opportunity for studying the interaction between hormones and nutrition.
Dehydroepiandrosterone, 17α‐hydroxyprogesterone and aldosterone responses to the low‐dose (1 µg) ACTH test in subjects with preclinical adrenal autoimmunity
Authors: Laureti Stefano , Candeloro Paola , Aglietti Maria Chiara , Giordano Roberta , Arvat Emanuela , Ghigo Ezio , Santeusanio Fausto , Falorni Alberto
Published: March 2003

objective The appearance of 21‐hydroxylase autoantibodies (21OHAbs) identifies subjects with preclinical adrenal insufficiency. In 21OHAb‐positive subjects, the adrenocortical function is best evaluated by peak cortisol (F) levels after the low‐dose (1 µg) ACTH stimulation test (LDT). No information is currently available on the correlation between F and other adrenocortical hormone responses to the LDT in subjects with an ongoing autoimmune adrenal process. In this study, we tested the hypothesis that the dehydroepiandrosterone (DHEA), 17α‐hydroxyprogesterone (17OHP) and aldosterone (A) responses to the LDT are consensual to that of F during the preclinical phase of autoimmune adrenal insufficiency.

design and patients We studied 12 subjects positive for 21OHAb, in the absence of clinical signs of adrenal insufficiency. On the basis of peak F levels after the LDT, and according to the lower level of normal observed in 15 healthy volunteers (510·4 nmol/l), patients were subdivided into two groups: group A, n = 6 subjects with normal F response; and group B, n = 6 subjects with impaired F response. Results were expressed as absolute delta increase (Δ) between peak and basal levels.

results ΔF was significantly higher in group A (314·5 ± 115·8 nmol/l) than in group B (151·7 ± 88·2 nmol/l) (P = 0·041). ΔDHEA and Δ17OHP were also significantly higher in group A (17·0 ± 13·5 nmol/l and 6·1 ± 4·4 nmol/l, respectively) than in group B (0·69 ± 2·25 nmol/l and 1·9 ± 1·7 nmol/l, respectively) (P = 0·002 and P = 0·041). The difference in ΔA between the two groups did not reach statistical significance (group A 321·8 ± 272·0 pmol/l vs. group B 157·0 ± 154·0 pmol/l). ΔDHEA, Δ17OHP and ΔA tended to correlate positively with ΔF (P = 0·039, P = 0·039 and P = 0·044, respectively), but the correlations did not reach significance after correction of the P‐value.

conclusions Our study demonstrates a high concordance between F and DHEA, 17OHP and A responses to the LDT in subjects with preclinical adrenal autoimmunity, thus strengthening the concept that the LDT is an accurate test to identify early adrenal dysfunction.
Intima‐media thickness in cardiovascularly asymptomatic hypopituitary adults with growth hormone deficiency: relation to body mass index, gender, and other cardiovascular risk factors
Authors: Leonsson Maria , Hulthe Johannes , Oscarsson Jan , Johannsson Gudmundur , Wendelhag Inger , Wikstrand John , Bengtsson Bengt‐Åke
Published: March 2003

Objective Increased cardiovascular mortality and carotid atherosclerosis have been observed in hypopituitary patients with untreated GH deficiency (GHD), but results are contradictory and relations to cardiovascular risk factors are not clear. The aim of this study was to investigate intima‐media thickness (IMT) in relation to cardiovascular risk factors in adults with GHD.

Design Cross‐sectional observational study of 21 men and 13 women with GHD, but without cardiovascular disease, compared to two healthy control groups matched for age, sex and smoking habits. One control group was matched for body mass index (BMI) and the other group was nonobese.

Measurements IMT of the carotid and femoral arteries, blood pressure, blood samples and anthropometric data.

Results Patients had 12% thicker composite carotid IMT [(IMT of common carotid artery + IMT of bulb)/2] compared to nonobese controls (P = 0·022), but IMT was not different compared to BMI‐matched controls. Femoral IMT did not differ between patients and controls. Patients had higher waist : hip ratio (WHR), heart rate, serum triglycerides and fasting insulin concentrations in combination with lower high‐density lipoprotein (HDL) cholesterol and smaller low‐density lipoprotein (LDL) peak particle size compared to both nonobese and to BMI‐matched controls. This cardiovascular risk pattern was more pronounced in female patients than in male patients compared to their gender controls. Carotid IMT was related to age, serum cholesterol, LDL cholesterol and smoking in the patient group. Only age was independently related to carotid IMT in multivariate analysis.

Conclusions These results indicate that high BMI in GH‐deficient patients contribute to their increased intima‐media thickness. However, several cardiovascular risk factors are present in this patient group independent of their increased BMI, especially in women.
Expression of pituitary tumour transforming gene (PTTG) and fibroblast growth factor‐2 (FGF‐2) in human pituitary adenomas: relationships to clinical tumour behaviour
Authors: McCabe C. J. , Khaira J. S. , Boelaert K. , Heaney A. P. , Tannahill L. A. , Hussain S. , Mitchell R. , Olliff J. , Sheppard M. C. , Franklyn J. A. , Gittoes N. J. L.
Published: March 2003

objective Pituitary tumour transforming gene (PTTG) encodes a multifunctional protein that is implicated in initiating and perpetuating pituitary adenoma growth. PTTG appears to have key regulatory functions in determining control of many fundamental cellular events including mitosis, cell transformation, DNA repair and gene regulation. Several of these events are mediated through interactions with PTTG binding factor (PBF) and fibroblast growth factor‐2 (FGF‐2). Given this background, we have determined the expression of PTTG, PBF, FGF‐2 and its receptor FGF‐R‐1 in a large cohort of pituitary adenomas and have sought associations between levels of gene expression and clinical markers of tumour behaviour.

patients and methods We used real‐time reverse transcriptase‐polymerase chain reaction (RT‐PCR) and Western blot analyses to measure PTTG, PBF, FGF‐2 and FGF‐R‐1 expression in ex vivo pituitary tumours (N = 121). Clinical data, including accurate radiological assessment of tumour characteristics, were used to determine any associations between gene expression and tumour behaviour.

results PTTG was increased significantly (fivefold, P = 0·005) in adenomas compared with normal pituitaries. We also demonstrated that PBF was similarly raised in adenomas (sixfold, P = 0·0001), and was significantly correlated with PTTG expression. FGF‐2 and its receptor FGF‐R‐1 were also raised in adenomas compared with normal pituitary tissue. Moreover, significantly enhanced expression of FGF‐R‐1 was observed in invasive adenomas compared with other pituitary tumours.

conclusions Our data support a fundamental role for PTTG‐mediated upregulation of FGF‐2 signalling in pituitary tumorigenesis and growth, and suggest that receptor‐mediated mechanisms of growth factor action may be critically important. Further prospective studies are required to determine whether measurement of FGF‐R‐1 mRNA will be of clinical use as a prognostic marker in patients with pituitary adenomas.
Long‐term outcome and mortality after transsphenoidal adenomectomy for acromegaly
Authors: Beauregard Catherine , Truong Uyen , Hardy Jules , Serri Omar
Published: March 2003

objective Acromegaly has long been associated with increased mortality but few long‐term follow‐up data are available in patients treated for this disease. We therefore studied a group of 103 patients who underwent transsphenoidal adenomectomy for acromegaly between 1970 and 1999 and were followed for one to 30 years.

design and patients A retrospective chart review was performed on 103 patients living in the province of Quebec, Canada. Mortality data were obtained by hospital charts, contact with the patient's family or death certificates. Stringent biochemical criteria were used to define remission (random GH < 2·5 µg/l, or GH nadir after an oral glucose load is < 1 µg/l and IGF‐I within the normal range) and patient survival in the group in remission and the group with persistent disease were compared to survival of the population of Quebec, Canada, using the probabilities of the Poisson distribution.

results There were four deaths in the perioperative period, one of which was directly related to surgery. Initial remission was obtained in 82% of microadenomas, 60% of macroadenomas and 24% of invasive adenomas. The long‐term (≥ 10 years) remission rate for surgery alone was 52%. A second transsphenoidal surgery, radiation therapy and/or octreotide were used in a subset of patients with persistent disease. Long‐term remission was obtained in 63% of patients. Five (mean age, 64 years) of the 57 patients in remission died; this rate did not differ significantly from the mortality rate expected in the general population (P = 0·18). Thirteen (mean age, 59·8 years) of the 34 patients with persistent disease died; this rate was significantly higher than that expected in the general population (P = 0·008).

conclusions Our observations confirm that uncontrolled acromegaly increases mortality compared to the general population and that mortality rates similar to the general population are restored once remission is induced.
Recombinant human growth hormone treatment in elderly patients undergoing elective total hip replacement
Authors: Weissberger Andrew J. , Anastasiadis Anastasios D. , Sturgess Ian , Martin Finbarr C. , Smith Michael A. , Sönksen Peter H.
Published: March 2003

objective Measures to prevent postoperative catabolism may be of greatest benefit in the elderly because of their reduced lean tissue reserve. We examined the effects of recombinant human growth hormone (GH) treatment on body composition and physical performance in elderly patients undergoing elective total hip replacement.

methods We recruited 33 patients (aged 60–82 years) scheduled for hip replacement. The study was double‐blind and placebo‐controlled with parallel groups. GH or placebo was administered for 14 weeks preoperatively (target GH dose 0·04 U/kg/day) and 4 weeks postoperatively (with dose doubled for first 2 weeks postoperatively). Serum IGF‐I, body composition, mid‐thigh muscle cross‐sectional area, muscle strength and 4‐min walking distance were measured at baseline, 2–3 days preoperatively and 4 weeks postoperatively.

results Mean serum IGF‐I doubled during GH treatment. Lean body mass increased preoperatively by an average of 5·2% (representing 1·8 kg) with GH treatment (P < 0·05 vs. placebo), but fell postoperatively by 3% in both groups. Similar changes pre‐ and postoperatively were seen for mid‐thigh muscle cross‐sectional area, such that there was no net loss in the GH group but a fall of more than 10% in the placebo group (P < 0·005 vs. GH). There was a trend towards a favourable effect of GH on strength in the majority of muscles tested, but this was significant only for the abductors of the nonoperated hip (P < 0·02), where there was a 7% increase in strength over the whole study compared with a 25% decrease in the placebo group. Four‐minute walking distance improved postoperatively by a mean of 26·9 m in the GH group compared with a 19·5 m reduction in the placebo group (P < 0·05). Dose‐related side‐effects were seen in the majority of patients receiving GH.

conclusions In elderly patients undergoing total hip replacement, preoperative GH treatment results in improvements in lean body mass and skeletal muscle mass that are sufficient to offset postoperative losses. The treatment may also preserve or improve muscle strength and postoperative walking ability.
TSH‐R expression and cytokine profile in orbital tissue of active vs. inactive Graves’ ophthalmopathy patients
Authors: Wakelkamp I. M. M. J. , Bakker O. , Baldeschi L. , Wiersinga W. M. , Prummel M. F.
Published: March 2003

objective From in vitro studies using cultures of orbital fibroblasts, it has become clear that cytokines play an important role in the orbital inflammation in Graves’ ophthalmopathy (GO). Orbital fibroblasts seem to be the key target cells of the autoimmune attack, and they are able to express the TSH receptor (TSH‐R). In vivo data on the presence of cytokines in orbital tissues are sparse, and mostly limited to samples obtained from patients with endstage, inactive GO; the same holds true for the presence of the TSH‐R. The aim of the present study was to determine whether the cytokine profile and TSH‐R expression differ in the active vs. the inactive stage of GO.

design and measurements Orbital fat/connective tissue was obtained from six patients with active, untreated GO undergoing emergency orbital decompression, and from 11 patients with inactive GO subjected to rehabilitative decompressive surgery. The mRNA levels of various cytokines and the TSH‐R were assessed by real‐time polymerase chain reaction (PCR) using the LightCycler. Data are expressed as ratios (unknown mRNA/β‐actin mRNA).

results Active GO patients had much higher TSH‐R expression than inactive patients: 4/0–24 (median value/range) vs. 0/0–9, P = 0·01. TSH‐R expression was related to the Clinical Activity Score (r = 0·595, P = 0·015). Patients with active GO compared to those with inactive GO had higher mRNA levels of the proinflammatory cytokines interleukin‐1β (IL‐1β) (445/153–877 vs. 0/0–455, P = 0·001), IL‐6 (1583/968–18825 vs. 559/0–7181, P = 0·01), IL‐8 (1422/38–7579 vs. 32/0–1081, P = 0·046) and IL‐10 (145/58–318 vs. 27/0–189, P = 0·002). In active GO there also existed a trend towards a predominance of T helper 1 (Th1)‐derived cytokines as evident from higher IL‐2 (37/0–158 vs. 0/0–68, P = 0·043), interferon‐γ (IFN‐γ) (20/0–79 vs. 0/0–16, P = 0·12) and IL‐12 (2·3/0–14·8 vs. 0/0–1·6, P = 0·10) mRNAs. IL‐1 receptor agonist (IL‐1RA), IL‐2 receptor (IL‐2R), IL‐3, IL‐4, IL‐5, IL‐13, IL‐18 and tumour necrosis factor‐α (TNF‐α) mRNAs were similar in both groups.

conclusions These data show that at the mRNA level, TSH‐R expression is largely present only during the active stages of GO. The active phase is characterized by the presence of proinflammatory and Th1‐derived cytokines, whereas other cytokines, among them Th2‐derived cytokines, do not seem to be linked to a specific stage of GO.
Is inhibin B a potential marker of gonadotoxicity in prepubertal children treated for cancer?
Authors: Crofton P. M. , Thomson A. B. , Evans A. E. M. , Groome N. P. , Bath L. E. , Kelnar C. J. H. , Wallace W. H. B.
Published: March 2003

background and objective Chemotherapy treatment of childhood cancer may impair gonadal function, which may be manifested only in adulthood as permanent sterility. Detection of gonadal dysfunction in prepubertal children has been hampered by the absence of a sensitive marker. Inhibin B is secreted by small antral follicles and Sertoli cells in females and males, respectively, and may be a marker of gonadal function in prepubertal children. The aim of this pilot study was to evaluate inhibin B in relation to sensitive measurements of gonadotrophins as markers of the early gonadotoxic effects of chemotherapy in prepubertal children treated for cancer.

study design and subjects Twenty‐five prepubertal children (9 females), median age 4·5 years (range 1·2–12·8 years) with cancer (16 solid tumours, nine acute lymphoblastic leukaemia, ALL) were studied longitudinally. Blood samples were collected before and during chemotherapy (solid tumours) or immediately following induction and first intensification (ALL). Post‐treatment (1–6 months) samples were collected in 12 of the patients (5 females).

measurements Dimeric inhibin B was measured by double antibody enzyme‐linked immunosorbent assay (ELISA). FSH and LH were measured by sensitive time‐resolved immunofluorescence.

results Girls: Pretreatment inhibin B was slightly high in one girl but normal for age and sex in all others: median 16·1 (range 9·4–186·2) ng/l, median SD score +0·2 (−1·3 to +2·6). Inhibin B decreased to undetectable levels (< 8 ng/l) in 8/9 girls during treatment (P = 0·03), with no accompanying rise in FSH or LH. Post‐treatment recovery of inhibin B was variable: median 16·1 (range < 8·0–44·2) ng/l, median SD score +0·1 (range < −2·4 to +1·8). Sustained undetectable inhibin B levels were observed in 2/5 girls with correspondingly elevated FSH concentrations (11·8 and 10·9 U/l).

Boys: Inhibin B was normal for age and sex in all boys before treatment with no significant change during or after treatment (medians 93 ng/l, 85 ng/l and 94 ng/l, SD scores −0·3, −0·6 and −0·2, respectively). Inhibin B decreased to undetectable levels in one boy post‐treatment with no accompanying increase in FSH or LH.

conclusions In prepubertal girls with cancer, chemotherapy is associated with suppression of inhibin B, usually transient, which may indicate arrest of follicle development. Sustained suppression of inhibin B following treatment may be indicative of permanent ovarian damage. In prepubertal boys, chemotherapy had little immediate effect on Sertoli cell production of inhibin B, although one boy showed a delayed effect. Inhibin B, together with sensitive measurements of FSH, may be a potential marker of the gonadotoxic effects of chemotherapy in prepubertal children with cancer.
Forearm bone density in primary hyperparathyroidism: long‐term follow‐up with and without parathyroidectomy
Authors: Rao D. Sudhaker , Wallace Elizabeth A. , Antonelli Rosella F. , Talpos Gary B. , Ansari Mohammed R. , Jacobsen Gordon , Divine George W. , Parfitt A. Michael
Published: March 2003

objective The long‐term effects of primary hyperparathyroidism (PHPT), whether treated or untreated, on cortical bone are unclear, but the balance of evidence suggests that fracture risk is modestly increased in this patient group. We therefore compared changes in forearm cortical bone mineral density (BMD), at the site most relevant for PTH‐mediated bone loss, in two groups of patients with PHPT; one with and one without surgery.

design and patients We followed the course of forearm bone mineral/bone width (BM/BW, g/cm2) measured by single‐energy photon absorptiometry at the standard proximal site, and Z‐scores (deviations from the mean value expected for age, sex and race, calculated from a large local reference population) in 108 patients who underwent successful surgery (mean duration 47 months, range 12–120 months) and 108 who remained unoperated (mean duration 52 months, range 12–132 months). Criteria for recommending surgery had been formulated in 1975 and were generally similar to those of the NIH consensus conference published in 1991. At the time of diagnosis the Z‐score was significantly reduced in both groups, indicating an earlier period of accelerated cortical bone loss.

results In the entire operated population there was no difference between the initial and final BM/BW. As the age‐expected mean value declined, the Z‐score became significantly less negative, and if the rate of change remained constant the values would have reached zero, indicating recovery of all bone lost as a result of the disease, after about 20 years. In the unoperated patients BM/BW fell significantly but there was no change in Z‐score, indicating that the rate of bone loss was the same as expected for normal ageing.

conclusions It is reasonable to assume that cessation of further bone loss consequent on successful parathyroid surgery would eventually lead to abatement of the excess fracture risk, but the benefit to individual patients will depend mainly on their remaining life expectancy.
Menopause is associated with the stiffness of the common carotid artery in 50‐year‐old women
Authors: Jonason  , Henriksen  , Kangro  , Vessby  , Ringqvist
Published: March 2003

To determine if menopause has an effect on the elasticity of the arteries, the stiffness index of the common carotid artery was studied in 84 premenopausal and 139 post‐menopausal women. The study group was age‐homogeneous, all women being 50 years of age. There were no significant differences between pre‐ and post‐menopausal women regarding atherosclerosis, when measured as the number of subjects with plaques or intimal‐medial thickness. The diameter of the common carotid artery was significantly larger in post‐menopausal women. The diameter was correlated to measurements of body size which did not, however, differ between the two groups. The mean stiffness indexes were 4·99 ± 1·02 and 5·38 ± 1·21 in the pre‐ and post‐menopausal groups respectively (P<0·05). In a multivariate analysis, menopause (P<0·05), and also serum insulin levels (P<0·01) and smoking (P<0·05) were found to have independent significant associations to the stiffness index. In conclusion, menopause is associated with reduced elasticity of the carotid arteries in 50‐year‐old women.
Adding ischaemic hand exercise during occlusion of the brachial artery increases the flow‐mediated vasodilation in ultrasound studies of endothelial function
Authors: Wendelhag  , Fagerberg  , Wikstrand
Published: March 2003

A non‐invasive method has been introduced to study endothelial function by evaluating flow‐mediated, endothelium‐dependent vasodilation of the brachial artery. One weakness of this method is that the post‐occlusion vasodilation response is very small in subjects above the age of 60 years, which is a problem when quantifying endothelial dysfunction above this age. We have therefore evaluated whether a higher post‐occlusion flow stimulus and a larger vasodilation response can be achieved by adding ischaemic hand exercise during the occlusion of the brachial artery. The subject population was men (n=12), aged 60 years, free from cardiovascular disease. B‐mode ultrasound images for the measurement of lumen diameter of the brachial artery were recorded before and after reactive hyperaemia induced by occlusion of the artery. Blood flow velocity was recorded intermittently using a Doppler technique. Hyperaemia was induced in two different ways: first by occlusion only and then by adding ischaemic hand exercise during the occlusion. The results showed that flow velocity was higher and the duration of flow increase was longer after ischaemic hand exercise compared with occlusion only. Two minutes after cuff pressure release, the increase in blood flow velocity was significantly higher after ischaemic hand work compared with occlusion only (P<0·01). The corresponding maximal lumen diameters after cuff pressure release were 4·63 ± 0·35 and 4·45 ± 0·34 respectively (P<0·01). The flow‐mediated vasodilation increased significantly from 2·24 ± 2·00% after occlusion only to 7·42 ± 3·32% after occlusion plus ischaemic hand exercise (P<0·01). In conclusion, this study showed that a maximal endothelial‐dependent vasodilation was not achieved after occlusion only in these 60‐year‐old men. Adding ischaemic hand exercise may therefore be of value when quantifying endothelial dysfunction in this age group.
Influence of gender on the sympathetic neural adjustments to alterations in systemic oxygen levels in humans
Authors: Jones P. Parker , Davy  , Seals
Published: March 2003

The purpose of this investigation was to determine whether gender influences the muscle sympathetic nerve activity (MSA) and systemic cardiovascular adjustments to alterations in systemic oxygen levels. To accomplish this, we performed direct (intraneural) measurements of muscle sympathetic nerve activity in 11 male and seven female young healthy adults during room air breathing, moderate isocapnic hypoxaemia and hyperoxaemia. During hypoxaemia, arterial oxygen saturation declined similarly in men and women. The magnitudes of the peak increases in MSA and stimulus–response `gain' were not different between groups. However, the women had a shorter latency of response (P<0·05). Women also demonstrated a greater increase in heart rate and a modest elevation in diastolic blood pressure, whereas the ventilatory responses were identical in the two groups. During normoxic recovery, MSA returned to baseline more quickly in women than in men (P<0·05). During hyperoxaemia, muscle sympathetic nerve activity decreased only in the men (P<0·05). Heart rate decreased slightly (P<0·05) in both men and women, whereas blood pressure and minute ventilation were unchanged from normoxic control levels. Our findings fail to support an effect of gender on the peak muscle sympathetic nerve activity response to moderate isocapnic hypoxaemia in healthy young adult humans, although women demonstrate a shorter latency for sympathoexcitation and recovery under these conditions. In response to hyperoxaemia, women fail to demonstrate the sympathoinhibition consistently observed in men, possibly because of the low resting levels of MSA characteristic of young adult women. Thus, gender appears to contribute to the interindividual variability in sympathetic and cardiovascular responses to alterations in systemic oxygen levels.
The role of glucose, long‐chain triglycerides and amino acids for promotion of amino acid balance across peripheral tissues in man
Authors: Svanberg Elisabeth , Möller‐Loswick Ann‐Charlotte , Matthews Dwight E , Körner Ulla , Andersson Marianne , Lundholm Kent
Published: March 2003

The role of amino acids, glucose and lipids in improving amino acid balance in peripheral tissues was evaluated. Primed constant infusion of L‐[ring‐2H5]phenylalanine in combination with flux measurements of glucose, free fatty acids (FFA) and amino acids across arm and leg tissues were applied in male volunteers after an overnight fast with subsequent primed constant infusions of amino acids (0·2 g N kg−1 body weight day−1), long‐chain triglycerides (0·98–1·079 g kg−1 day−1) and glucose (3·13–3·62 g kg−1 day−1). Amino acids and phenylalanine tracer infusion continued for 6 h; the lipid infusion was provided during 2–6 h from the start, and glucose infusion was provided between 4 and 6 h. Flux measurements were performed at steady state before the next infusion started. Arterial concentrations of infused substrates increased during provision, but remained constant thereafter. Plasma insulin increased when glucose was provided, whereas insulin‐like growth factor (IGF) I was unchanged during all infusions. Blood flow was unchanged in arm tissue during all infusions, while leg blood flow increased during fat and glucose infusion. FFA and glucose balance were unchanged during amino acid infusion but improved during lipid and glucose infusions. Amino acid balance was negative across arm and leg tissues in the fasted state, but reached balance during amino acid infusion. This effect was equally dependent on protein synthesis and protein degradation without any contribution from lipids and glucose. 3‐Methylhistidine release from tissues was not influenced by any substrate. Our results suggest that extracellular amino acid concentrations determine amino acid balance across peripheral tissues independently of non‐protein calories, insulin and IGF‐I.
Acute physiological effects of exhaustive whole‐body vibration exercise in man
Authors: Rittweger  , Beller  , Felsenberg
Published: March 2003

Vibration exercise (VE) is a new neuromuscular training method which is applied in athletes as well as in prevention and therapy of osteoporosis. The present study explored the physiological mechanisms of fatigue by VE in 37 young healthy subjects. Exercise and cardiovascular data were compared to progressive bicycle ergometry until exhaustion. VE was performed in two sessions, with a 26 Hz vibration on a ground plate, in combination with squatting plus additional load (40% of body weight). After VE, subjectively perceived exertion on Borg’s scale was 18, and thus as high as after bicycle ergometry. Heart rate after VE increased to 128 min–1, blood pressure to 132/52 mmHg, and lactate to 3·5 m
M. Oxygen uptake in VE was 48·8% of VO2max in bicycle ergometry. After VE, voluntary force in knee extension was reduced by 9·2%, jump height by 9·1%, and the decrease of EMG median frequency during maximal voluntary contraction was attenuated. The reproducibility in the two VE sessions was quite good: for heart rate, oxygen uptake and reduction in jump height, correlation coefficients of values from session 1 and from session 2 were between 0·67 and 0·7. Thus, VE can be well controlled in terms of these parameters. Surprisingly, an itching erythema was found in about half of the individuals, and an increase in cutaneous blood flow. It follows that exhaustive whole‐body VE elicits a mild cardiovascular exertion, and that neural as well as muscular mechanisms of fatigue may play a role.