bluuebunny/crossref_metadata_2025 huggingface dataset:
Monocyte-derived RANTES is intrinsically elevated in periodontal disease while MCP-1 levels are related to inflammation and are inversely correlated with IL-12 levels
Authors: FOKKEMA S J , LOOS B G , VAN DER VELDEN U
Published: March 2003

Bacteria colonizing tooth surfaces are essential in the induction of an inflammatory response in the periodontal tissues, but do not cause periodontitis in everyone, implicating differences in the host immune response. These possible differences were studied using lipopolysaccharide (LPS)-stimulated whole blood cell cultures (WBCC), which revealed a down regulation of monocyte derived interleukin-12 (IL-12p70) in untreated periodontitis patients and an up regulation after therapy. IL-12p70 is a crucial factor in the differentiation of Th1 cell responses. Since CC chemokines are able to influence the T cell differentiation via cytokine secretion in antigen-presenting cells, the production of CC chemokines in periodontitis was evaluated. Therefore WBCC were stimulated with LPS from Escherichia coli for 18 h and the levels of IL-12p70 and CC chemokines were measured in the supernatants by ELISA. Untreated periodontitis patients released 2 fold more RANTES (regulated on activation normal T cell expressed and secreted) (P = 0·01) and lower levels of IL-12p70 in comparison to controls (P < 0·05). A trend towards higher levels of macrophage chemoattractant protein-1 (MCP-1) (P = 0·07) was also seen in untreated periodontitis patients; while similar levels of monocyte derived chemokine (MDC) and macrophage inflammatory proteins-1α and -1β (MIP-1α and -1β) were found. After periodontal therapy no changes were seen with regard to MDC, MIP-1α, MIP-1β and RANTES, whereas the MCP-1 levels decreased (P < 0·05) and the IL-12p70 levels strongly increased (P < 0·01). The data showed a consistent inverse correlation between the levels of MCP-1 and IL-12p70, and their proportional changes after therapy correlated with the clinical inflammatory response after therapy. This indicates that the disease state regulates the release of IL-12p70 and MCP-1 in E. coli LPS-stimulated WBCC. In contrast, the persistent augmented levels of RANTES after therapy are suggestive for an intrinsic behaviour.
The antibody response to HBs antigen is regulated by coordinated Th1 and Th2 cytokine production in healthy neonates
Authors: JAFARZADEH A , SHOKRI F
Published: March 2003

A proportion of healthy neonates fail to produce protective levels of anti-HBs antibody following vaccination with recombinant hepatitis B vaccine. This study was undertaken to investigate contribution of Th1 and Th2 responses to anti-HBs antibody production and to explore the mechanism(s) of unresponsiveness to HBsAg in human neonates. Peripheral blood manonuclear cells (PBMCs) were isolated form 28 nonresponder (anti-HBs antibody <10 IU/l) and 25 responder neonates. The cells were stimulated in vitro with recombinant HBsAg and PHA mitogen and concentrations of IL-4, IL-10 and IFN-γ were quantified in culture supernatants by sandwich ELISA. Our results demonstrated significantly increased production of all cytokines, including IL-4 (P < 0·001), IL-10 (P < 0·002) and IFN-γ (P < 0·01) in responder compared to nonresponder vaccinees. No significant differences, however, were observed between the two groups of neonates in the levels of cytokines induced by PHA or secreted in absence of antigen and mitogen. Our findings suggest that unresponsiveness to recombinant HBsAg in healthy neonates is linked to inadequate secretion of both Th1 and Th2 cytokines.
Luteinizing hormone secreting adrenal tumour as a cause of precocious puberty
Authors: Romer Tomasz E. , Sachnowska Katrzyna , Savage Martin O. , Wozniewicz Bogdan , Lowe David G. , Kula Krzysztof K. , Janas Roman , Malendowicz Ludwik , Besser G. Michael
Published: March 2003

A boy aged 6 years presented with genital precocity, enlarged testes and advanced linear growth. An ovoid mass 3–4 cm in diameter was identified by MRI scan in the right adrenal gland. Serum concentrations of LH, testosterone, α‐subunit, dehydroepiandrosterone sulphate, androstenedione and oestradiol were persistently elevated. LH was unresponsive to bolus i.v. injection of GnRH or to GnRH analogue therapy. Serum FSH was normal. After removal of the adrenal tumour, serum LH, α‐subunit, testosterone and adrenal androgen levels fell to normal. In incubation medium of cultured disaggregated tumour cells, LH concentrations were greater than twice the mean serum concentration and 4–5‐fold higher than in the medium of cultured non‐neoplastic adrenal cells. Specific immunostaining of the tumour was positive for LH and α‐subunit in many areas and these were not found in the adjacent non‐neoplastic adrenal. Testicular biopsy showed almost complete spermatogenesis although germinal cell types were numerically lower than in normal men. These findings are consistent with an adrenocortical adenoma secreting LH being the cause of the patient's precocious puberty.
Long‐term therapy with long‐acting octreotide (Sandostatin‐LAR®) for the management of acromegaly
Authors: Davies Peter H. , Stewart Susan E. , Lancranjan Ioana , Sheppard Michael C. , Stewart Paul M.
Published: March 2003

OBJECTIVES

To evaluate the efficacy and safety of a long‐acting preparation of the somatostatin analogue octreotide, Sandostatin‐LAR® (SMS‐LAR) for the treatment of acromegaly.

DESIGN AND PATIENTS

Thirteen patients with acromegaly received intramuscular injections of SMS‐LAR 20–40 mg at 4–6‐week intervals for a period of up to 3 years.

MEASUREMENTS

Serial measurement of serum GH and IGF‐1 concentrations were obtained. Symptoms related to acromegaly were scored by patients at baseline and following each injection. Serial gallbladder ultrasound and pituitary imaging was performed throughout the study.

RESULTS

One patient was withdrawn from the study after 6 months because of continued gastrointestinal side effects; 4 patients were treated with monthly injections for 12 months and 8 patients with injections at either 1 month or 6‐week intervals for 36 months; hence data is presented for n = 12 for up to 12 months and thereafter n = 8. SMS‐LAR significantly reduced serum GH and IGF‐1 values: for the whole group GH concentrations fell from 24.8 ± 4.2 mU/l (mean ± SE) at baseline to 5.2 ± 0.8 mU/l at 12 months (P < 0.01, n = 12). In the 8 patients treated for 3 years GH fell from 27.8 ± 6.1 mU/l at baseline to 4.2 ± 0.8 mU/l at the end of 3 years (P < 0.01, n = 8). GH fell to <10 mU/l in all subjects and was <5 mU/l in 50% after both 1 and 3 years. IGF‐1 concentrations fell from 95 ± 13 nmol/l at baseline to 63 ± 13 nmol/l after 1 year (P < 0.01, n = 12; reference range <65 nmol/l). In the 8 patients treated for 3 years IGF‐1 concentrations fell from 119 ± 14 nmol/l at baseline to 60 ± 13 nmol/l after 3 years (P < 0.001, n = 8). IGF‐1 was <65 nmol/l in 60% of patients after 1 year and 75% after 3 years. Treatment resulted in trends towards improvement in symptoms of acromegaly and statistically significant improvement in sweating. There was no evidence of tachyphylaxis or evidence to suggest development of glucose intolerance. Only 2 patients (15%) developed gallbladder sludge which was asymptomatic; no patient developed gallstones.

CONCLUSIONS

We conclude that SMS‐LAR is a safe, effective and well tolerated treatment, making it an important therapeutic option in the management of acromegaly.
TSH suppression combined with carbimazole for Graves' disease: effect on remission and relapse rates
Authors: Pujol Pascal , Osman Abdul , Grabar Sophie , Daurès Jean‐Pierre , Galtier‐Dereure Florence , Boegner Catherine , Baldet Line , Raye Regine , Bringer Jacques , Jaffiol Claude
Published: March 2003

OBJECTIVE

We studied the influence of TSH suppressive therapy combined with carbimazole (CBZ) on treatment outcome in Graves' disease.

DESIGN

Open non‐randomized prospective study.

SETTING

University Hospital of Montpellier, France.

SUBJECTS

Sixty‐six consecutive patients without prior treatment were included. All the patients were treated initially with 30 mg of CBZ. After 1 month of treatment, one group continued CBZ alone (n = 23), another group received a combination of CBZ plus T3 (n = 19) and a third group received CBZ and 3,5,3′‐triiodothyroacetic acid (Triac, n = 24). Therapy was stopped when remission was obtained based on clinical euthyroidism, normalization of FT4 and of early radioiodine uptake. Nine patients with medical treatment failure or major side effects requiring to stop antithyroid drugs underwent surgery or radioiodine therapy. Nine patients were lost to follow‐up. The remaining 48 patients were available for analysis of both remission and relapse.

RESULTS

The median duration of therapy was 18 months (range, 4–41 months). Based on clinical examination, goitre size at 4 months decreased more in the CBZ + T3 and CBZ + Triac groups than in the CBZ group (P = 0.02). The overall remission rate tended to be higher in the groups treated with CBZ + T3 and CBZ + Triac than in the group treated with CBZ alone, but the difference did not reach statistical significance (P = 0.17). No difference in the relapse rate was observed between the three groups.

CONCLUSION

TSH suppression combined with CBZ has little or no effect on remission and relapse rates in Graves' disease patients.
Gonadotrophin pulsatility in girls with the Turner syndrome: modulation by exogenous sex steroids
Authors: Nathwani N. C. , Hindmarsh P. C. , Massarano A. A. , Brook C. G. D.
Published: March 2003

OBJECTIVES

The endocrine manisfestation of puberty, nocturnal pulsatile secretion of gonadotrophins precedes the physical manifestations by 2 years. Whether gonadal steroids and inhibin have a role to play in the regulation of pulsatile gonadotrophin release is unclear. The agonadal model, girls with Turner's syndrome (TS), has been used to determine the role of the hypothalamic pulse generator in the ontogeny of gonadotrophin secretion in man. We evaluated the ontogeny of gonadotrophin secretion in TS girls with respect to amplitude and frequency and compared these results to those obtained in a group of normal girls. The effects of treatment with ethinyloestradiol (EE2) or oxandrolone (OX) on parameters of gonadotrophin secretion were also evaluated.

PATIENTS

We studied 32 girls with TS, aged 4.3–12.4 years. All were prepubertal at the start of the study and longterm follow up revealed that none entered spontaneous puberty. The pulse amplitude and frequency was evaluated and compared to the results obtained in 23 normal girls, aged 4.9–12.8 years who acted as controls.

MEASUREMENTS

Samples were taken at 20 minute intervals for 24 h for the measurement of serum concentrations of luteinising (LH) and follicle stimulating (FSH) hormones. The girls were than randomized to receive EE2 or OX and were then re‐admitted 6 months into the course of the treatment for a repeat 24 h serum profile of LH and FSH levels.

RESULTS

The girls with TS showed a clearly defined dominant pulse periodicity of 180 min and that in the normal cohort was 160–220 min. The girls with TS had an increased oscillatory activity between 120 and 260 min compared to the normal. Mean 24 h serum gonadotrophin concentration in TS girls was always higher than in the normal cohort. The inflection points of the fitted polynominal regression equation relating sex hormone concentration with age was similar for the two groups. EE2 lead to a significant change in pulse periodicity in TS girls but OX had no significant effect on the pulse periodicity.

CONCLUSION

These results demonstrate that girls with Turner syndrome have gonadotrophin pulse periodicity in the prepubertal years similar to those of normal girls. The oscillatory activity was much greater in girls with Turner syndrome at all ages in the prepubertal years, suggesting a role for the ovary in modulating gonadotrophin secretion in the prepubertal years. Our data confirm that in girls with Turner syndrome the normal pattern of gonadotrophin secretion evolving with time is preserved.
Age‐dependent decline in cortisol levels and clinical manifestations in patients with ACTH‐independent Cushing's syndrome
Authors: Katayama  , Nomura  , Ujihara  , Obara  , Demura
Published: March 2003

OBJECTIVE

Adrenocortical cells change with age in both subcellular morphology and level of steroidogenesis. This study evaluates the influence of aging on hypercortisolism and clinical manifestations in patients with ACTH‐independent Cushing's syndrome due to a cortisol‐secreting adrenal adenoma (CS).

DESIGN

Restrospective study.

PATIENTS

Thirty‐six (33 females and 3 males) with CS. 31 healthy controls were age‐ and sex‐matched to CS patients.

MEASUREMENT

Patient age at diagnosis was compared to the degree of hypercortisolism and clinical manifestations. The degree of hypercortisolism was estimated using serum cortisol levels and urinary free cortisol excretion. Positive clinical manifestations were quantified using 12 symptoms and signs which resulted in a clinical score for each patient. Endogenous creatinine clearance, estimated disease duration and gender were analysed as possible factors affecting adenoma‐secreated cortisol.

RESULTS

Patient age correlated negatively with serum cortisol level (r = −0.417, P = 0.0107, n = 36) and urinary excretion of free cortisol (r = −0.613, P = 0.0002, n = 31). Analysis of Spearman's rank correlation showed that the clinical score decreased with age (ρ = −0.631, P = 0.0004, n = 33). Oedema, weakness/myopathy, hirsutism, striae and psychological changes were infrequent symptoms in the elderly. Using stepwise multiple regression analysis, we estimated the clinical score (Y) by factors of serum cortisol levels (X1:nmol/l), age (X2: years of age) and gender (X3: gender; female = 1, male = 0), i.e. Y = 4.771 + 0.004 X1− 0.064 X2+ 2.548 X3 (r = 0.743, P < 0.0001, n = 33). Results suggested that aging both suppressed cortisol secretion and repressed manifestations directly as an independent factor, although its direct effect may be weak.

CONCLUSIONS

Our findings indicated the importance of age as a factor modulating hormonal levels and possible clinical manifestations in patients with cortisol‐secreting adenomas.
The IGF‐I/IGFBP system in congenital partial lipodystrophy
Authors: Janssen J. A. M. J. L. , Hoogerbrugge N. , Van Neck J. W. , Uitterlinden P. , Lamberts S. W. J.
Published: March 2003

BACKGROUND AND OBJECTIVES

Insulin and IGF‐I interact at many levels. Little is known about the insulin‐like growth factor‐I/insulin‐like growth factor binding proteins (IGF‐I/IGFBP) system in congenital partial lipodystrophy, a syndrome characterized by insulin resistance, hyperinsulinaemia and absence of truncal and limb fat. Some cases have acromegaloid features with thick skin and large hands and feet in association with normal levels of circulating growth hormone.

METHODS

In four females known with congenital partial lipodystrophy, hyperinsulinaemia with acromegaloid features, the number and affinity of the IGF‐I receptors on peripheral blood mononuclear cells (PBMCs), and the concentration of circulating insulin, total and free IGF‐I, IGFBP‐1 and IGFBP‐3 levels were measured in the fasting and the fed state. Cultures of PBMCs of the patients with lipodystrophy were also used to study the effect of IGF‐I stimulation on thymidine uptake in vitro.

MEASUREMENTS

In the subjects with lipodystrophy the affinity and the number of the IGF‐I receptors on peripheral mononuclear cells (PBMCs) and erythrocytes did not differ significantly from controls in the fasting state. Insulin levels were significantly higher in subjects with lipodystrophy both in the fasting as well in the fed state. Total IGF‐I, free IGF‐I and IGFBP‐3 levels did not differ but serum IGFBP‐1 levels were lower in lipodystrophy subjects than in healthy controls. The free IGF‐I/IGFBP‐1 ratio was increased in lipodystrophy subjects both in the fasting and the fed states. The effects of IGF‐I stimulation on thymidine uptake by PBMCs of lipodystrophy subjects in the absence of IGFBP‐1 were not different from healthy controls cultures in vitro. When a combination of IGFBP‐1 (in a concentration comparable to the fasting serum IGFBP‐1 levels in lipodystrophy patients found in our study) and IGF‐I was added to PBMC cultures from lipodystrophy patients no decrease in thymidine uptake by PBMCs was found.

CONCLUSIONS

In the four subjects with lipodystrophy hyperinsulinaemia, lowered free IGF‐I and IGFBP‐1 levels, but increased free IGF‐I/IGBP‐1 ratios were observed. Low IGFBP‐1 concentrations in culture media did not reduce the stimulating IGF‐I effect on thymidine uptake by PBMCs from lipodystrophy patients. Our data suggest that the observed increased IGF‐I/IGFBP‐1 ratio in lipodystrophy patients contributes to an unopposed biological effect of IGF‐I on IGF‐I receptors, thereby inducing the development of acromegaloid features, acanthosis nigricans and polycystic ovaries in some patients with congenital partial lipodystrophy.
The relationship between the growth hormone and insulin‐like growth factor axis in long‐term survivors of childhood brain tumours
Authors: Achermann John C. , Hindmarsh Peter C. , D. Brook Charles G.
Published: March 2003

OBJECTIVE

We compared IGF‐1 and IGFBP3 concentrations in a group of adults treated for brain tumours in childhood with those of matched controls, and investigated the relationship between the GH secretory pattern and IGF‐1/IGFBP3 concentrations in the entire group.

DESIGN

We performed 24 h serum GH profiles using 20 minute sampling and measured corresponding fasting concentrations of IGF‐1 and IGFBP3.

PATIENTS

Fourteen adult male long‐term survivors of childhood brain tumours were studied. All had received high dose cranial irradiation ( 30Gy; median 12.8 (range 5.8–14.5) years previously). Nine healthy male volunteers acted as controls.

MEASUREMENTS

IGF‐1 and IGFBP3 concentrations were measured at 06.00 hours. Peak and trough GH activity within the GH profile was analysed by a distribution method which determined the concentration at or below which the serum GH concentration in the profile spent 95% (peak) and 5% (trough) of the total time.

RESULTS

Serum IGF‐1 levels were significantly lower in the irradiated group (Irradiated: 200 μg/l vs Control: 265 μg/l; P = 0.001) but the difference in serum IGFBP3 (Irradiated: 2.3 mg/l vs Controls: 2.77 mg/l; P = 0.03) was less marked. Peak GH activity was lower in the irradiated subjects (2.59 mU/l vs 9.04 mU/l; P = 0.0004) and correlated strongly with IGF‐1 (r = 0.62; P = 0.002) but less so with IGFBP3 (r = 0.35; P = 0.09). This was strengthened when the range of activity within the profle (peak − trough) was considered. Trough GH activity had a nonsignificant negative correlation with IGF‐1 and IGFBP3 levels.

CONCLUSION

The difference in serum IGF‐1 concentrations between irradiated subjects and controls was greater than the difference in serum IGFBP3. Peak GH activity and the range of activity within the profile correlated strongly with IGF‐1 concentrations but less so with IGFBP3.
The effects of oestrogen exposure on bone mass in male to female transsexuals
Authors: Reutrakul S. , Ongphiphadhanakul B. , Piaseu N. , Krittiyawong S. , Chanprasertyothin S. , Bunnag P. , Rajatanavin R.
Published: March 2003

OBJECTIVE

The importance of oestrogen on bone mineral density (BMD) in males was suggested by reports of patients with oestrogen resistance and aromatase deficiency who demonstrated osteoporosis and epiphyseal plate maturation defect despite high testosterone levels. In the present study, we examined the effects of oestrogen exposure on BMD in transsexual men.

DESIGN

Cross‐sectional study of BMD in male to female transsexuals.

PATIENTS

Subjects consisted of two groups of transsexual male dancers aged 16–34 years who did not receive transsexual operations (n = 28). Group 1 (n = 11) and group 2 (n = 17) had used oestrogen for 2 years or less and more than 2 years, respectively. Twenty‐four healthy adult males served as controls.

RESULTS

signs of feminization were presented in both group 1 and group 2, with Tanner's stage II–III breast development. BMD at various sites were correlated only to body weight and not to smoking or milk consumption. After controlling for body weight, it was found that group 2 had significantly higher BMD at L2–4 than controls (1.22 ± 0.03 vs. 1.14 ± 0.03 g/cm2, P < 0.05) and group 1 (1.22 ± 0.03 vs. 1.08 ± 0.04 g/cm2, P < 0.05). BMD at femoral neck was also higher in group 2 compared to controls (1.10 ± 0.03 vs. 1.01 ± 0.03 g/cm2, P < 0.05) and group 1 (1.10 ± 0.03 vs. 0.95 ± 0.04 g/cm2, P < 0.05). Group 1 subjects had lower BMD compared to controls at femoral trochanter (0.70 ± 0.04 vs. 0.83 ± 0.03 g/cm2, P < 0.05) and total femur (0.96 ± 0.05 vs. 1.07 ± 0.03 g/cm2, P < 0.05).

CONCLUSIONS

Long‐term oestrogen exposure transsexual men result in an increase in bone mineral density despite signs of feminization. This suggests that oestrogen has positive effects on bone density in males. The finding of the trend towards reduced bone density in group 1 remains unexplained.
Addison's disease in Africa—a teaching hospital experience
Authors: Soule Steven
Published: March 2003

OBJECTIVE

Addison's disease may present with diverse and non‐specific clinical and biochemical features. Contentious issues include the appropriate criteria for the interpretation of the ACTH stimulation test and the necessary extent of investigation to identify a specific aetiology for the hypoadrenalism. The experience of Addison's disease at a South African teaching hospital was reviewed to (1) record the aetiology and spectrum of presentation, (2) examine the performance of the ACTH stimulation test and (3) determine the utility of adrenal CT scan and biopsy.

METHODS

Retrospective study of patients admitted to a South African teaching hospital from 1980 to 1997 with a diagnosis of acute Addison's disease.

PATIENTS AND MEASUREMENTS

Fifty patients presenting with acute Addison's disease were identified by a search of hospital records. Pretreatment biochemical and haematological parameters were recorded. The cortisol response at 20 and 60 min to an intravenous injection of 250 μg synacthen (Cortrosyn®) was analysed. In a subgroup of affected subjects, the bone mineral density (BMD) in the lumbar spine and femoral neck was measured during long‐term follow‐up.

RESULTS

Presenting features included hyperpigmentation (86%), weight loss (67%), abdominal pain (20%) and diarrhoea (16%). Thirty‐nine patients (78%) were hyponatraemic, while 26 (53%) were hyperkalaemic. Nine patients (18%) were hypoglycaemic and 21% had hypercalcaemia. The mean basal cortisol was 148 nmol/l (range 10–487) and 16 patients (40%) had a normal basal cortisol. The mean cortisol 20 min after ACTH stimulation was 172 nmol/l (range 19–588). There was no significant increase in serum cortisol following ACTH stimulation (P > 0.05). Adrenal CT scans were performed in only 24 patients (48%) and were normal in 10, while abnormalities were detected in 14 patients (bilateral enlargement in 11, calcification in two and atrophic adrenals in one). Eight patients had a DEXA scan performed during follow‐up—four were osteopaenic in the lumbar spine and five at the femoral neck. The probable aetiology of Addison's was idiopathic in 42%, related to active TB in 18%, old TB in 16%, autoimmune in 12% and malignancy with metastases in 6%—single cases were due to sarcoid, iron overload and adrenoleukodystrophy. Adrenal biopsy was performed in two patients and was diagnostic of malignancy in both cases. The mortality within the first month after hospitalization was 12%.

CONCLUSIONS

In our experience, Addison's disease is frequently idiopathic, presents with protean manifestations and should be considered in patients with unexplained hyperpigmentation or gastrointestinal complaints, particularly when associated with hyponatraemia and hyperkalaemia. A normal basal cortisol does not exclude the diagnosis which requires ACTH stimulation testing.
Insulin regulation of leptin synthesis and secretion in humans: the model of myotonic dystrophy
Authors: Gómez José Manuel , Molina Ana , Fernández‐Castañer Miquel , Casamitjana Roser , Martínez‐Matos Juan Antonio , Soler Juan
Published: March 2003

OBJECTIVE

Myotonic dystrophy (MyD) is a systemic disorder in which insulin resistance is well recognized. In the present study we have characterized plasma leptin levels in patients with MyD and in age, sex and body mass index (BMI) matched controls and assessed the influence of leptin on the clinical manifestations of MyD.

DESIGN AND PATIENTS

Body composition, plasma leptin, fasting and post‐oral glucose tolerance test insulin, IGF‐I and IGFBP3 were studied in 34 MyD patients and 33 controls.

MEASUREMENTS

Body composition was measured using a bioelectrical impedance analyzer, and circulating levels of insulin, leptin, IGF‐I, IGFBP3 were measured by IRMA or RIA. Insulin sensitivity was modelled according to a homeostasis model assessment (HOMA) computer‐solved model.

RESULTS

Percentage body fat was higher in patients than in controls (25.6 ± 2.28% vs 18.8 ± 1.53%, P = 0.013). Insulin levels, both fasting and after oral glucose were higher in patients than in controls, and insulin sensitivity was lower in patients than in controls. Serum leptin was higher in patients than in controls (20.98 ± 3.11 μg/l vs 10.4 ± 1.31 μg/l, P = 0.004), and higher in women than in men, both in patients and in controls. In patients, leptin levels were correlated with age, BMI, fasting insulin, insulin area under curve and lower insulin sensitivity, whereas leptin levels were not correlated with body fat or other parameters of body composition. In controls, leptin levels were correlated with BMI and body fat. The results were evaluated using logistic regression models for each of the 2 populations. In the model of MyD, insulin resistance and age correctly identified higher leptin levels in relation to controls out of 87.88% of patients, and in the model of controls male sex with a negative correlation and BMI correctly identified their leptin levels out of 84.33% cases.

CONCLUSIONS

These findings show that MyD provides a different model of leptin regulation in humans, and suggest that in MyD patients there are correlations between leptin and insulin resistance and age, irrespective of body fat. In contrast, leptin levels in controls, correlate with sex and BMI. The data on leptin in this population of patients can not be related aetiologically to the muscle disease itself.
Constitutional delay in growth and puberty (CDGP) is associated with hypoleptinaemia
Authors: Gill Matthew S. , Hall Catherine M. , Tillmann Vallo , Clayton Peter E.
Published: March 2003

OBJECTIVE

Serum leptin concentrations are higher in early adolescence compared with childhood and may play a facilitatory role in pubertal development. Constitutional delay in growth and puberty (CDGP) is a disorder of the tempo of physical maturation and may be associated with relative hypoleptinaemia. We have therefore compared serum leptin concentrations in normal boys with those in boys exhibiting constitutional delay of growth, controlling for pubertal status, age and body mass index (BMI).

PATIENTS

23 boys with constitutional delay in growth (n = 17, prepubertal) and puberty (n = 6, early pubertal) and 88 normal boys (n = 64 prepubertal, n = 24 Tanner stage 2).

MEASUREMENTS

Serum leptin was measured in a single, non‐fasted morning serum sample by radioimmunoassay. Using the data from normal boys, leptin standard deviation scores (sds) were calculated, to account for the independent influences of age and body mass index (BMI) sds. Both chronological age and bone age were used in the calculation of leptin sds in those with delay.

RESULTS

BMIsds was significantly lower in prepubertal delays compared with controls but was not different in pubertal subjects. Leptin concentrations were higher in early puberty compared with prepuberty (P < 0.001) in normal boys but were not significantly elevated in pubertal boys with delay compared with prepubertal delays. Although leptin sds, for both chronological age and bone age, was similar in prepubertal controls and delays, it was significantly lower in the pubertal delay group (P < 0.05). In controls leptin sds did not correlate with age. However, in delays leptin sds was negatively correlated with both chronological age (r = − 0.43, P < 0.05) and bone age (r = − 0.68, P < 0.01), indicating that in the older delays leptin levels were lower than expected given their age and BMIsds.

CONCLUSIONS

These data indicate that significantly higher leptin levels in Tanner stage 2 compared with prepuberty are not a prerequisite for progression into puberty. However, the absence of elevated leptin concentrations may be associated with delayed puberty in boys.
Effects of administration of 17β‐oestradiol on serum leptin levels in healthy postmenopausal women
Authors: Elbers Jolanda M. H. , De Roo Gerdien W. de Valk‐. , Popp‐Snijders Corrie , Nicolaas‐Merkus Ans , Westerveen Edo , Joenje Bas W. , Netelenbos J. Coen
Published: March 2003

OBJECTIVE

Women have higher leptin levels than men at a certain degree of adiposity. The role of oestrogens in the regulation of serum leptin levels remains inconclusive. The aim of the present study was to investigate the effect of unopposed oestrogen replacement therapy, during two months, on serum leptin levels in postmenopausal women.

DESIGN

A double‐blind, placebo‐controlled, randomized study.

SUBJECTS

Twenty‐five healthy postmenopausal women were studied (mean (± SD) age: 52.9 ± 2.7 years, range of age: 48.7–57.4 years; mean body mass index (BMI): 26.4 ± 4.2 kg/m2, range of BMI: 21.0–39.0 kg/m2). Twelve of these women were treated with 2 mg 17β‐oestradiol daily, and 13 postmenopausal women received placebo.

MEASUREMENTS

Before and at the end of a 2‐month study period, anthropometric and bio‐electrical impedance measurements were performed, and fasting blood samples were taken, to determine serum levels of sex hormones and leptin.

RESULTS

During the 2‐month study period, body weight had increased significantly in the placebo group compared with the treatment group, but no significant changes were observed in percentage of body fat or the amount of body fat in kg between the groups. Following administration of 17β‐estradiol, the median leptin level increased from 17.6 μg/l to 24.1 μg/l after 2 months (P = 0.008 compared with baseline). This increase was significantly different from the placebo group (P = 0.019), which showed no change in circulating leptin levels.

CONCLUSION

This study demonstrates that unopposed oestrogen replacement therapy during 2 months in postmenopausal women slightly, but significantly, increases total serum leptin levels. This observation suggests a role for oestrogens in the regulation of leptin.
Mutations in the type II 3β‐hydroxysteroid dehydrogenase (HSD3B2) gene can cause premature pubarche in girls
Authors: Marui  , Castro  , Latronico  , Elias  , Arnhold  , Moreira  , Mendonca
Published: March 2003

OBJECTIVE

Most previous studies have failed to demonstrate any mutations in the type II 3β hydroxysteroid dehydrogenase (HSD3B2) gene in patients satisfying the hormonal criteria of nonclassic 3β‐hydroxysteroid dehydrogenase deficiency, suggesting that a mutant 3β‐hydroxysteroid dehydrogenase protein is not the cause of this disorder. We screened the HSD3B2 gene for mutations in girls with premature pubarche and a hormonal diagnosis of 3β‐hydroxysteroid dehydrogenase deficiency.

DESIGN

From 30 girls with premature pubarche, we selected 9 whose ACTH‐stimulated 17‐hydroxypregnenolone levels were elevated (≥6 SD) and screened the HSD3B2 gene for mutations.

MEASUREMENTS

All patients were submitted to a standard ACTH stimulation test. Serum steroids were measured and compared to the mean level of pubertal stage matched control subjects. The four exons and exon‐intron boundaries of the HSD3B2 gene were amplified by polymerase chain reaction and screened for mutations by denaturing gradient gel electrophoresis. The fragments with abnormal migration on denaturing gradient gel electrophoresis were directly sequenced.

RESULTS

A homozygous T259M mutation was identified in one girl and a new compound heterozygous G129R/P222H mutation was identified in two sisters. The highest ACTH‐stimulated 17‐hydroxypregnenolone levels, 147, 339 and 351 nmol/l, were found in those patients with mutations in the HSD3B2 gene. In the patients without mutations, ACTH‐stimulated 17‐hydroxypregnenolone ranged from 48 to 111 nmol/l. ACTH‐stimulated dehydroepiandrosterone levels had an overlap among the girls with and without mutations and the normal controls.

CONCLUSIONS

Premature pubarche can be caused by mutations in the type II 3β hydroxysteroid dehydrogenase gene.
Effects of growth hormone administration on protein dynamics and substrate metabolism during 4 weeks of dietary restriction in obese women
Authors: Nørrelund Helene , Børglum Jens , Jørgensen Jens Otto Lunde , Richelsen Bjørn , Møller Niels , Sreekumaran Nair  , Christiansen Jens Sandahl
Published: March 2003

OBJECTIVE

Treatment of obesity with very low calorie diet (VLCD) is complicated by protein loss. We evaluated the effects of coadministration of GH on protein turnover, substrate metabolism, and body composition in VLCD treated obesity.

DESIGN AND PATIENTS

Fifteen obese women underwent 4 weeks of very low calorie diet (VLCD) in parallel with GH treatment (n = 7) or placebo (n = 8).

MEASUREMENTS

Protein metabolism and total glucose turnover were isotopically assayed. Plasma concentrations of amino acids were determined by an HPLC system. Estimated rates of lipid and glucose oxidation were obtained by indirect calorimetry. Fat free mass was determined by DEXA‐scan.

RESULTS

Protein breakdown decreased in both groups (tyrosine flux μmol/h): −12% ± 3 (GH) vs. − 9% ± 3 (placebo)). Phenylalanine degradation in relation to phenylalanine concentration decreased by 9% in the GH group, whereas an increase of 8% was observed in the placebo group (P = 0.1). Plasma concentrations of several amino acids were significantly decreased in the placebo group, while urea excretion decreased in the GH group. A decrease in FFM was found in placebo treated patients (2.14% ± 1.9 (GH) vs. − 3.54% ± 1.6 (placebo), P < 0.05). Rates of lipid oxidation tended to be increased by GH treatment (lipid oxidation (mg/minutes): 79.7 ± 5.9 (GH) vs. 64.6 ± 5.9 (placebo), P = 0.1).

CONCLUSION

During dietary restriction GH primarily seems to conserve protein by a reduced hepatic degradation of amino acids.
Pre‐treatment IGF‐I level is the major determinant of GH dosage in adult GH deficiency
Authors: Murray R. D. , Howell S. J. , Lissett C. A. , Shalet S. M.
Published: March 2003

OBJECTIVE

Severe GH deficiency in adults is a definite clinical entity, the effects of which can be reversed by administration of subcutaneous recombinant GH. The ideal dosing regimen and determinants of the maintenance dose have, however, yet to be elucidated.

PATIENTS

In an open study of GH replacement we treated 65 GH‐deficient adults of mixed adult‐ and childhood‐onset, of mean age 35.5 (range 17–72) years, and comprising 38 females and 27 males, using an individualized low‐dose titration regimen aimed at normalization of the serum IGF‐I and induction of clinical improvement.

RESULTS

Before initiation of GH therapy, median IGF‐I SD was significantly lower in female than male patients (− 3.3 vs. − 1.9, P = 0.007) and in childhood‐onset compared with adult‐onset patients (− 3.9 vs. − 2.0, P < 0.001). Once maintenance dosage had been achieved, the median GH requirement was significantly greater in female than male patients (1.6 vs. 0.8 IU/day, P = 0.013) and childhood‐onset compared with adult‐onset patients (1.6 vs. 0.8 IU/day, P = 0.019). The median maintenance GH dose for the cohort overall was 1.2 (range 0.4–2.4) IU/day. By univariate analysis a significant negative correlation was observed between the maintenance GH dose and baseline IGF‐I SD (r = ‐ 0.63, P < 0.001). No significant correlation was demonstrated between maintenance GH dose and either age or weight. Multiple linear regression analysis using age, gender, weight, time of onset of GH deficiency, peak GH to the insulin tolerance test (ITT) and baseline IGF‐I SD as independent variables demonstrated baseline IGF‐I SD to account for 51% of the variation in GH dose required to normalize the IGF‐I SD (P < 0.001). Those patients with the lower IGF‐I SD at initiation of GH therapy required the greater GH dose. None of the other variables studied significantly influenced the maintenance dose.

CONCLUSION

We have demonstrated that the GH dose required in an individual is dependent on the serum IGF‐I SD before commencement of replacement. In contrast, the severity of GH deficiency as judged by the peak GH response to an ITT was unrelated to the maintenance GH requirement. The effect of age, gender and age at onset of GH deficiency on the final GH dose are accounted for by the lower pretreatment IGF‐I SD in young, female and childhood‐onset patients relative to older, male and adult‐onset patients, respectively.
Soluble interleukin‐1 receptor antagonist concentration in patients with Graves' ophthalmopathy is neither related to cigarette smoking nor predictive of subsequent response to glucocorticoids
Authors: Bartalena Luigi , Manetti Luca , Tanda Maria Laura , Dell'Unto Enrica , Mazzi Barbara , Rocchi Roberto , Barbesino Giuseppe , Pinchera Aldo , Marcocci Claudio
Published: March 2003

OBJECTIVE

The aim of the present study was to evaluate serum soluble interleukin‐1 receptor antagonist (sIL‐1RA) concentration and its relationship with the degree of cigarette smoking in patients with Graves' ophthalmopathy (GO).

DESIGN AND SUBJECTS

Twenty‐two consecutive GO patients (20 women, two men; age range 25–68 years, mean 48 years; 12 smokers, 10 non‐smokers) submitted to IV glucocorticoid pulses over a 3‐month period.

MEASUREMENTS

sIL‐1RA levels were measured by an immunoenzymatic assay (sensitivity, 4 ng/l; normal range, 50–290 ng/l) before glucocorticoid treatment, after two months of therapy, and 3 months after drug withdrawal.

RESULTS

Thirteen patients responded to treatment (59%; five smokers and eight non‐smokers), nine were non‐responders (41%; seven smokers and two non‐smokers). Baseline median sIL‐1RA concentration did not differ in smokers and non‐smokers (222 and 173 ng/l, respectively; P = 0.69). Likewise, no significant differences were found between the two groups during treatment (537 and 389 ng/l, respectively; P = 0.28); sIL‐1RA concentration after treatment was higher in smokers (258 vs. 94 ng/l; P = 0.02). There was no correlation between basal sIL‐1RA levels and the degree of cigarette smoking. Likewise, there was no difference in sIL‐1RA levels in responders and non‐responders, either at baseline (186 vs. 216 ng/l; P = 0.83), during or after treatment.

CONCLUSION

Our study suggests that circulating soluble interleukin‐1 receptor antagonist levels, both at baseline and during glucocorticoid treatment, are neither influenced by cigarette smoking nor predictive of subsequent response to glucocorticoid treatment.
Adrenal responsiveness to high, low and very low ACTH 1–24 doses in obesity
Authors: Maccario M. , Grottoli S. , DiVito L. , Rossetto R. , Tassone F. , Ganzaroli C. , Oleandri S. E. , Arvat E. , Ghigo E.
Published: March 2003

OBJECTIVE

To investigate adrenal activity in visceral obesity in which adrenal hyperactivity has been hypothesized. This could reflect hypothalamus–pituitary alterations leading to slight hyperfunction of the adrenal. Primary adrenal hypersensitivity to ACTH drive in obesity has also been suggested. However, it has also been reported that dehydroepiondrosterone (DHEA) levels in obesity are reduced and it has been hypothesized that this could play a role in the increased cardiovascular risk in obese patients.

SUBJECTS

We have studied seven obese women with visceral adiposity (OB, age: 33.6 ± 3.3 years, BMI: 33.8 ± 1.3 kg/m2, WHR: 0.88 ± 0.01). The results in OB were compared with those recorded in a group of age‐matched normal women (NS, age: 30 ± 1.3 years, BMI: 19.9 ± 0.4 kg/m2, WHR: 0.76 ± 0.02).

METHODS

We have studied the cortisol (F), aldosterone (A) and DHEA responses to ACTH 1–24 administered at low (LD, 0.5 μg/m2) or very low (VLD, 0.125 μg/m2) dose followed by a second challenge with supramaximal dose (HD, 250 μg).

RESULTS

Basal F, A and DHEA levels in OB were similar to those in NS. The peak F responses to ACTH were dose‐related in both groups. At each dose the F peaks in OB (VLD: 495.6 ± 43.9 nmol/l, HD: 722.3 ± 67.7 nmol/l; LD: 519.2 ± 46.0 nmol/l, HD: 729.6 ± 44.7 nmol/l) were similar to those in NS (VLD: 556.7 ± 45.9 nmol/l, HD: 704.8 ± 20.7 nmol/l; LD: 511.8 ± 22.8 nmol/l, HD: 726.7 ± 26.5 nmol/l). The peak A responses to ACTH were dose‐related in both groups. At each dose, the A peaks in OB (VLD: 0.55 ± 0.03 pmol/l, HD: 0.79 ± 0.09 pmol/l; LD: 0.63 ± 0.04 pmol/l, HD: 0.78 ± 0.09 pmol/l) were similar to those in NS (VLD: 0.8 ± 0.10 pmol/l, HD: 0.86 ± 0.09 pmol/l; LD: 0.8 ± 0.10 pmol/l, HD: 0.95 ± 0.12 pmol/l). The peak DHEA responses to ACTH were dose‐related in both groups. At each dose the DHEA peaks in OB (VLD: 58.6 ± 13.3 nmol/l, HD: 61.9 ± 13.1 nmol/l; LD: 55.18 ± 6.4 nmol/l, HD: 72.3 ± 9.8 nmol/l) were similar to those in NS (VLD: 54.3 ± 8.2 nmol/l, HD: 57.8 ± 8.2 nmol/l; LD: 42.2 ± 3.7 nmol/l, HD: 56.9 ± 4.3 nmol/l).

CONCLUSIONS

This study shows that the cortisol, aldosterone and dehydroepiondrosterone responses to high, low and very low ACTH doses in obese women overlap with those in age‐matched lean controls; these findings suggest normal sensitivity of the different zones of the adrenal cortex to ACTH in obesity.
Complete histological regression of metastatic carcinoid tumour after treatment with octreotide
Authors: Imtiaz K. E. , Monteith P. , Khaleeli A.
Published: March 2003

A 69‐year‐old woman was admitted with facial flushing, weight loss and intermittent diarrhoea. Urinary 5‐hydroxyindole‐acetic acid (5‐HIAA) level was elevated at 200 μmol/24 h (normal: < 50). Computerized tomography (CT) demonstrated multiple enhancing liver metastases with biopsy proven carcinoid metastases with no evidence of primary tumour at this stage. Octreotide was initiated, resulting in marked improvement in carcinoid symptoms. Nine years later, she presented with abdominal pain and slightly deranged liver function tests. Repeat colonoscopy at this stage, showed an ileal tumour causing impending obstruction, necessitating urgent right hemicolectomy. Histology demonstrated primary carcinoid tumour. She continued on octreotide. Three years later at the age of 81 years, she suffered a fatal haemorrhagic stroke. Autopsy revealed complete regression of hepatic carcinoid metastases.
Cholinergic modulation of growth hormone responses to growth hormone‐releasing hormone in uraemic patients on peritoneal dialysis
Authors: Díez Juan J. , Iglesias Pedro , Selgas Rafael , Bajo María A. , Aguilera Abelardo
Published: March 2003

BACKGROUND

Hypothalamic cholinergic neurotransmission plays a major role in the regulation of GH secretion. Pyridostigmine, a cholinesterase inhibitor, is able to decrease hypothalamic somatostatinergic tone and release GH in normal subjects. Blockade of muscarinic receptor with pirenzepine blunts the GH release in several clinical situations. However, little information is available on the role played by central cholinergic pathways in GH regulation in uraemic patients.

OBJECTIVE

We aimed to assess GH responses to GHRH after pretreatment with pyridostigmine and pirenzepine in a group of uraemic patients undergoing peritoneal dialysis (PD). GH responses of the patients treated with recombinant human erythropeitin (rhEPO) were compared to patients without treatment.

DESIGN

We studied 14 male patients on PD and nine control subjects. All subjects underwent three endocrine test in random order after an overnight fast. Each subject received GHRH (100 μg, i.v. in bolus at 0 minutes). Sixty minutes before the injection of GHRH subjects were given oral placebo, pyridostigmine (120 mg), or pirenzepine (100 mg).

MEASUREMENTS

Blood samples for GH were collected at −60, 0, 15, 30, 45, 60 and 90 minutes The hormonal secretory responses were studied by a time‐averaged (area under the curves, AUC) and time‐independent (peak values) analysis.

RESULTS

Baseline GH concentrations were similar in patients and controls. GH responses to placebo plus GHRH were also comparable in patients and controls (peak 26.6 ± 3.8 vs. 33.2 ± 4.4 mU/l, AUC 28.2 ± 3.4 vs. 27.8 ± 4.6 mU/h/l). Pyridostigmine administration induced a significant potentiation of GH responses to GHRH both in patients (peak 43.2 ± 5.2 mU/l, AUC 47.6 ± 6.0 mU/h/l; P < 0.01) and in control subjects (peak 79.2 ± 8.6 mU/l, AUC 78.0 ± 9.4 mU/h/l; P < 0.01). However, the increment in GH peak and AUC was significantly (P < 0.05) greater in controls in relation to values found in patients. Pirenzepine administration induced an abolishment of GH release after GHRH stimulation both in PD patients (peak 5.4 ± 2.6 mU/l, AUC 6.0 ± 2.4 mU/h/l; P < 0.01) and in healthy controls (peak 3.8 ± 0.6 mU/l, AUC 4.0 ± 0.4 mU/h/l; P < 0.05). Responses to pyridostigmine plus GHRH and pirenzepine plus GHRH were similar in patients on chronic therapy with recombinant human erythropeitin and in patients without rhEPO therapy.

CONCLUSION

These results suggest that the cholinergic regulation of GH release is preserved in uraemic patients on peritoneal dialysis. The significantly lower increase in GH response to GHRH induced by pyridostigmine suggests that cholinergic stimulatory tone is attenuated in patients in relation to control subjects. Long‐term therapy with rhEPO seems not to affect GH responses to cholinergic stimulation or blockade.
Long‐term mifepristone (RU486) therapy resulting in massive benign endometrial hyperplasia
Authors: Newfield Ron S. , Spitz Irving M. , Isacson Christina , New Maria I.
Published: March 2003

Mifepristone (RU486) is a potent antiprogestagen, and at high doses it also acts as an antiglucocorticoid drug. Mifepristone, administered as a single 600 mg dose, is commonly employed to induce medical abortion in conjunction with prostaglandins. The long‐term safety profile of mifepristone, especially at high doses, is less well‐established. Long‐term mifepristone is considered efficacious in treating uterine myomas, endometriosis (25–100 mg/day), and possibly in inoperable meningiomas (200 mg/day), as well as inoperable Cushing's syndrome. Many animal studies document an antiproliferative effect (antioestrogenic), as do some reports in humans. However, there are also data to suggest that, as an antiprogestagen, mifepristone may promote an unopposed oestrogen milieu, and thus have a proliferative effect upon the endometrium.

We hereby describe the first reported case of an adolescent female with Cushingoid features and morbid osteoporosis who was treated with mifepristone for its antiglucocorticoid effect (400 mg/day) in an attempt to prevent further bone loss. The patient's striae, weight gain, and buffalo hump markedly improved, and further bone loss was halted. However, with each of the two 6‐month courses of mifepristone (9 months apart) she developed massive simple endometrial hyperplasia and a markedly enlarged uterus. This reversed to normal after cessation of mifepristone treatment.

In conclusion, High doses of the antiprogestagen mifepristone over a prolonged period of time may promote an unopposed oestrogen milieu leading to endometrial hyperplasia. Therefore, interval pelvic imaging in women who receive long‐term mifepristone may be prudent.