bluuebunny/crossref_metadata_2025 huggingface dataset:
Optimal dosage interval for depot somatostatin analogue therapy in acromegaly requires individual titration
Authors: Jenkins P. J. , Akker S. , Chew S. L. , Besser G. M. , Monson J. P. , Grossman A. B.
Published: March 2003

The recent introduction of the depot somatostatin analogues octreotide LAR and lanreotide represent major advances in the medical treatment of acromegaly. However, it is uncertain whether the recommended dose intervals of 4 weeks and 10–14 days, respectively, are applicable to all patients.

To determine the optimum intervals between depot injections of either octreotide LAR and lanreotide for the suppression of serum GH and IGF‐I in patients with acromegaly.

Twenty‐seven patients with acromegaly were randomly allocated to receive either three injections at 4 week intervals of octreotide LAR (n = 18) or five injections at 14 day intervals of lanreotide (n = 11); two patients participated in both arms. Prior to the first injection, at 4 and 6 weeks after the last injection of LAR, and at 10, 14 and 21 days after the last injection of lanreotide, serum mean GH and IGF‐I levels were measured.

In the LAR‐treated group, at 4 and 6 weeks after the third injection 13 patients (72%) and 12 patients (67%), respectively, had a mean GH < 5 mU/l. IGF‐I was normalized in 12 and 11 patients at these times. In the lanreotide‐treated group, five (45%), four (36%) and three (27%) patients, respectively, had a GH < 5 mU/l at 10, 14 and 21 days after the last injection and eight, six and five patients had a normal serum IGF‐I.

There is marked variability in individual patient responses to depot somatostatin analogues. The establishment of optimal drug intervals requires careful assessment. For octreotide LAR many patients may be as adequately controlled with 6 weekly injections as with 4 weekly injections. It is important to measure serum GH profiles at intervals after initiating therapy with these drugs to individualize doses for each patient and hence minimize cost.
Hypertension is a major risk factor for aortic root dilatation in women with Turner's syndrome
Authors: Elsheikh M. , Casadei B. , Conway G. S. , Wass J. A. H.
Published: March 2003

Women with Turner's syndrome (TS) have a threefold increase in mortality, primarily as a result of their cardiovascular complications. Recently, the risk of fatal aortic dissection has come to light as a major cause of mortality in women with TS. The aim of this study was to assess the prevalence of aortic root dilatation in a group of women with TS and to investigate the factors contributing to its development.

Thirty‐eight women with TS attending a dedicated adult Turner clinic were examined clinically and by M‐mode and two‐dimensional echocardiography on at least one occasion. Aortic root dilatation was defined as an aortic root diameter greater than the 95th centile for body surface area. Fasting serum lipid concentrations were measured in all women. Additionally, 18 subjects underwent noninvasive assessment of central arterial stiffness using applanation tonometry.

Fifty percent of subjects were hypertensive and a similar number had an abnormal echocardiogram. A bicuspid aortic valve was present in 33% of subjects, 16 women (42%) had ascending aortic root dilatation. This was associated with a bicuspid aortic valve in four women and hypertension in 11. Two women had isolated aortic root dilatation. Aortic root diameter was significantly associated with systolic blood pressure (r = 0·5, P = 0·003) and left ventricular thickness (r = 0·5, P = 0·02). There was no association with serum lipids or arterial compliance.

Structural cardiac abnormalities are present in up to 50% of women with Turner's syndrome. Aortic root dilatation is a significant risk in women with Turner's syndrome and is closely dependent on blood pressure. Aortic root dilatation does not appear to be related to atherosclerosis and is more likely to be due to a mesenchymal defect. Regular surveillance of the aortic root diameter is essential in all women with Turner's syndrome and hypertension should be treated aggressively when present in order to minimize the risk of potentially fatal aortic dissection.
Novel application of IGF‐I and IGFBP‐3 generation tests in the diagnosis of growth hormone axis disturbances in children with β‐thalassaemia
Authors: Chrysis Dionisios C. , Alexandrides Theodore K. , Koromantzou Era , Georgopoulos Neoklis , Vassilakos Pavlos , Kiess Wieland , Kratsch Jürgen , Beratis Nicholas G. , Spiliotis Bessie E.
Published: March 2003

OBJECTIVE

Children with β‐thalassaemia major (β‐thal) frequently have growth retardation in the presence of low serum IGF‐I and a normal GH response to pharmacological stimulation suggesting that they have GH insensitivity (GHIS). This study was carried out to study the cause of their growth retardation.

DESIGN

We studied IGF‐I and IGFBP‐3 generation after exogenous GH administration for four days, in 15 prepubertal controls (C) and 41 prepubertal β‐thal patients divided into three groups according to their growth status: (Group 1) 15 with normal growth (N‐thal) (Group 2) 16 with decelerated growth (D‐thal) and (Group 3) 10 with short stature (S‐thal), in order to determine whether GHIS is the cause of their growth retardation.

MEASUREMENTS

IGF‐I and IGFBP‐3 were measured daily, before and for 4 days after daily administration of 0·1 IU/kg hGH, in 3 groups of prepubertal β‐thal patients and normal controls.

RESULTS

N‐thal and C had similar basal serum IGF‐I (142 ± 52 and 196 ± 56 ng/ml, respectively) and IGFBP‐3 concentrations (2·07 ± 0·49 and 2·66 ± 0·41 mg/l, respectively) as well as a similar percent increase of IGF‐I (101 ± 23% and 104 ± 37%, respectively) and IGFBP‐3 (52 ± 36%, and 38 ± 14%, respectively) during the generation tests. S‐thal and D‐thal had significantly lower basal IGF‐I and IGFBP‐3 concentrations (85 ± 42 and 101 ± 36 ng/ml; and 1·60 ± 0·49 and 1·79 ± 0·52 mg/l, respectively) as compared to N‐thal and C (P < 0·001 and P < 0·005, respectively), and a significantly higher percent increase of IGF‐I and IGFBP‐3 during the generation tests (249 ± 43 and 161 ± 76%; and 121 ± 99 and 73 ± 35%, respectively) as compared to N‐thal and C (P < 0·0001 and P < 0·01, respectively). Twenty‐five percent of the growth retarded patients had classic GH deficiency (GHD) and percent increases of IGF‐I and IGFBP‐3 in the generation tests (164 ± 86% and 80 ± 49%, respectively) which were similar to those of the remaining growth‐retarded children.

CONCLUSION

The greater percent increases of IGF‐I and IGFBP‐3 in the generation tests of the growth retarded β‐thal patients, both with and without GHD, strongly suggest impaired GH secretion rather than GHIS as the cause of their growth retardation. We conclude that the IGF‐I and IGFBP‐3 generation tests are useful tools for the study not only of GHIS but also of GH secretory disorders in patients with β‐thal and short stature that can easily be performed in an outpatient setting as an initial test to identify the patients that may benefit from GH therapy.
Hydrocortisone replacement dosage influences intraocular pressure in patients with primary and secondary hypocortisolism
Authors: Li Voon Chong J. S. W. , Sen J. , Johnson Z. , Kyle G. , MacFarlane I. A.
Published: March 2003

BACKGROUND

It has been suggested that the variation of intraocular pressure (IOP) during the day follows the diurnal variation of serum cortisol. There is also a higher risk of ocular hypertension and glaucoma in patients taking excessive oral steroid treatment. We assessed whether different replacement doses of hydrocortisone (HC) influenced IOP.

METHODS

Seventeen patients (six Addison's disease, 11 hypopituitarism; seven males) aged 24–58 years mean 42·7 years and 20 control subjects (nine males) aged 20–59 years mean 38·7 years were studied. On the first visit, the 17 patients had been taking HC replacement doses, 20 mg morning and 10 mg afternoon. Serum cortisol and IOP in both eyes (Goldmann applanation tonometer) were measured at 0900, 1100, 1300, 1500, 1700 hours with HC 20 mg taken after the 0900 h assessment. The dose of HC was then reduced to 10 mg morning and 10 mg afternoon for 1 week and the measurements were repeated in 16 patients, with HC 10 mg taken at 0900 h.

RESULTS

In the patients the peak serum cortisol occurred at 1100 h after the 0900 h HC dose. Cortisol levels were significantly higher at 1100, 1300, 1500 and 1700 h after taking 20 mg compared to 10 mg HC. The mean (SEM) IOP (mmHg) was significantly higher after 20 mg HC compared with 10 mg HC at 1300 h: 14·7(0·6) v 13·1(0·6) (P = 0·004) and at 1500 h: 14·4(0·6) v 13·1(0·5) (P = 0·04). The total mean (SEM) daily IOP score was significantly higher after 20 mg HC compared with 10 mg HC: 14·5(0·3) v 13·5(0·3) (P = 0·0002). The total mean (SEM) daily IOP score after the 20 mg HC dose compared with the control subjects was: 14·5(0·3) v 13·7(0·3) (P = 0·08).

CONCLUSION

Intraocular pressures during the day are influenced by the morning hydrocortisone replacement dosage with significantly higher intraocular pressure levels in the early afternoon following 20 mg compared with 10 mg. A morning hydrocortisone dose of 10 mg leads to a more physiological intraocular pressure profile during the day. These data support the view that a daily replacement dose of 30 mg hydrocortisone may be excessive.
Undermasculinized genitalia in a boy with an abnormally expanded CAG repeat length in the androgen receptor gene★
Authors: Ogata Tsutomu , Muroya Koji , Ishii Tomohiro , Suzuki Yasuhiro , Nakada Teruhiro , Sasagawa Isoji
Published: March 2003

We report an 11‐year‐old boy with undermasculinized genitalia and an abnormally expanded CAG repeat length at exon 1 of the androgen receptor (AR) gene. He had microphallus and scrotal hypospadias with chordee, and underwent urethroplasty at 4 years of age. At 11 years of age, a gonadotropin releasing hormone (GnRH) test yielded a relatively high leutinizing hormone (LH) response (0·7→20·4 IU/l) and a relatively low follicle‐stimulating hormone (FSH) response (1·7→4·8 IU/l), and an human chorionic gonadotropin (hCG) test showed sufficient responses of testosterone (0·7→23·0 nmol/l) and dihydrotestosterone (0·38→2·95 nmol/l). The CAG repeat length was 44 for the boy and ranged from 12 to 32 for 100 control males. The DNA sequences of the AR gene were normal for the exons 1–8 and for the splice donor, splice acceptor and branch sites. The markedly expanded CAG repeat length appears to be relevant to the undermasculinized genitalia of this boy, because such an expandsion, which has previously been reported only in spinal and bulbar muscular atrophy, is known to reduce AR function.
Serum antibodies to human pituitary membrane antigens in patients with autoimmune lymphocytic hypophysitis and infundibuloneurohypophysitis
Authors: Nishiki Masateru , Murakami Yoshio , Ozawa Yasunori , Kato Yuzuru
Published: March 2003

Serum antipituitary antibodies were investigated by the immunoblotting method using human anterior pituitary membrane preparation as the antigen.

Thirteen patients with autoimmune lymphocytic hypophysitis, two patients with infundibuloneurohypophysitis, four patients with isolated ACTH deficiency, 21 patients with diabetes mellitus (type 1 and type 2) and 38 healthy subjects were studied.

Human pituitary membrane antigens were electrophoresed by sodium dodecylsulphate‐polyacrimide gel electrophoresis (SDS‐PAGE). The antigens were transferred to polyvinylidene difluoride membrane and reacted with the sera followed by incubation with biotinylated anti‐human IgG goat serum.

Serum antibodies to 68, 49, 43 kD human pituitary membrane antigens were detected in five of 13, one of 12 patients with infundibuloneurohypophysitis and none of four patients with isolated ACTH deficiency. These antibodies were not detectable when human thyroid, liver or rat pituitary preparations were used as the antigen.

These findings suggest that serum antibodies to 68, 49, 43 kD human anterior pituitary antigen are specific but not so frequently detected in autoimmune lymphocytic hypophysitis.
Increased levels of insulin‐like growth factor binding protein‐2 in sera and tumours from patients with colonic neoplasia with and without acromegaly
Authors: Miraki‐Moud F. , Jenkins P. J. , Fairclough P. D. , Jordan S. , Bustin S. A. , Jones A. M. , Lowe D. G. , Monson J. P. , Grossman A. B. , Besser G. M. , Camacho‐Hübner C.
Published: March 2003

OBJECTIVE Patients with acromegaly are at increased risk of developing colorectal carcinoma and premalignant tubulovillous adenoma. The pathogenesis of these neoplasms could involve a stimulatory effect of serum growth factors on colonic epithelial cell proliferation. The aim of this study was to evaluate changes in (1) serum IGF‐I, IGF‐II, IGFBP‐3 and IGFBP‐2 and (2) changes in local expression of IGFBPs and p53 in colonic epithelium in patients with colonic neoplasia with and without acromegaly.

DESIGN A cross‐sectional retrospective study was performed. Fasting serum samples were obtained at the time of colonoscopy for patients with acromegaly and at the time of surgery for patients with colonic neoplasia without acromegaly.

MEASUREMENTS Serum IGF‐I, IGF‐II, IGFBP‐2 and IGFBP−3 were measured using specific immunoassays. Tissue expression of IGFBP‐2, IGFBP‐3 and p53 status were determined by immunohistochemistry.

PATIENTS Group 1: 26 age‐ and sex‐matched control subjects (range 40–69 years); group 2: 18 patients with acromegaly without colonic neoplasia (range 39–68 years); group 3: 18 patients with acromegaly and colonic neoplasia (range 41–74 years, 11 = adenoma, seven = carcinoma); group 4: 19 patients with colonic neoplasia without endocrine disease (range 43–91 years, four = adenoma, 15 = carcinoma). Immunohistochemical staining of colonic biopsies was performed for IGFBP‐2, IGFBP‐3 and p53 in groups 3 and 4.

RESULTS Mean serum IGF‐I and IGFBP‐3 levels were significantly elevated in group 2 (371 ± 131 µg/l and 6·5 ± 1·8 mg/l, respectively) and group 3 (379 ± 174 µg/l and 5·8 ± 1·6 mg/l, respectively), and significantly reduced in group 4 (103 ± 36 µg/l and 2·4 ± 1 mg/l) compared to controls (165 ± 40 µg/l and 4·7 ± 1 mg/l; P < 0·0001, P < 0·001, respectively). However, median serum IGFBP‐2 levels were significantly elevated in group 3 (P < 0·01) and group 4 (P < 0·0001). Immunostaining for IGFBP‐2 showed strong areas of immunoreactivity in the cytoplasm of malignant colonic epithelium compared to benign epithelium. IGFBP‐3 immunostaining showed strong areas of immunoreactivity in the cytoplasm and in the nucleus of malignant and benign colonic epithelium compared to the normal epithelium. Nuclear staining for p53 was observed in three patients from group 3 (two carcinoma, one adenoma) and four patients from group 4 (all carcinoma).

CONCLUSION Our results describe changes in IGFBP‐2 expression in colonic neoplasia in patients with and without acromegaly, which suggest that this binding protein may regulate local bioavailability of IGF, which in turn could modulate colonic cell proliferation and/or differentiation.
Characterization of premature atherosclerosis of carotid arteries in acromegalic patients
Authors: Otsuki Michio , Kasayama Soji , Yamamoto Hiroyasu , Saito Hiroshi , Sumitani Satoru , Kouhara Haruhiko , Saitoh Youichi , Ohnishi Takanori , Arita Norio
Published: March 2003

OBJECTIVEAcromegalic patients have increased mortality from vascular diseases. Although atherosclerotic risk factors such as hypertension, diabetes mellitus and dyslipoproteinaemia are highly associated with acromegaly, the prevalence of premature atherosclerosis in acromegalic patients and its relationship to these risk factors have not been reported.

DESIGNWe measured mean intima‐media thickness (IMT) of the carotid arteries in 21 acromegalic patients without symptomatic atherosclerotic vascular disease, by ultrasound high‐resolution B‐mode imaging. In analysis 1, it was compared with the predicted mean IMT based on data from existing risk factors (age, male sex, dyslipoproteinaemia, hypertension, diabetes mellitus, smoking status) in 282 non‐acromegalic subjects. In analysis 2, the mean IMT in the 21 acromegalic patients was compared with that in 42 non‐acromegalic subjects matched for age, sex and the other atherosclerotic risk factors. We also analysed clinical characteristics between the acromegalic patients with and without the atherosclerosis.

RESULTSMean IMT in 21 acromegalic patients was 0·92 ± 0·21 (mean ± SD) mm. It was significantly (P < 0·05) lower than the mean IMT (1·03 ± 0·12 mm) predicted from their existing risk factors (analysis 1). It was also less than that in 42 non‐acromegalic subjects matched for atherosclerotic risk factors (1·07 ± 0·37 mm;P < 0·05) (analysis 2). Among the acromegalic patients, 10 patients (48%) had increased mean IMT (≧ 1·1 mm) and/or plaque lesions whereas the other 11 had no such atherosclerotic changes. In the patients without the atherosclerotic changes, plasma insulin‐like growth factor‐I (IGF‐I) concentration was significantly (P < 0·01) higher, and the prevalence of hypertension was significantly (P < 0·05) lower than in those with the atherosclerotic changes.

CONCLUSIONSThe extent of carotid atherosclerosis in the acromegalic patients was not higher than that in non‐acromegalic subjects, considering their atherosclerotic risk factors. Increased concentration of IGF‐I might be involved in the lack of susceptibility to atherosclerosis in some acromegalic patients.
Hormone replacement therapy and risk of falling in early postmenopausal women – a population‐based study
Authors: Randell Kaisa M. , Honkanen Risto J. , Komulainen Marja H. , Tuppurainen Marjo T. , Kröger Heikki , Saarikoski Seppo
Published: March 2003

OBJECTIVE The purpose of this study was to examine the effect of hormone (oestrogen) replacement therapy (HRT) on the risk of falling among early postmenopausal women.

METHODS We assessed the incidence of falls in HRT users compared to non‐users using population‐based data from the Kuopio Osteoporosis Risk Factor and Prevention (OSTPRE) Study. The study group consisted of 9792 postmenopausal women who responded to the OSTPRE baseline and follow‐up inquiries.

RESULTS A total of 3049 women reported sustaining a fall during the previous 12 months. The association between current continuous use of HRT and overall risk of falling was non‐significant − 9% (P = 0·10). However, current continuous HRT use was associated with a decreased risk (− 30%) of non‐slip falls (N = 1129) (P = 0·0001) but not with the risk (+ 9%) of slip falls (N = 1757) (P = 0·23). In early postmenopausal women (time since menopause < 5 years) the protective effect of current continuous HRT was strengthened: the risk of non‐slip falls was 71% lower in HRT users than non‐users (P = 0·0035) if menopause had occurred within the past 2·5 years, and 43% lower (P = 0·0015) if time since menopause was 2·5–5 years.

CONCLUSION Hormone replacement therapy may reduce the risk of non‐slip falls in early postmenopausal women.
Additive effect of alfacalcidol on bone mineral density of the lumbar spine in Taiwanese postmenopausal women treated with hormone replacement therapy and calcium supplementation: a randomized 2‐year study
Authors: Chen Ming , Chow Song‐Nan
Published: March 2003

OBJECTIVETo evaluate the effect of 1α‐hydroxyvitamin D3on bone mineral density of the lumbar spine in postmenopausal women receiving hormone replacement therapy and calcium supplement.

DESIGNA randomized, prospective 2‐year clinical trial.

PATIENTS AND MEASUREMENTSA total of 240 postmenopausal women were enrolled with randomized assignment of 120 patients to each treatment group (the D + E group of 1α‐hydroxyvitamin D3+ sequential combined HRT + calcium supplement; the E group: sequential combined HRT + calcium supplement). None of the patients had received HRT for menopausal syndrome or osteoporosis before being enrolled in our study. Serum biochemical assays, electrolytes and calcitonin were performed at baseline and after 6 and 12 months of treatment. Bone mineral density (BMD) of L2–L4 was measured by dual energy X‐ray absorptiometry (DXA) at the initial assessment and after 12 and 24 months of treatment.

RESULTSOne hundred and five patients (87·5%) in the D + E group and 92 patients (76·7%) in the E group completed the first 1‐year study. Ninety‐six patients (80%) in the D + E group and 80 patients (66·7%) in the E group completed the 2‐year trial. Renal function, liver function, electrolytes and calcitonin showed no significant changes during the first year of follow‐up. In the D + E group, the BMD of L2–4 increased 3·24 ± 0·32% from baseline after 1 year (P < 0·05) and 5·32 ± 0·23% after 2 years of treatment (P < 0·05). On the other hand, the changes of BMD in the E group were 1·12 ± 0·34% after 1 year (P < 0·05) and 2·42 ± 0·26% after 2 years of treatment (P < 0·05). The changes of BMD of L2–L4 of the D + E group were higher than the changes of the E group after both 1 and 2 years of treatment (P < 0·05).

CONCLUSIONSOur study demonstrated that combination of 1α‐hydroxyvitamin D3with HRT is superior to HRT alone for the preservation of bone mineral density in postmenopausal women under calcium supplementation.
Prevalence of gestational thyrotoxicosis in Asian women evaluated in the 8th to 14th weeks of pregnancy: correlations with total and free beta human chorionic gonadotrophin
Authors: Yeo Chin Pin , Khoo Daphne Hsu Chin , Eng Peter Hsi Ko , Tan Hak Koon , Yo Sui Lan , Jacob Edward
Published: March 2003

OBJECTIVES The prevalence of gestational transient thyrotoxicosis (GTT) in Europeans evaluated during the 8th to 14th weeks of pregnancy is 2–3%. However, there is evidence that GTT may be more common in some Asian populations. The aims of this study were to evaluate the prevalence of thyroid hormone abnormalities in Asian women in their 8th to 14th weeks of pregnancy using highly sensitive free T4 and TSH assays and to correlate these with total and free β‐hCG levels.

DESIGN AND PATIENTS One hundred and eighty‐four consecutive unselected Asian (Singaporean) pregnant women seen at ante‐natal clinics for the first time and who were in their 8th to 14th weeks of pregnancy were tested.

MEASUREMENTS Serum free T4, free T3, TSH, total β‐hCG and free β‐HCG levels were measured on the Vitros ECi system (Johnson & Johnson Ortho‐Clinical Diagnostics, Amersham, UK) which employs chemiluminescent immunochemical technology. This free T4 assay is free of biases related to serum binding capacity. The TSH assay used was a third generation assay. Thyrotrophin‐receptor antibody (TRAb) levels were measured using LUMItest TRAK (BRAHMS Diagnostica, Berlin, Germany).

RESULTS Two subjects (1·1%) were found to have Graves' disease. Elevated free T4, free T3, total T3 and suppressed TSH were seen in 14·8%, 3·3%, 26·4% and 33·0% of the remaining 182 pregnant women, respectively. Total and free β‐hCG correlated negatively with TSH (r = −0·30, P < 0·0001 and r = −0·29, P < 0·0001, respectively), positively with fT4 (r = 0·283, P < 0·001 and r = 0·253, P < 0·001) and fT3 (r = 0·273, P < 0·001 and r = 0·204, P < 0·01). 11·0% of cases had gestational thyrotoxicosis (GT) defined as elevated free T4 (> 19·1 pmol/l), suppressed TSH (< 0·36 mIU/l) and TRAb levels within the reference interval (0–0·9 U/l). The prevalence of GT was significantly higher in patients tested at 8–11 weeks compared to those evaluated at 12–14 weeks (14·4% vs. 4·7%, P < 0·05). Total β‐hCG (P = 0·0002), free β‐hCG (P < 0·0001) and free T4 (P = 0·02) levels were higher and TSH levels (P = 0·01) lower in patients tested at 8–11 weeks. Significant positive correlations between both total and free β‐hCG with free T4 were seen at 8–11 weeks but not in patients tested at 12 weeks or later. TT3 levels were similar in the two groups.

CONCLUSIONS Using sensitive assays, the prevalence of gestational thyrotoxicosis in Asian women was found to be 11·0% and was significantly higher in subjects at 8–11 weeks of gestation than at 12–14 weeks. The positive correlation between hCG and free T4 seen in patients tested at 8–11 weeks was absent in patients tested at later stages of the first trimester. Future studies investigating the entity of gestational thyrotoxicosis, at least in Asian patients, should focus on patients at earlier stages of gestation than currently practised.
A placebo‐controlled trial of long‐term oral combined continuous hormone replacement therapy in postmenopausal women: effects on arterial compliance and endothelial function
Authors: Teede Helena J. , Liang Yu‐Lu , Kotsopoulos Dimitra , Zoungas Sophia , Craven Robyn , McGrath Barry P.
Published: March 2003

OBJECTIVE To study the effects of long‐term combined continuous oral hormone replacement therapy (HRT) on vascular function in healthy postmenopausal women.

BACKGROUND The cardiovascular effects of HRT are controversial. Improvement in vascular function is a proposed mechanism of oestrogen action but there are no long‐term controlled human trials in this area. In this study, we examined the effects of HRT on lipid profiles and vascular function, encompassing both biomechanical arterial properties [systemic arterial compliance (SAC) and pulse wave velocity (PWV)] and endothelial function [flow‐mediated vasodilation (FMD)].

METHODS In this 2‐year, double‐blind, placebo‐controlled study, 59 healthy postmenopausal women were randomized to oral combined continuous oestrogen and progesterone [Kliogest®, oestradiol (2 mg), norethisterone (1 mg)] or placebo, with end‐points measured at baseline, 6 weeks and after 6, 12 and 24 months of treatment.

RESULTS Oral combined HRT reduced lipoprotein a [Lp(a)], although other lipid benefits were not observed. There were no significant changes in SAC, PWV or FMD with oral combined HRT, compared to placebo.

CONCLUSION In this long‐term, randomized placebo‐controlled trial, oral continuous HRT with combined oestradiol and norethisterone in healthy postmenopausal women did not improve a spectrum of indices of arterial function compared to placebo. These results suggest that HRT might not be of cardiovascular benefit in postmenopausal women.
The CAG repeat polymorphism in the androgen receptor gene affects bone density and bone metabolism in healthy males
Authors: Zitzmann Michael , Brune Maik , Kornmann Britta , Gromoll Jörg , Junker Ralf , Nieschlag Eberhard
Published: March 2003

OBJECTIVE Bone metabolism and bone density (BD) are influenced by sex hormones. Testosterone (T) action is exerted through the androgen receptor (AR). We investigated the potential impact of the CAG repeat (CAGR) polymorphism within the AR gene on BD and bone metabolism in healthy younger males.

PATIENTS AND MEASUREMENTS The number of CAGRs in 110 healthy men aged 20–50 years was determined by sequence analysis. We assessed BD by the radiation‐free method of quantitative ultrasound (QUS) of the phalanges. Serum levels of bone‐specific alkaline phosphatase (BAP) and urine secretion of free deoxypyridinoline (DPD, corrected for creatinine), serum levels of sex hormones, body fat content and lifestyle factors were determined.

RESULTS In stepwise multiple regression models controlling for age, body fat content and lifestyle factors, the number of CAGRs was an independent negative predictor of BD (partial r = − 0·286, P = 0·001), whereas it was positively associated with markers of bone turnover (for BAP: partial r = 0·32, P = 0·001; for DPD: partial r = 0·241, P = 0·013). Levels of free T and oestradiol showed an independent and positive association with BD; age contributed significantly to lower BD. Age and free T were negatively associated with markers of bone turnover, whereas oestradiol showed a positive correlation with BAP and DPD. anova in groups according to age and the CAGR length suggested an increased age‐dependent bone loss in subjects with a CAGR length of 22–31 compared with 14–21 CAGRs (overall P < 0·01).

CONCLUSIONS A high number of CAG repeats within the androgen receptor gene attenuates testosterone effects on bone density and bone metabolism. This seems to be associated with accelerated age‐dependent bone loss.
An ultrasensitive assay revealed age‐related changes in serum oestradiol at low concentrations in both sexes from infancy to puberty
Authors: Ikegami Saiko , Moriwake Tadashi , Tanaka Hiroyuki , Inoue Masaru , Kubo Toshihide , Suzuki Satoshi , Kanzaki Susumu , Seino Yoshiki
Published: March 2003

OBJECTIVE Intensive studies of oestrogen receptors have suggested extragonadal functions of oestrogen. However, the in vivo extragonadal functions of oestradiol remain unclear because of the lack of an adequate assay system at low concentrations. In this study, we assessed the usefulness of a new ultrasensitive assay for children.

METHODS Serum oestradiol was measured with an ultrasensitive assay (assayable concentration: 5– 1835 pmol/l: ESTR‐US‐CT, CIS biointernational, France). Intra‐ and interassay coefficients of variation at low concentrations (< 36·7 pmol/l) were 8·2 ± 6·8 (0·1–31·2)% and 8·3 ± 3·7 (7·5–12·9)%, respectively.

SUBJECTS Sera from 88 healthy children (55 males and 33 females; 1 month to 16 years old) and 31 patients who underwent gonadal suppression therapy were analysed.

RESULTS Age‐related changes were observed in both sexes. Serum oestradiol concentrations in childhood decreased slightly compared to those in infancy, then increased at puberty. Most prepubertal children showed oestradiol concentrations lower than 36·7 pmol/l. A study on patients who underwent gonadal suppression therapy revealed oestradiol changes within low concentrations, depending on the stage of the therapy.

CONCLUSIONS The new assay was considered precise enough for the assessment of oestradiol secretion at low concentrations in childhood. Age‐related changes in serum oestradiol suggested gonadal activity in the prepubertal period. This assay could be a powerful tool for investigating novel oestradiol functions in vivo.
Factors predicting adult height in girls with idiopathic central precocious puberty: implications for treatment*
Authors: Adan Luis , Chemaitilly Wassim , Trivin Christine , Brauner Raja
Published: March 2003

objectives To optimize the indications for treating girls with idiopathic central precocious puberty with GnRH analogues, since outcomes may vary.

design Comparison of adult heights with the data at initial evaluation and the target heights.

patients Group 1 patients (n = 43) were treated with GnRH analogue from 7·9 ± 0·2 years to 10·8 ± 0·1 years (bone age: 10·3 ± 0·2 years to 12·2 ± 0·1 years) and group 2 patients (n = 29) were monitored without treatment because their predicted adult heights were > 155 cm. The criteria for treatment were a predicted height < 155 cm and/or a LH/FSH peaks ratio of > 0·6.

results At initial evaluation, group 1 patients had greater breast development (P = 0·001) and bone age advances (2·0 ± 0·2 years) than those of group 2 (1·3 ± 0·2 years, P < 0·03), and higher plasma oestradiol concentrations (139 ± 11 pmol/l vs. 62 ± 7 pmol/l, P = 0·0001), LH peak (12·2 ± 1·8 IU/l vs. 5·8 ± 2·2 IU/l, P = 0·0001) and LH/FSH peaks ratio (1·3 ± 0·2 vs. 0·5 ± 0·1, P = 0·0001). The predicted height for group 1 at the onset of treatment (156 ± 1·2 cm) was lower than the adult height (159·5 ± 0·8 cm, P = 0·002), but the two were similar (164·1 ± 1·2 cm vs. 162·7 ± 0·9 cm) for group 2. In group 1, the difference between these heights (mean 3·4 cm) was positively correlated with the bone age advance (r = 0·51, P = 0·001), but not with chronological or bone ages, oestradiol, LH peak, LH/FSH peaks ratio before treatment or its duration. It was 5·3 ± 1·2 cm in the 28 patients with a bone age advance of > 2 years and 0 ± 1·3 cm in the other 15 (P < 0·02). It was 6·1 ± 1·3 cm in the 24 patients with predicted height < 155 cm, and –0·1 ± 1·1 cm in the other 18 (P = 0·002). The 72 patients included nine who attained an adult height over 5 cm shorter than the target height (seven treated and two untreated). The seven treated subjects included two who had retarded intrauterine growth.

conclusions Treatment of girls with idiopathic central precocious puberty with GnRH analogues produced a mean height increase of 3·4 cm between the predicted and adult heights. The increase was greater for girls with a bone age advance of > 2 years and a predicted height < 155 cm. Adult height is spontaneously preserved in the slowly progressing form. The classical and slowly progressing forms can be distinguished by the degrees of breast development and bone age advance.
Acromegaly: evidence for a direct relation between disease activity and cardiac dysfunction in patients without ventricular hypertrophy
Authors: Herrmann B. L. , Bruch C. , Saller B. , Bartel T. , Ferdin S. , Erbel R. , Mann K.
Published: March 2003

background and aims Cardiac abnormalities, such as cardiomegaly and congestive heart failure, occur frequently in advanced acromegaly. Abnormalities of systolic and diastolic function, mostly associated with left ventricular (LV) hypertrophy, have been reported. The impact of disease activity on LV performance in patients with normal or slightly elevated LV muscle mass has not been demonstrated.

patients and methods Conventional two‐dimensional/Doppler echocardiography and tissue Doppler imaging (TDI) of the mitral annulus were performed in 13 patients with active acromegaly (AA) and normal or slightly elevated LV muscle mass (< 140 g/m2) and in 19 cured/well‐controlled patients (CA). A group of 21 volunteers without symptoms or signs of cardiac disease served as controls (CON). The combined myocardial performance index (Tei‐Index) was determined in all patients and controls.

results Muscle mass index of the left ventricle, ejection fraction, fractional shorting, E/ET‐ratio, systolic (ST) and late diastolic (AT) annular velocities did not differ significantly between the three groups. In the AA group, the early diastolic annular velocity ET[7·13 ± 2·11 (AA); 9·83 ± 3·29 (CA); 10·10 ± 1·70 m/s (CON); P < 0·05 AA vs. CA, P < 0·005 AA vs. CON] and the ET/AT‐ratio [0·71 ± 0·26 (AA); 0·95 ± 0·33 (CA); 1·00 ± 0·15 m/s (CON); P < 0·05 AA vs. CA, P < 0·005 AA vs. CON] were significantly reduced. Patients with AA had a longer deceleration time [209 ± 19 (AA); 179 ± 22 (CA); 185 ± 26 ms (CON); P < 0·05]. The Tei‐Index was significantly higher in AA in comparison with CON [0·50 ± 0·15 (AA); 0·48 ± 0·12 (CA); 0·41 ± 0·10 (CON); P < 0·05 AA vs. CON]. Subjects with CA did not differ significantly from controls with respect to 2‐D/Doppler echo‐ and TDI‐derived parameters.

conclusion The data demonstrate that diastolic dysfunction can be verified by tissue Doppler imaging in patients with active acromegaly with normal or slightly elevated muscle mass of the left ventricle and seems to be related to disease activity. The Tei‐Index as a sensitive combined myocardial performance index can be used to complete the assessment of systolic and diastolic LV performance in acromegalic patients.
The GH‐releasing effect of ghrelin, a natural GH secretagogue, is only blunted by the infusion of exogenous somatostatin in humans
Authors: Di Vito Lidia , Broglio Fabio , Benso Andrea , Gottero Cristina , Prodam Flavia , Papotti Mauro , Muccioli Giampiero , Dieguez Carlos , Casanueva Felipe F. , Deghenghi Romano , Ghigo Ezio , Arvat Emanuela
Published: March 2003

objective Ghrelin, a 28‐amino‐acid peptide purified from the stomach and showing a unique structure with an n‐octanoyl ester at the serine 3 residue, is a natural ligand of the GH secretagogue (GHS) receptor (GHS‐R). Ghrelin strongly stimulates GH secretion in both animals and humans, showing a synergistic effect with GH‐releasing hormone (GHRH) but no interaction with synthetic GHS. However, the activity of ghrelin as well as that of non‐natural GHS is not fully specific for GH; ghrelin also induces a stimulatory effect on lactotroph and corticotroph secretion, at least in humans.

design To further clarify the mechanisms underlying the GH‐releasing activity of this natural GHS, we studied the effects of somatostatin (SS, 2·0 µg/kg/h from −30 to +90 min) on the endocrine responses to ghrelin (1·0 µg/kg i.v. at 0 min) in seven normal young male volunteers [age (mean ± SEM) 28·6 ± 2·9 years; body mass index (BMI) 22·1 ± 0·8 kg/m2] . In the same subjects, the effect of SS on the GH response to GHRH (1·0 µg/kg i.v. at 0 min) was also studied.

measurements Blood samples were taken every 15 min from −30 up to +120 min. GH levels were assayed at each time point in all sessions; PRL, ACTH and cortisol levels were assayed after ghrelin administration alone and during SS infusion.

results The GH response to ghrelin (hAUC0′→120′ 2695·0 ± 492·6 µg min/l) was higher (P < 0·01) than that after GHRH (757·1 ± 44·1 µg min/l). SS infusion almost abolished the GH response to GHRH (177·0 ± 37·7 µg min/l, P < 0·01); the GH response to ghrelin was inhibited by SS (993·8 ± 248·5 µg min/l, P < 0·01) but GH levels remained higher (P < 0·05) than with GHRH. Ghrelin induced significant increases in PRL, ACTH and cortisol levels and these responses were not modified by SS.

conclusions Ghrelin, a natural GHS‐R ligand, exerts a strong stimulatory effect on GH secretion in humans and this effect is only blunted by an exogenous somatostatin dose which almost abolishes the GH response to GHRH. The stimulatory effect of ghrelin on lactotroph and corticotroph secretion is refractory to exogenous somatostatin, indicating that these effects occur through pathways independent of somatostatinergic influence.
What is the role of the insulin‐like growth factor system in the pathophysiology of cancer cachexia, and how is it regulated?
Authors: Crown A. L. , Cottle K. , Lightman S. L. , Falk S. , Mohamed‐Ali V. , Armstrong L. , Millar A. B. , Holly J. M. P.
Published: March 2003

objective and background The cancer cachexia syndrome is characterized by anorexia, weight loss with muscle wasting and increased energy expenditure. It is associated with increased morbidity and mortality, but its aetiology is poorly understood and no effective therapeutic intervention is available. It may result from an imbalance between the activity or effect of anabolic and catabolic hormones, mediated by the inflammatory cytokines. IGF‐I is a potent anabolic agent, with therapeutic potential. Our objective was to investigate the role and regulation of the IGF system in cancer cachexia.

design and patients We set up a prospective study of 30 patients with newly diagnosed unresectable non‐small cell lung cancer, together with a cross‐sectional comparison group of healthy volunteers.

measurements We examined the relationship between aspects of the IGF system, including IGFBP‐3 proteolysis (using Western ligand and immunoblotting and an in vitro IGFBP‐3 protease assay); the inflammatory cytokines and their soluble receptors; and food intake and nutritional status (including biochemical and anthropometric assessments).

results Although we did not observe a marked reduction in food intake in the cancer patients, the majority lost weight and functionally important lean body mass. We observed GH resistance in the cancer patients, and intermittent proteolysis of IGFBP‐3, which correlated with the circulating interleukin‐6 (IL‐6) concentration. The pattern of IGFBP‐3 proteolysis was unusual, with a prominent 17‐kDa fragment. Less IGFBP‐3 proteolysis was associated with more weight loss, suggesting that this could be a protective counter‐regulatory mechanism, increasing IGF‐I bioavailability to the tissues.

conclusions Cancer cachexia in humans is a complex condition. Patients tend to be GH resistant. The significance of the intermittent increases in IGFBP‐3 proteolysis, which may be regulated by IL‐6, remains uncertain. A better understanding of the pathophysiology should enable the development of novel therapeutic approaches.
Sympathetic nerve hyperactivity is associated with increased peripheral vascular resistance in hypopituitary patients with growth hormone deficiency
Authors: Scott Eleanor M. , Greenwood John P. , Stoker John B. , Mary David A. S. G. , Gilbey Stephen G.
Published: March 2003

objective Hypopituitary patients with untreated GH deficiency have increased cardiovascular mortality. Sustained vasoconstriction is an important factor in the development of hypertension and insulin resistance. This study was designed to see whether peripheral vascular resistance was increased in subjects with GH deficiency and to examine the mechanisms involved.

methods Nine patients with GH deficiency and nine matched control subjects were studied. Calf vascular resistance was measured by venous occlusion plethysmography and sympathetic vasoconstrictor nerve activity by peroneal microneurography.

results Subjects with GH deficiency had a significantly lower blood flow (by 31%) and higher vascular resistance (by 48%) than the control group. In addition, they had a significantly higher sympathetic vasoconstrictor activity (by 67%) and this correlated with the vascular resistance (r = 0·45; P < 0·04).

conclusions Patients with GH deficiency have an increased peripheral vascular resistance that is contributed to by an increase in central sympathetic vasoconstrictor discharge to the peripheral vasculature. This could be important in the development of cardiovascular disease in this condition.
A comparison of the relative efficacy of antiandrogens for the treatment of acne in hyperandrogenic women
Authors: Carmina Enrico , Lobo Rogerio A.
Published: March 2003

objectives To compare the relative effectiveness of two newer antiandrogens (flutamide and finasteride) with cyproterone acetate (CPA), at both low and high doses in the treatment of moderate to severe acne in hyperandrogenic women.

subjects and design Forty‐eight hyperandrogenic women were prospectively randomized to the following treatments for 1 year: CPA 2 mg with 35 µg ethinylestradiol; CPA 50 mg with 25 µg ethinylestradiol (reverse sequential regimen); flutamide 250 mg daily; and finasteride 5 mg daily. Assessment of Cook scores was the primary end‐point of the trial. Blood for androgens was obtained at baseline in these women and 30 ovulatory age‐matched controls.

results Serum androgens were elevated in all 48 women and was similar in each of the four treatment groups. Cook scores were significantly and equally decreased (59–71%) with flutamide and both low and high doses of CPA (P < 0·01). The decrease with finasteride (−36 ± 2%) was statistically significant but lower than that obtained with the other agents. All treatments were well tolerated.

conclusions In hyperandrogenic women with moderate to severe acne, low doses of certain antiandrogens appear to be effective. Low and high doses of CPA with ethinylestradiol were equally effective and were comparable to the effects of a low dose of flutamide. Finasteride was less beneficial.
Relationship between autonomic cardiac activity, b‐cell function, anthropometrics and metabolic indices in type II diabetics
Authors: Manzella Daniela , Carbonella Marco , Ragno Emilia , Passariello Nicola , Grella Rodolfo , Paolisso Giuseppe
Published: March 2003

objective Recent studies have demonstrated that C‐peptide exerts beneficial effects on the diabetic state, including improvements in kidney and nerve function. Thus, we investigated the effect of residual pancreatic C‐peptide secretion on the cardiac autonomic nervous system in well‐ and poorly controlled type II diabetic patients.

design Randomised cross‐sectional study.

patients Forty type II diabetic patients free from diabetic neuropathy, with similar anthropometric parameters, volunteered for our study.

measurements Insulin action, residual pancreatic C‐peptide secretion and the cardiac autonomic nervous system were investigated by euglycaemic hyperinsulinaemic clamp, glucagon bolus test and heart rate variability, respectively. M‐values were used as an index of insulin sensitivity. High frequency (HF) and low frequency (LF) oscillations in heart rate were analysed.

results The patients were categorized into those with good (HbA1c ≤ 7·0) and poor (HbA1c ≥ 8·0) metabolic control. The patients with good metabolic control had fasting plasma glucose and C‐peptide levels, plasma area under the curve (auc) insulin and C‐peptide levels, M‐values, LF values and LF/HF ratio significantly lower than patients with poor metabolic control. In contrast, RR interval, total power and HF values had an opposite trend. Basal plasma C‐peptide correlated with LF/HF in patients with good (r = −0·42; P < 0·05) and poor metabolic control (r = −0·45; P < 0·05). An even stronger correlation between auc C‐peptide and LF/HF in patients with good (r = −0·53, P < 0·002) and poor metabolic control (r = −0·49; P < 0·03), as well as in the whole group (r = −0·83; P < 0·001) was found. By multiple regression analyses performed in all patients, LF/HF were independently associated with auc C‐peptide (t = −8·618; P < 0·001) but not basal C‐peptide levels (t = −0·137; P < 0·88).

conclusion Our study demonstrated that preserved C‐peptide secretion is associated with a well balanced cardiac autonomic activity in type II diabetic patients.
Bone metabolism and mass in women with Cushing's syndrome and adrenal incidentaloma
Authors: Francucci Cristiano Maria , Pantanetti Paola , Garrapa Gabriella Giuseppina , Massi Fernando , Arnaldi Giorgio , Mantero Franco
Published: March 2003

objective The aim of this study was to compare bone turnover and mass in women with either Cushing's syndrome (CS) or adrenal incidentaloma (AI), which is a possible model for minimal hypersecretion of cortisol.

design and patients We studied 15 patients with CS (seven premenopausal and eight postmenopausal women); 23 patients with AI (five premenopausal and 18 postmenopausal women) and 20 matched controls (seven premenopausal and 13 postmenopausal women). Alkaline phosphatase (ALP), bone alkaline phosphatase (bALP), osteocalcin (BGP), 24‐h urinary pyridinoline (Pyr) and deoxypyridinoline (D‐Pyr) and serum and 24‐h urinary calcium and phosphorus were determined in all subjects. Bone mineral density (BMD) at lumbar spine and proximal femur was measured by dual energy X‐ray absorptiometry (DEXA).

results We found a significant reduction of BGP and serum phosphorus in CS and AI (P < 0·05) vs. controls and significantly lower levels of Pyr only in CS (P < 0·05) vs. AI and controls. Spinal and femoral BMD z‐values were significantly lower (P < 0·05) in patients with CS (z‐score: lumbar spine −1·44 ± 1·5 and femoral neck −1·07 ± 1; mean ± SD) compared to AI and controls.

conclusions Our data show that hypercortisolism reduces osteoblastic function and bone resorption and that osteocalcin can contribute to the precocious diagnosis of silent glucocorticoid excess. Patients with active CS were found to have lower BMD, particularly at vertebral level.