bluuebunny/crossref_metadata_2025 huggingface dataset:
Growth hormone (GH) replacement therapy reduces serum sialic acid concentrations in adults with GH‐deficiency: a double‐blind placebo‐controlled study
Authors: Christ Emanuel R. , Cummings Michael H. , Lumb Peter J. , Crook Martin A. , Sönksen Peter H. , Russell‐Jones David L.
Published: March 2003

OBJECTIVES

Patients with adult GH‐deficiency are thought to have an increased risk of cardiovascular disease. Sialic acid (SA) concentrations have been proposed as a marker of atherosclerotic disease probably related to an inflammatory response of the arterial wall. SA as a marker of cardiovascular disease in adult GH‐deficiency and its relation to changes in fasting lipid profile and hormone concentrations have not yet been investigated.

PATIENTS

We performed a randomised, double‐blind placebo‐controlled study in 18 patients with adult GH‐deficiency before and after 3 months GH replacement therapy (0.036 U/kg/d; GH‐treated group: 6 females, 3 males; age: 47.3 ± 5.4 years., mean ± SEM; placebo‐group: 5 females, 4 males; mean age 50.2 ± 4.7). In addition, SA concentrations were measured in 18 sex and age matched healthy control subjects.

METHODS

Blood samples were obtained after an overnight fast. Serum SA, triglycerides and cholesterol were measured using enzymatic methods. Lipoprotein classes were separated by ultracentrifugation. Insulin and IGF‐I were determined by radioimmunoassay, HbA1C was measured by anion exchange liquid chromatography.

RESULTS

SA concentrations of the patients with adult GH‐deficiency were not significantly different compared to the control group (GH‐deficient group: 2.29 ± 0.02 mmol/l, mean ± SEM vs. control group: 2.09 ± 0.13 mmol/l, P = 0.25). Before GH replacement therapy SA concentrations correlated positively with the patients age (r = 0.45; P < 0.04) and fasting insulin concentrations (r = 0.5; P < 0.03) but not with fasting lipid profile. GH replacement therapy significantly increased IGF‐I (GH: + 27 ± 2.6 vs. placebo: + 1.0 ± 0.8 nmol/l, P < 0.001) and fasting insulin concentrations (GH: + 71.9 ± 8.0 vs. placebo: + 19.6 ± 22.6 pmol/l, P < 0.04) compared to placebo therapy. SA concentrations (GH: − 0.41 ± 0.15 vs. placebo: − 0.01 ± 0.12 mmol/l, P < 0.05), total cholesterol (GH: − 0.71 ± 0.16 vs. placebo: 0.23 ± 0.21 mmol/l, P < 0.003) and LDL‐cholesterol (− 0.71 ± 0.14 vs. placebo: − 0.12 ± 0.21 mmol/l P < 0.04) significantly decreased after GH replacement therapy compared to placebo therapy. No significant correlation between changes in SA concentrations and changes in lipid profile were observed following GH replacement therapy.

CONCLUSION

These results suggest that, firstly, GH replacement therapy may have a beneficial effect on the pathogenesis of atherosclerosis despite the increase in insulin concentrations, a surrogate marker of insulin resistance, secondly, the proposed beneficial effect of GH on the atherosclerotic process is likely to be multifactorial and cannot only be explained by changes in lipid profile and finally, SA might be a useful marker for the process of atherosclerotic disease in interventional studies.
Increased pressor response to noradrenaline in pituitary dependent Cushing's syndrome
Authors: Heaney Anthony P. , Hunter Steven J. , Sheridan Brian , Brew Atkinson
Published: March 2003

OBJECTIVES

The mechanism of hypertension in Cushing's syndrome remains undetermined. Some studies have demonstrated an increased sensitivity to pressor agents but it is not clear if patients with Cushing's syndrome of different aetiologies demonstrate this finding. We have examined pressor sensitivity in a group of patients with Cushing's disease (pituitary dependent hypercortisolism) by measuring blood pressure during incrementally increasing infusions of noradrenaline.

METHODS

Eight subjects (7 female, 1 male), aged 42.2 ± 4.5 years (mean ± SEM) with Cushing's disease were studied. Eight age‐ and sex‐matched control subjects were also studied. Four of the eight controls and five patients with Cushing's disease had elevated blood pressure. All medication for this had been stopped at least seven days prior to the study. After subjects ate a light breakfast, ECG leads and a sphygmomanometer were attached, an intravenous cannula was inserted and all subjects then rested quietly for 60 minutes. Noradrenaline was then infused intravenously for 10‐minute periods at concentrations of 0.01, 0.03, 0.07, 0.11 and 0.18 μg/kg/minute.

RESULTS

On the day of the study the baseline blood pressures and pulse rates in the patients with Cushing's disease (blood pressure; 138/87 ± 6/3 mmHg, pulse 76.5 ± 4.8 beats/minute) and controls (blood pressure; 126/86 ± 6/6 mmHg, pulse 71.2 ± 3.7 beats/minute) were not significantly different. The mean change in diastolic blood pressure from baseline at the time of the peak increase or when the test was stopped was 21.5 ± 4.7 mmHg in Cushing's disease compared to 7.0 ± 2.5 mmHg in controls (P = 0.03). The mean change in mean arterial pressure from baseline at the time of the peak increase or when the test was stopped was 22.0 ± 4.0 mmHg in Cushing's disease compared to 13.0 ± 2.4 mmHg in controls (P = 0.03). No significant difference in mean change of systolic pressure (26.0 ± 4.6 vs. 25 ± 4.0 mmHg) or pulse rates (− 11.1 ± 1.8 vs. − 4.7 ± 2.6) was seen in the group with Cushing's disease as compared to the control group.

CONCLUSIONS

We conclude that patients with pituitary–dependent Cushing's syndrome have enhanced pressor diastolic and mean arterial responses to noradrenaline and this may be an important underlying mechanism for the hypertension seen in this particular group of Cushing's syndrome patients.
Syndrome of body fat redistribution in HIV‐1‐infected patients: relationships to cortisol and catecholamines
Authors: Renard Eric , Fabre Jacqueline , Paris Françoise , Reynes Jacques , Bringer Jacques
Published: March 2003

OBJECTIVE

Alterations of body fat distribution have been recently reported in HIV‐infected patients. We aimed to investigate whether the hormones modulating adipose tissue metabolism could be implicated.

SUBJECTS

We investigated twenty‐eight HIV‐infected patients who had developed abdominal fat, combined with peripheral lipodystrophy in 25 cases and ‘buffalo hump’ in 2 cases, but who had otherwise improved on antiretroviral therapies. Twelve patients with no change in body fat, matched for age, disease control and treatment, were studied as controls.

MEASUREMENTS

Body composition was assessed by bioelectrical impedance analysis. Subcutaneous (SAT) and visceral (VAT) compartments of total abdominal adipose tissue (TAT) were measured by computed tomography. Resting metabolic rate (RMR) was assessed by indirect calorimetry. Endocrine investigations included plasma thyroid hormones, cortisol, testosterone, oestradiol and 24‐hour urinary free cortisol (UFC) and catecholamines.

RESULTS

Despite similar body mass index, the patients with body fat alterations showed significantly larger VAT and higher VAT:TAT ratio than controls (P = 0.002 and 0.0001, respectively). In these patients, RMR was significantly higher than estimated according to the Harris‐Benedict formula (+ 19.7 ± 11.6 %, P = 0.0001) and correlated with VAT (r = 0.58, P = 0.003) and 24‐hour urinary output of catecholamines (r = 0.67, P = 0.002), that was significantly increased in comparison withcontrols (1737 ± 1228 vs 476 ± 292 nmol, P = 0.013). We also found a significant correlation between VAT and UFC (r = 0.41, P = 0.042) that was absent in controls, although levels of UFC were similar in the two groups.

CONCLUSIONS

Our data suggest that body fat redistribution may involve cortisol and catecholamine actions. While high release of catecholamines may enhance RMR through increased lipolysis, cortisol may promote central fat storage. These effects might be related both to persistent hormonal responses to stress becoming inappropriate while disease control improved and to an increased sensitivity of visceral adipose tissue to cortisol in affected patients.
Sexual dimorphism in circulating monomeric and dimeric inhibins in normal boys and girls from birth to puberty
Authors: Bergadá  , Rojas  , Ropelato  , Ayuso  , Bergadá  , Campo
Published: March 2003

BACKGROUND AND OBJECTIVE

Inhibins are peptides, mainly of gonadal origin, that suppress FSH production. Dimeric forms of inhibin (A and B) have been proposed as peripheral markers of Sertoli and granulosa cell function. The aim of this study was to establish the relationship between circulating dimeric and monomeric inhibins, and gonadotrophins and sex steroids, in normal boys and girls from birth to puberty.

SUBJECTS

One hundred and forty‐six normal children (females: 57; males: 89) were studied.

MEASUREMENTS

Serum LH and FSH were measured by an immunofluorometric assay. Serum oestradiol and testosterone were measured by radioimmunoassay. Serum inhibin A and B, and Pro‐αC, were measured by specific two‐site enzyme‐linked immunosorbent assays.

RESULTS

In boys from birth to 6 months of age, the mean serum inhibin B concentration was as high (477 ± 53.7 ng/l) as that found at puberty (400 ± 70.2 ng/l). After the first year, inhibin B gradually decreased to reach its lowest concentration (153 ± 23.6 ng/l) at age 4–6 years. At approximately age 10, it rose progressively to reach pubertal concentrations. Pro‐αC showed a similar pattern but at lower concentrations. Inhibin A was not detected at any age. In girls from birth to 6 months, inhibin B levels (83.0 ± 18.3 ng/l) were approximately 50% lower than those found at puberty (181 ± 25.7 ng/l). After 6 months of age, these levels dropped (17.5 ± 1.6 ng/l) and remained low until the prepubertal years. Thereafter, they increased to pubertal concentrations. The serum inhibin A concentration after birth (29.9 ± 8.7 ng/l) was similar to that found at puberty (18.3 ± 5.7 ng/l); after 6 months, it fell to undetectable levels until the prepubertal years.

CONCLUSION

The sex difference in serum levels of gonadotrophins is associated with sex differences in the levels and proportions of circulating dimeric and monomeric inhibins.
Audit of selected patients with nonfunctioning pituitary adenomas treated without irradiation — a follow‐up study
Authors: Turner  , Stratton  , Byrne  , Adams  , Wass
Published: March 2003

OBJECTIVE

Non‐functioning pituitary adenomas (NFA) are the commonest type of pituitary macroadenoma. Although the initial definitive management of these tumours is almost always trans‐sphenoidal surgery, the use of postoperative radiotherapy remains controversial. Radiotherapy has been shown to significantly reduce the risk of tumour regrowth. An audit of patients with NFAs treated with trans‐sphenoidal surgery without irradiation was performed at our centre five years ago, and suggested that careful selection and follow‐up could avoid the need for adjuvant radiotherapy. We have repeated this audit to assess the longer term effects of this management strategy.

METHODS AND PATIENTS

The case notes and imaging of the original cohort of 65 of 73 patients (50 males, mean age 52) who had undergone trans‐sphenoidal surgery (TSA) for NFA between July 1979 and 1992, had not received irradiation and were followed up by imaging were reviewed. Tumour regrowth was defined as enlargement of the pituitary tumour. Mean follow‐up was 76 months (range 12–173).

RESULTS

Pituitary tumour regrowth has occurred in 21 of the 65 patients (32%) during a mean follow‐up of 76 months compared with 8/73 (11%) in 1994 (P = 0.002). The tumour regrowth was detected at a mean of 5.4 years (range 2–14 years). Lifetable analysis of the whole unirradiated group showed 82% recurrence free survival at 5 years (95% confidence limits 72–92%), and 56% at 10 years (95% confidence limits 38–74%). Eight (12%) patients required a second surgical procedure (6 TSA and 2 craniotomies). There was no relationship between recurrence and whether a total surgical removal was thought to have been performed.

CONCLUSION

Despite careful selection of patients with non‐functioning pituitary adenomas, tumour regrowth occurs in a significant proportion. These results show that continued follow‐up in these patients is essential as significantly more patients showed evidence of tumour regrowth at this second assessment compared with the 1994 data. Until we are able to predict which tumours are likely to regrow postoperatively, radiotherapy should be considered for all patients with non‐functioning pituitary adenomas as even in carefully selected cases, the regrowth rate is approaching 50% at 10 years.
Endogenous inhibitors of 11β–hydroxysteroid dehydrogenase type 1 do not explain abnormal cortisol metabolism in polycystic ovary syndrome
Authors: Walker Brian R. , Rodin Andrew , Taylor Norman F. , Clayton Richard N.
Published: March 2003

OBJECTIVE

The aetiology of enhanced adrenal androgen secretion in polycystic ovary syndrome is poorly understood. Previous reports suggest that enhanced peripheral metabolism of cortisol results in decreased negative feedback suppression of ACTH secretion, either by enhanced inactivation of cortisol by 5α‐reductase or impaired reactivation of cortisol by 11β–hydroxysteroid dehydrogenase type 1 (11β–HSD1). Endogenous inhibitors of hepatic 11β–HSD1 can be extracted from urine. We have tested the hypothesis that these are increased in patients with polycystic ovary syndrome.

DESIGN

A case‐control study.

PATIENTS

57 patients with polycystic ovary syndrome and 27 healthy control women.

MEASUREMENTS

Aliquots from 24 h urine samples were extracted with Sep‐Paks and incubated with rat liver microsomes in which 11β–HSD1 activity was quantified by conversion of 3H‐corticosterone to 3H‐11‐dehydrocorticosterone.

RESULTS

Inhibition of 11β–HSD1 activity was not different in extracts from patients compared with controls (40.8 ± 18.9 arbitrary units in patients vs. 42.7 ± 16.6 in controls, mean (± SEM, P > 0.60) and did not correlate with ratios of cortisol metabolites in urine or with body mass index.

CONCLUSIONS

The altered cortisol metabolism in polycystic ovarian syndrome, which is consistent with impaired 11β–HSD1 activity, cannot be accounted for by increased production of measurable endogenous inhibitors of this enzyme.
Combined pituitary hormone deficiency and pituitary hypoplasia due to a mutation of the Pit‐1 gene
Authors: Frisch Herwig , Kim Christiane , Häusler Gabriele , Pfäffle Roland
Published: March 2003

Several mutations of the pituitary‐specific transcription factor Pit‐1 have been identified. We describe a girl with a mutation of the Pit‐1 gene leading to a complete lack of GH, TSH and prolactin and a marked hypoplasia of the anterior pituitary gland. The patient had a homozygous nonsense‐mutation at position 172 (CGA to TGA), converting arginine into a stop codon, leading to an early termination of protein translation. During the infancy period the girl had very conspicuous symptoms of hypothyroidism and the diagnosis of thyroid insufficiency preceded the diagnosis of GH‐deficiency by 1.5 years. Treatment with thyroxine and GH resulted in excellent catch‐up growth.
Raised plasminogen activator inhibitor‐1 (PAI‐1) is not an independent risk factor in the polycystic ovary syndrome (PCOS)
Authors: Atlorno William U. , Fox Robert , Condon John E. , Shaw Stephen , Friend J. , Prentice Archibald G. , Wilkin Terence J.
Published: March 2003

BACKGROUND It has been postulated that an insulln‐driven increase in plasminogen activator inhibitor‐1 (PAI‐1) levels may link insulin resistance to anovulatory infertility in women with PCOS and that It may place them at increased risk of thromboembolic disease. However, previous studies have been conflicting because many have failed to control for body mass index (BMI) which may affect PAI‐1. The aim of this study was to investigate PAI‐1 activity in women with PCOS and to compare it with unaffected controls of a similar BMI.

DESIGN AND PATIENTS 41 Women with Pcos and 25 weight‐matched controls participated in this cross‐sectional study. Patients were evaluated clinically and by pelvic ultrasound and fasting blood samples were taken for haematological and biochemical tests. MEASUREMENTS PAI‐1 activity, insulin, glucose, trlglycerides, total cholesterol, LDL cholesterol, HDL cholesterol, FSH, LH, PRL, testosterone, SHBG, 17–hydroxyprogesterone, plasminogen, fibrinogen (α2 antiplasmin, blood pressure and insulin sensitivity with a homeostasis model assessment (HOMA) computer programme.

RESULTS There was no significant difference in BMI or in (log) PAI‐1 activity in women with PCOS compared with controls (BMI 29.5 ± 5.6 vs. 28.4 ± 6.3 kg/m2, P=0.25 and PAI‐12.56 (SD 0.85) vs. 2.14 (SD 0.98) au/ml, P=0.07). The median fasting insulin level was significantly higher (17 (4.6–134.5) vs. 9.6 (3.7–41.5) mU/l, P<0.01), and insulin sensitivity signiflcantly lower In the PCOS group, (43.17% (5.48–160) vs. 82.8% (21.8–193), P<0.01). Women with PCOS also had a significantly higher free androgen index, LW/FSH ratio and a lower HDL/total cholesterol ratio. However blood pressure and all other lipid and haematological measurements were not significantly different between both groups. There were significant positive correlations between (log) PAL1 activity and BMI (ρ= 0.61), triglycerides (ρ= 0.49) and fasting insulin (ρ= 0.60) and a negative correlation with HDL cholesterol (ρ=−0.46). Triglyceride concentrations showed the most Significant relationship with (log) PAI‐1 activity on multiple regression. 29% of PCO women (12/41) gave a positive family history of thrombosis compared to 8% (2/25) in the control group. CONCLUSION Plasminogen activator inhibitor‐1 activity is not raised in women with PCOS independent of obesity and these results do not support the hypothesis that it may contribute to their anovulatory infertility, or increase their risk of thrombosis. The only significant metabolic features of the PCOS independent of obesity are insulin resistance, hyperinsu‐linaemia and lower HDUtotal cholesterol ratio. The higher frequency of a positive family history of thrombosis in these women nevertheless requires further explanation.
Is monoclonality in pituitary adenomas synonymous with neoplasia?
Authors: Levy Andy
Published: March 2003

The objective of clonality analysis is to help differentiate hyperplasia from neoplasia. If the clonality of different pituitary subpopulations is skewed rather than uniform it is possible that a physiological trophic response could, by displacing trophically inert cells, give rise to a potentially evanescent monoclonal expansion in the absence of spontaneous somatic mutation. Such a clonal temtory model would allow for the presence of cellular subsets (a feature difficult to explain in terms of classical neoplasia) and account for a number of unusual characteristics of pituitary adenomas including monoclonality, cyclical activity, lack of oncogene involvement. spontaneous resolution and quantitative but not qualitative changes in secretory activity seen, for example, in Cushing's disease.
Oestrogen‐receptor‐α gene polymorphism affects response in bone mineral density to oestrogen in post‐menopausal women
Authors: Ongphiphadhanakul B. , Chanprasertyothin S. , Payatikul P. , Tung S. Sae , Piaseu N. , Chailurkit L. , Chansirikarn S. , Puavilai G. , Rajatanavin R.
Published: March 2003

OBJECTIVE

An oestrogen‐receptor‐α (ERα) gene polymorphism has been variably reported to be related to bone mass. To investigate whether this ERα gene polymorphism is associated with a functional difference, we assessed the response in bone mineral density (BMD) to oestrogen therapy in post‐menopausal women in relation to ERα gene polymorphism.

PATIENTS AND MEASUREMENTS

Subjects consisted of 124 Thai post‐menopausal women. Sixty‐three of the women were less than 6 years post‐menopausal and 61 were more than 10 years post‐menopausal with vertebral or femoral osteoporosis as defined by BMD T‐score less than − 2.5. Subjects were randomly allocated to receive 0.3 mg (n = 67) or 0.625 mg (n = 57) of conjugated equine oestrogen (CEE). All subjects also took 5 mg medroxyprogesterone acetate. Vertebral and femoral neck BMD were measured at baseline and 1 year after treatment. Data were expressed as mean ± SEM. Capital P represents the absence of the restriction site while lower‐case p indicates the presence of the restriction site.

RESULTS

For subjects on 0.625 mg CEE, BMD at L2–4 increased significantly after 1 year in those with pp (n = 20) Pp (n = 29) and PP genotypes (n = 8) (P < 0.001). However, in subjects on 0.3 mg CEE, BMD at L2–4 increased significantly after 1 year in subjects with Pp (n = 34, + 7.6 ± 1.5%, P < 0.001) and PP genotypes (n = 13, + 6.9 ± 1.0%, P < 0.001), but not in those with pp genotype (n = 20, + 2.3 ± 2.1%, P = NS). After adjusting for age and years since menopause, the change in vertebral BMD was still lower in those without the P allele compared to those with the P allele (P < 0.05). Femoral BMD did not significantly change regardless of dose of CEE and genotype.

CONCLUSIONS

We conclude that ERα gene polymorphism affects skeletal response to oestrogen in post‐menopausal women. The effect of ERα gene polymorphism appears to be site‐specific and does not relate to biochemical markers of bone turnover. Determination of ERα genotype may help identify post‐menopausal women who will have more skeletal benefit from oestrogen therapy.
Increase of adhesion molecules, fibrinogen, type‐1 plasminogen activator inhibitor and orosomucoid in growth hormone (GH) deficient adults and their modulation by recombinant human GH replacement
Authors: Kvasnička Jan , Marek Josef , Kvasnička Tomáš , Weiss Vladimír , Marková Markéta , Štìěpán Jan , Umlaufová Anna
Published: March 2003

OBJECTIVE

GH deficiency (GHD) is usually associated with a higher incidence of cardiovascular disease (CVD). The aim of this study was to establish whether patients with GHD, like those with CVD, show an increase in fibrinogen (FBG), type‐1 plasminogen activator inhibitor (PAI‐1), acute phase response proteins (APR), and soluble adhesion molecules. The effect of recombinant human GH (rhGH) replacement, on these parameters was also investigated.

PATIENTS AND DESIGN

Concentrations of PAI‐1 antigen (Ag), adhesion molecules sE‐selectin, sP‐selectin, and intercellular adhesion molecule‐1 (sICAM‐1), FBG and levels of APR orosomucoid (ORM), and ‘negative APR’ transferrin (TRF) were established in 11 panhypopituitary (PHP) patients (eight men and three women, age median 39.0 years, body mass index (BMI) 27.49 ± 3.89 kg/m2) before and after 12‐month replacement with rhGH. Control values were obtained by examination of 33 healthy age and sex matched subjects (24 men and nine women with BMI 24.16 ± 1.99 kg/m2).

RESULTS

PHP patients had higher concentrations of ORM (0.80 ± 0.25, vs. 0.61 ± 0.20 g/l; P = 0.05), FBG (3.22 ± 0.48, vs. 2.57 ± 0.47 g/l; P = 0.001), PAI‐1 Ag (97.12 ± 33.23, vs. 44.11 ± 21.40 μg/l; P = 0.001), sE‐selectin (72.42 ± 28.35, vs. 42.80 ± 12.60 μg/l; P = 0.004), sP‐selectin (221.26 ± 75.12, vs. 104.79 ± 26.01 μg/l; P = 0.001) sICAM‐1 (409.75 ± 137.78, vs. 228.10 ± 37.54 μg/l; P = 0.001), and lower levels of TRF (2.14 ± 0.40, vs. 2.76 ± 0.39 g/l; P = 0.001) than controls. After 12‐month rhGH replacement the patients showed an increase of TRF (2.64 ± 0.84 g/l, P = 0.037) and decrease of soluble adhesion molecules (sE‐selectin 57.98 ± 27.04 μg/l, P = 0.01, sP‐selectin 121.74 ± 50.42 μg/l, P = 0.007; and sICAM‐1 279.95 ± 88.32 μg/l, P = 0.005), which then, similarly to the ORM (0.67 ± 0.12 g/l) and FBG level (2.82 ± 0.51 g/l), did not statistically differ from the values in the control group.

CONCLUSION

rhGH replacement led to modulation of the ‘inflammatory response’ in panhypopituitary patients. This modulation occurred locally at vascular endothelium level where after rhGH replacement, sE‐selectin, sP‐selectin and sICAM‐1 concentrations decreased, a similar effect as in the systemic inflammatory response, as was also apparent from the changes in acute phase response protein levels.
Phenotype and phenocopy: the relationship between genotype and clinical phenotype in a single large family with multiple endocrine neoplasia type 1 (MEN 1)
Authors: Burgess John R. , Nord Brita , David Ruben , Greenaway Tim M. , Parameswaran Venkateswaran , Larsson Catharina , Shepherd Joseph J. , Teh Bin T.
Published: March 2003

BACKGROUND

The majority of reports describing the natural history and prognosis of multiple endocrine neoplasia type 1 (MEN 1) utilize phenotypic rather than molecular genetic criteria to establish a diagnosis of MEN 1.

OBJECTIVES AND PATIENTS

We sought to determine the spectrum of endocrine abnormality amongst 152 members (64 gene carriers and 88 noncarriers) of a large MEN 1 family in whom a determination of MEN 1 status had previously been made by phenotype screening. The predictive utility of both clinical and molecular screening techniques are described.

RESULTS

A novel IVS2–3 (C‐G) MEN1 mutation was identified in affected members of this family. Seven (10%) of 71 individuals satisfying clinical diagnostic criteria for MEN 1 were found to be genetically negative (excluded by mutation analysis and haplotyping) for MEN 1. These cases of MEN 1 phenocopy comprised four cases of primary hyperparathyroidism, two ‘nonsecretory’ pituitary adenoma and one case of coincident prolactinoma and hyperparathyroidism. Three of the patients with hyperparathyroidism had previously required parathyroidectomy and each had achieved normocalcaemia following parathyroid resection. Predictive genetic testing prospectively identified three children with the MEN 1 genotype. Serum calcium was normal at the time of their initial molecular genetic diagnosis. In each case hyperparathyroidism subsequently developed during adolescence.

CONCLUSION

Multiple endocrine neoplasia type 1 phenocopy is an important differential diagnosis in patients exhibiting an multiple endocrine neoplasia type 1 phenotype. This is a relevant consideration, particularly when the diagnosis of multiple endocrine neoplasia type 1 is made using sensitive, but nonspecific, criteria such as mild hyperparathyroidism, pituitary micoadenoma, and hyperprolactinaemia. Confirmatory genetic testing should be undertaken to confirm clinical diagnoses of multiple endocrine neoplasia type 1.
Placental growth hormone and IGF‐I in a pregnant woman with Pit‐1 deficiency
Authors: Verhaeghe J. , Bougoussa M. , Van Herck E. , De Zegher F. , Hennen G. , Igout A.
Published: March 2003

The respective contributions of pituitary and placental GH to circulating IGF‐I in pregnant women have not been well established. We measured the serum concentrations of placental growth hormone (PGH) and IGF‐I in a woman with pit‐1 deficiency before, during and after pregnancy, resulting in the birth of a healthy child (not pit‐1 deficient). Both PGH and IGF‐I concentrations were below the assay detection limit before and after pregnancy. During pregnancy, PGH and IGF‐I levels increased steadily; the concentrations of PGH and IGF‐I in late pregnancy were comparable with levels previously measured in normal pregnancies. PGH and IGF‐I concentrations were strongly correlated throughout pregnancy (r = 0.90; P = 0.002). PGH was undetectable in cord serum, whilst the IGF‐I concentration was within the normal range. The findings of this case study corroborate the notion that PGH is the prime regulator of maternal serum IGF‐I during pregnancy.
Growth hormone deficiency and replacement in elderly hypopituitary adults
Authors: Monson John P. , Abs Roger , Bengtsson Bengt‐Åke , Bennmarker Helge , Feldt‐Rasmussen Ulla , Hernberg‐Ståhl Elizabeth , Thorén Marja , Westberg Björn , Wilton Patrick , Wüster Christian
Published: March 2003

OBJECTIVE

Although elderly hypopituitary adults demonstrate an increase in total and central fat compared with age‐matched controls and are distinguishable from control subjects in terms of growth hormone (GH) responsiveness on dynamic testing, there are few data available on response to GH replacement. The objective of this study was to compare the baseline characteristics and longitudinal response to GH replacement in patients aged > 65 years with that observed in younger patients enrolled in KIMS (Pharmacia and Upjohn International Metabolic Database). KIMS is a physician‐managed, open, long‐term surveillance study of adult GH‐deficient patients receiving GH replacement. Patients were entered and data provided by interested physicians.

PATIENTS

Baseline characteristics were studied in 109 patients (66 males) aged > 65 years commencing GH replacement at time of entry into KIMS and the effects of GH replacement on blood pressure, lipids and quality of life in 64 patients who had completed at least 6 months of GH replacement. Data were compared with baseline data on 863 patients aged < 65 years with adult onset GH deficiency, who had not received GH for at least 6 months prior to entry into KIMS, 220 of whom went on to complete > 6 months GH therapy in KIMS.

RESULTS

Blood pressure, cholesterol and LDL cholesterol were positively correlated with age, particularly in females, and older patients had a predictably higher prevalence of diabetes mellitus and history of hypertension. The frequency of previous fractures was increased in females but not in males aged > 65 years. Body mass index, waist/hip ratio and quality of life (AGHDA score) was similar in both groups prior to commencement of GH therapy. GH replacement doses were similar in younger and older patients and the percentage of patients with serum IGF‐I of > 2SD above the age‐related normal mean was not significantly different between the groups (< 65 years, 20%; > 65 years, 11%). After 6 months of GH replacement significant improvements were evident in waist circumference, waist/hip ratio, diastolic blood pressure, total and LDL cholesterol and AGHDA score in patients aged < 65 years. Similar significant reductions in total and LDL cholesterol were evident in patients > 65 years. In addition, male patients aged > 65 years demonstrated significant reductions in diastolic blood pressure and AGHDA score but no change in waist circumference whereas females aged > 65 years demonstrated a trend to reduction in waist circumference and AGHDA score.

CONCLUSIONS

These data, derived from the largest series of GH‐treated hypopituitary patients published to date, confirm similar baseline characteristics and positive benefit from GH replacement in older compared with younger hypopituitary patients particularly in relation to quality of life.
Growth and endocrine disorders in multisystem Langerhans' cell histiocytosis
Authors: Nanduri V. R. , Bareille P. , Pritchard J. , Stanhope R.
Published: March 2003

INTRODUCTION

Langerhans' cell histiocytosis is a rare disorder, with diabetes insipidus occurring in up to half of patients. Causes of growth failure include the illness itself, treatments used and growth hormone insufficiency.

PATIENTS AND METHODS

We identified all patients with an endocrinopathy secondary to Langerhans' cell histiocytosis (LCH). Growth data were analysed from all patients with multisystem involvement.

RESULTS

Of 144 patients with multisystem LCH, 50 had an endocrinopathy, 49 of whom had diabetes insipidus. Growth hormone insufficiency (GHI) was present in 21 patients, seven of whom had other anterior pituitary deficiencies as well (gonadotrophin deficiency + GHI n = 2, gonadotrophin deficiency + TSH deficiency + GHI n = 2, panhypopituitarism n = 3). GH insufficiency, the development of which appeared to be independent of pituitary radiation, occurred at a median age of 8.3 years (4.7–18 years) and at a median interval of 3.5 years (0–11.8 years) after diagnosis of LCH. The median height SDS at diagnosis of growth hormone insufficiency was −2.9. Thirteen of the patients with growth hormone insufficiency attained final height with a median height SDS of −1.2. The final height SDS of 15 patients without GH insufficiency was closer to target height SDS, but not statistically different from that of the GH insufficient group.

CONCLUSIONS

GH therapy significantly improves growth in GH insufficient patients with Langerhans' cell histiocytosis. Early institution of GH therapy may further improve height outcome. However, most children with Langerhans' cell histiocytosis regardless of endocrine function, failed to reach target height.
Comparison of octreotide acetate LAR and lanreotide SR in patients with acromegaly
Authors: Chanson P. , Boerlin V. , Ajzenberg C. , Bachelot Y. , Benito P. , Bringer J. , Caron P. , Charbonnel B. , Cortet C. , Delemer B. , Escobar‐Jiménez F. , Foubert L. , Gaztambide S. , Jockenhoevel F. , Kuhn J. M. , Leclere J. , Lorcy Y. , Perlemuter L. , Prestele H. , Roger P. , Rohmer V. , Santen R. , Sassolas G. , Scherbaum W. A. , Schopohl J. , Torres E. , Varela C. , Villamil F. , Webb S. M.
Published: March 2003

BACKGROUND AND OBJECTIVE

The most effective option for the medical treatment of patients with acromegaly is the use of somatostatin analogues. Long‐acting depot formulations for intramuscular injection of two somatostatin analogues have recently become available: octreotide acetate LAR (Sandostatin®LAR®, Novartis Pharma AG) and lanreotide SR (Somatuline®, Ipsen Biotech). We wished to compare efficacy of octreotide LAR and lanreotide SR in acromegalic patients.

PATIENTS AND METHODS

A group of 125 patients with acromegaly (67 females; mean age, 47 years; 59 patients had previous pituitary irradiation) from 26 medical centres in France, Spain and Germany were studied. Before the study, all patients had been treated with intramuscular injections of lanreotide SR (mean duration, 26 months) at a dose of 30 mg which was injected every 10 days in 64 and every 14 days in 61 patients, respectively. All patients were switched from lanreotide SR to intramuscular injections of 20 mg of octreotide LAR once monthly for three months. In order to obtain efficacy and safety data of lanreotide SR under study conditions, it was decided to randomly assign at day 1, in a 3 : 1 ratio, the time point of the treatment switch; 27 of the patients were randomly assigned to continue the lanreotide SR treatment for the first 3 months of the study (group A); they were on octreotide LAR 20 mg from month 4–6. The other 98 patients were assigned to be switched to treatment with octreotide LAR 20 mg at day 1 (group B). In group B patients, octreotide LAR treatment was continued until month 6, with an adjustment of the dose based on GH levels obtained at month 3.

RESULTS

The mean GH concentration decreased from 9.6 ± 1.3 mU/l at the last evaluation on lanreotide SR to 6.8 ± 1.0 mU/l after three injections of octreotide LAR (P < 0.001). The percentages of patients with mean GH values ≤ 6.5 mU/l (2.5 μg/l) and ≤ 2.6 mU/l (1.0 μg/l) at the last evaluation on lanreotide SR were 54% and 14%, and these values increased after 3 months treatment with octreotide LAR to 68% and 35% (P < 0.001), respectively. IGF‐I levels were normal in 48% at the last evaluation on lanreotide SR and in 65% after 3 months on octreotide LAR (P < 0.001). Patients with pre‐study pituitary irradiation had lower mean GH and IGF‐I concentrations. But the effects of the treatment change did not differ between the irradiated and the nonirradiated patients. In general both drugs were well tolerated.

CONCLUSION

Octreotide LAR 20 mg administered once monthly was more effective than lanreotide SR 30 mg administered 2 or 3 times monthly in reducing GH and IGF‐I in patients with acromegaly.
Developmental changes in steroidogenic enzymes in human postnatal adrenal cortex: immunohistochemical studies
Authors: Suzuki Takashi , Sasano Hironobu , Takeyama Junji , Kaneko Chika , Freije William A. , Carr Bruce R. , Rainey William E.
Published: March 2003

Adrenarche is considered to occur as a result of intra‐adrenal changes in steroidogenic enzymes involved in C19 steroid production. The present study was conducted because developmental changes in steroidogenic enzymes have not been examined well in human postnatal adrenal.

Twenty‐four specimens of nonpathological human adrenals from 7 months to 62 years retrieved from autopsy files. Immunohistochemistry for P450 side‐chain cleavage (P450scc), 17α hydroxylase (P450c17), dehydroepiandrosterone sulfotransferase (DHEA‐ST), P450 oxidoreductase, cytochrome b5, and 3β‐hydroxysteroid dehydrogenase (3βHSD) was per‐formed in these specimens, and the immuno‐intensity was evaluated using CAS 200 computed image analysis system.

Immunoreactivity of P450scc was marked in the zona glomerulosa, fasciculata and reticularis in the adrenal glands of all the cases examined. P450c17 and DHEA‐ST immunoreactivity was weak in the zona fasciculata and reticularis in the adrenals of age 7 months to 5 years, but thereafter became prominent in the zona reticularis. Immunoreactivity of P450 oxidoreductase and cytochrome b5, components of the electron transfer system hypothesized to regulate the 17–20 lyase activity of P450c17, was weak in all three zones of adrenal cortex from 7 months to 5 years, and became more marked in the zona reticularis after age 5 years. 3βHSD immunoreactivity was marked in all three zones of the adrenal cortex from 7 months to 8 years but thereafter decreased in the zona reticularis.

These data suggest that the human adrenal zona reticularis markedly begins to develop morphologically and functionally at around 5 years of age. The increased level of P450c17, DHEA‐ST, P450 oxidoreductase, and cytochrome b5, and the decreased level of 3βHSD in the reticularis is likely to contribute to increased C19 steroid production during adrenarche.
Subclinical hyperthyroidism and the risk of dementia. The Rotterdam study
Authors: Kalmijn Sandra , Mehta Kala M. , Pols Huibert A. P. , Hofman Albert , Drexhage Hemmo A. , Breteler Monique M. B.
Published: March 2003

We investigated the prospective relationship between thyroid status and the risk of dementia and Alzheimer's disease among a random sample of 1843 participants, aged 55 years and over, from the population‐based prospective Rotterdam Study.

Thyroid status was measured at baseline (1990–93), through assessment of serum antibodies to thyroid peroxidase (TPO‐Abs, positive: >10 IU/ml), serum TSH levels, and when TSH was abnormal (<0·4 or >4·0 mU/l), serum thyroxin levels (T4). At baseline and at follow up, after on average 2 years, participants were screened for dementia. Diagnoses were based on international criteria.

Persons with reduced TSH levels at baseline had a more than threefold increased risk of dementia (RR = 3·5, 95%CI: 1·2–10·0) and of Alzheimer's disease (RR = 3·5, 95%CI: 1·1–11·5), after adjustment for age and sex. Among persons with reduced TSH levels, T4 levels appeared to be positively related to the risk of dementia (RR per SD increase = 2·9, 95%CI: 0·7–12·2), although none of those who became demented had a T4 level above the normal range (>140 nmol/l). The risk of dementia was especially increased in subjects with low TSH who were positive for TPO‐Abs (RR = 23·7, 95%CI: 4·0–140).

This is the first prospective study to suggest that subclinical hyperthyroidism in the elderly increases the risk of dementia and Alzheimer's disease.
Non‐functioning pituitary adenomas: indications for postoperative radiotherapy
Authors: Woollons Andrew C. , Hunn Martin K. , Rajapakse Yasantha R. , Toomath Robyn , Hamilton David A. , Conaglen John V. , Balakrishnan V.
Published: March 2003

To determine the indications for postoperative radiotherapy after surgical resection of a nonfunctioning pituitary macroadenoma.

A retrospective chart review of 72 patients with histologically proven chromophobe adenoma who presented for pituitary surgery between January 1985 and June 1998, with a minimum follow‐up period of 12 months. The study endpoint was tumour recurrence or progression detected either by routine follow‐up imaging or by clinical progression with subsequent confirmation by imaging. A proportional hazards model was used to determine independent prognostic factors.

Mean follow‐up was 64 months. In the radiotherapy group 13 of 50 recurred (or progressed) (26%), while in the nonradiotherapy group 10 of 22 recurred (46%), logrank test, P = 0·025. In patients assessed as having complete excision of tumour (n = 20) only two recurred (10%), both in patients without radiotherapy. No further treatment has been required in either case to date. In patients with residual tumour (n = 52), 41 had radiotherapy with 13 recurrences (32%), while 11 patients had no radiotherapy with eight subsequent recurrences (73%); logrank test, P = 0·007. Further treatment has been required in the majority of these cases. Cox's proportional hazards model analysis showed that only complete tumour removal and postoperative radiotherapy were independent favourable prognostic factors.

The goal of surgery should be complete surgical excision where possible. The risk of recurrence in patients with no residual tumour on postoperative imaging is low enough to justify withholding routine postoperative radiotherapy in this group. In patients with residual tumour, conventional external beam radiotherapy administered within 12 months of surgery is effective at reducing recurrence or progression.
Determinants of changes in plasma homocysteine in hyperthyroidism and hypothyroidism
Authors: Diekman M. J. M. , Van Der Put N. M. , Blom H. J. , Tijssen J. G. P. , Wiersinga W. M.
Published: March 2003

OBJECTIVE

Hyperhomocysteinaemia is a risk factor for premature atherosclerotic vascular disease and venous thrombosis. The aim of the present study was to assess plasma total homocysteine (tHCys) concentrations in hypo‐ as well as hyperthyroid patients before and after treatment, and to evaluate the role of potential determinants of plasma tHCys levels in these patients.

DESIGN

Prospective follow up study.

PATIENTS

Fifty hypothyroid and 46 hyperthyroid patients were studied in the untreated state and again after restoration of euthyroidism.

MEASUREMENTS

Fasting plasma levels of tHCys and its putative determinants (plasma levels of free thyroxine (fT4), folate, vitamin B12, renal function, sex, age, smoking status and the C677T polymorphism in the methylenetetrahydrofolate reductase (MTHFR) gene were measured before and after treatment.

RESULTS

Restoration of the euthyroid state decreased both tHCys (17·6 ± 10·2–13·0 ± 4·7 µmol/l; P < 0·005) and creatinine (83·9 ± 22·0–69·8 ± 14·2 µmol/l; P < 0·005) in hypothyroid patients and increased both tHCys (10·7 ± 2·5–13·4 ± 3·3 µmol/l; P < 0·005) and creatinine (49·0 ± 15·4–66·5 ± 15·0 µmol/l; P < 0·005) in hyperthyroid patients (values as mean ± SD). Folate levels were lower in the hypothyroid group compared to the hyperthyroid group (11·7 ± 6·4 and 15·1 ± 7·6 nmol/l; P < 0·05). Pretreatment tHCys levels correlated with log fT4 (r = − 0·47), folate (r = − 0·21), plasma creatinine (r = 0·45) and age (r = 0·35) but not with C677T genotype. Multivariate analysis indicated that pretreatment log(fT4) levels and age accounted for 28% the variability of pre‐treatment tHCys (tHCys = 14·2–5·50 log(fT4) + 0·14 age). After treatment the logarithm of the change (Δ) in fT4 (expressed as the post‐treatment fT4/pre‐treatment fT4 ratio) accounted for 45% of the variability in change of tHCys ( tHCys =− 0·07–4·94 log ( fT4)); there was no independent contribution of changes in creatinine which was, however, strongly related to changes in tHCys (r = 0·61).

CONCLUSIONS

Plasma tHCys concentrations increased in hypothyroidism and decreased in hyperthyroidism. Plasma fT4 is an independent determinant of tHCys concentrations. Lower folate levels and a lower creatinine clearance in hypo‐thyroidism, and a higher creatinine clearance in hyperthyroidism only partially explain the changes in tHCys.
Oestradiol improves arterial endothelial function in healthy men receiving testosterone
Authors: Sader Mark A. , McCredie Robyn J. , Griffiths Kaye A. , Wishart Susan M. , Handelsman David J. , Celermajer David S.
Published: March 2003

OBJECTIVE

To assess prospectively the effects of low dose oestradiol on arterial endothelial and smooth muscle function in healthy men. Oestrogen use is associated with reduced cardiovascular disease in oestrogen‐deficient women, however, the vascular effects of low‐dose oestradiol in healthy men have not been investigated previously.

PATIENTS and DESIGN

Twenty‐three men (aged 32 ± 8 years) were randomized to receive depot implants of testosterone (T) alone (group 1, n = 10), or T with either 10 mg (group 2, n = 7) or 20 mg (group 3, n = 6) of oestradiol (E).

MEASUREMENTS

Hormone levels, lipids and vascu‐lar reactivity were measured before, 1 month and 6 months after hormone implantation. Using high‐resolution ultrasound, brachial artery diameter was measured at rest, during reactive hyperaemia (leading to flow‐mediated dilatation, FMD, which is endothelium‐dependent) and after sublingual nitroglycerin (GTN, an endothelium‐independent dilator).

RESULTS

Oestradiol produced a dose‐dependent increase in plasma oestradiol (at 1 month 96 ± 7, 149 ± 6, 192 ± 23 pmol/l in the 3 groups, respec‐tively, P < 0·001 by anova for trend). Minor side‐effects (gynaecomastia, nipple tenderness) indicated that 20 mg oestradiol was the maximum tolerated dose. There was also a dose‐dependent increase in FMD with oestradiol dose: at 1 month, − 0·2, + 0·2 and + 1·8% for groups 1–3, respectively (P = 0·31 by anova for trend); and at 6 months, − 0·8, + 0·4 and + 2·2% (P = 0·02). The rise in oestradiol levels following treatment correlated with the improvement in FMD (P = 0·01). GTN responses were similar in the 3 groups throughout the study.

CONCLUSION

In healthy young men, oestradiol supplementation is associated with enhanced arterial endothelial function, a key marker of vascular health.