bluuebunny/crossref_metadata_2025 huggingface dataset:
Characterization of 24‐hour growth hormone secretion in acromegaly: implications for diagnosis and therapy
Authors: Ho Ken K. Y. , Welssberger Andrew J.
Published: March 2008

OBJECTIVE Early studies of acromegaly undertaken before the general availability of insulin‐like growth factor I (IGF‐I) assays have used arbitrary and varying growth hormone (GH) threshold levels for diagnosing and assessing outcome of treatment for this disease. We have undertaken a detailed study of GH secretion and its relationship to IGF‐I levels to assess the usefulness of GH and IGF‐I measurements in the assessment of acromegaly.

PATIENTS Thirty acromegalic subjects (12 untreated and 16 previously treated) and 30 age and sex‐matched normal subjects were studied.

MEASUREMENTS Twenty‐four‐hour GH secretion was obtained from 20‐minute sampling and serum IGF‐I was measured. Comparisons were made of IGF‐I, mean 24‐hour GH concentration, and of the pulsatile and diurnal characteristics of GH secretion between the two groups.

RESULTS IGF‐I levels In untreated acromegaly were elevated and clearly separated from the normal range. Mean 24‐hour GH concentrations in untreated and treated acromegalic subjects with elevated IGF‐I (>40 nmol/l) were greater than (P < 0.01), and showed good separation from, those of normal subjects only after age‐matching. From the 24‐hour prollfes, nadir GH levels In normal subjects fell below the level of detectability while those in untreated acromegalic subjects did not. Pulse amplitude (P<0.01), ratio of pulsatile to non‐pulsatile GH release and the night to daytime GH ratio (P<0 05) were significantly reduced in acromegaly. In the six patients who attained normal IGF‐I levels after surgery, pulsatile characteristics remained abnormal in four. Mean 24‐hour GH was significant related (r = 0.57) to IGF‐I. A random GH concentration >2.5 μg/l (5 mlU/l) has a sensitivity of 77% and specificity of 95% In identifying acromegalic patients who have biochemically active disease (elevated IGF‐I) after treatment.

CONCLUSIONS Patients with active acromegaly secrete more GH than age‐matched normal controls. GH secretion in acromegaly is characterized by marked blunting of pulsatile secretion and, in contrast to normal subjects, the failure of GH to fall to undetectable levels at any time during the 24‐hour day. IGF‐I measurement is a more practical alternative in the diagnosis of acromegaly and in the assessment of therapeutic outcome. Since abnormalities of GH regulation may persist despite normalization of IGF‐I, a distinction between remission and cure should be made. Detailed post‐treatment evaluation of GH secretion is necessary to define the nature of underlying GH regulation and to evaluate the risk of disease recurrence.
Determinants of clinical outcome and survival in acromegaly
Authors: Rajasoorya C. , Holdaway I. M. , Wrightson P. , Scott D. J. , Ibbertson H. K.
Published: March 2008

OBJECTIVE The extent to which treatment modifies the excess in morbidity and mortality in acromegaly remains uncertain. This study investigates the determinants of final outcome following therapy for acromegaly. DESIGN A retrospective analysis of patients treated at the Departments of Endocrinology and Neurosurgery, Auckland Hospital, New Zealand.

PATIENTS One hundred and fifty‐one patients (63 females and 88 males) with acromegaly or gigantism treated between the years 1964 and 1989. The mean duration of follow‐up was 12 years (median 11 years).

MEASUREMENTS Patients had their age, estimated duration of symptoms preceding diagnosis, serum GH at diagnosis, presence of diabetes mellitus, cardiovascular disease, hypertension and/or osteoarthritis at diagnosis and the last known serum GH documented. The final outcome at the time of study was graded under three classes: dead (n = 32), those with major complications (n =47) and those with minor/no complications (n = 67).

RESULTS The mean age at diagnosis of acromegaly was 41 years and the average estimated duration of symptoms prior to diagnosis was 7 years, with older patients showing longer duration of symptoms preceding diagnosis (P= 0.0002). Final outcome (dead, alive with major complications, alive and well) was significantly worse in those with older age at diagnosis (P= 0.008), longer duration of symptoms before diagnosis (P= 0.03) and higher GH at last follow‐up (P=0.0001). In multivariate analysis, survival was significantly Influenced by the last known GH (P = 0.0001), presence of hypertension (P = 0.02) or cardiac disease (P = 0.03) at diagnosis, and duration of symptoms prior to diagnosis (P = 0.04). Survival In the acromegalic group, irrespective of treatment, was reduced by an average of 10 years compared with the non‐acromegalic population.

CONCLUSIONS Acromegaly has a significant adverse effect on well‐being and survival. The predominant determinant of outcome is the final serum GH level following treatment.
Congenital euthyroid goitre with impaired thyroglobulin transport
Authors: Ohyama Yoshlhido , Hosoya Toichiro , Kameya Toru , Suzukl Noriaki , Nakamura Shinya , Kazaharl Kojl , Shlbayama Keiko , Yokota Yukifuml , Matsuura Nobuo
Published: March 2008

A case of congenital goitre with defective thyroglobulin (Tg) synthesis was studied from the clinical, biochemical and morphological perspectives. The patient, a 5.5‐year‐old boy, who was clinically euthyroid, showed a positive perchlorate discharge test (37.2%). However, the lodlna‐tion system seemed to be normal since radioiodine uptake into the thyroid was very high, and inspection of the H2O2‐generating system using thyroid slices and an assay for peroxidase activity In microsomes showed no abnormalities. On the other hand, virtually no Tg was detected In the serum, and the amount of Tg in thyroid tissue, estimated with gel electrophoresis, was below 10% of the normal value, the quality of Tg being unchanged. Morphological observations demonstrated the presence of Tg in the markedly distended rough endoplasmic reticulum of the cytoplasm of follicular cells and a lack of Tg in the colloid of the follicular lumen. These results suggest that the thyroid is defective in Tg synthesis, probably associated with Impaired transport of Tg from the cells to the lumen.
Short‐term fasting in obesity fails to restore the blunted GH responsiveness to GH‐releasing hormone alone or combined with arginine
Authors: Bouloux P‐M. G. , Fakeeh M.
Published: March 2008

OBJECTIVE Fasting is known to clearly increase both spontaneous and GHRH‐stimulated GH secretion in normal subjects and this effect is likely to be due to hypothalamic mechanism(s). Our aim was to clarify the effect of a 3 or 4‐day fast, on the GH response to GHRH alone or combined with arginine, an amino acid probably acting via inhibition of hypothalamic somatostatin release.

DESIGN Two tests with GHRH (1 μg/kg i.v.), administered either alone or in combination with arginine (ARG, 0.5 g/kg i.v.) were performed, in a randomized order at least 3 days apart. In obese women the two tests were repeated after a 3 or 4‐day fast.

PATIENTS Seven obese women (06, aged 17–54 years, BMI 42.4 ± 3.6 kg/m2, waist‐hip ratio (WHR) 0.85±0.01) and ten healthy women, as control subjects (CS, aged 20–44 years, BMI 23.1 ±1.1 kg/m2, WHR 0.79 ± 0.01) were studied.

MEASUREMENTS Serum GH and IGF‐I levels were measured by radioimmunoassay. The GH secretory responses were expressed either as absolute values (mU/l) or as areas under the curve (AUC, mU/l/h) calculated by trapezoidal integration. IGF‐I concentrations were expressed as absolute values (μg/l) with reference to a pure recombinant IGF‐I preparation. Results are expressed as mean ± SEM.

RESULTS Basal GH and IGF‐l levels in OB were lower than in CS (0.8 ± 0.2 vs 4.8±1.0 mU/I, P<0.0001 and 120.1 ± 21.4 vs 188.7 ± 13.1 μg/l, P <0.02, respectively). The GHRH‐induced GH rise in OB was lower (P <0.00001) than in CS (AUC 340.2 ± 81.0 vs 2125.0 ± 199.6 mU/l/h). ARG increased the GHRH‐induced GH rise in both groups, but in OB the GH response to ARG + GHRH (1458.4 ± 439.0 mU/l/h, P < 0.03 vs GHRH alone) remained lower (P <0.0001) than in CS (6396.2 ± 772.2 mU/l/h, P < 0.01 vs GHRH alone). In spite of a reduction in body weight and IGF‐I, Insulin and glucose levels, in OB fasting failed to modify both the basal GH levels and the somatotroph responsiveness to GHRH when administered either alone or combined with ARG. An increase in free fatty acids (FFA) was also found after fasting.

CONCLUSIONS The results of this study demonstrate that in obesity the somatotroph hyporesponsiveness to GHRH, either alone or combined with arginine, is not improved by short‐term fasting. As fasting is considered a CNS mediated stimulus to GH secretion, its ineffectiveness in obesity does not support a hypothalamic pathogenesis and suggests that long standing metabolic alterations, such as hyperinsulinaemia and/or elevated free fatty acids, could play a major role in causing GH insufficiency in obese patients.
Prevalence of Helicobacter pylori in acromegalic patients during treatment with octreotide
Authors: Jones S. L. , Patchett S. , Anderson J. V. , Farthing M. J. G. , Besser G. M. , Wass J. A. H.
Published: March 2008

BACKGROUND Octreotide, a synthetic long‐acting analogue of somatostatin, now has an establlshed role in the treatment of acromegaly. In acromegalic patients treated with octreotide there is an increased incidence of gallstones and possibly gastritis.

OBJECTIVES (1) To compare the seroprevalence of Helicobacter pylori (H. pylori) infection, in acromegalic patients treated with octreotide to that in patients given other treatment modalities. (2) To study retrospectively the temporal relatlon between H. pylori acquisition and octreotide treatment.

PATIENTS Three groups of acromegalic patients were studied; 35 (20 M) had been treated wlth octreotide, 17 (10 M) with bromocriptine and 19 (12 M) had received no pharmacological intervention (untreated, surgically treated or treated with radiotherapy).

DESlGNlMEASUREMENTS The presence of H. pylori infection was assessed serologically (Bio‐Rad GAP test for IgG), using stored serum, on the most recent sample from each patient and on serial samples from patients treated with octreotlde.

RESULTS The prevalence of H. pylori seropositivity was similar in each treatment group, 34, 35 and 37%, respectively. Mean age and duration of acromegaly were similar in the first two groups. Patients who had never received medical treatment were slightly younger. GH levels were similar in all three groups. Patients on octreotide who were seropositive for H. pylori did not differ from those with negative serology with respect to age, duration of acromegaly, duration of octreotide treatment or serum GH level. Serial samples in octreotide treated patients showed a change in status in only one patient; 18 patients continued with negative serology during a mean period of 30 (range 4–62) months. In each of the 6 patients with persistently positive serology during octreotide treatment, stored samples predating octreotide therapy were shown to have already been positive.

CONCLUSIONS The seroprevalence of H. pylori infection in acromegalic patients does not appear to be increased in a manner dependent on the type or duration of medical treatment. In particular, octreotide therapy, while causing the development of histological gastritis in some patients, does not appear to induce the development of H. pylori infection.
Whole body and regional soft tissue changes in growth hormone deficient adults after one year of growth hormone treatment: a double‐blind, randomized, placebo‐controlled study
Authors: Hansen T. B. , Vahl N. , Jergensen Jens O.L. , Christlansen Jens S. , Hagen C.
Published: March 2008

OBJECTIVE Adults with GH deficiency (GHD) exhibit changes in body composition. Studies of the effects of GH substitution on body composition have been short‐term or not adequately controlled. The purpose of this study was to evaluate the long‐term effects of GH on soft tissue using dual‐energy X‐ray absorptlometry (DEXA). This technique enables assessment of whole body as well as regional soft tissue composition.

DESIGN A double‐blind, randomized, placebo‐controlled study in patients with acquired GHD. The therapeutic regime consisted of biosynthetic human GH (2.0 lU/m2 per day) or placebo, given as a daily subcutaneous injection at 2000 h for 12 months.

PATIENTS Twenty‐nine patients with acquired GHD (GH < 10 μg/l (< 20 mU/I) following standard provocative tests) in whom additional hormone replacement was maintained.

MEASUREMENTS Soft tissue determinations by DEXA scan, height, weight, foot volume and finger clrcumference were recorded together with serum IGF‐I at baseline and after 12 months.

RESULTS Twelve months of GH therapy induced a total fat mass (FM) reduction of (mean ± SEM) 4.88 ± 0.58 kg (P < 0–002) (n= 13) corresponding to 21.5% of the total FM. The reduction in fat was most marked in the trunk, i.e. 3.07 ± 0.29 kg (P < 0–002) corresponding to 61% of the total FM reduction. Total lean soft tissue mass (LSTM) increased by 3.31 ± 0.81 kg (P < 0.001). Regional changes for arm and leg in the GH group amounted to 0.32 ± 0.08 kg (P < 0002) and 0.71 ± 0.14 kg (P < 0.002), respectively, without accompanying significant changes in truncal LSTM between the groups.

The foot volume was Increased by 55.8 ± 15.7 ml (P < 0007) and the finger circumference by 2.67 ± 0.5 mm (P < 0005) on active treatment with no significant changes in the placebo group.

CONCLUSIONS Twelve months of GH therapy induced marked changes in soft tissue; fat mass was reduced, particularly in the trunk (61 % of total fat mass reduction) whereas lean soft tissue mass increased more in the extremities. The data imply that GH‐induced changes in body composition are maintained with long‐term therapy.
Peripheral glucose metabolism in human hyperprolactinaemia
Authors: Foss M. C. , Paula F. J. A. , Paccola G. M. G. F. , Piccinato C. E.
Published: March 2008

OBJECTIVE Prolactin has important biological actions in several species which include metabolic control and waterlelectrolyte balance. However, human PRL has generally been characterized as a mammotrophic hormone and it is unknown whether PRL has any important metabolic actions. This study was thus conducted to evaluate the effect of hyperprolactinaemia on peripheral muscle glucose metabolism.

DESIGN The study was designed to determine forearm muscle glucose uptake and utilization (oxidative and non‐oxidative metabolism) in normal and hyperprolactinaemic subjects in the post‐absorptive state and lor 3 hours after the ingestion of 75 g of glucose. Peripheral glucose metabolism was analysed by the forearm technique to estimate muscle exchange of substrates combined with local indirect calorimetry.

PATIENTS Eight hyperprolactinaemic patients (HP group, 6 females and 2 males) and ten normal sublects (N group, 7 females and 3 males) were studied. The hyperprolactinaemic patients showed no clinical or laboratory evidence of acromegaly or hypothyroidism and were not using any PRL releasing drugs.

MEASUREMENTS Forearm blood flow was measured by capacitance plethysmography and arterial and venous blood samples were drawn simultaneously to determine plasma glucose, serum FFA, total blood CO2 and O2 and serum insulin in the post‐absorptive state (0 time) and at 30, 60, 120 and 180 minutes after glucose Ingestion.

RESULTS No significant difference in glucose uptake by the forearm muscle tissue was observed between the N and HP groups (823 plusmn; 103 vs 828 ± 110 μmol/100 ml forearm 3h, respectively), nor were any significant differences observed in the intracellular utilization of glucose (oxidative and non‐oxidative metabolism). However, the serum insulin levels after glucose ingestion were significantly higher in hyperprolactinaemic patients than in normal subjects, especially at 30 (N 283 ± 46 vs HP 581 ± 133 pmol/l) and 60 minutes (N 291 ± 37 vs HP 544 ± 61 pmol/l). Furthermore, after glucose ingestion the suppression of serum FFA levels was smaller in the hyperprolactinaemic patients than in normal subjects.

CONCLUSIONS This study demonstrated that insulin resistance is associated with the presence of spontaneous human hyperprolactinaemia. The hyperinsulinaemia detected in the hyperprolactinaemic patients after the oral glucose stimulus did not determine a proportional Increase in forearm glucose uptake and utilization, which were similar to the normal levels. The suppression of serum free fatty acid concentrations was also smaller in hyperprolactlnaemlc patients during the oral glucose challenge, suggesting an impaired antilipolytic effect of Insulin.
Ovaries in sexual precocity
Authors: Bridges Nicola A. , Cooke Alex , Healy Michael J. R. , Hindmarsh Peter C. , Charles G. D. Brook
Published: March 2008

BACKGROUND AND OBJECTIVE Ovarian Uh8SOnOgra‐phy may be helpful in distinguishing the various types of precocious puberty, and the ovarian appearances Increasingly influence choice of therapy In these girls. We examined retrospectively the ovarian volume and prevalence of polycystic ovarian appearance at ultrasound in girls with sexual precocity.

DESIGN Ultrasound examinations were obtained from girls who presented with sexual precocity. If there were several scans from the same Individual, the latest was analysed.

PATIENTS The girls were divided Into groups: untreated central precoclous puberty (n= 25), central precocious puberty treated with GnRH analogue (n= 18) or with GnRH analogue and recombinant human OH (n= 11), girls who had stopped treatment with GnRH analogue and GH (n= 12), premature thelarche and thelarche variant (n= 15) and premature adrenarche (n= 14).

MEASUREMENTS Ovarian volume was calculated and the ovaries were assessed for polycystic appearance using standard criteria. Ovarian volume standard deviation (SD) scores were calculated using means and standard deviations derived from a control population and compared using analysis of variance. Differences from control data were assessed using Student's t‐test.

RESULTS Ovarian volume SD scores for all the groups studied were greater than those for control subjects. Girls who had stopped treatment with GnRH analogue and GH had mean ovarian volume of 6.98 mi and ovarian volume SD score (+1·72) greater than that of girls having treatment with GnRH analogue alone (+1·24). Polycystic appearance ovaries were found in 83% of scans in girls who had stopped treatment with GnRH analogue and GH. The ovarian volume SD score of girls with premature adrenarche was less than that of girls with untreated central precoclous puberty.

CONCLUSIONS Girls with central precocious puberty had large ovaries which did not return to a volume appropriate for age. Girls treated with GnRH analogue and GH developed very large ovaries when they stopped treatment, and had an Increased prevalence of ovaries with a polycystic appearance. Central precocious puberty, or some aspect of Its treatment, results In an Increased prevalence of polycystic ovarian appearance.
Effect of age on bone density and bone turnover in men
Authors: Wishart J. M. , Need A. O. , Horowitz M. , Morris† H. A. , Nordin B. E. C.
Published: March 2008

OBJECTIVE Little Is known about the pattern of age‐related bone loss in men, and although androgens are required for optimum bone mass it Is not clear whether the fall in bone mass with age in men is related to failing androgens.

DESIGN Cross‐sectional measurement of bone density, at five sites, and markers of bone resorption and formation in 147 normal volunteers aged 20‐83 years.

SUBJECTS Healthy laboratory workers, hospital staff, their relatives, and husbands of women attending our osteoporosis clinic.

MEASUREMENTS Forearm density (fat corrected), spine L2‐L4, femoral neck, Ward's triangle and trochanter density; serum procollagen I C‐terminal extension peptide, osteocalcin, bone alkaline phosphatase and collagen I C‐terminal telopeptlde; fasting urine hydroxy‐proline/creatinine, pyridinoline/creatinine and deoxy‐pyridinoline/creatinine; and free androgen Index (FAI), measured as serum testosterone/sex hormone binding globulin.

RESULTS Bone loss accelerated at most sites after age 50. There was a significant fall In FAI from the third decade onwards. The levels of ail bone markers fell with age.

CONCLUSIONS Bone loss In men appears to accelerate from age 50 and is associated with decreased bone formation which may be associated with falling levels of free androgen.
Reduced growth hormone secretion with maintained periodicity following cranial irradiation in children with acute lymphoblastic leukaemia
Authors: Lannering B. , Rosberg S. , Marky I. , Moëll C. , Albertsson‐Wikiand K.
Published: March 2008

OBJECTIVE Low dose cranial irradiation in children with acute lymphoblastic leukaemia (ALL) has been reported to reduce GH secretion in puberty. A recent study also reported a disturbed periodicity of GH secretion during puberty. We have focused on the different stages of puberty in studying these two parameters of GH secretion and have also compared the effects of 18 vs 24 Gy radiation dose.

PATIENTS AND MEASUREMENTS Thirty‐four children previously treated for ALL were compared with a control group of 208 healthy normally growing children. GH secretion was measured as 24‐hour profiles. RESULTS In children treated for ALL, OH Secretion rate and OH peak amplitude were below the median values for controls, both before puberty and during all stages of puberty. The difference between patients and controls was most pronounced in late puberty. Radiation with 18 or 24 Gy gave similar results. However, time sequence analysis showed a similar periodicity of GH secretion in both patient and control groups before, as well as during, puberty. Thus, before puberty a broad range of cycles per 24 hours was seen. These synchronized during puberty to a predominant OH peak frequency of one every 3‐4 hours.

CONCLUSIONS After low dose cranial irradiation with 18 or 24 Gy, the total amount of GH secreted is reduced both before and during puberty. We could not confirm previous findings of impaired periodicity of GH secretion in these Children.
Growth hormone responses to dexamethasone in healthy females throughout the menstrual cycle
Authors: Thakore Jogin H. , Dinan Timothy G.
Published: March 2008

OBJECTIVE In health, acute administration of dexamethasone (DEX) leads to growth hormone release. As sex steroids have a profound Influence on the somatotrophic axis, we decided to investigate the effects of DEX on OH release throughout the menstrual cycle.

DESIGN A within subjects, randomized double‐blind counter‐balanced design was employed.

METHODOLOGY Baseline levels Of GH, oestradiol and progesterone were taken at three the points In two consecutive menstrual cycles, after which 4mg of oral DEX or placebo was administered. Plasma samples for OH estimation were taken at 60,180,240 and 300 minutes. Each woman was tested 6 times, 3 times with placebo and 3 times with DEX.

SUBJECTS Six women with regular menstrual cycles were studied.

MEASUREMENTS Plasma OH, oestradiol and Progesterone were measured by radioimmunoassay. RESULTS When expressed as maximum change from base line (AGH) mean OH responses to DEX Increased Incrementally from early (12·2 ± 2·5 μ/I), through mid (25·6 ± 33 μ/I) to late (37·2 ± 3·5 μ/I) cycle. This represents a significant effect of cycle phase on GH responses to DEX (P < 0.05). GH responses at both the mid‐cycle and the luteal the points are different from those during the follicular phase (P < 0.05) and differences between mid‐cycle and luteal phases just fall to reach significance (P < 015). Responses to placebo did not vary from baseline. Plasma oestradiol values were significantly correlated with GH responsivity to active drug throughout the cycle (P < 0.05); the same was not true of progesterone. CONCLUSION Our study has demonstrated that dexa‐methasone‐mediated GH release shows a stepwise Increase throughout the menstrual cycle.
Plasma catecholamines in patients with Addison's disease
Authors: Bornstein S. R. , Breldert M. , Ehrhart‐Bornstein M. , Kloos B. , Scherbaum W. A.
Published: March 2008

BACKGROUND AND OBJECTIVE TWO endocrine tissues are present within the adrenal gland: the steroid producing cortical cells and the catecholamine producing chromaffin cells. Glucocorticolds occur in high concentrations in the adrenal medulla. In vitro, glucocorticolds have been shown to induce the enzyme phenyl‐N‐methyl‐transferase which is necessary for the production of adrenaline in adrenal medullary cells. The purpose of this study was to evaluate the possible significance of a local glucocorticold effect on adrenomedullary function. DESIGN Plasma catecholamine levels were measured in patients with autoimmune Addison's disease where local production of corticosterolds is deficient In the presence of intact chromaffin tissue.

MEASUREMENTS Catecholamines were measured by high pressure liquid chromatography and ACTH, renin and adrenal steroids by radioimmunoassay.

PATIENTS Nineteen Addisonian patients (9 females, 10 males) were treated according to a standard reglie with oral cortisone acetate (37·5 mg/day) and fludrocortisone (0·1 mg/day). All patients were clinically well.

RESULTS Mean plasma adrenallne in patients with Addison's disease was significantly reduced compared to a sex and age matched control group (males (n= 10) 143 ± 36 pmol/1, controls (n= 27) 303 ± 30 pmol/1, P < 0·01; females (n= 9) 77 ± 25pmol/1, controls (n= 27) 293 ± 21 pmol, P < 0·001). The noradrenallne: adrenallne ratio was clearly higher in patients with Addison's disease (males 24 ± 4, controls 9 ± 1, P < 0·01; females 45 ± 6, controls 9 ± 1, P < 0·01

CONCLUSION We conclude that the physiologically high local glucocorticold concentration may be responsible for normal adrenaline production under basal conditions.
Increased 17a‐hydroxyprogesterone response to ACTH in silent adrenal adenoma: cause or effect?
Authors: Del Monte P. , Bernasconi D. , Bertoiazzi L. , Meozzi M. , Badaracco B. , Torre R. , Marugo M.
Published: March 2008

OBJECTIVE Recent studies suggest a possible connection between silent adrenal nodules and mild forms of 21‐hydroxylase deficiency. It remains unclear whether the enzymatic deficiency is generalized or Intrinsic to the adrenal mass. To help to clarify this, we have studied 17a‐OH‐progesterone (17OH‐P) response to ACTH stimulation in a group of patients with adrenal ‘incidentaloma’ in comparison with normal subjects. In patients who underwent surgical treatment, the test was repeated to evaluate possible modifications in 17OH‐P behaviour after resection of the adrenal mass.

SUBJECTS AND METHODS Fifteen subjects with incidentally discovered asymptomatic adrenal masses were studied. Basal hormone evaluations were normal, with normal cortisol suppression after low‐dose dexamethasone. Iodocholesterol scanning, performed in 12 patients, showed normal bilateral adrenal uptake in 2 subjects and an increased uptake on the side of the lesion in 10 subjects. In every patient, ACTH stimulation was performed to evaluate the secretory response of cortisol, 17OH‐P, progesterone and dehydroeplandrosterone sulphate. An identical test was performed in 10 control subjects with normal adrenal glands, matched for age and sex.

In Six patients with an adrenal lesion >3·5cm, the ACTH stimulation test was repeated one month after surgery.

RESULTS The 17OH‐P response to ACTH stimulation was significantly higher in subjects with adrenal ‘Incidentaloma’ than In controls (P< 0·01). In particular, 10 subjects out of 15 (66%) evidenced a 17OH‐P peak > 18 nmol/l at 60 minutes. No differences were seen in baseline 17OH‐P or cortisol levels or in cortisol response to ACTH between the two groups. Dehydroepiandrosterone sulphate concentrations were significantly lower in patients with adrenal ‘Incidentaloma’ than in normals.

In SIX patients who had an increased 17OH‐P response to ACTH on initial evaluation, the ACTH test was repeated one month after surgery. In five of these patients, 17OH‐P response to ACTH was clearly reduced, suggesting that in these cases the enzymatic defect was restricted to the adenoma. In the other patient, however, stimulated 17OH‐P levels remained unchanged. In this case, therefore, all of the adrenal tissue seems to be involved, suggesting a late‐onset 21‐hydroxylase deficiency. No significant modifications in cortisol response to ACTH were observed.

CONCLUSION It seems therefore that in some cases of incidentaloma the steroidogenic enzymatic defect may be secondary to the adenomatous proliferation, while in others such defects may Induce the development of silent adrenal nodules.
The contribution of hypogonadism to the development of osteoporosis in thalassaemia major: new therapeutic approaches
Authors: Anapllotou Margarita L. G. , Kastanias Isidoros T. , Psara Panagiota , Evangelou Evangelos A. , Liparaki Maria , Dimitriou Panaglotis
Published: March 2008

OBJECTIVE The osteoporosis seen in thaiassaemia major is of multifactorial origin. The aim of the study was to evaluate the contribution of hypogonadism to the development of this osteoporosis and to assess the efficacy of new sex hormone replacement therapy regimens.

DESIGN AND PATIENTS Sixty‐Seven patients were studied: 12 were hypogonadal, 32 had been on previous hormone replacement therapy (conjugated oestrogens plus medroxyprogesterone for females, depot testosterone esters for males): 10 had received continuous courses of treatment and 22 3‐monthly on/off courses, and 22 were eugonadal without previous replacement therapy. Twenty‐seven of the above patients were evaluated prospectively at 16 and 32 months during different therapeutic approaches (12 without treatment, 7 on continuous replacement and 8 on/off schemes followed by continuous therapy during the second observation period). The continuous schemes comprised either trans‐dermal oestradiol (100 μg) plus medroxyprogesterone for females or hCG to produce serum testosterone concentrations within normal range, for males.

MEASUREMENTS Bone mineral density (BMD) and bone mineral content (BMC) of lumbar spine and distal end of radius were measured by dual‐energy X‐ray absorptiometry.

RESULTS Spinal BMD was found to be more than 30% lower than that of controls matched for sex and age with no difference between sexes. Radial BMD was less impaired and showed significantly (P<0·01) higher levels in males (decrease of 5·8±2·3, mean±SD) than In femalea (‐14·5±3·4%, mean±SD). In the retrospective evaluation it was found that the hypogonadal group had the lowest (P<0·0001) BMD levels (0·62±0·01, mean ± SE) and the highest were observed on the continuous replacement group (0·83 ± 0·04), whereas the values of the other groups were similar. In a multiple regression analysis model it was found that only sex steroid levels were related to the BMD measurements (for oestradiol t=2·6, P= 0·01 and for testosterone t= 6·5, P= 0·0001), whereas parameters related to haemolytic anaemia and desferrioxamine treatment were not. In the prospective study the continuous replacement group increased BMD and BMC values more than the on/off treatment courses (P= 0·01).

CONCLUSIONS Hypogonadism seems to play an important role in the development of osteopenia‐osteoporosis in thalassaemia major; continuous hormone replacement therapy with transdermal oestrogen for females or hCG for responding males best improves the bone density parameters.
Characteristics of acromegalic patients with a good response to octreotide, a somatostatin analogue
Authors: Yang I.M. , Woo J.T. , Kim S.W. , Kim J.W. , Kim Y.S. , Choi Y.K.
Published: March 2008

BACKGROUND AND OBJECTIVES In GH‐secreting pituitary tumours somatostatin receptor density has been correlated with octreotide responsiveness. Little is known about the other endocrine characteristics of patients with good responses to octreotide. The purpose of this study was to determine the characteristics of these patients.

PATIENTS We studied 30 patients with active acromegaly. Five had been treated with either transsphenoidal adenomectomy or conventional radiotherapy without cure of GH excess.

DESIGN Patients were divided into good or poor octreotide responders. Patients whose GH level decreased to less than 20% of basal and below 20 mU/l after a subcutaneous injection of 100 μg of octreotide were defined as good octreotide responders. We compared tumour size, basal GH secretory pattern, responses to TRH, GnRH and bromocriptine, and mutation of the α‐subunit of stimulatory GTP‐binding protein (Gα) between the two groups.

MEASUREMENT Tumour size was determined by CT or MRI. Basal GH level was measured hourly between 0800 and 1600 h. GH responses to TRH and GnRH were measured every 30 minutes for 2 hours, and the GH response to oral bromocriptine was measured hourly for 6 hours. The mutation of Gα gene between codons 184 and 251 was examined by direct sequencing using PCR in 5 patients of each group whose tumour tissues were available for the genomic DNA extraction.

RESULTS Seventeen patients (57%) were good octreotide responders (group I) and 13 (43%) were poor responders (group II). The mean age, sex, tumour size, tumour grade and the basal OH secretory pattern were not significantly different between the two groups. Group I responded more frequently than group II to TRH (65 vs 25%). Fifty‐three per cent of group I patients and none of group II were good bromocriptine responders. Forty‐one per cent of group I patients responded to both TRH and bromocriptine. Three of 5 group I tumours had point mutations at codon 201 of the Gα, gene, none of 5 group II tumours had mutations. CGT(Arg) was replaced with TGT(Cys) in two tumours and with AGT(Ser) in one. No mutations were found at codon 227. All three tumours with mutations were from patients responsive to TRH. Two of the three were also good bromocriptine responders.

CONCLUSIONS These data Suggest that good octreotide responders are more likely to respond to TRH or bromocriptine. Good octreotide responders may include subgroups with different levels of TRH and dopamine receptor expression. A possible relation between octreotide response and the mutation of Gα gene should be investigated.
Two cases of Wegener's granulomatosis involving the pituitary
Authors: Roberts G. A. , Eren E. , Sinclair H. , Pelling M. , Burns A. , Bradford R. , Maurice‐Williams R. , Black C. M. , Finer N. , Bouloux P‐M. G.
Published: March 2008

We describe two patients with Wegener's granulomatosis Involving the pituitary. The diagnosis of Wegener's granulomatosis was inferred from the histological appearance of biopsy tissue and the presence of anti‐neutrophil cytoplasmic antibodies with cytoplasmic distribution in the first case, in which disease remained confined to the pituitary, causing anterior and posterior pituitary dysfunction. In the second case the diagnosis was made by the progressive Involvement of other organ systems, compatible histology and the presence of anti‐neutrophil cytoplasmic antibodies with cytoplasmic distribution. In neither patient did posterior pituitary dysfunction respond to immunosuppressive therapy, despite remission of other features of systems vasculitis. Panhypopituitarism in association with isolated pituitary Wegener's granulomatosis has not previously been described.
The effects of high altitude on hypothalamic‐pituitary secretory dynamics in men
Authors: Ramirez German , Herrera Rafael , Plneda David , Blttle Polly A. , Rabb Hamld A. , Bercu Barry B.
Published: March 2008

OBJECTIVE Individuals adapted to high altitude (HA) have abnormalities In endocrine function and specifically In the pituitary‐thyroid axis and aldosterone regulation. In this study we assessed hypothalamic‐pituitary function In men adapted to high altitude living using exogenous administration of synthetic hypothalamic hormones

DESIGN Growth hormone releasing hormone (Geref 1‐29) 1 /μg/kg, TRH 500/μg, GHRH 100 μg and ovine cortlcotro‐phin releasing hormone (oCRH) 1 μg/kg were simultaneously administered Intravenously to two groups of men: 12 born and raised In the city of Pasto, Colombia, South America, located at an altitude of 2600 m In the southern Colombian Andes (HA group) and 10 men living at sea level (SL) in Tampa, Florida

MEASUREMENTS The following hormones were measured: GH, IGF‐I, TSH, T4, free T4, free T3, PRL, ACTH, β‐endorphln and Cortisol. IGF binding proteln‐3 (IGFBP‐3) and Cortisol binding globulin (CBG) were also measured.

RESULTS G H response to G H R H In HA men was exaggerated compared to SL men, and I G F‐I concentration was also significantly Increased In the presence of normal levels of IGFBP‐3. No differences in T S H or P R L responses were found following TRH. HA men had lower basal total T4 levels, but higher free T4 and free T3 concentrations. The basal ACTH concentrations in the HA men were significantly lower than SL, although the response to oCRH was still present. β‐Endorphln basal levels were similar at HA and SL but the response to oCRH at HA was blunted. At HA, basal Cortisol levels as well as C B G were elevated compared to SL and, In contrast to SL, did not increase significantly after endogenous ACTH secretion.

CONCLUSIONS This study Is the first description of exaggerated G H response to the administration of G H R H In HA men and also of a significant increase in I G F‐I concentration in the same subjects in the presence of normal levels of IGFBP‐3. An altered hypothalamic‐pituitary response was found in HA men after administration of oCRH characterized by a significantly lower basal ACTH concentration at HA, although the response to oCRH was present but the β‐endorphin response to oCRH was blunted. At HA, basal Cortisol levels, as well as C B G, were elevated and the Cortisol levels did not significantly Increase after endogenous ACTH secretion. We have characterized the differences in hypothalamic‐pituitary dynamics after the administration of TRH, GnRH and oCRH In HA men comparing their response to age/ sex matched SL men
Investigation, management and therapeutic outcome in 12 cases of childhood and adolescent Cushing's syndrome
Authors: Weber A. , Trainer P. J. , Grossman A. B. , Afshar F. , Medbak S. , Perry L. A. , Plowman P. N. , Rees L. H. , Besser G. M. , Savage M. O.
Published: March 2008

OBJECTIVE Cushing's syndrome In childhood and adolescence Is rare. We analysed the clinical presentation, Investigation, management and therapeutic outcome In 12 paediatric patients with Cushing's syndrome.

DESIGN Retrospective review of case notes.

PATIENTS Twelve patients, 7 males and 5 females, aged 7.6‐17.8 years with Cushing's syndrome who were admitted to St Bartholomew's Hospital between 1978 and 1993, were studied. Aetiologies of the Cushing's syndrome patients were: Cushing's disease (9), adrenal adenoma (1), nodular adrenocortical dysplasia (1) and ectopic ACTH syndrome (1). One further male patient, aged 17.8 years who presented with Nelson's syndrome after bilateral adrenalectomy for Cushing's disease In 1978, Is described.

MEASUREMENTS Presenting symptoms, endocrine tests for hypercortlsolism, Imaging studies, simultaneous bilateral Inferior petrosal sinus sampling and therapeutic strategies are discussed.

RESULTS The dominant clinical features were obesity, short stature, virillzation, headaches, fatigue and emotional lability. Investigations confirmed Cushing's syndrome by demonstrating absent Cortisol clrcadlan rhythm and Impaired suppression on low dose dexa‐methasone test and differentiated Cushing's disease from other aetiologies by high dose dexamethasone and hCRH tests. In Cushing's disease, pituitary CT scan Identified a microadenoma In 4 out of 9 subjects. In 5 of the 9 patients (3 with a normal pituitary CT, 2 with a suggested microadenoma), a pituitary MRI scan was performed and confirmed the CT findings. Inferior petrosal sinus catheterization for ACTH In 4 patients confirmed excess pituitary ACTH secretion, correctly lateralizing the tumour In all cases. Cushing's disease was treated by transsphenoidal surgery alone In 6 patients and combined with pituitary Irradiation In 3 patients. Of these 9 patients, 7 are cured and 2 are in remission. The patient with Nelson's syndrome Is cured after total hypophysectomy.

CONCLUSIONS This series describes the clinical features, aetiologies and management of juvenile Cushing's syndrome. Investigation with low and high‐dose dexamethasone suppression tests and hCRH test identified the aetiology In each case. Collaboration between paediatric and adult endocrine units together with an experienced neurosurgeon and a radiotherapist contributed to the successful therapeutic outcome of these patients
Low frequency of germline mutations in the RET proto‐oncogene in patients with apparently sporadic medullary thyroid carcinoma
Authors: Eng Charls , Mulligan Lois M. , Smith Darrin P. , Healey Catherine S. , Frilling Andrea , Raue Friedhelm , Neumann Hartmut P.H. , Ponder Margaret A. , Ponder Bruce A.J.
Published: March 2008

BACKGROUND AND OBJECTIVES Medullary thyroid carcinoma (MTC) occurs both sporadically and In the autosomal domlnantly inherited multiple endocrine neoplasia (MEN) type 2 syndromes. The distinction between true sporadic MTC and a new mutation familial case is important for future clinical managment of both the patient and family. The susceptibility gene for MEN 2 is theRET proto‐oncogene. Systematic analysis for germ‐line mutations of theRET proto‐oncogene was performed in a series of 67 patients with apparently sporadic MTC to determine whether they were true sporadic cases or unsuspected de novo MEN 2 cases.

DESIGN AND PATIENTS Sixty‐seven unselected patients with sporadic MTC were randomly ascertained from clinic patients from four centres. The diagnosis of MTC was confirmed by hlstopathology. Germline DNA was extracted from peripheral blood leucocytes or from paraffin‐embedded tissue and subsequently used for polymerase chain reaction amplification.

MEASUREMENTS Polymerase chain reaction basedRET mutation analysis was performed by direct double‐stranded cycle sequencing of axons 10, 11, 13 and 16, within which the majority ofMEN2 mutations have been shown to occur.

RESULTS In this series, there was one proven case of germline mutation InRET codon 620, which previously has been shown to be responsible for MEN 2, thus Indicating heritable disease. No germline mutation in codon 918, typical of MEN 2B, was found.

CONCLUSIONS A figure of 1.5% germline mutations In 67 apparently sporadic MTC Is lower than the incidence of familial disease reported in previous series Involving clinical and biochemical screening. The presence of a germline mutation in theRET proto‐oncogene in a patient with MTC indicates heritable disease. The absence of germlineRET exon 10,11,13 or 16 mutation appears to rule out MEN 2A to a high probability, although the presence of a familial form of MTC other than classical MEN 2A cannot be excluded conclusively.
Growth stimulating antibodies in endemic goitre: a reappraisal
Authors: Davies R. , Lawry J. , Bhatia V. , Weetman A. P.
Published: March 2008

OBJECTIVE Previous studies, using a variety of methods, have reported growth‐promoting Immunoglobulins (IGs) In a large proportion of patients with endemic goitre. We sought to determine whether thyroid growth‐promoting Immunoglobulins (TGI) are present in the serum of Indian patients with endemic goitre.

DESIGN IgG was prepared by protein G‐Sepharose affinity purification and added to FRTL‐5 thyroid cells In the presence of suboptimal concentrations of TSH.

PATIENTS We studied 30 sequential patients with endemic goitre and 16 euthyroid controls without a goitre from the same area

MEASUREMENTS Two assays for thyroid cell growth were used: 3H‐thymldine Incorporation, and flow cytometric measurement of the proportion of cells in the S phase and G2/M phase of the cell cycle.

RESULTS Both assays were shown to detect growth produced by TSH and by thyroid stimulating antibodies in IgG preparations from 3 patients with Graves' disease. There was no significant Increase In either 3H‐thymldine Incorporation or the distribution of cells In S or G2/M phase with IgGs from endemic goitre patients, and no difference between the effects of these IgGs and those from the normal subjects.

CONCLUSIONS Thyroid growth‐promoting immunoglobulins cannot be detected In Indian patients with endemic goitre.
Temperature‐induced down‐regulation of the glucocorticoid receptor in peripheral blood mononuclear leucocyte in patients with sepsis or septic shock
Authors: Molijn G. J. , Koper J. W. , van Uffelen C. J. C. , de Jong F. H. , Brinkmann A. O. , Bruinlng H. A. , Lamberts S. W. J.
Published: March 2008

OBJECTIVE Activation of the hypothalamic‐pituitary‐adrenal axis is of vital importance during critical Illness. We have studied the adaptive mechanisms which occur at the level of the glucocorticoid receptor in glucocorticoid target tissues in patients with sepsis or septic shock.

DESIGN The effects of hypercortlsolaemia, hyperthermia and cellular composition on number of glucocorticoid receptors per cell and their affinity were evaluated, both In vitro and In vivo, In peripheral blood mononuclear leucocytes of control subjects and In patients with sepsis or septic shock.

SUBJECTS Fifteen patients (age 25‐79) with sepsis or septic shock who were admitted to an Intensive care unit were studied. The control group consisted of 24 healthy laboratory employees.

MEASUREMENTS The binding capacity and affinity of the glucocorticoid receptors were measured and compared to clinical data and the plasma Cortisol concentrations.

RESULTS Hypercortlsolaemia, in vitro, resulted in a decreased affinity and a decreased binding capacity of the glucocorticoid receptor. In vitro, hyperthermia as well as variations In the cellular composition did not Influence the glucocorticoid receptor. In vivo, there was no change In the number of receptors per cell In patients with sepsis or septic shock as compared to healthy controls. However, a decreased affinity of the glucocorticoid receptor was observed. There was a weak but significant negative correlation between body temperature and the number of glucocorticoid receptors In the patient group. There was no relation between circulating Cortisol concentrations and glucocorticoid receptor affinity and number.

CONCLUSIONS There Is no obvious regulation of the number of glucocorticoid receptors by plasma Cortisol concentrations In vivo.

The decreased affinity of the glucocorticoid receptor together with the negative correlation between hyperthermia and the number of glucocorticoid receptors In patients with sepsis or septic shock suggest that hypo‐thalamlc‐pitultary‐adrenal axis activation during critical illness Is accompanied by peripheral adaptation in glucocorticoid receptor number and affinity.