bluuebunny/crossref_metadata_2025 huggingface dataset:
Serotoninergic control of gonadotrophin and prolactin secretion in women
Authors: Ulrich Uwe , Nowara Ingrid , Rossmanith Winfried G.
Published: March 2008

OBJECTIVE Due to conflicting observations from previous investigations, the role of serotonin (5‐HT) in the regulation of the human menstrual cycle has not been clearly established. We have therefore investigated the possible participation of 5‐HR in the control of gonadotrophin and PRL secretion in women, using the potent 5‐HT3 receptor antagonist ondansetron as a pharmacological probe.

DESIGN Serum profiles of LH, FSH and PRL were obtained in 9 normally cycling women during a control and a treatment cycle, during which ondansetron (8 mg orally) was administered daily. On day 10 of both cycles, the serum pulsatility of LH, FSH and PRL was assessed by frequent blood sampling (at 10‐minute intervals for 10 hours). Pituitary responsiveness was tested by administration of a GnRH bolus (25 μg I.v. after 8 hours).

MEASUREMENTS LH, FSH and PRL were serially determined in all blood samples by immunofluorescence assays. The resulting hormone data arrays were searched for significant fluctuations by the Cluster pulse algorithm.

RESULTS Compared with control cycles, the temporal organization and the endocrine characteristics of the treatment cycles remained virtually unaltered. Serotonin antagonism did not noticeably affect the LH pulse attributes (frequencies, interpulse intervals, amplitudes). Although FSH amplitudes declined markedly (P < 0·05), the remaining pulse attributes were unchanged. A clear increase (P < 0·05) in the PRL pulse frequency was noted, while PRL pulse amplitudes tended to increase (P= 0·1). Gonadotrophin and PRL release in response to GnRH administration was unaltered by ondansetron treatment.

CONCLUSIONS Serotoninergic blockade by a selective 5‐HT3 receptor antagonist failed to modify pulsatile LH secretion, but induced distinct changes in episodic FSH and PRL secretion. Since the pituitary gonadotrophin and PRL responsiveness remained unaltered during 5‐HT3 receptor blockade, the observed alterations in the FSH and PRL secretion presumably relate to altered hypo‐thalamic regulation of these pituitary hormones. Thus, the central regulation of pulsatile FSH and PRL release in women appears to involve 5‐HT3 receptor‐mediated processes.
Dissociation of adrenal androgen and cortisol secretion in Cushing's syndrome
Authors: Cunningham Sean K. , McKenna T. J.
Published: March 2008

OBJECTIVES While ACTH may modulate adrenal androgen production, there is evidence that other factors are required. Cushing's disease and ectopic ACTH secretion provide a little utilized opportunity to examine adrenal androgen levels in conditions of ACTH excess. We have compared plasma cortisol values with plasma levels of androstenedione, dehydroeplandrosterone (DHEA), DHEA‐sulphate (DHEAS), testosterone and an Index of free testosterone, the testosterone/sex hormone binding globulin ratio, prior to treatment in patients with Cushing's syndrome.

PATIENTS AND MEASUREMENTS Plasma from 15 adult patients with Cushing's disease and three adults with the ectopic ACTH syndrome was obtained prior to treatment and submitted to specific immunoassays for the measurement of the above steroids.

RESULTS Plasma cortisol values of 15 patients with Cushing's disease (range 326–1140 nmol/l, normal range 190–690 nmol/l) were elevated in 9; In contrast, plasma androstenedione (4·1–11·3 nmol/l, normal range, men 2·1–7·7, women 3·3–9·9 nmol/l) was elevated in only two patients, plasma DHEAS (3·3–17·8 μmol/l, normal range, men 4·5–18·4, women 3·5–11·8 μmol/l) was elevated in only 4 patients and plasma DHEA (4·8–45·2 nmol/l, normal range 11–48 nmol/l) was normal or low in all 15 patients. Plasma androstenedione was markedly elevated (74 nmol/l) in one of three patients with ectopic ACTH syndrome, moderately elevated in another, and normal in the third patient. In contrast, plasma DHEA and DHEAS levels were suppressed in the patient with the highest androstenedione level and low or normal in the other two patients.

CONCLUSIONS These data suggest that ACTH alone does not control adrenal androgen Secretion. The data also suggest that variability in the processing of proopiomelanocortin (the precursor of ACTH and related peptides) occurring in Cushing's disease and ectopic ACTH syndrome may account for differences in the relation of cortisol to androgens observed between the disorders and when compared to that in normal subjects.
Gsα and Gi2α mutations in clinically non‐functioning pituitary tumours
Authors: Williamson Elizabeth A. , Daniels Mark , Foster Sally , Kelly William F. , Kendall‐Taylor Pat , Harris Philip E.
Published: March 2008

BACKGROUND AND OBJECTIVE Activating mutations of Gsα (gsp) and Gi2α (gip) have been described in various endocrine neoplastic conditions. The objective of this study was to assess the prevalence of gsp and gip mutations in clinically non‐functioning pituitary tumours (NFTs) and to compare the clinical phenotypic characteristics of tumours bearing G protein gene mutations with wild‐type tumours.

DESIGN Twenty‐two NFTs and 20 normal anterior pituitary glands screened for G protein gene mutations.

PATIENTS Twenty‐two patients; 14 female (median age 59 years, range 19–76) and 8 males (median age 66·5 years, range 50–77).

MEASUREMENTS Site‐directed hybridization or direct sequencing of polymerase chain reaction amplified Gsα and Gi2α DNA.

RESULTS G protein gene mutations were identified in 3/22 (13%) of NFTs. Two tumours demonstrated gsp mutations, one at codon 201 arginine to cysteine, and the second at codon 227 giutamine to arginine. Three tumours demonstrated gip mutations at codon 205 giutamine to arginine. Two tumours with gsp mutations also harboured gip mutations. All tumours with G protein gene mutations demonstrated local bone infiltration into the surrounding structures.

CONCLUSIONS G protein gene mutations have been demonstrated in a proportion of non‐functioning pituitary tumours. The presence of dual gsp and gip mutations in two tumours suggests the possibility of multiple hits in a stepwise pathogenesis of pituitary neoplasia.
Plasma 18‐oxocortisol levels in the patients with adrenocortical disorders
Authors: Yamakita Noriyoshi , Mune Tomoatsu , Morita Hiroyuki , Yasuda Keigo , Miura Kiyoshi , Gomez‐Sanchez Celso E.
Published: March 2008

OBJECTIVES 18‐Oxocortisol (18oxoF) shares structural characteristics with cortisol and aldosterone and is secreted from the adrenal cortex. It has been reported that 18oxoF has weak gluco and mineralo‐corticoid activities and increases blood pressure when administered to animals. We tried to clarify the characteristics of the production of 18oxoF in patients with adrenocortical disorders compared with the control subjects.

DESIGN AND PATIENTS In patients with primary aldosteronism due to aldosterone producing adenoma (APA) (n= 21) and Cushing's disease or syndrome (Cushing's disease n= 13; adrenocortical adenoma n= 10), plasma 18oxoF level early in the morning following an overnight fast was evaluated as well as plasma cortisol and aldosterone levels.

RESULTS The plasma 18oxoF levels were significantly higher in the patients with adrenocortical disorders than in control subjects. The ratios of 18oxoF/cortisol and 18oxoF/ aldosterone were high in APA and in Cushing's disease and syndrome patients, respectively. In the control subjects and combined group of patients with Cushing's disease and syndrome, plasma 18oxoF level significantly correlated with plasma cortisol level but not with aldosterone level. However, in APA patients plasma 18oxoF level correlated significantly with both cortisol and aldosterone levels.

CONCLUSION The production of 18oxoF was elevated as a result of the hyperactivity of 18‐hydroxylase and excess cortisol production in APA patients and in patients with Cushing's disease and syndrome, respectively. An excess 18oxoF production could be playing a role in the pathogenesis of hypertension in these patients. The correlation of plasma 18oxoF levels with plasma cortisol and aldosterone levels suggests that the production of 18oxoF is more dependent on the supply of cortisol than on 18‐hydroxylase activity in normal subjects and patients with Cushing's disease and syndrome.
Effect of atrial natriuretic factor infusion on basal and CRH‐stimulated ACTH, cortisol and aldosterone levels in patients with Cushing's or Addison's disease
Authors: Ambrosi B. , Sala C. , Bochicchio D. , Colombo P. , Gazzano G. , Fadin C. , Morganti A. , Faglia G.
Published: March 2008

OBJECTIVES While it has been shown that atrial natriuretic factor (ANF) is able to inhibit CRH‐stimulated ACTH secretion in vitro, in normal men conflicting results on its effect on ACTH/cortisol responses to insulin and CRH have been reported. Since no data are available concerning the possible influence of ANF on the hypothalamic‐pituitary‐adrenal axis in states of ACTH hypersecretion, the effect of ANF on pituitary‐adrenal function in basal conditions and after CRH stimulation has been investigated in patients with Cushing's (n= 4) and Addison's disease (n= 4).

DESIGN On two different days all patients underwent the following procedures: (a) α‐human ANF was infused, after a priming dose of 100 ng i.v., at a rate of 0·01 μg/kg/min over 5 hours. After 120 minutes of ANF infusion, oCRH (1 μg/kg) was i.v. injected as a bolus; (b) vehicle infusion was given over 5 hours and at 120 minutes oCRH was injected. Plasma ANF, ACTH, cortisol, aldosterone, renin activity and K+ were measured; heart rate and blood pressure were monitored.

RESULTS In Cushing's disease plasma ANF rapidly increased within 30 minutes of the exogenous peptide infusion (from 27 ± 5 to 73 ± 14 pmol/l; mean ± SE), whereas in the vehicle study its concentration was unchanged. During the first 2 hours of both tests no significant modifications in ACTH levels were observed. After CRH the plasma ACTH peak was unchanged. Serum cortisol levels progressively declined during the first 2 hours of ANF infusion (from 778 ± 150 to 461 ± 48 nmol/l; P < 0·05), whereas no changes were observed during vehicle. After CRH serum cortisol rose to similar peaks. Plasma aldosterone levels were significantly reduced during the first 2 hours of ANF infusion (from 81 ± 20 to 35 ± 7 pmol/l P < 0·05), whereas no changes were found during vehicle. A similar aldosterone rise was induced by CRH during either vehicle or ANF. Mean plasma renin activity slightly declined and the changes were similar on both occasions. In Addison's disease ANF levels rose within 30 minutes of the peptide infusion (from 12·1 to 49·8 pmol/l), while they were unchanged during vehicle. A slight decline in ACTH levels in the first 2 hours was observed during either vehicle or ANF infusion. After CRH the plasma ACTH peaks were similar. Mean plasma renin activity was unaffected by vehicle, while ANF caused a decline during the first 2 hours (from 13·4 ± 0·8 to 7·7 ± 0·3 ng/ml/h). In all patients, heart rate, blood pressure and K+ were only slightly affected on both occasions.

CONCLUSIONS (1) In patients with corticotrophin hypersecretion ANF does not influence basal and CRH‐stimulated ACTH secretion; (2) in Cushing's disease ANF inhibits cortisol and aldosterone basal secretion; this effect is not mediated by ACTH and is over‐ridden by CRH stimulation.
Seasonal variation in the diagnosis of Graves' disease
Authors: Westphai Sydney A.
Published: March 2008

OBJECTIVE Heat intolerance is a well known symptom of Graves' disease. Therefore, it is possible that increased ambient temperature could influence the recognition of Graves' disease by unmasking or enhancing the symptom of heat intolerance. Our aim was to determine if there is a seasonal variation in the diagnosis of Graves' disease.

DESIGN A retrospective study. SETTING A county hospital and clinic.

PATIENTS Two hundred and seven patients with Graves' disease diagnosed from 1985 to 1992.

RESULTS A high correlation was found between the temperature and the number of cases of Graves' disease diagnosed. A larger proportion of patients (68%) was diagnosed during the warmer half of the year, May‐October, than during the cooler half. The peak incidence of the diagnosis occurred in May, when 17–4% of the patients were diagnosed. Although the peak average monthly temperature occurs in July, the month of May corresponds to the time of the year when the temperature is making its largest positive change In the month‐to‐month variation. CONCLUSIONS Seasonal variations in the temperature can affect the incidence of the diagnosis of Graves' disease. The diagnosis is more common during the months of higher temperature.
Short‐term fasting in obesity fails to restore the blunted GH responsiveness to GH‐releasing hormone alone or combined with arginine
Authors: Procopio M. , Maccario M. , Grottoli S. , Oleandri S. E. , Boffano G. M. , Camanni F. , Ghigo E.
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.
Thyroid cancer and thyroiditis in the goitrous region of Salta, Argentina, before and after iodine prophylaxis
Authors: Ruben Harach H. , Williams E. Dillwyn
Published: March 2008

OBJECTIVE The importance of iodine intake and thyroiditis in the pathogenesis of thyroid cancer remains controversial. We have investigated the natural history of thyroid cancer and thyroiditis in a goitrous region before and after iodine prophylaxis over a 31‐year period.

DESIGN For the analysis of thyroid cancer the material was divided in two periods. The first 15 years (59 cases), including 5 years before prophylaxis, was compared with the second 16 years (85 cases), a period well after iodine supplementation of salt. Histological diagnosis of the tumours was based on the WHO system. Moderate to severe thyroiditis in the non‐tumoral surrounding thyroid from female patients was recorded. For this, the material was analysed in the two periods In relation to the introduction of iodine prophylaxis in 1963, taking account of the age of the patients.

RESULTS Papillary carcinomas formed the largest group of tumours in both periods, with nearly twice as many in the second period as the first, while the numbers of follicular and medullary carcinomas remained about the same. The ratio of papillary to follicular carcinoma rose from 1.7:1 in the first period to 3.1:1 in the second. All three thyroid lymphomas were of the non‐Hodgkin's type, and all occurred in the second period in females aged over 50. A severe lymphoid thyroiditis was present in the two cases with assessable background thyroid tissue.

The frequency of lymphoid infiltrate in females rose from 8% 11/12) before 1963 to 25% (18172) after prophylaxis in the whole series. After salt prophylaxis, thyroiditis was more frequent in patients with papillary carcinoma in general (31%), and clinically significant papillary carcinomas in particular (35%), than in those with non‐papillary tumours (6%) (X2, P < 0.05 and P < 0.025, respectively).

CONCLUSIONS Our observations indicate that a high dietary intake of iodine may be associated with a high frequency of papillary carcinoma and thyroiditis, and that thyroiditis is more commonly associated with papillary carcinoma than with other thyroid tumours. The occurrence of non‐Hodgkin's lymphomas only in the post‐prophylaxis period may be linked to an increase in thyroiditis.
Melatonin and the pituitary‐thyroid axis status in blind adults: a possible resetting after puberty
Authors: Bellastella A. , Sinisi A. A. , Criscuolo T. , De Bellls A. , Carella C. , Lorio S. , Sinisi A. M. , Parlato F. , Venditto T. , Pisano G.
Published: March 2008

OBJECTIVE Increased levels of free thyroid hormones have been previously described in prepubertal blind subjects and have been thought to be a consequence of a partial target organ refractoriness due to the early and prolonged lack of light perception. The aim of this study was to clarify whether this abnormality is permanent or transient and the interrelationships between melatonin and thyroid hormone secretion.

MEASUREMENTS Total and free thyroid hormones, TSH, thyroxine‐binding globulin (TBG), reverse trilodothyronine (rT3) and melatonin were measured In plasma samples obtained at 0800 h (two hours after lights‐on) In a group of 11 totally (group 1) and 16 partially (group 2) blind adult patients and in 10 age‐matched healthy subjects.

RESULTS Both totally and partially blind patients showed melatonin levels higher than in controls (330 ± 106 pmol/l, group 1 and 361 ± 159 pmol/l, group 2, respectively; controls: 53 ± 12 pmol/l, P < 0.001 vs both groups), but fT4, fT3, T4, T3 TSH, rT3 and TBG concentrations showed no significant differences from controls.

CONCLUSIONS A possible resetting of pltuitary‐thyroid axis regulation can occur in blindness after puberty; variations of melatonin secretion could play a role in this. The inhibitory effect of melatonin on thyroid gland function found in animals does not seem to occur in humans. Elevated melatonin levels, both in patients with total blindness and in those with light perception only, suggest that more complex mechanisms other than light signalling are involved in the changes of melatonin secretion in blindness.
Spontaneous follicular and luteal function in infertile women with oligomenorrhoea: role of luteinizing hormone
Authors: Fleming R. , McQueen D. , Yates R. W. S. , Coutts J. R. T.
Published: March 2008

OBJECTIVE There is a paucity of longitudinal endocrine studies of infertile patients with oligomenorrhoea. We have assessed the frequency and quality of spontaneous follicular development and Meal function in patients with ollgomenorrhoea and infertility (PCOS), and have related the observed criteria to circulating LH activity.

DESIGN Prospective detailed investigations in a cohort of unselected patients.

PATIENTS Infertile women with oligomenorrhoea (PCOS, n= 131) presenting to the Infertility clinic at the Royal Infirmary, Glasgow.

MEASUREMENTS Patients were monitored with frequent plasma oestradiol (E2) concentration assessments over a minimum period of 3 weeks, starting more than 2 weeks after a menstrual bleed. When follicular maturation was identified the patient provided daily blood samples through to her ensuing menstrual bleed, and E2, progesterone, total testosterone, FSH and LH were assessed in these samples. Luteal phase progesterone profiles were assessed between the days LH surge +2 and LH surge +6 by means of a progesterone Index.

RESULTS Forty‐eight per cent of the patients showed evidence of follicular development. The oestradiol profiles in the patients showing follicular growth were normal, but the progesterone curve was sub‐normal in the early luteal phase, due to a high proportion of deficient luteal phases. The mean LH concentrations were elevated in the whole group, but no difference was observed between the mean LH values for those patients showing spontaneous follicular development and those who did not, and the incidence of ovulation was similar In the normal LH and elevated LH groups. Similarly, no relation was established between LH and the quantitative assessment of luteal phase progesterone profiles (progesterone Index), and the distribution of progesterone Indices was similar in the normal LH and elevated LH groups.

Testosterone concentrations were positively correlated with LH (p= 0.008) but not with the incidence of spontaneous follicular growth. There was no significant difference in the incidence of spontaneous ovulation between the patients with elevated or normal mean follicular phase testosterone concentrations.

CONCLUSION The data indicate that both LH and testosterone secretion in PCOS were closely linked, but that neither was directly linked to the incidence or inhibition of spontaneous follicular development in PCOS, or to the disturbance in luteal phase progesterone profiles.
Osteoporosis in Turner's syndrome and other forms of primary amenorrhoea
Authors: Davies Melanie C. , Gulekli Bulent , Jacobs Howard S.
Published: March 2008

OBJECTIVE Osteopenia in Turner's syndrome is well recognized. This study is aimed to elucidate whether this is an intrinsic feature of the disorder, or is a nonspecific feature resulting from oestrogen deficiency.

DESIGN Comparison of bone mineral density and fracture rate in Turner's patients and in 46,XX women with equivalent oestrogen deprivation from other causes. SUBJECTS One hundred and twenty women In the reproductive age range (16‐45 years): 40 with Turner's syndrome, 40 with other forms of primary amenorrhoea, and 40 healthy controls matched to patients for duration of oestrogen usage.

MEASUREMENTS Measurement of bone mineral density in the lumbar spine (and femoral neck in some subjects) by dual‐energy X‐ray absorptiometry, and reported history of fracture.

RESULTS Vertebral bone mineral density was similar In women with Turner's syndrome (mean 0.84, SD 0.11 g/cm2) and those with other causes of primary amenorrhoea (mean 0.81, SD 011 glcm2; P= 026). Both groups had severe osteopenia compared with healthy controls (mean 1‐06, SD 0.09 g/cm2, P < 0.0005, confirmed after correction for height and weight). Fractures had been sustained by 45% (10/22) of Turner's patients for whom information was available, a high frequency compared with controls (P= 0.014); half of these were at ‘osteoporotic’ sites of fracture (wrist, vertebra, femoral neck).

CONCLUSION Osteopenia in Turner's syndrome is not an intrinsic feature specific to this disorder, but results from extreme oestrogen deprivation. Early treatment with oestrogen is therefore recommended.
Effect of octreotide on circulating IGF‐I chromatographic profile: evidence for an inhibitory action on the formation of the 150‐kDa ternary complex
Authors: Barreca A. , Carlola G. , Ponzanl P. , Arvigo M. , Foppianl L. , Glordano G. , Minuto F.
Published: March 2008

OBJECTIVE The increasing use In clinical practice of octreotide (a somatostatin analogue which inhibits the secretion of GH and other peptide hormones) led us to study the effects of this treatment on GH, Insulin‐like growth factors (IGF)‐I and II and IGF‐binding protein (IGFBP)‐3, as well as on circulating IGFBP complexes in acromegalic patients.

DESIGN The circulating concentrations of GH, IGF‐I, IGF‐II and IGFBP‐3 were measured In acromegaiic patients before and after 3, 6, 9, and 12 months of treatment with octreotide (group I: n = 5), and compared with those found In a group of patients (group II) treated with bromocriptine (n= 3), cabergoline (n= 7) radiotherapy (n= 3) or surgical therapy (n= 2). In pools of serum obtained from patients treated with octreotide, dopaminergic drugs, surgery and radiation, before and after therapy, immunoreactive IGF‐I and IGFBP‐3 were also evaluated after Superdex 200 gel filtration in neutral conditions.

RESULTS Before treatment, the concentration of IGF‐I and IGFBP‐3 were above the normal range in all patients, while IGF‐II levels were slightly reduced. After treatment with octreotide, IGF‐I (P= 0·004), IGF‐II (P= 0·02) and IGFBP‐3 (P<0·001) were significantly reduced as compared to basal levels. In subjects of group II, only IGF‐I concentration was significantly reduced by the treatment (P= 0.02), and a negative correlation between IGF‐I and IGF‐II concentrations was found (r=−0·58, P < 0·0001). After gel filtration immunoreactive IGF‐I and IGFBP‐3 were found in the 150‐kDa mol.wt. region in serum obtained from untreated patients and from treated patients of group II, while in the serum of octreotide‐treated patients the IGF‐I and IGFBP‐3 peaks were shifted to the 60‐kDa mol.wt. region, thus suggesting that the acid‐lablle subunit of the 150‐kDa complex was drastically reduced. Since the GH concentrations in groups I and II were similar (M ± SEM; 13·8 ± 7·4 and 21·2±10·6mu/l respectively), the marked reduction in acid‐labile submit in the octreotide treated patients can be explained by a direct Inhibitory effect of somatostatin on the subunit.

CONCLUSIONS Octreotide exerts an Inhibitory effect not only on IGF‐I but also on IGF‐II. The reduced formation of the 150‐kDa complex probably causes an increased metabolic clearance rate of IGF peptides which can account for the reduced concentration of both IGFs after treatment with octreotide.
The IGF‐I receptor sub‐membrane domain is intact in GH‐secreting pituitary tumours
Authors: Greenman Yona , Prager Dlane , Melmed Shlomo
Published: March 2008

BACKGROUND AND OBJECTIVE Clinical acromegaly is Characterized by dysregulation of somatotroph GH secretion In the presence of high circulating serum IGF‐I levels. Physiologically, IGF‐I exerts a negative feedback on GH secretion at both the hypothalamic and the pituitary levels. We have previously shown that the 943 and 950 tyrosine residues In the IGF‐I receptor β‐subunit are required for ligand signalling to the GH gene, as substitution of these residues abrogates IGF‐I signal transduction. To determine whether a mutation within the IGF‐I receptor sub‐membrane domain may be Involved In the pathogenesis of GH secreting tumours, we studied this region In these tumours.

DESIGN Exon 15 of the IGF‐I receptor containing both the 943 and 950 tyrosines was analysed In 19 GH‐secreting tumours by single‐strand conformation polymorphism (SSCP) analysis of polymerase chain reaction (PCR) products. Tumour DNA and patients’lymphocyte DNA, which served as normal controls, were analysed.

RESULTS All samples exhibited normal migration patterns In the SSCP analysis which was further confirmed by direct DNA sequencing.

CONCLUSIONS We conclude that mutations In the IGF‐I receptor sub‐membrane domain which disrupt the negative feedback loop are not Involved In the pathogenesis of acromegaly.
Growth hormone secretion after the administration of GHRP‐6 or GHRH combined with GHRP‐6 does not decline in late adulthood
Authors: Micle Dragan , Popovic Vera , Kendereski Aleksandra , Macut Djura , Casanueva Fellpe F. , Dieguez Carlos
Published: March 2008

OBJECTIVE Growth hormone (GH) secretion in middle and late adulthood declines with age. However, the precise mechanisms causing this impairment in OH release are unknown. HIs‐D‐Trp‐Ala‐Trp‐D‐Phe‐Lys‐NH2(GHRP‐6) Is a synthetic compound that releases OH in a dose related and specific manner in several species, including man. In order to gain a further Insight Into disrupted GH secretion in late adulthood, we evaluated GH responses to GHRP‐6 or GHRH, administered either alone or in combination, in healthy young and late adulthood groups of subjects.

DESIGN All subjects underwent three different tests carried out in random order and separated by at least one week. Tests were performed at 0900 h after an overnight fast. GHRH (100 μg), GHRP‐6 (90 μg) either alone or In combination were administered as an I.v. bolus.

SUBJECTS Groups of healthy young (mean ± SEM 22 ± 1·1 years, n= 9) and older adult subjects (59·5 ± 1·7 years, n= 9) were studied.

MEASUREMENTS Serum GH levels were measured by radioimmunoassay.

RESULTS In the group of young adult subjects the combined administration of GHRH and GHRP‐6 elicited a greater GH increase than GHRH alone (F= 21·9, P < 0·001) or GHRP‐6 alone (F= 6·2, P= 0·01). Similarly, the response to the combined stimuli was also greater than with GHRH alone (F= 21·8, P < 0·001) or GHRP‐6 alone (F= 23·9, P < 0·001) In the late adulthood group of subjects. OH responses to GHRH were greater in younger than in older subjects (F= 3·45, P= 0·03). In contrast, OH responses to either GHRP‐6 (F= 0·71, P= NS) or combined GHRH plus GHRP‐6 administration (F= 0·68, P= NS) were not significantly different between the two groups.

CONCLUSIONS These data show that OH responses to GHRP‐6 are much greater than to GHRH In late adulthood. The marked Increase of plasma GH levels observed after administration of GHRP‐6 alone or in combination with GHRH Indicates that Impaired GH secretion in late adulthood is a functional and potentially reversible state.
Human chorionic gonadotrophin immunoactivity in cystic intracranial tumours
Authors: Honegger Jürgen , Mann Klaus , Thlerauf Paul , Zrinzo Anthony , Fahlbusch Rudolf
Published: March 2008

BACKGROUND AND OBJECTIVE With regard to intracranial tumours, elevated hCG in CSF or serum has been considered to be specific for germ‐cell tumours. Recently however, elevated hCG has also been shown to be present In cyst fluid and CSF of patients with craniopharyngiomas. While germ‐cell tumours are generally non‐cystic, the aim of our study was to determine the significance of hCG In cystic intracranial lesions.

DESIGN in a prospective study, hCG Immunoactivity and subunits of hCG were measured in cyst fluid, CSF, and serum of patients harbouring intracranial cyst lesions.

PATIENTS AND MEASUREMENTS hCG immunoactivity was measured in cyst fluid and serum samples of 42 patients. CSF samples were available from 12 patients with craniopharyngiomas. In order to fully characterize the hCG immunoactivity, we used immunoradiometric assays for total hCG activity (measuring both intact hCG and the free β‐subunit of hCG), and those specific for intact, dimeric hCG (hCG), free β‐subunit of hCG (hCGP) and free α‐subunit. Furthermore, immunostaining of tumour tissue was performed using monoclonal antibodies directed against the free β‐subunit of hCG.

RESULTS Total hCG immunoactivity was markedly elevated in cyst fluid of all 17 craniopharyngiomas (range 36·7–4558 IU/I; normal <5IU/I). Moderately elevated levels of hCG in cyst fluid were detected In three of four pituitary adenomas, in two metastases from lung cancer and in two arachnoid cysts. hCGβ was detected in cyst fluid from all hCG positive cysts, while specific determination of intact (dimer) hCG and α‐subunit mostly yielded negative results. No hCG immunoactivity was found in cystic giiomas, meningiomas or haemangioblastomas. hCG was elevated in CSF of two patients with craniopharyngiomas, but no hCG immunoactivity was detected in any serum sample. Subtle immunostaining of epithelial cell groups was shown in five of ten craniopharynglomas. Clear immunostaining for hCGβ was also found in scattered epithelial cells of one pituitary adenoma.

CONCLUSIONS hCG immunoactivity in cystic intracranial lesions is due mainly to hCGβ. Measurement of hCG immunoactivity in cyst fluid can be helpful in the differential diagnosis of intracranial cystic lesions, if surgery is restricted to cyst decompression and no histology is available. High levels suggest a craniopharyngioma.
Short‐term effects of octreotide on blood pressure and plasma catecholamines and neuropeptide Y levels in patients with phaeochromocytoma: a placebo‐controlled trial
Authors: Plouin P.‐F. , Bertherat J. , Chateiller O. , Billaud E. , Azizi M. , Grouzmann E. , Epelbaum J.
Published: March 2008

OBJECTIVE The observation that phaeochromocytoma possess specific somatostatin binding sites led us to test the hypothesis that octreotide may have antisecretory potential in patients with phaeochromocytoma. We therefore compared the effects of octreotide and placebo on blood pressure and plasma catecholamines and neuropeptide Y. PATIENTS Ten consecutive patients referred to a tertiary care centre for the diagnosis and treatment of a phaeochromocytoma.

DESIGN AND MEASUREMENTS We performed a crossover comparison of either three 100 μg subcutaneous injections of octreotide over one day or 3 injections of octreotide vehicle over another. Blood pressure was measured over 24 hours on each test day using an automatic ambulatory recorder. Blood samples were collected before (at 0800 and 0900 h) and after (at 1000, 1100, 1200, 1300 and 1500h) placebo or octreotide injection. Plasma catecholamines were assayed by high‐performance liquid chromatography and neuropeptide Y was determined using a two‐site amplified enzyme immunoassay. All patients then underwent surgery and tumoral somatostatin binding site density was determined by quantitative autoradiography.

RESULTS Compared to placebo, octreotide did not alter mean 24‐hour ambulatory blood pressure or plasma neuropeptide Y, or plasma or urinary catecholamine, levels. Although a moderate reduction in plasma noradrenaline was found in the two patients with the highest tumoral somatostatin binding site densities, overall octreotide induced variations in plasma noradrenaline did not correlate with somatostatin binding site density. Blood glucose increased from 5·4 ± 0·3 on placebo to 7·8 ± 0·5 mmol/l on octreotide (P< 0·01).

CONCLUSION In the present controlled conditions, short‐term administration of octreotide had no antisecretory effect in patients with phaeochromocytoma.
Benzodiazepines attenuate the pituitary‐adrenal responses to corticotrophin‐releasing hormone in healthy volunteers, but not in patients with Cushing's syndrome
Authors: Korbonits M. , Trainer P. J. , Edwards R. , Besser G. M. , Grossman A. B.
Published: March 2008

OBJECTIVE The corticotrophin‐releasing hormone (CRH) stimulation test has become established as a powerful tool in differentiating the source of ACTH In patients with Cushing's syndrome. Psychiatric symptoms are common In patients with Cushing's syndrome, and many patients with psychiatric illnesses may show disturbances of function of the pituitary‐adrenal axis; both of these groups of patients may be receiving benzodiazepine drugs when presenting for evaluation of their possible endocrine problems. Both animal and human studies suggest that Interactions occur between benzodiazepines and the hypothalamopituitary‐adrenal axis. We have therefore evaluated the effects of a benzodiazepine drug on the pituitary‐adrenal response to CRH.

DESIGN We have Investigated the effects of 20 mg oral temazepam or placebo on serum Cortisol and plasma ACTH after the administration of 100μg i.v. human CRH in 12 healthy volunteers and In 9 patients with Cushing's syndrome.

RESULTS Temazepam significantly inhibited the peak serum/plasma levels and area under the curve for circulating Cortisol and ACTH in normal subjects after CRH, but there was no such difference after temazepam in patients with Cushing's syndrome.

CONCLUSIONS Our results have shown that temazepam Inhibits the pituitary‐adrenal responses to human CRH in normal subjects, but not in those with Cushing's syndrome. We believe that Inhibition of endogenous AVP by temazepam is the most likely explanation for our findings in healthy volunteers: the hypercortisolaemia in Cushing's syndrome suppresses the release of both endogenous CRH and AVP In portal blood which then results in abolition of the temazepam induced reduction In the pituitary‐adrenal response to exogenous CRH, as seen in our patients. These effects of benzodiazepines should clearly be taken Into account in patients using these compounds while undergoing endocrine assessment.
Oestrogen formation from androstenedione in human bone
Authors: Schweikert Hans‐Udo , Wolf Lutz , Romalo Gabriela
Published: March 2008

BACKGROUND AND OBJECTIVE Peripheral aromatization of testosterone and androstenedione Is the principal source for circulating oestrogens In men and In castrated and post‐menopausal women. Since human bone is a target organ for androgens and oestrogens, aromatase activity was assessed In human sponglosa obtained from patients who were undergoing orthopaedic surgery.

DESIGN AND PATIENTS In Initial experiments for assessing aromatization, oestrogen formation from 1,2,6,7‐3H‐androstenedlone was compared with the release of trltlated water from 1β‐3H‐androstenedlone. Since the rates of enzyme activity were similar with the two methods, rates of oestrogen formation were determined under standardized conditions with the trltlated water generation technique In bone specimens obtained from 4 men and 11 post‐menopausal women.

RESULTS The apparent Km of the aromatase ranged between 6 and 50 nm (20.4 ± 3.9; mean ± SEM), values In the range of those reported for human placental mlcrosomes. The maximum velocity (Vmax) of the aromatase activity ranged between 0‐14 and 1.23 nmol/g DNA/h.

CONCLUSIONS Oestrogens formed in human bone may play a physiological role In steroid hormone action in this tissue.
High dose testosterone therapy for reduction of final height in constitutionally tall boys: does it influence testicular function in adulthood?
Authors: de Waal W. J. , Vreeburg J. T. M. , Bekkering F. , de Jong F. H. , de Muinck Keizer‐Schrama S. M. P. F. , Drop S. L. S. , Weber R. F. A.
Published: March 2008

OBJECTIVE We have studied the effect of treatment with high doses of androgens during puberty on testicular function In adult men with constitutionally tall stature, taking Into account confounding factors interfering with sperm quality, since existing published data do not include whether testicular function is impaired by such treatment.

DESIGN Historical cohort study.

PATIENTS Forty‐three previously androgen treated tall men (cases) and 30 non‐treated tall men (controls).

MEASUREMENTS Physical examination, semen analysis and plasma levels of LH, FSH, testosterone (T), sex hormone binding globulin (SHBG) and Inhlbin.

RESULTS Sperm quality and testis volume were comparable between cases and controls. Mean sperm concentration was 66.4 ± 106/ml in cases and 66.2 ± 106/ml in controls. A left‐sided varicocele was found In 45% of the cases and 37% of the controls. In cases we observed a significant effect of the age at start of androgen therapy on sperm motility (regr. coeff. (SE): 4.92 (2.41)%,P= 0.048). In addition, testicular size at start of therapy had a significant effect on sperm concentration (regr. coeff. (SE): 5.57 (1.54) ± 106/ml,P= 0.0012) and on total sperm count (regr. coeff. (SE): 43.1 (7.73) ± 106,P= 0.0001). Plasma levels of T, SHBG and Inhibin were not statistically different between the groups. Cases had significantly higher FSH levels (mean (SD) 3.3 (2.2)vs2.1 (0‐8) IU/I,P= 0.004) and significantly lower LH levels (mean (SD) 2.3 (0.9)vs3.1 (1.4) IU/I,P= 0.019). We found a significant effect of age at start of therapy on plasma FSH level In the treated men (regr. coeff. (SE): −0.73 (0.18) IU/I,P= 0.0003).

CONCLUSIONS Treatment with high doses of androgens for reduction of final height in constitutionally tall stature has no long‐term side‐effect on sperm quality, testicular volume or plasma testosterone levels. However, treated men had significantly higher plasma levels of FSH compared with controls. The meaning of this difference remains to be established. Varicocele was present in 42% of the adult tall men.
Investigation of delayed puberty
Authors: Albanese A. , Stanhope R.
Published: March 2008

Delayed puberty is defined arbitrarily on the basis of statistical consideration, when no signs of puberty have occurred at 2.0 SD (13.4 years in girls and 13.8 in boys) above the mean chronological age for the onset of puberty. The vast majority of these patients have no endocrine abnormality and their pubertal development and growth spurt are simply consequences of primary delay (constitutional delay of growth and puberty (CDGP)) or secondary delay due to a chronic disease of childhood, such as asthma. However, a small proportion may have pathological causes of delayed puberty which must be careful Identified as specific management may be required. Associated with delayed puberty, the growth spurt is always delayed which is why the condition Is described as delayed growth and puberty. Short stature and lack of sexual development may lead to emotional and social difficulties and In some patients their consequences can persist when ‘normal’ height and full sexual maturation are attained. Recent data also suggest that a delay in the ‘tempo’ of pubertal maturation may Interfere with the normal bone accretion occurring during puberty, later causing osteoporosis. Such findings suggest that a new approach In delayed puberty may be necessary not only for psychological reasons but also for optimizing bone mass accretion.
A new deletion of the 5α‐reductase type 2 gene in a Turkish family with 5α‐reductase deficiency
Authors: Boudon Christel , Lobaccaro Jean Marc , Lumbroso Serge , Ösgur Gönül , Öcal Gönül , Belon Charles , Sultan Charles
Published: March 2008

The molecular basis for male pseudohermaphroditism produced by the 5α‐reductase deficiency is becomining Increasingly understood.

OBJECTIVE We have performed biochemical and molecular analyses of the 5α‐reductase type 2 gene In a Turkish family with a 5α‐reductase deficiency.

PATIENT A 46,XY prepubertal Turkish patient with female phenotype showing clltoral hypertrophy, high plasma testosterone and dihydrotestosterone, and normally differentiated and developed testosterone‐dependent internal genitalia.

MEASUREMENTS 5α‐Reductase activity, measured by the conversion of 3H‐T Into 5α‐reduced compounds, was determined from cultured genital skin fibroblasts by both Intact monolayer assay and cell‐free extracts at various pH values. The five exons of the 5α‐reductase type 2 gene were sequenced after enzymatic amplification (PCR) of the patient's genomic DNA. Labelled PCR of the consanguineous parents’DNA was submitted to electrophoresis on a sequencing gel.

RESULTS A marked decrease In the transformation of T into 5α‐reduced compounds by Intact cells and a diminished 5α‐reductase activity at acidic pH by sonicated cell extracts strongly suggested a 5α‐reductase type 2 deficiency. Molecular analysis of the 5α‐reductase type 2 gene showed a trinucleotide deletion straddling codons 156 and 157, responsible for a methionine residue deletion at position 157 of the protein. The parents’DNA contained both normal and deleted alleles.

CONCLUSIONS This Is the third deletion described in the 5α‐reductase type 2 gene. The deleted methionine 157 Is conserved in both types 1 and 2 of human and rat 5α‐reductase, which suggests Its crucial role In the functioning of the enzyme. This gene rearrangement was thus clearly responsible for the reduced 5α‐reductase activity and abnormal genital development in this patient.
Isolated combined growth hormone and gonadotrophin deficiency due to hypothalamic dysfunction, associated with insulin resistance
Authors: Mantzoros Chrlstos S. , Moses Alan C.
Published: March 2008

A 47‐year‐old woman was evaluated for congenital dwarfism, primary amenorrhoea due to hypogonadotrophic hypogonadism, severe hyperlipidaemla with pancreatitis, and overt diabetes mellltus associated with severe Insulin resistance requiring 2.5‐3 units of Insulin per kilogram body weight. Chromosomal analysis with trypsin banding was normal and biochemical evaluation revealed low oestrogen levels, inappropriately low gonadotropins, very low IGF‐I concentrations and GH concentrations unresponsive to Insulin or l‐dopa administration. Prolactin, pituitary‐adrenal and pituitary‐thyroid axes were normal. Dynamic testing with GnRH and GHRH produced increases in FSH, LH and GH concentrations. A MRI of the brain revealed no discernible hypothalamic abnormalities and a small pituitary. The presence of congenital combined growth hormone and gonadotrophin deficiency on the basis of a suprapltultary defect suggests the existence of common or related pathways regulating GnRH and GHRH synthesis or secretion and may have contributed to the ultimate development of Insulin resistance and hyperlipidaemla.
Thirst induced by a suckling episode during breast feeding and its relation with plasma vasopressin, oxytocin and osmoregulation
Authors: James R. J. A. , Irons D. W. , Holmes C. , Charlton A. L. , Drewett R. F. , Baylis P. H.
Published: March 2008

OBJECTIVE There have been anecdotal reports of increased maternal thirst during breast feeding, but the physiological mechanisms remain obscure. We have assessed and quantified the stimulation of maternal thirst during breast feeding (suckling), and Correlated the changes with plasma oxytocin and vasopressin levels.

DESIGN A within subject design was used with each subJect acting as her own control. Each subject participated in a suckling period and a control non‐suckling period the order of which was counterbalanced.

SUBJECTS Ten healthy breastfeeding women ranging from 28 to 52 days post partum.

MEASUREMENTS Thirst (assessed by a visual analogue scale), plasma vasopressin, plasma oxytocin (POT), plasma osmoiality and haematocrit, blood pressure, volume of milk transferred to baby, volume of water drunk immediately following each experimental period. RESULTS Thirst increased significantly more over a suckling period than over a comparable control period (P=0.013). The peak level of thirst correlated with the volume of water consumed to satiety following the suckling period (r=0.7, P=0.024). As expected, POT levels rose significantly in response to suckling (P <0.001). Six women demonstrated a close relation between thirst and oxytocin response during the suckling period. Despite significant changes in thirst during suckling there was no increase in plasma vasopressin or in osmoregulatory parameters.

CONCLUSIONS This study confirms that suckling is a potent stimulus to thirst in the mother, and is not associated with vasopressin release or dependent on any measurable alterations In osmoregulation. What actually stimulates thirst during breast feeding remains unknown, but there are two potential explanations for these observations: (i) suckling sends nerve impulses to the para‐ventricular and supraoptic nuclei In the hypothalamus which may have afferents within the central nervous system which stimulates a thirst response simultaneous with oxytocin release; (ii) a learned anticipation of thirst may be occurring in a situation associated with expectant fluid loss to preserve homeostasis.