bluuebunny/crossref_metadata_2025 huggingface dataset:
EFFECT OF ORAL GLUCOSE ON THE LATE GROWTH HORMONE RISE AND GROWTH HORMONE RESPONSES TO GHRH IN NORMAL SUBJECTS
Authors: VALCAVI R. , ZINI M. , DIEGUEZ C. , PORTIOLI Í. , SCANLON M. F.
Published: March 2008

A late rise in serum GH occurs 3‐5 h following oral glucose in man. In order to investigate the mechanisms through which this occurs we have studied the late GH rise after oral glucose during administration of a supramaximal dose of GHRH. In eight normal subjects, oral glucose (100 g) greatly enhanced the GH responses to a supramaximal dose of GHRH (50 μg bolus, followed immediately by 100 μg/h infusion for 3 h) given 3.5 h after the glucose. GH peak (mean±SEM) elicited by GHRH (bolus + infusion) rose from 55.2±20.4 to 133.4±29.6 mU/1 (P< 0.02) after glucose pretreatment. In conclusion, it is likely that the late rise in GH secretion induced by oral glucose occurs via a non‐GHRH‐dependent mechanism. These data are consistent with the hypothesis that the delayed GH response to glucose is a consequence of reduced release of somatostatin from the hypothalamus.
PHARMACOKINETICS OF THE LONG‐ACTING SOMATOSTATIN ANALOGUE OCTREOTIDE (SMS 201‐995) IN ACROMEGALY
Authors: NICHOLLS J. , WYNICK D. , DOMIN J. , SANDLER L. M. , BLOOM S. R.
Published: March 2008

A single‐dose study was performed to examine the pharmacokinetics of subcutaneous octreotide in acromegalic patients and to investigate the relationship between growth hormone and the elimination half‐life of the drug. Fourteen acromegalic patients (six men and eight women; age range 35‐59 years) who had previously received conventional treatment were studied. Two subjects were on long‐term octreotide which had been discontinued 72 h before the study. Octreotide 100 μg was administered subcutaneously and plasma samples taken every 10 min for 1 h and then hourly for up to 8 h. Growth hormone was measured at 0, 2 and 8 h. Octreotide was rapidly absorbed with a mean (± SEM) t1/2abs of 5‐4 min (± 0.8) peaking at a mean plasma concentration of 3.4 nmo1/1 (± 0.2) in 27.4 min (± 3.7). The monoexponential elimination phase had a mean half‐life of 110 min (± 9.6). The apparent volume of distribution was 29.4 1 (± 1.9) and total clearance was 172 ml/min (± 10.4). These results were similar to those obtained in normal volunteers. There was no simple relationship between the level of growth hormone and the half‐life of octreotide. Growth hormone levels ranged from 2.5 to 34.0 mIU/1 but were only > 10 mIU/l in three subjects. Further studies of octreotide pharmacokinetics are needed in untreated patients with acromegaly with raised growth hormone levels.
LONG‐TERM FOLLOW‐UP OF‘CURED’PROLACTINOMA PATIENTS AFTER SUCCESSFUL ADENOMECTOMY
Authors: CICCARELLI ENRICA , GHIGO EZIO , MIOLA CATALDO , GANDINI GIOVANNI , MULLER EUGENIO E. , CAMANNI FRANCO
Published: March 2008

The long‐term follow‐up (±Mg4 years) of clinical, hormonal and radiological aspects in 22‘cured’prolactinoma patients after adenomectomy was studied. Dynamic secretion of PRL and TSH was also evaluated, in order to identify the persistence of any underlying abnormality of hypothalamic pituitary control and to predict relapses. A relapse into hyperprolactinaemia was shown in 36% of patients 5‐90 months (mean 46) after surgery. This was accompanied by reappearance of clinical symptoms but not by the radiological demonstration of the adenoma in any patients. A significant PRL rise after domperidone, a dopaminergic antagonist drug, was shown in cured patients after surgery (mean±SEM peak, 2977±645 mU/1) but this was markedly lower than that observed in control subjects (5732±440 mU/1). In fact, normal PRL increments were shown in only 6/16 (37%) patients. TSH hyper‐responsiveness to domperidone normalized in only 46% of patients. Similar PRL responses to those obtained with domperidone were shown when a TRH test was given. A relapse into hyperprolactinaemia was observed in six of ten (60%) non‐responders to domperidone and in four of seven (57%) non‐responders to TRH, whereas six normal responders to domperidone and TRH had not relapsed at that time. Plasma PRL levels during pregnancy showed increments lower than those observed in normal pregnant women only in domperidone and TRH non‐responder patients. These results indicate that a relapse into hyperprolactinaemia and a blunted PRL rise during pregnancy were present only in patients with persistently reduced PRL response to dynamic tests.
SERUM FREE 1,25‐DIHYDROXYVITAMIN D AND THE FREE 1,25‐DIHYDROXYVITAMIN D INDEX DURING A LONGITUDINAL STUDY OF HUMAN PREGNANCY AND LACTATION
Authors: WILSON SCOTT G. , RETALLACK ROBERT W. , KENT JACQUELINE C. , WORTH GRAEME K. , GUTTERIDGE DONALD H.
Published: March 2008

The changes in three different indices of 1,25‐dihydroxyvitamin D (1,25(OH)2D) biological activity were studied longitudinally in 35 women during late pregnancy and lactation and in 26 control women. Measurements were made of maternal serum total 1,25(OH)2D and free 1,25(OH)2D concentration (by centrifugal ultrafiltration) and the free 1,25(OH)2D index (the molar ratio of total 1,25(OH)2D and vitamin D binding protein (DBP)). During late pregnancy total 1,25(OH)2D concentrations were significantly elevated when compared to controls, as were free 1,25(OH)2D and DBP concentrations and the free 1,25(OH)2D index. Serum total 1,25(OH)2D, free 1,25(OH)2D and DBP concentrations all fell dramatically during the first 2 weeks of lactation with total 1,25(OH)2D and free 1,25(OH)2D concentrations falling to levels below those of controls. During the course of lactation both total I,25(OH)2D and free 1,25(OH)2D levels rose significantly although they were not different from controls at 18 weeks of lactation. In contrast, the free 1,25(OH)2D index fell during the first 2 weeks of lactation, but remained at this level, significantly lower than controls. Neither urinary calcium excretion nor dietary calcium intake correlated with total or free 1,25(OH)2D, DBP, or the free 1,25(OH)2D index. The disagreement in the results of free 1,25(OH)2D concentration and free 1,25(OH)2D index demonstrates that these two approaches to measuring biologically active 1,25(OH)2D are not equivalent. In attempting to account for the increased calcium requirements of human reproduction we conclude that in pregnancy any of the 1,25(OH)2D measurements may be appropriate. In lactation, however, either 1,25(OH)2D is not a major factor or 1,25(OH)2D biological activity is inadequately represented by any of the currently available methods.
POTENCY AND SELECTIVITY OF THE NON‐STEROIDAL AROMATASE INHIBITOR CGS 16949A IN POSTMENOPAUSAL BREAST CANCER PATIENTS
Authors: DOWSETT M. , STEIN R. C. , MEHTA A. , COOMBES R. C.
Published: March 2008

A selective inhibitor of aromatase is widely sought for the treatment of postmenopausal women with breast cancer. CGS 16949A has been shown to be a highly selective, potent inhibitor of aromatase in vitro. Its potency as an oestrogen suppressant and its selectivity were examined by treating 24 postmenopausal patients with advanced breast cancer for 4 weeks with doses of 0.3, 1‐0 and 2‐0 mg twice daily. The study was conducted in two parts which compared the two lower doses and the two higher doses separately in a cross‐over design protocol. All doses significantly suppressed serum oestradiol and oestrone levels below pretreatment levels. Cross‐over analysis indicated that the 2.0 mg twice daily dose achieved significantly greater suppression of oestradiol levels than 1‐0 mg twice daily but there was no significant difference between any of the doses in the suppression of oestrone. No significant effects were noted on serum levels of LH, FSH, SHBG, prolactin, testosterone, androstenedione, 17‐ hydroxyprogesterone or cortisol. For the four steroids this was true both for basal samples and those collected after Synacthen stimulation. However, serum aldosterone levels were significantly suppressed by 1‐0 mg twice daily CGS 16949A and further suppressed by 2‐0 mg twice daily. It is concluded that CGS 16949A is a potent oestrogen suppressant in postmenopausal patients but that its effect is not totally selective.
RELATIVE CHANGES IN LH PULSATILITY DURING THE MENSTRUAL CYCLE: USING DATA FROM HYPOGONADAL WOMEN AS A REFERENCE POINT
Authors: ROSSMANITH W. G. , LIU C. H. , LAUGHLIN G. A. , MORTOLA J. F. , SUH B. Y. , YEN S. S. C.
Published: March 2008

The basic premise of this study is that the GnRH‐LH pulsatile activity, particularly its frequency characteristics, constitutes, in the absence of any considerable ovarian feedback, the intrinsic rhythm of the hypothalamic‐pituitary unit at its maximal rate. Thus, LH pulse attributes determined in postpubertal hypogonadal subjects may be used as a reference in assessing the degree of influence exerted by endocrine factors that modulate GnRH‐LH pulses. Accordingly, serum LH levels were determined in samples obtained at 15‐min intervals for 24 h in 20 hypogonadal women: 13 postmenopausal women (PMW) and seven women with premature ovarian failure (POF). Similar measurements were performed in 60 normally cycling women: 25 in the early follicular phase (EFP), 13 in the late follicular phase (LFP), seven at midcycle surge (LH surge) and 15 in the midluteal phase (MLP). Significant pulses were identified by the cluster algorithm utilizing factors appropriate for 24 h data series of a sampling frequency of 15‐min intervals. The results show a 24‐h mean (± SE) LH pulse frequency of 78.2±2.8 and 85.5±2.4 min per pulse for young (POF) and older (PMW) hypogonadal women, respectively. During the follicular phase of the cycle, the LH pulse frequency is not significantly different from that of hypogonadal women, but there is a significant (P < 0.05) increase from early to late follicular phases (95.4±3.3 vs 78.8±2‐2 min per pulse). However, when the sleep periods are excluded from the 24‐h data series because of the associated decrease of LH pulse frequency in EFP women, the resulting pulse frequencies are almost identical for EFP, LFP and PMW. An elevation beyond the basic pulse rhythm determined in PMW or POF is not observed in any phase of the menstrual cycle studied, including the midcycle surge. The decrease in LH pulse frequency during the luteal phase of the cycle (151.8±8.0 min per pulse, P < 0.001 vs hypogonadal women) beyond the reference pulse frequency of hypogonadal women is unequivocal. By contrast, the pulse amplitude varies markedly among the groups with the largest found in POF (36.6±4.5 IU/1). It follows, in descending order, PMW (22.7±3.1 IU/1), midcycle surge (17.3±2.8 IU/1), MLP women (7.0±1.3 IU/1) and the EFP (4.9±0.3 IU/I) and LFP (4.0 ±0.4 IU/I). These data support the concept that the changes in the LH pulse frequency during the menstrual cycle can be reduced, but do not exceed the periodicity of the basic rhythm of the GnRH‐LH pulse generator determined in hypogonadal women. Our observations also demonstrate that the pulse amplitude is subject to profound modulation by ovarian factors. Thus, the basic rhythm of GnRH‐LH pulses may serve as a meaningful reference in assessing influences by endocrine factors on GnRH‐LH pulsatile activity.
RELATIONSHIP BETWEEN SOMATOSTATIN AND GROWTH HORMONE MESSENGER RIBONUCLEIC ACID IN HUMAN PITUITARY ADENOMAS: AN IN‐SITU HYBRIDIZATION HISTOCHEMISTRY STUDY
Authors: LEVY A. , LIGHTMAN S. L.
Published: March 2008

We have used quantitative in‐situ hybridization histochemistry to assess the somatostatin (SRIH) and GH messenger ribonucleic acid (mRNA) content of 81 pituitary adenomas. SRIH mRNA was found in the absence of GH mRNA in only one tumour and in the five cases in which GH and SRIH mRNA were both present, SRIH mRNA prevalence was approximately two orders of magnitude less than GH mRNA. However, no direct correlation between GH mRNA, SRIH mRNA and circulating GH levels was evident at the time of surgery. In contrast, there was no detectable SRIH mRNA probe binding to a thyrotroph adenoma, a gonadotroph adenoma, 29 endocrinologically inactive pituitary adenomas, nine lactotroph adenomas, two first trimester fetal and two normal adult pituitary glands obtained 24 and 36 h post‐mortem. These findings corroborate previous reports of SRIH release from somatotroph adenomas in vitro and suggest that paracrine or autocrine mechanisms linking SRIH and GH mRNA operate within normal pituitary tissue. As somatotroph adenomas are thought to be predominantly clonal in origin, the data further suggest that GH and SRIH are synthesized in the same or closely related cells.
RADIOIMMUNOASSAY MAY OVERESTIMATE INSULIN IN NON‐INSULIN‐DEPENDENT DIABETICS
Authors: TEMPLE ROSEMARY C. , CLARK PENELOPE M. S. , NAGI DINESH K. , SCHNEIDER ANNEROSE E. , YUDKIN JOHN S. , HALES C. NICHOLAS
Published: March 2008

We have compared insulin concentrations measured by radioimmunoassay (RIA) in plasma from 50 fasting non‐insulin‐dependent diabetics (NIDDM) with those measured by a new monoclonal antibody‐based two‐site immunoradiometric assay (IRMA) of insulin (which has no significant cross‐reaction with proinsulin‐like molecules). We find that the RIA measures the sum of the insulin and proinsulin like molecules and that the IRMA insulin concentrations are 38% of those measured by the RIA in those diabetic subjects. We conclude that the importance of insulin deficiency in NIDDM may have been obscured by this error.
CLINICAL AND BIOCHEMICAL EFFECTS OF INCREMENTAL DOSES OF THE LONG‐ACTING SOMATOSTATIN ANALOGUE SMS 201‐995 IN TEN ACROMEGALIC PATIENTS
Authors: SHI Y. F. , HARRIS A. G. , ZHU X. F. , DENG J. Y.
Published: March 2008

Ten patients (seven women, three men) with active acromegaly, five previously treated and five newly diagnosed, were included in an open‐label prospective trial of 3 daily subcutaneous injections of the long‐acting somatostatin analogue SMS 201‐995 (Sandostatin) at increasing doses in order to obtain maximum growth hormone (GH) suppression. Four patients had received surgery, radiotherapy or bromocriptine. SMS 201‐995 doses were increased in a stepwise fashion from 100 μg every 8 h (three times daily) to 200, 300 and finally 500 μg three times daily at monthly intervals if mean serum GH values failed to decrease to undetectable levels in over 75% of the samples. The optimal dose was maintained for up to 28 months. Significant clinical improvement of headache, soft tissue swelling, facial features, hyperhidrosis and paraesthesia occurred in all patients. Mean 12‐h GH levels were significantly suppressed in four patients and fell to normal values in four. Suppression of GH levels was not achieved in two patients. Comparison of the mean interindividual GH values shows that the optimal efficacious dose is 100 μg t. i. d. in 7/10 patients. Somatomedin‐C (SM‐C) was also significantly reduced to below 50% of pretreatment levels in nine patients in whom it was measured. The subsequent increments of SMS 201‐995 up to 500 μg three times daily did not produce further clinically relevant GH or SM‐C suppression. Pituitary tumour shrinkage occurred in five patients. Thyroid function remained normal. Impaired glucose tolerance occurred in four patients. Side‐effects (diarrhoea, abdominal discomfort) were mild and transient. Asymptomatic gallstones occurred in three patients on 1500 μg/day and one patient on 600 μg/day after 6‐12 months treatment. This dose‐finding study shows that 100 μg three times daily SMS 201‐995 is an effective therapy for most of the acromegalic patients we treated.
FAMILIAL ACROMEGALY: STUDIES IN THREE FAMILIES
Authors: McCARTHY M. I. , NOONAN K. , WASS J. A. H. , MONSON J. P.
Published: March 2008

Acromegaly is usually regarded as a disease which arises sporadically except on those rare occasions in which it occurs as one component of an inherited pluriglandular syndrome. Familial acromegaly occurring in isolation has been reported only rarely. We have studied three families in each of which two first‐degree relatives have developed acromegaly without clinical evidence of other endocrinopathies, in order to clarify the relationship of familial acromegaly to multiple endocrine neoplasia, type 1 (MEN 1). No further subclinical cases of acromegaly have been detected in those first‐degree relatives of the index cases who were screened. In two of the families, we have found no evidence of abnormal pancreatic or parathyroid function either in the acromegalic index cases or their asymptomatic relatives: a diagnosis of MEN 1 is therefore effectively excluded. In the third family, the presence of multiple subcutaneous lipomata in several members of the family and elevations of PTH levels in two (normocalcaemic) acromegalic index cases, might indicate a highly atypical presentation of MEN 1. None of the six acromegalic index cases had elevations of circulating growth hormone releasing hormone levels. We conclude that isolated familial acromegaly may be more common than has hitherto been realized and that, in these families at least, ectopic production of growth hormone releasing hormone is not responsible.
THE APPLICATION OF DECONVOLUTION ANALYSIS TO ELUCIDATE THE PULSATILE NATURE OF GROWTH HORMONE SECRETION USING A VARIABLE HALF‐LIFE OF GROWTH HORMONE
Authors: HINDMARSH P. C. , MATTHEWS D. R. , BRAIN C. , PRINGLE P. J. , BROOK C. G. D.
Published: March 2008

A deconvolution analysis model to calculate pituitary growth hormone (GH) secretion rate from measured serum GH concentration has been developed. This uses an iterative method of‘curve‐stripping’based on an estimate of the half‐life. The model has been applied to serum GH profiles and demonstrates that GH secretion occurs in discrete bursts with quiescent periods between secretory episodes, an‘on‐off’phenomenon. The model can clearly dissect complicated concentration profiles such as the serum GH concentration response to growth hormone releasing hormone. The estimate was derived from calculating the half‐life of serum GH in 10 subjects following an intravenous bolus injection of 50 mU of biosynthetic human growth hormone (b‐hGH) and following infusions of the exogenous hormone (3 mU/kg/h) for 15, 30, 60 and 180 min. Endogenous GH secretion was suppressed by a continuous infusion of somatostatin (1‐14). An asymptotic relationship between the duration of GH infusion and the GH half‐life was established. A half‐life of 15.3 min was achieved after exposure to GH for 60 min and a maximum half‐life of 15.7 min after 180 min exposure.
ARGININE POTENTIATES THE GHRH‐ BUT NOT THE PYRIDOSTIGMINE‐INDUCED GH SECRETION IN NORMAL SHORT CHILDREN. FURTHER EVIDENCE FOR A SOMATOSTATIN SUPPRESSING EFFECT OF ARGININE
Authors: GHIGO EZIO , BELLONE JAELE , MAZZA ENRICO , IMPERIALE ELISEO , PROCOPIO MASSIMO , VALENTE FRANCESCA , LALA ROBERTO , DE SANCTIS CARLO , CAMANNI FRANCO
Published: March 2008

To investigate the mechanism underlying the GH‐releasing effect of arginine (ARG), we studied the interactions of ARG (0.5 g/kg infused i. v. over 30 min) with GHRH (1 μg/kg i. v.) and with pyridostigmine (PD, 60 mg orally) on GH secretion in 15 children and adolescents with familial short stature (5.1‐15.4 years). In a group of eight subjects ARG induced a GH increase not statistically different to that observed after GHRH (peak, mean±SEM: 38.0±10.4 vs 64.0±14.4 mU/1). The combined administration of ARG and GHRH led to GH levels (101±15.2 mU/1) higher than those observed after GHRH (P < 0.025) or ARG alone (P < 0.001) and overlapping with those recorded after combined PD and GHRH administration (111±22.4 mU/1). In the other seven subjects, ARG and PD administration induced a similar GH response either when administered alone (25.2±13.6 and 27.8±4.0 mU/1, respectively) or in combination (33.8±5.4 mU/1). In conclusion, our results show that in children ARG administration potentiates GHRH‐ but not PD‐induced GH increase. These findings agree with the hypothesis that the GH‐releasing effect of both ARG and PD is mediated via the same mechanism, namely, by suppression of endogeneous somatostatin release. Combined administration of either ARG or PD with GHRH has a similar striking GH‐releasing effect which is clearly higher than that of GHRH alone.
THE EFFECTS OF IMPROVED BLOOD GLUCOSE ON GROWTH HORMONE AND CORTISOL SECRETION IN INSULIN‐DEPENDENT DIABETES MELLITUS
Authors: WÜRZBURGER M. I. , PRELEVIC G. M. , SÖNKSEN P. H. , PERIC L. A. , TILL S. , MORRIS R. W.
Published: March 2008

Growth hormone and cortisol secretion were studied in 25 patients with insulin‐dependent diabetes before (Study 1) and 2 weeks after improved glucoregulation (Study 2). Blood samples for serum growth hormone (GH) and blood glucose determination were collected at hourly intervals whilst blood samples for cortisol and C‐peptide were collected every 6 h during the 24‐h period in Study 1 and Study 2. Glycaemic control was significantly improved in Study 2 compared to that in Study 1 (8.5 vs 13.3 mmol/1; P <0.001). With improved control, growth hormone levels rose by 21% (5.7 vs 4.7 mU/1; P < 0.05). Throughout both study periods growth hormone levels were higher in patients with no residual C‐peptide secretion (10 CpN patients) compared with patients with residual beta‐cell function (15 CpP patients) (7.1 vs 3.2 mU/1 in Study 1; 8‐9 vs 4.2 mU/1 in Study 2; P < 0.001). Characteristic shapes of the 24‐h blood glucose profile curves during both study periods were significantly different between the CpN and CpP group. Plasma cortisol decreased in both groups with improved metabolic control (P < 0.001) but the observed different diurnal pattern did not change. These results demonstrate the importance of residual endogenous insulin secretion in determining growth hormone secretion in insulin‐dependent diabetes and have important implications for glycaemic control and risk of microvascular complications.
OVARIAN SENSITIVITY TO GONADOTROPHINS IN PATIENTS WITH PCO IS UNAFFECTED BY SUPPRESSION OF LH
Authors: FLEMING R. , HAMILTON M. P. R. , CONAGHAN C. , BLACK W. P. , COUTTS J. R. T.
Published: March 2008

Infertile women with oligomenorrhoea and elevated LH concentrations (presumed polycystic ovary disease, PCO) were treated with exogenous gonadotrophins, HMG and HCG, for induction of follicular growth and ovulation, respectively. This was effected in the absence or presence of a gonadotrophin releasing hormone analogue (GnRH‐A) to suppress basal LH and the positive feedback surge of LH. Analyses of the duration of HMG therapy required to attain the degree of stimulation for HCG to be administered showed no difference between those with and without LH suppression. Analyses of the ultrasound estimations of rates of follicle growth and continued recruitment during the course of HMG also failed to show any effect of LH suppression. These data show that the high sensitivity of these patients to HMG is not related to the circulating LH concentrations.
SERUM INHIBIN LEVELS DURING THE PERIOVULATORY INTERVAL IN NORMAL WOMEN: RELATIONSHIPS WITH SEX STEROID AND GONADOTROPHIN LEVELS
Authors: MCLACHLAN ROBERT I. , COHEN NANCY L. , DAHL KRISTINE D. , BREMNER WILLIAM J. , SOULES MICHAEL R.
Published: March 2008

Inhibin is a gonadal glycoprotein believed to be important in the regulation of pituitary FSH secretion and/or to function as a paracrine factor within the ovary and testis. We studied serum levels of inhibin, oestradiol (E2), progesterone (P), FSH and LH during the periovulatory interval in order to determine whether there is differential control of sex steroid and inhibin secretion by the mature follicle and the emerging corpus luteum. Seven normal cyclic women were admitted 3–4 days prior to midcycle and blood samples drawn every 3 h for 5–7 days. Serum E2, P, FSH, LH and inhibin were measured by radioimmunoassay. Data were normalized around the peak LH value (0 h). Serum E2 and inhibin rose in parallel (r = 0.92, P < 0.001) between – 69 and – 18 h, E2 reached a peak of 1296 ± 154 (mean±SEM) pmol/1 at −18 h, then fell to 1050± 139 pmol/1 at 0 h. Serum inhibin, on the other hand, continued to rise to a peak of 837±95U/lat – 6 h, fell to 455±48 U/lat +45 h, then rose again. On average, the peak inhibin level occurred 10.4± 5.1 h after the peak E2 (P < 0.05). Inhibin levels were positively correlated with both serum LH and FSH between – 24 and +24 h (P<0.01). Serum E2 was negatively correlated with LH, FSH and inhibin between – 24 and 0 h (P < 0.01). Serum P levels increased from 1.8 ± 0.3 nmol/1 at – 24 h to 14.3 ± 1.0 nmol/1 at +60 h. Serum inhibin was positively correlated with serum P from −24 to 0 h (P<0.01) and +45 to +60 h (P < 0.01), but was inversely correlated from 0 to +45 h(P< 0.01). We conclude that the maturing follicle secretes both E2 and inhibin in parallel until – 18 h, at which time the process of luteinization is initiated by the onset of the midcycle LH surge, as evidenced by the rise in P. E2 secretion then falls while inhibin secretion rises, indicating different regulation of secretion of these two hormones by the maturing follicle. Furthermore, the close positive correlation between inhibin and gonadotrophin levels around midcycle suggests that FSH and/or LH stimulate inhibin secretion and that the presumed negative feedback effect of inhibin on FSH secretion is overcome at this time. After midcycle, inhibin secretion initially falls, then rises, while P rises progressively. This transient divergence of P and inhibin secretion may occur during the transformation of the preovulatory follicle into the corpus luteum.
EFFECT OF OCTAPEPTIDE SOMATOSTATIN ANALOGUE (SMS 201‐995) ON PLASMA 7B2 (A NEUROENDOCRINE POLYPEPTIDE) LEVELS IN PATIENTS WITH ACROMEGALY
Authors: NATORI SHOICHI , IGUCHI HARUO , OHASHI MASAO , NAKAO RYUSUKE , BLOOM STEPHEN R. , NAWATA HAJIME
Published: March 2008

We studied the sequential changes of plasma levels of immunoreactive ‘7B2’(IR‐7B2), a neuroendocrine polypeptide, after a subcutaneous injection of 50 μg of synthetic octapeptide somatostatin analogue (SMS 201‐995) in seven patients with acromegaly due to GH‐producing pituitary adenoma. Compared to the basal levels, mean plasma IR‐7B2 and GH levels significantly decreased, until 5 and 10 h respectively after the administration of SMS 201‐995. The mean (±SEM) nadir levels of plasma IR‐7B2 and GH were 68.1 ± 101 and 13.1 ±6.9%, respectively, compared to mean plasma levels before treatment (100%). Plasma IR‐7B2 as well as GH levels did not change significantly when saline was administered subcutaneously to three acromegalic patients. In addition, plasma IR‐7B2 levels did not change significantly after the administration of SMS 201.995 in normal subjects or in patients with primary hypothyroidism in whom SMS 201.995 induced a decrease of plasma TSH levels. These results strongly suggest that SMS 201‐995 has an unequivocal suppressive effect on the synthesis and/or the secretion of 7B2 in human somatotroph adenoma cells.
OESTROGEN AND PROGESTERONE RECEPTORS IN MEN WITH BILATERAL OR UNILATERAL PUBERTAL MACROMASTIA
Authors: LEE KOK‐ONN , CHUA DIXIE Y. F. , CHEAH JIN‐SENG
Published: March 2008

Abnormalities at the tissue receptor level may be important in the pathophysiology of pubertal macromastia, which may be unilateral or bilateral. We studied breast tissue removed from seven boys of age 16–17 years, five with bilateral and two with unilateral gynaecomastia. We confirmed that their physical features, karyotype, and plasma concentrations of testosterone, oestradiol, LH, FSH, and prolactin were all normal for adolescent males. Oestrogen and progesterone receptors were measured with a steroid binding (dextran coated charcoal) assay which was used for breast cancer receptor studies. Oestrogen receptors were not detectable in any of the 12 breasts studied. Progesterone receptors were detectable at a low level in two patients with bilateral gynaecomastia, one breast from each patient. We conclude that although the development of bilateral or unilateral male macromastia in puberty may yet be mediated by a local tissue receptor abnormality, this disorder is probably not mediated by an abnormal increase in oestrogen receptor number.
SUPEROVULATION INDUCTION IN WOMEN SUPPRESSES LUTEINIZING HORMONE SECRETION AT THE PITUITARY LEVEL
Authors: MESSINIS IOANNIS E. , TEMPLETON ALLAN
Published: March 2008

In superovulated women the pituitary response to GnRH is markedly attenuated by an unspecified ovarian factor(s). To examine the site of attenuation, the response of the pituitary to GnRH was investigated in five normally ovulating women during the late follicular phase of 3 cycles, i.e. a spontaneous (control) cycle, a cycle treated with ‘pure’ FSH, and a cycle treated with a combination of ‘pure’ FSH and pulsatile GnRH, via a pump (15 νg/ pulse). The oestradiol levels (mean ± SEM) at the time of the GnRH challenge were respectively 646 ±35, 1692 ±282 and 5976±1129 pmol/1. The size of the leading follicle was similar in all groups. Serum LH levels during treatment with FSH decreased significantly, while during treatment with FSH plus GnRH they increased initially and then decreased progressively. The response of pituitary LH to GnRH was significantly attenuated during treatment with FSH and FSH plus GnRH, as compared to the spontaneous cycles, but was not abolished. The attenuation was significantly greater in the FSH plus GnRH cycles (94%) than in the FSH cycles (59%). We conclude that in superovulated cycles, the attenuation of the pituitary response to GnRH increases with the degree of ovarian hyperstimulation. It is suggested that the responsible unspecified ovarian factor(s) exerts its effects at least at the pituitary level.
PATTERNS OF ACTH AND CORTISOL PULSATILITY OVER TWENTY‐FOUR HOURS IN NORMAL MALES AND FEMALES
Authors: HORROCKS P. M. , JONES A. F. , RATCLIFFE W. A. , HOLDER G. , WHITE A. , HOLDER R. , RATCLIFFE J. G. , LONDON D. R.
Published: March 2008

Patterns of plasma ACTH and Cortisol concentrations were studied in 10 healthy subjects (five male, five female in the early follicular phase, overall age range 21–32 years) by sampling through an indwelling cannula every 15 min for 24 h. The subjects were in hospital, ambulant, and taking normal meals. Plasma ACTH was measured by a two‐site immunoradiometric assay with a detection limit of 3.9 ng/1 (0.9 pmol/1). Pulses were identified by the method of Clayton et al. (1987) using stringent criteria to minimize false positive peaks. All subjects showed a circadian rhythm of ACTH, the acrophase occurring between 0615 and 0920 h in all but one subject and the mesor value was between 9.2 and 18.6 ng/1 (2.0 and 4.1 pmol/I). There were significantly fewer pulses between 1800 and 2400 h compared with the other three 6‐h periods. The pattern of ACTH differed between males and females in several respects: more pulses (18 vs 10), greater mean peak amplitude (16.8 vs 10.3 ng/1), greater area under the 24‐h profile (350.9 vs 206.6 ng/1 h) and higher mean level (14.7 vs 8.6 ng/1) in the males. In contrast, the Cortisol pattern did not show statistically different sex differences. The sex differences suggest greater sensitivity to, or availability of, ACTH to the female adrenal cortex, or different set points in Cortisol feedback.
Allgrove syndrome: an autosomal recessive syndrome of ACTH insensitivity, achalasia and alacrima
Authors: Moore P. S. J. , Couch R. M. , Perry Y. S. , Shuckett E. P. , Winter J. S. D.
Published: March 2008

Allgrove syndrome (Isolated glucocorticoid deficiency, achalasia and alacrima) was found in eight members of an inbred French Canadian/North American Indian pedigree. The high degree of consanguinity supports an autosomal recessive mode of inheritance for this disorder. Six patients presented with hypoglycaemia and other evidence of cortisol deficiency between 2·5 and 8 years of age; however, two others became cortisol deficient after Initial testing showed normal cortisol responses to ACTH, evidence that the glucocorticoid Insufficiency of this syndrome may not be congenital, but may develop as late as the third decade. No evidence of mineralocorticoid deficiency has been found during 65 patient‐years of follow‐up. Aiacrima was the earliest and most consistent clinical sign of Allgrove syndrome. Other manifestations of peripheral or autonomic neuropathy were found in four patients. The patients showed similar facial features, and three had significant veto‐pharyngeal Incompetence. Ail showed oesophageal dysmotility even in the absence of symptomatic dysphagia. In‐vitro studies of lymphocyte ACTH binding showed no differences from normal controls. If such lymphocyte binding, as has been suggested, reflects adrenal ACTH receptor activity, these data would suggest that the glucocorticoid deficiency of Allgrove syndrome is not the result of a defect in that receptor. However, the observation that ACTH does not elicit increased adenylate cyclase activity even in normal lymphocytes casts considerable doubt on the physiological significance of ACTH binding to lymphocytes. It seems likely, therefore, that true ACTH receptors are not expressed on peripheral lymphocytes, and any conclusions regarding a possible receptor defect in Allgrove syndrome must await studies of receptor expression on adrenal cell membranes
Metabolic effects of pharmacological adrenergic blockade in phaeochromocytoma
Authors: Krentz Andrew J. , Hale Peter J. , Horrocks Peter M. , Heslop Kirsten E. , Johnston Desmond G. , Wright Alex D. , Nattrass Malcolm
Published: March 2008

Twelve‐hour hormonal and metabolic profiles were performed in a 68‐year‐old woman with a benign adrenal phaeochromocytoma (a) prior to adrenergic blockade, (b) after the establishment of pharmacological alpha‐blockade with phenoxybenzamine, (c) after combined alpha and beta‐blockade with phenoxybenzamine and propranolol, and (d) after successful surgery and withdrawal of medication. Pretreatment, (a) vs (d), significant elevations (12‐h mean ± SD) were observed In the concentrations of noradrenaline (44·9 ± 14 ± 4 vs 2·3 ± 0.7 nmol/l, p > 0·01), glucose (6·9 ± 1·9 vs 5·0 ± 1·0 mmol/l, p > 0·05), glycerol (0·22 ± 0.02 vs 0·07 ± 0·01 mmol/l, p > 0·01), non‐esterifled fatty acids (0·71 ± 0·28 vs 0·34 ± 0·08 mmol/l, p>0·01), and total ketone bodies (0·08 ± 0·03 vs 0·03 ± 0·02 mmol/l, p > 0·01). Alpha‐blockade, (b) vs (a), was associated with an increase in noradrenaline levels (P > 0·01) but not with any significant alterations in intermediary metabolite concentrations. Following the establishment of combined alpha and beta‐blockade, (c) vs (b), plasma noradrenaline returned to its pretreatment level while the concentrations of glycerol, fatty acids and ketone bodies were normalized. A completely physiological 12‐h blood glucose profile, however, was observed only post‐operatively. No significant differences were observed in mean plasma insulin levels between the four studies. These results indicate impaired regulation of multiple aspects of carbohydrate, lipid and ketone body metabolism in our patient. Alpha‐blockade did not ameliorate the abnormalities in any aspect of intermediary metabolism and was associated with an increase in noradrenaline levels. Combined alpha and beta‐blockade effectively normalized lipolysis and ketone body metabolism but did not fully correct the abnormality in glucose metabolism.
Heterogeneity of circulating TSH‐receptor antibodies in thyroid disease demonstrated directly by chromatography
Authors: Worthington J. , Byfield P. G. H. , Hlmsworth R. L.
Published: March 2008

The heterogeneity of circulating TSH‐receptor antibodies (TRAb) has been demonstrated directly by affinity chromatography on the dye Remazol Yellow‐GGL. The technique resolved these antibodies Into discrete peaks within the general serum Immunoglobulln background. Peaks were detected initially by a binding (radioreceptor) assay and then characterized by their ability to stimulate the uptake of iodine‐125 Into FRTL‐5 cells. Thirteen subjects with high serum levels of TRAb were studied. The two hypothyrold patients each produced a single peak of TRAb activity with no ability to stimulate uptake of iodine‐125 into cultured cells. The remaining 11 patients had Graves’ disease; their sera produced a range of elution profiles after chromatography with TRAb activity resolved Into as many as five peaks. Considerable differences were seen in the relative abilities of the resolved TRAb components to bind to receptors and to stimulate cellular uptake of Iodine‐125 both between and within individual samples. No two patients produced components which chromatographed in the same position on the gradients employed for elution from the dye
Iodine intake and the seasonal incidence of thyrotoxicosis in New Zealand
Authors: Ford H. C. , Johnson L. A. , Feek C. M. , Newton J. D.
Published: March 2008

We explored a possible relationship between the seasonal variation In the Incidence of thyrotoxicosis In our area and Iodine Intake, as assessed by measuring the 24‐h urinary iodide excretion rate eight times at 3‐month Intervals in a group of normal subjects and in 992 outpatient specimens over a 2‐year period (1988–1990). For the period 1978–1990, 139 cases of thyrotoxicosis were diagnosed during the warmer half of the year (November‐April) and 100 cases during the cooler half (May‐October). This difference was statistically highly significant (P = 0·013). A similar disproportionality in the incidence of thyrotoxicosis was observed between the warmer (57%) and cooler (43%) halves of the year for the period 1988–1990. During the 1988–1990 period there was no discernible seasonal variation In either the milk iodide concentration or In the cumulative mean 24‐h urinary iodide excretion rates for the normal subjects or the outpatients. We conclude that the higher proportion of thyrotoxic patients diagnosed during the warmer 6‐month period of the year In our area is best explained by the fact that symptoms tend to be less tolerable in warm weather. A comparison of our findings on 24‐h urinary Iodide excretion rates with data collected in our area 25 years ago suggested that Iodine Intake may have declined
Growth hormone, insulin‐like growth factor I, insulin and C‐peptide during human fetal life: in‐utero study
Authors: Salardl S. , Orsini L. F. , Cacciari E. , Righetti F. , Donati S. , Mandini M. , Cicognani A. , Bovlcelli L.
Published: March 2008

Serum growth hormone (GH), Insulin‐like growth factor (IGF‐I), insulin and C‐peptide were measured by RIA In fetal blood collected in utero by umbilical cord puncture performed for a variety of Indications. Eighty‐four fetuses were aged 19–25 weeks and 14 were 26–37 weeks. IGF‐I values were lower than the sensitivity of the method. The range for GH was 3–197 μ g/I (GH‐μ g/I × 2= mU/I), for Insulin 14·3–117 pmol/l, for C‐peptide 66·2–827·5 pmol/l. GH significantly Increased from week 19 to 25; insulin and C‐peptide levels Increased from week 19 to 37. GH levels at 19–25 weeks were significantly higher in fetuses with femoral length less than the 5th compared with those with femoral length greater than the 95th centlle for that age. GH and insulin levels did not correlate with weight at birth or with maternal hormone levels. These data provide evidence for a presence in living fetuses, from the 19th week, of high levels of GH and of Insulin levels not very different from those In adults but these hormones do not seem to be directly responsible for fetal growth.
Effect of growth hormone therapy on thyroid status of girls with Turner's syndrome*
Authors: Massa Guy , de Zegher Francis , Vanderschueren‐Lodeweyckx Magda
Published: March 2008

The effect of recombinant human growth hormone (rhGH) administration on thyroid function was studied in 14 girls with Turner's syndrome for 18 months. All patients were euthyroid and had no documented GH deficiency. Treatment with rhGH, administered as daily subcutaneous Injections In a dose of 0·15 IU/kg/day, led to a decrease of serum T4 levels from 124·4 (mean±SEM) to 106·4 nmoi/l (P > 0·05) after 6 months of therapy. Thereafter serum T4 levels returned progressively to baseline levels. Serum TBG levels Increased consistently from 21·9 ± 0·5 to 24·4±0·9 mg/I (P > 0·05) after 3 months. Serum T3 and TSH levels did not change significantly during rhGH administration. The T3/T4 ratio (X 100) Increased from 1·9±0·1 to 2·2±0·1 (P > 0·05) after 6 months of treatment and returned thereafter to baseline levels. The observed changes in T3/T4 ratio demonstrated a striking parallelism with the changes in height velocity and plasma IGF‐I levels. We conclude that rhGH treatment results In a transient alteration of the thyroid status In girls with Turner's syndrome. The functional Importance of this phenomenon, In particular Its role In the concomitant growth acceleration, remains to be established.
Skeletal responsiveness to parathyroid hormone in healthy females: relationship to menopause and oestrogen replacement
Authors: Joborn Charlotte , LJunghall Sverker , Larsson Karln , Lindh Erlk , Naessén Tord , Wide Lelf , Åkerström Göran , Restad Jonas
Published: March 2008

In order to directly evaluate the role of parathyroid hormone (PTH) and Its Interaction with oestrogens for postmenopausal bone loss, studies were performed where synthetic human (1–38) PTH was Infused s.c. over 24 h in 15 healthy females. Measurements were made of serum electrolytes, PTH and biochemical Indices of bone turnover: serum osteocalcin and alkallne phosphatase and fasting urinary hydroxyproline and calcium.

During the Infusion of PTH there were significant Increases of serum calcium (15%), fasting urinary calcium (55%) and hydroxyproline (80%) but a reduction of the serum osteocalcin concentrations (15%). There were significant relations between the calcaemic response and the Increases of urinary calcium and hydroxyproline and the two latter were also closely related. There was, however, no correlation between the responses to PTH for the formative vs the resorptive indices.

Postmenopausal women displayed greater increases of serum calcium and fasting urinary hydroxyproline indicating greater skeletal sensitivity to exogenous PTH. Follow ing treatment with oestrogens the indices of skeletal responsiveness were reversed towards the premenopausal values.

The findings demonstrate that during short‐term infusion of PTH there Is a dissociation between bone resorptlon and formation and, furthermore, that the menopause is associated with an enhanced skeletal sensitivity for PTH.
Cognitive abilities in androgen‐insensitive subjects: comparison with control males and females from the same kindred
Authors: Imperato‐McGlnley Jullanne , Plchardo Marino , Gautier Teofilo , Voyer Daniel , Bryden M. Philip
Published: March 2008

To determine the effect of androgen Insensitivity on cognitive abilities, subjects with the syndrome of complete androgen Insensitivity (Al) were compared to control males and females from the same kindred on the Spanish version of the Wechsler Adult Intelligence Scale (WAIS). All subjects had similar sociocultural backgrounds and only right‐handed subjects were used In the primary analysis. This design was chosen to diminish the effect of critical variables on test performance, thereby highlighting the effect of androgen unresponslveness on cognition.

The results indicated that control males and females were superior to androgen Insensitive subjects on the Perceptual Organization factor, which Included five visuospatlal subtests. Separate analysis of these subtests revealed that males performed significantly better than females on Block Design, Picture Completion, and Object Assembly, and better than androgen Insensitive subjects on all five subtests. Females were superior to androgen Insensitive subjects on four subtests (Block Design, Picture Completion, Digit Symbol, and Picture Arrangement). Despite the small sample size, when female siblings were compared to their Al sisters, they were also superior on these four visuospatlal subtests.

The difference between the Verbal Comprehension and Perceptual Organization factors was greatest In androgen‐insensitive subjects, while control males demonstrated the least difference.

Females and Al subjects did not differ from one another on the Freedom from Distractlblllty factor nor on the subtests comprising it, but their performances were poorer than control males.

None of the groups differed significantly on Full Scale IQ, Verbal IQ, the Verbal Comprehension factor, or any subtests Included In this category.

These data Indicate that Al subjects differ from normal males and normal females on subtests relating to visuospatial ability, and suggest that androgens play a role In the development of spatial ability In humans.
Effects of antibodies against octreotide in two patients with acromegaly
Authors: Ørskov Hans , Christensent Stig Engkjær , Weeket Jargon , Kaal Andreas , Harris Alan G.
Published: March 2008

Two patients developed specific IgG antibodies against octreotide after 2–3 years’ treatment for acromegaly with this long acting somatostatln analogue. The presence of these antibodies reduced the plasma disappearance rate of total extractable octreotide by 60 and 80% respectively. When compared to that of non‐Immune acromegalic patients, the plasma half‐life of octreotide in these two patients was 300 and 450 vs 110 min in those with no detectable octreotide antibodies. The sole observed con‐sequence of the immunization was a marked prolongation of the Interval of maximum GH Inhibition from a mean of 5 to 8 and 10 h in the two patients described after octreotide injection.
Reproducibility of 24‐hour serum growth hormone profiles in man
Authors: Saint S. , Hindmarsh P. C. , Matthews D. R. , Pringle P. J. , Jones J. , Preece M. A. , Brook C. G. D.
Published: March 2008

objectiveTo study the reproducibility of 24‐h serum growth hormone (GH) concentration profiles in adults. DESIGN 24‐h serum GH concentrations were constructed by drawing blood samples at 20‐min Intervals. Four study occasions over a period of 1 year were chosen to assess the reproducibility

subjectsSix healthy adult male volunteers of normal height and weight and aged between 20 and 22 years. MEASURES The resulting GH data arrays were analysed by Fourier transformation. Between and within individual variations were calculated and expressed in terms of coefficients of variation and data plotted to show variations between groups and individuals

resultsThe frequency component of GH secretion occurred with a dominant periodicity of between 160 and 240 min. Precise estimates of spectral power (strength of oscillatory activity) and period were obtained for group data, but such estimates cannot be inferred from a single profile. There was no significant difference in 24‐h mean serum GH concentration over the year of study: occasion 1 (February) mean 2·0 mU/l (SD 0·5); occasion 2 (March) mean 3·7 mU/l (SD 2·8); occasion 3 (July) mean 2·7 mU/l (SD 1·4); occasion 4 (February) 2·5 mU/l (SD 1·5) (mean within individual coefficient of variation 35%, range 9–58). The concentrations of factors known to influence GH synthesis and secretion, insulin‐like growth factor I, thyroxine, testosterone and oestradiol, varied little over the year of study

conclusionsThese data demonstrate that group data are reproducible in terms of oscillatory activity and the amount of GH secreted and that 24‐h GH profiles should be used predominantly for analysing group data. The varlabllity between individual profiles limits their value in the investigation of children with growth failure and suspected GH insufficiency