bluuebunny/crossref_metadata_2025 huggingface dataset:
EFFECT OF HIGH DOSE EXOGENOUS OESTROGEN ON MIDCYCLE LUTEINIZING HORMONE SURGE IN HUMAN SPONTANEOUS CYCLES
Authors: MESSINIS I. E. , TEMPLETON A.
Published: March 2008

Induction of multiple follicular development in women results in supraphysiological serum oestradiol (E2) levels and marked reduction of the endogenous LH surge. To examine whether high serum E2 levels at midcycle can suppress gonadotrophin secretion during the LH surge, five normally ovulating women were given an intramuscular injection of 10 mg oestradiol benzoate 6‐42 h before the expected endogenous LH surge. The results were compared with the preceding untreated control cycle. Serum E2 levels at the onset of the LH surge (mean ± SEM) were significantly higher in the oestrogen‐treated cycles (13 600 ± 1963 pmol/1) than in the control cycles(1012±116pmol/l)(P<0.001). The duration of the LH surge (64‐8 ± 2‐2 h) and LH peak levels (136 ± 9‐6 mIU/ ml) in the oestrogen treated cycles were similar to those in the control cycles (61.2 ± 3‐9 and 119 ± 9‐4 mlU/ml respectively) (mean ± SEM). The cycle day on which the LH surge started and the size of the dominant follicle, as assessed by ultrasound, did not differ significantly between the two groups of cycles. These results show that in spontaneous cycles the endogenous LH surge is neither reduced nor amplified by the induction of supraphysiological serum E2 levels during the immediate preovulatory stage.
RESPONSE OF PITUITARY‐ADRENAL AXIS TO CORTICOTROPHIN RELEASING HORMONE IN PATIENTS WITH CUSHING'S DISEASE BEFORE AND AFTER KETOCONAZOLE TREATMENT
Authors: BOSCARO M. , SONINO N. , RAMPAZZO A. , MANTERO F.
Published: March 2008

Ketoconazole is an antimycotic agent and a potent inhibitor of gonadal and adrenal steroidogenesis. It has been used successfully as a palliative treatment of Cushing's syndrome due to its ability to lower Cortisol production. However, the effects of ketoconazole on ACTH and aldosterone secretion have not yet been clarified. We evaluated the effect of ovine corticotrophin releasing hormone (oCRH) (100 μg bolus) on plasma ACTH, Cortisol and aldosterone levels in six patients with Cushing's disease before and after 4 to 6 weeks of treatment with ketoconazole 600 mg/d. Before treatment, plasma Cortisol levels were high and significantly increased after oCRH stimulation in all cases, while various patterns of aldosterone secretion were observed. Patients with higher levels showed a greater response to oCRH, while two patients with very low aldosterone showed no response. ACTH showed a marked rise after oCRH administration in all patients with a maximum peak at 30‐45 min. After ketoconazole treatment, both plasma Cortisol and aldosterone were lowered and their response to oCRH was impaired. Basal ACTH levels were increased in four patients and ACTH response to oCRH was enhanced in all, compared to pretreatment. These findings confirm the inhibitory action of ketoconazole on basal and stimulated Cortisol secretion. A similar inhibition affected aldosterone production, indicating that ketoconazole also interferes with the mineralocorti‐coid pathway. The enhanced response of ACTH to oCRH after the administration of ketoconazole argues against an inhibitory effect of this agent at the pituitary level and might best be explained by reduced negative Cortisol feedback.
A STUDY OF BETA‐CELL FUNCTION AFTER GLUCAGON STIMULATION IN THALASSAEMIA MAJOR TREATED BY HIGH TRANSFUSION PROGRAMME
Authors: LIVADAS D. P. , ECONOMOU E. , SOFRONIADOU K. , FOTIADOU‐PAPPA H. , VAN MELLE G. D. , And E. TEMLER , FELBER J. P.
Published: March 2008

An increased incidence of diabetes mellitus and glucose intolerance has been reported in thalassaemia major treated with a high transfusion programme (HTP). To investigate beta‐cell function, serum immunoreactive insulin (IRI), C‐peptide (CP) and glucose were measured fasting and at 3, 6 and 10 min after i.v. administration of 1 mg glucagon in 20 thalassaemia patients treated by many transfusions and in nine healthy control subjects. Fasting C‐peptide concentrations (mean ± SEM) were higher in the thalassaemic group (2 15 ± 0 17 ng/ml) than in the controls (1 41 ± 0 13 ng/ml). After stimulation with glucagon, C‐peptide concentrations were consistently higher (P<0 01) by approximately 50% in the thalassaemic than in the control group (5‐29 ± 0‐31 vs 3 36 ± 0 21 ng/ml, at 3 min; 5 22 ± 0 30 vs 3 53 + 0 21 ng/ml at 6 min and 4 69 ± 0 27 vs 3 30 ± 0 17 ng/ml after 10 min). Plasma IRI concentrations increased in both groups after glucagon stimulation but were not significantly different. The glucose values were approximately 15% higher at each sampling time in the thalassaemic group than those of the normal subjects. It is concluded that disturbances in carbohydrate metabolism in thalassaemia major treated with HTP are the consequence of hepatic cirrhosis which accompanies secondary haemosiderosis, and possibly iron deposition in the beta‐cells of the pancreas.
PLASMA IMMUNOREACTIVE GHRH AND SERUM GH CONCENTRATIONS FOLLOWING PULSATILE GHRH 1‐40 ADMINISTRATION IN GH DEFICIENT CHILDREN
Authors: SMITH P. J. , PRINGLE P. J. , BROOK C. G. D. , SCHULSTER D. , RAFFERTY B.
Published: March 2008

We have studied the clearance from plasma of immunoreactive growth hormone releasing hormone 1‐40 (IR‐GHRH) following intravenous (i.v.) and subcutaneous (s.c.) administration and the relationship between exogenous plasma IR‐GHRH concentrations and GH secretion in five GH insufficient children receiving long term nocturnal pulsatile GHRH 1‐40. The i.v. studies with GHRH 140 1μg/kg demonstrated a distribution half life (t1/2) of 3‐9 (SD 0‐9) min and an elimination t1/2 of 53‐1 (SD 3‐2) min. In the s.c. studies the elimination phase was similar to the i.v. results but the transit time to the GHRH peak was slower than the i.v. distribuition t1/2 9‐9 (SD 3‐6) min. These characteristics were maintained during successive pulses of subcutaneous GHRH. The mean IR‐GHRH peaks following s.c. GHRH 1‐40 administration of 1 μg/kg and 2 μg/kg were 37‐ and 18‐fold lower respectively than the mean IR‐GHRH peak observed after the i.v. 1 μg/kg bolus study. A significant correlation was shown between peak plasma IR‐GHRH and serum GH concentrations during the s.c. (r= 0‐75) but not the i.v. studies. Pulsatile GHRH administration has been shown to stimulate GH secretion and growth acceleration in GH insufficient children. Knowledge of the relationship between GHRH 1^40 absorption from the subcutaneous site and GH secretion is important for the development of an optimal GHRH treatment regimen in GH insufficient children.
AUTOIMMUNE POLYGLANDULAR SYNDROME, PRIMARY EMPTY SELLA, AND ACUTE LYMPHOCYTIC LEUKAEMIA
Authors: DE ROSA G. , CASA S. DELLA , CORSELLO S. M. , And L. CECCHINI , CALLA C.
Published: March 2008

A young man is reported with an autoimmune polyglandular syndrome (APS) characterized by Addison's disease, primary hypothyroidism, primary hypogonadism, vitiligo, associated with primary empty sella and partial impairment of pituitary hormone secretion. Two years later the patient showed a null cell type acute lymphocytic leukaemia, immediately after surgery for an inguinal hernia. Pathogenetic mechanisms are postulated on the basis of HLA studies and lymphocytic typing.
DOES TESTOSTERONE INFLUENCE THE POST‐STIMULATORY LEVELS OF CALCITONIN IN NORMAL MEN?
Authors: GARCIA‐AMEIJEIRAS A. , DE LA TORRE W. , RODRIGUEZ‐ESPINOSA J. , PEREZ‐PEREZand A. , DE LEIVA A.
Published: March 2008

We have analysed the sex difference of calcitonin (CT) levels after combined stimulation with calcium and pentagastrine (Ca‐PG) in the normal population, and the relationshp of the post‐stimulatory CT levels with free testosterone (FT). We have also studied the correlation between CT values and the anthropometric parameters, body mass index (BMI) and body surface area (BS), as well as the relationship between CT levels and calcium. A positive and statistically significant correlation was found between post‐stimulatory CT and the increment over the base‐line of CT and basal FT, and with the anthropometric parameters. However, the increment of CT and the peak values of CT did not have any significant correlation with the Ca levels (basal or post‐stimulation). We conclude that the enhanced CT response found in normal men compared to normal women is at least partially determined by the higher testosterone levels found among normal men.
INVESTIGATION OF THE CRITERIA FOR ASSESSING THE OUTCOME OF TREATMENT IN ACROMEGALY
Authors: LINDHOLM J. , GIWERCMAN B. , GIWERCMAN A. , ASTRUP J. , And P. BJERRE , SKAKKEBÆK N. E.
Published: March 2008

The outcome of treatment in acromegaly is usually assessed by measuring plasma concentrations of growth hormone (GH) – either basal spontaneous levels or during hyperglycaemia. There is no consensus on how cure should be defined. Many studies have considered basal plasma growth hormone concentrations below 20 mU/1 (10 ng/ml) as proof of cure, although some recent studies have applied lower values. At present a limit of 10 mU/1 (5 ng/ml) seems to be accepted as evidence of cure. We have studied 28 acromegalic patients after transsphenoidal adenomectomy. Plasma GH concentrations (basal and during hyperglycaemia) as well as plasma somatomedin C (SMC) concentrations were measured and compared to the clinical symptoms. There was a close correlation between plasma GH and SMC concentrations (except when plasma GH levels were low) and between the clinical assessment and SMC concentrations. Very low plasma GH levels (< 1 mU/1 or 0‐5 ng/ml) were associated with normal SMC values and clinical cure, high GH levels (> 10 mU/1 or 5 ng/ml) with elevated SMC levels and persisting acromegaly. Moderately elevated plasma GH concentrations (1.0‐9‐6 mU/1) did not allow any conclusions on the outcome of treatment as assessed from SMC determinations and clinical evaluation. It is concluded that the usual criteria for cure in acromegaly may not be sufficiently strict.
THE RELATIONSHIP BETWEEN HEIGHT VELOCITY AND GROWTH HORMONE SECRETION IN SHORT PREPUBERTAL CHILDREN
Authors: HINDMARSH P. , SMITH P. J. , BROOK C. G. D. , MATTHEWS D. R.
Published: March 2008

We have performed 24 h growth hormone (GH) profiles in 50 short prepubertal children aged between 5.2 and 12‐9 years, growing with height velocity standard deviation scores (SDS) between 0.4 and ‐3.9. There was an asymptotic relationship between height velocity and spontaneous G H secretion described by the equation: height velocity SDS = A – B(e cx), where A B and C are constants and x is a measure of spontaneous G H secretion. We considered G H pulse amplitude to be the better description of spontaneous G H secretion as duration of the G H pulse (the time component of area under the curve) contributed little to the relationship between height velocity and area under the pulse. The distribution of G H secretion was continuous and there was no dividing point between G H insufficiency and sufficiency. Similar overlap was observed when the results of G H responses to insulin induced hypoglycaemia were considered; 14% of slowly growing children (height velocity S D S < –0‐8), had a response >15mU/l. Likewise serum I G F‐I concentrations could not clearly separate slowly growing children from normal individuals. We conclude that height velocity, which ultimately determines height achieved, is controlled predominately by G H pulse amplitude. The findings suggest that short normal children growing along or parallel to the third height centile could be made to grow faster by the administration of exogenous G H.
SOMATOMEDIN‐C/INSULIN‐LIKE GROWTH FACTOR‐1 IN INFANTS WITH CONGENITAL HYPOTHYROIDISM DURING THE FIRST WEEK OF LIFE
Authors: MITCHELL M. L. , HERMOS R. J. , MOSES A. C.
Published: March 2008

Levels of somatomedin‐C/insulin‐like growth factor‐1 (Sm‐C/IGF‐1) were determined in whole blood collected on filter paper from 41 newborns with congenital hypothyroidism and 183 full‐term neonates with normal thyroid function. The mean Sm‐C/IGF‐1 value of the untreated hypothyroid infants (0‐10 U/ml) was virtually identical with that of the normal controls (0‐11 U/ml). We are unable to confirm earlier findings of others that Sm‐C/IGF‐1 concentrations are lower in hypothyroid newborns than in normal infants.
VARIABILITY IN PRODUCTION and IMMUNOREACTIVITY OF IN‐VITRO SECRETED HUMAN THYROGLOBULIN
Authors: FELDMAN A. , SINGH A. , DIAMOND E. J. , SCHWARTZ A.E. , FRIEDMAN E. W. , DAVIES T. F.
Published: March 2008

We examined basal and bTSH‐stimulated human thyreoglobulin (hTg) secretion by autologous normal and abnormal (benign and malignant) human thyroid cell monolayers. Basal and bTSH‐stimulated hTg secretion was highly variable and ranged from 50‐700 ng/ml/105 cells over a 6 day period. All normal and benign ‘non‐functioning’ adenoma cells demonstrated a dose and time related stimulation of hTg secretion in response to bTSH. Comparison of hTG secretion by autologous normal and abnormal cells showed that in six of eight pairs, the normal thyroid cells had a greater output of hTg than the benign adenoma cells in contrast to our previous studies using non‐autologous cells. Malignant thyroid cell hTg production was less predictable than that obtained with normal and benign thyroid cells varying from absent to normal responses to bTSH. Characterization studies of the secreted hTg showed no difference between normal, benign and malignant thyroid cell hTg with reference to molecular weight. However, hTg secreted in vitro was non‐iodinated and had a marked reduction (up to 200‐fold) in immunoreactivity assessed by both polyclonal and monoclonal antibodies to hTg when compared to hTg standard prepared from intact thyroid tissue (which had 4.58 μg iodine/mg). This reduction in hTg immunoreactivity was greatest for hTg secreted by malignant thyroid cells. These data demonstrate the wide variability in the hTg secretory capacity of human thyroid cell monolayers and indicate, when compared to autologous normal cells, that abnormal human thyroid epithelial cells may be relatively deficient in their ability to secrete hTg in vitro. There were also qualitative differences in the immunoreactivity, and iodine content, of in‐vitro secreted hTg. These observations suggest that there may be much greater heterogeneity in hTg secreted in vitro than previously realized, perhaps secondary to differences in iodine content and/or degree of glycosylation.
IODIDE ADMINISTRATION ENHANCES THYROTROPHIN RESPONSIVENESS TO THYROTROPHIN‐RELEASING HORMONE DURING FASTING: EVIDENCE FOR NORMAL PITUITARY FEEDBACK REGULATION
Authors: BURMAN K. D. , SMALLRIDGE R. C. , BURGE J. R. , O'BRIAN J. T. , WARTOFSKY L.
Published: March 2008

Short‐term fasting in humans is associated with diminished Δ TSH to TRH. The purposes of the present study were to reassess basal TSH levels and TRH responsiveness during fasting utilizing a sensitive radioimmunoassay (RIA: sensitivity 0.3 μU/ml; normal range 0.66‐2.98 μU/ml) and to determine if normal feedback regulation is maintained during the fasting state. Eight control subjects (C) and six iodide‐treated (I) subjects (262 mg/d) were studied in the fed state and on day 10 of fasting. T3, T4, and TSH were measured by RIA, and free T4 and free T3 by equilibrium dialysis. Basal serum TSH levels in the control group were 2.0 ± 0.3 μU/ml (mean ± SEM) in the fed state and increased to 14.7 ± 3.5 μU/ml 20 min after TRH administration. The fasting basal TSH level of 1.6 ± 0.3 μU/ml was significantly decreased (P < 0.01) compared to control, as was the level of 8.8 ± 2.3 μU/ml (P < 0.01) obtained 20 min after TRH. In the iodide‐treated group the basal TSH level was 1.4 ± 0.2 μU/ml during feeding which increased (P < 0.025) to 2.9 ± 0.7 μU/ml during fasting; the TSH value 20 min after TRH was 12.6 ± 2.5 μU/ml while feeding and 17.3 ± 2.9 μU/ml while fasting. Free and total T3 decreased during fasting in both groups. Total T4 was unchanged between the fed and fasted periods in the two groups. That free T4 (pmol/l) rose significantly during fasting (28.7 ± 1.3 vs 33.8 ± 1.3, P < 0.01) in the control group but was unaltered in the iodide‐treated group (23.8 ± 1.3 vs 26.2 ± 2.5) suggests an aetiological role for free T4 in blunting TSH responsiveness. The abolition by iodide of the fasting‐related changes in TSH further suggests that normal pituitary feedback regulation is maintained during fasting.
HYPOTHALAMIC FUNCTION IN WOMEN WITH SECONDARY HYPOGONADISM AND UNRESPONSIVE TO CLOMIPHENE THERAPY
Authors: WILLIAMS C. A. VAUGHAN
Published: March 2008

Seven women with secondary hypogonadism who had been previously unresponsive to two 5‐d courses of clomiphene citrate, were treated with clomiphene citrate 100 mg daily for 10 d. LH and FSH concentrations were measured in serum collected at 15‐min intervals for 5 h before and on the 10th day of treatment and oestradiol was measured in the first two samples on each day. Four women responded with an increase in the amplitude of LH pulses and in mean LH values and in three there was a marked increase in serum oestradiol concentrations. Three women who showed no gonadotropin response were subsequently unresponsive to pulsatile LHRH therapy. These preliminary data are consistent with the hypothesis that hypothalamic hypogonadotrophism may result from hypersensitivity of the hypothalamus to oestrogen negative feedback and that the hypothalamic potential for secretion of LHRH is unimpaired. Prolonged treatment with clomiphene may provide a simple test of hypothalamic function in women with normal pituitary function.
CLINICAL EVALUATION OF A TWO‐SITE IMMUNORADIOMETRIC ASSAY FOR ADRENOCORTICOTROPIC IN UNEXTRACTED HUMAN PLASMA USING MONOCLONAL ANTIBODIES
Authors: WHITE A. , SMITH H. , HOADLEY M. , DOBSON S. H. , RATCLIFFE J. G.
Published: March 2008

We have developed a sensitive two‐site immunoradiometric assay (IRMA) for intact ACTH and its precursors, pro‐opiomelanocortin and 22 kDa peptide in unextracted human plasma. The assay uses two monoclonal antibodies. Antibody 1A12, specific for ACTH 10–18, is radiolabelled and antibody 2A3 specific for the C‐terminal region (ACTH 24–39), is coupled to Sephacryl S300 for the solid‐phase. Samples are incubated for 18 h with labelled antibody followed by 2 h with solid‐phase antibody. Separation employs the sucrose layering technique. Using human pituitary ACTH 1–39 (code 74/555) in diluent containing 10% horse serum to standardize the assay, the sensitivity (upper 99% confidence limit of zero standard) is 3.5 ± 0.8 ng/l (n= 7). The mean coefficient of variation is 5.9% within‐assay and 6.7% between‐assay and is less than 10% between 22 and >5000 ng/l. Mean recovery of ACTH 1–39 added to dexamethasone‐suppressed human plasma is 109% and endogenous ACTH behaves indistinguishably from standard ACTH on dilution. In normal subjects, mean plasma ACTH levels are 30 ng/l at 0730 h, and 15 ng/1 at 1630 h at rest. ACTH concentrations are between 60 and 330 ng/l, 8–10.5 h after metyrapone (2 g orally at 2300 h), between 140 and 320 ng/1, 30–60 min after insulin‐induced hypoglycaemia, and < 4 ng/1, 8 h after dexamethasone (1.5 mg orally at 2300 h). In a range of pathological conditions ACTH concentrations accurately reflect the disorders of the pituitary‐adrenal axis. Endogenous ACTH immunoactivity is stable in vitro at 22°C for at least 1 h in whole blood and at least 4 h in plasma. It is concluded that this two‐site IRMA for ACTH in unextracted plasma offers a reliable assay for clinical purposes.
EFFECTIVE LONG‐TERM TREATMENT OF ACROMEGALY WITH A LONG‐ACTING SOMATOSTATIN ANALOGUE (SMS 201–995)
Authors: SANDLER L. M. , BURRIN J. M. , WILLIAMS G. , JOPLIN G. F. , CARR D. H. , BLOOM S. R.
Published: March 2008

Nine acromegalic patients, six previously untreated, were studied before and after 3–15 months of treatment with a long‐acting somatostatin analogue (SMS 201–995; 100 μg injected s.c. three times daily). During treatment, the mean (± SEM) 24‐h GH concentration fell from 82 ± 22 mIU/1 to 33 ± 7 mIU/1 (P < 0.001), and eight of the 9 patients showed a reduction of at least 50% in GH levels in the fasting state and/or during a glucose tolerance test. There was a significant 30% fall in serum concentrations of insulin‐like growth factor (IGF‐1) with SMS. All patients showed rapid clinical improvement, with diminished sweating and headaches, and reduction in skinfold thickness, hand volumes and finger size. Computer tomographic scanning of the pituitary in eight patients showed no change in the size of the pituitary tumour during treatment. The only side‐effects of SMS noted were transient abdominal discomfort and loose stools in two patients on initiating therapy. Although fasting plasma glucose concentration did not change during treatment (5.4 ± 0.3 vs 5.5 ± 0.3 mmol/l), mean 24‐h plasma glucose concentration was higher with SMS (6.6 ± 0.5 mmol/l vs 6.0 ± 0.4 mmol/l; P < 0.02). Mean 24‐h plasma insulin concentration fell from 87 ± 11 mIU/1 before treatment to 39 ± 6 mIU/1 during treatment (P < 0005). No change in other anterior pituitary hormones was observed. SMS appears to be a safe, rapidly effective, long‐term treatment for certain patients with acromegaly.
CHANGES IN THE RESPONSIVENESS OF LUTEINIZING HORMONE SECRETION TO INFUSION OF THE OPIOID ANTAGONIST NALOXONE THROUGHOUT MALE SEXUAL MATURATION
Authors: ULLOA‐AGUIRRE A. , MENDEZ J. P. , GONZALEZ‐CASTILLO A. , CARRANZA‐LIRA S. , GARZA‐FLORES J. , PERES‐PALACIOS G.
Published: March 2008

The present study investigated the time of male sexual maturation during which hypothalamic inhibitory opioid activity can be detected. Normal prepubertal (Tanner stage G 1 (Ts‐G1) (n=4)), early pubertal (Ts‐G2 (n=5)), pubertal (Ts‐G3 (n=4), and Ts‐G4 (n=2)) and adult subjects (Ts‐G5 (n=4)) receives a rapid infusion of the selective opiate antagonist nalocone (NAL) (20 mg over 10 min). LH secretion was assessed by frequent (every 10 min for 2 h) venous sampling before and after administration of the opiate blocker, as well as by the LH response to exogenous GnRH. All but one (a Ts‐G2 subject) pubertal boys showed a prompt and sustained increase in serum LH concentrations after NAL administration, as disclosed by the areas under the LH curve (aLHc) calculated from samples obtained before and after NAL infusion (aLHc in four Ts‐G2 responders, 162·20 (mean ± SEM) vs 314·56 mIU/ml/min before and after NAL respectively, P>0·025; Ts‐G3, 227·35 vs 362·56 mIU/ml/min, P>0·025; Ts‐G4 and Ts‐G5, 432·77 vs 687·91 mIU/ml/min, P>0·05). In contrast, none of the prepubertal children had significant changes in LH secretion after the NAL challenge (154·17 vs 154·9 mIU/ml/min). Although all NAL responders exhibited serum testosterone (T) levels above 5 nmol/1, a positive correlation between individual T values and magnitude of LH responses to NAL was not found. All subjects had significant serum LH increments after GnRH administration. In a second series of studies, additional groups of Ts‐G1 subjects were primed during 5 days either with GnRH alone or with GnRH plus sex steroids (ethinyl oestradiol 12·5 μg/12 h or testosterone enanthate 1·8 mg/kg body weight (single dose)), before NAL administration, to investigate whether hypothalamic opioid activity might be unmasked by additional sex steroids. None of the priming schemes significantly modified the pituitary LH responses to NAL infusion (GnRH‐primed group, 145 & 48 us 139 f 43 mIU/ml/min before and after NAL, respectively; GnRH plus ethinyl oestradiol‐primed group, 124 f 42 us 107 f 34 mIU/ml/min; GnRH plus testosterone enanthate‐primed group, 64 f 10 us 57 f 24 mIU/ml/min). This study suggests that the development and/or maturation of the opioid control of LH secretion is temporally related with the onset of puberty. This surge of opioid inhibitory signals at early puberty might be reflecting a further stage of hypothalamic maturation and the re‐establishment of an additional biological system for the control of the maturing reproductive functions.
REVERSIBLE TRABECULAR BONE DENSITY LOSS FOLLOWING INDUCED HYPO‐OESTROGENISM WITH THE GnRH ANALOGUE BUSERELIN IN PREMENOPAUSAL WOMEN
Authors: MATTA W. H. , SHAW R. W. , HESP R. , EVANS R.
Published: March 2008

Thirteen premenopausal women who each received 400 μg three times daily of intranasal buserelin for 6 months as treatment for endometriosis participated in this study. Cortical bone mineral content (BMC) in the mid‐shaft of the right femur measured by dual photon densitometry, and trabecular bone density (TBD) in the lumbar vertebrae (L2–4) measured by quantitative computed tomography, were evaluated prior to, at the end of 6 months’ buserelin treatment and after 6 months off treatment. Significant hypo‐oestrogenism (P>0·001) was sustained during the period on treatment. The significant reduction in the mean lumbar vertebral TBD of 5·9% (P>0·02) observed at the end of treatment with buserelin was regained within 6 months following resumption of ovarian activity. There was a marginally significant (P=0·07) reduction of only 0·9% in the mean femoral cortical BMC at the end of treatment. Six months after the end of treatment cortical BMC values were not significantly different from the pretreatment values. There was no significant correlation between the degree of hypo‐oestrogenism and the corresponding change in vertebral TBD, (r=0·20; P>0·10).
HYPOTHALAMIC HYPOGONADISM FOLLOWING MAJOR HEAD INJURY
Authors: CLARK J. D. A. , RAGGATT P. R. , EDWARDS O. M.
Published: March 2008

Endocrine studies, using the four hypothalamic releasing hormones, gonadotrophin releasing hormone, thyrotrophin releasing hormone, corticotrophin releasing hormone and growth hormone releasing hormone, were performed in 33 males after admission with a major head injury. The test was repeated 7 days later in all 33 patients and after 3–6 months in 21 patients. All patients had a period of unconsciousness followed by post‐traumatic amnesia of greater than 24 h. The results obtained from investigating the gonadal axis are reported in this paper. The levels of total and free testosterone, basal FSH and basal LH fell significantly during the first 3 days after injury, when the LH and FSH responses to GnRH achieved their highest peak levels. This hormone pattern has not previously been reported in the gonadal axis and may be a consequence of hypothalamic dysfunction. The severity of the injury was negatively correlated to the testosterone concentration on admission and to the basal and peak FSH concentrations 1 week later. Persistent hypogonadism was found in five of the 21 patients retested after 3–6 months, with low testosterone concentrations and three continued to have an exaggerated LH response to GnRH. Thus major head injury frequently results in hypogonadism shortly after injury, with an increased gonadotrophin response to GnRH. In addition, a substantial minority of patients continue to be hypogonadal after 3–6 months. In view of these findings we strongly suggest that all patients should be endocrinologically assessed at intervals following severe head injury.
CHANGES IN THE QUALITATIVE AND QUANTITATIVE SECRETION OF LUTEINIZING HORMONE (LH) FOLLOWING ORCHIDECTOMY IN MAN
Authors: TSATSOULIS A. , SHALET S. M. , ROBERTSON W. R.
Published: March 2008

The effect of orchidectomy and thus withdrawal of testicular hormones on the biological and immunological properties of plasma LH was studied. Plasma samples were obtained from five men (mean age 71, range 65–81 years) with advanced carcinoma of the prostate, before orchidectomy and 1, 4, 8 and 16 weeks after surgery. LH bioactivity was estimated by a mouse Leydig cell bioassay and immunoreactivity by radioimmunoassay, using the same human pituitary LH standard 68/40. FSH and testosterone were measured by radioimmunoassay. Similar baseline data were obtained from a group (n = 17) of normal adult men (26, 19–36 years).

Baseline bioactive (40 IU/l, median) and immunoreactive (10.8 IU/l) LH levels in the patients were higher (p>0.01) than in the controls (15.1 and 5.7 IU/l respectively), but bioactive to immunoreactive (B:I) LH ratios (3.4 ± 0.2 versus 2.8 ± 0.7) and testosterone levels (15.3 vs 18.7 nmol/l) were no different, consistent with compensated Leydig cell failure in the elderly men. After orchidectomy there was a greater increase in immunoreactive (46.6 IU/1 at 16 weeks) than bioactive (80.3 IU/l) LH levels i.e. a fourfold vs two fold increase from baseline values. Consequently the B:I LH ratio decreased significantly (1.8 ± 0.4 at 16 weeks) from the baseline ratio (P> 0.0001) and that of the controls (P> 0.01).

These data indicate that acute withdrawal of testicular sex steroids results not only in quantitative change in LH secretion but also in qualitative change that decreases the biopotency of the LH molecules.
SEX HORMONE BINDING GLOBULIN IN SALIVA
Authors: SELBY C. , LOBB P. A. , JEFFCOATE W. J.
Published: March 2008

Measurement of salivary steroid hormone concentrations has frequently been advocated as a convenient alternative to plasma measurements. This is partly due to the belief that salivary steroid concentrations are a reliable reflection of the plasma free hormone level, a belief reinforced by earlier inability to demonstrate the presence of significant quantities of steroid binding proteins. Recent reports confirm that such quantities of these proteins are present in saliva and that they retain their steroid binding activity. We have measured sex hormone binding globulin (SHBG) and albumin in saliva from 14 men, 21 non‐pregnant women and 36 pregnant women. No differences in the concentration of salivary albumin was evident in any of the groups studied whereas a significant difference in the concentration of SHBG was evident between men and non‐pregnant women, and non‐pregnant and pregnant individuals. Although much lower, salivary SHBG and albumin concentrations broadly reflect those found in plasma. Furthermore, a highly significant correlation existed between salivary SHBG and albumin concentrations in all groups studied. It now seems generally accepted that the albumin present in saliva arises from contamination by either traces of blood or gingival fluids. The close relationship between the concentrations of albumin and SHBG in saliva suggests that they both gain entry by a similar route. Furthermore, their presence may significantly influence the concentration of certain steroids in saliva, and this may explain the occasional failure of salivary steroid concentrations to accurately reflect the plasma free hormone levels.
GROWTH HORMONE RESPONSE TO GROWTH HORMONE RELEASING FACTOR IN DIABETIC MEN
Authors: KOPELMAN P. G. , MASON A. C. , NOONAN K. , MONSON J. P.
Published: March 2008

Increased plasma concentrations of growth hormone (GH) are reported in diabetes and it is suggested that this may be important in the development of complications. We have investigated fasting GH levels and the response to 100 μg i.v. growth hormone releasing factor, GRF(1‐29)NH2, in age‐matched men: six normal weight controls, six obese controls, six insulin‐dependent diabetics, six normal weight non‐insulin dependent diabetics and six obese non‐insulin dependent diabetics. None of the diabetic men had clinical evidence of diabetic complications. Fasting GH values did not differ significantly between the five groups. The peak GH response to GRF was similar in the controls, insulin‐dependent diabetics (IDD) and non‐insulin dependent (NIDD) normal weight diabetics (mean peak±SEM: controls 25.5 ± 5 mU/1, IDD 26‐5 + 6 mU/1, NIDD 19.7 ± 5 mU/1) but was significantly reduced in the two obese groups (obese 6.4 ± 3mU/l, obese diabetics 4.5 ± 1 mU/1, P<001). This impairment of GH secretion was unrelated to either fasting plasma insulin or glucose concentration. We conclude that our results do not confirm the previous reports of abnormal GH secretion in diabetes but do demonstrate a markedly impaired GH response to GRF to be a feature of obesity.
IODINE IN MILK AND THE INCIDENCE OF THYROTOXICOSIS IN ENGLAND
Authors: PHILLIPS D. I. W. , NELSON M. , BARKER D. J. P. , MORRIS J. A. , WOOD T. J.
Published: March 2008

Because iodine is added to cattle feed, milk and dairy products have become a major source of dietary iodine in Britain. The mean iodine concentrations of milk supplied to seven towns in England were measured each month throughout 1 year. Values were more than twice those recorded 20 years ago. There were large differences between the towns, with average annual concentrations ranging from 130 to 200 μ/l. Within the towns there were up to four‐fold variations between the peak values in February/March and lowest values in June. The similarity between the monthly variations in milk iodine and seasonality in the onset of thyrotoxicosis suggests that iodine concentrations in milk and dairy products may now have reached harmful levels. Control of high winter levels in areas of Britain which were previously iodine deficient may now be necessary.
THE MECHANISM OF THE ADOLESCENT GROWTH SPURT INDUCED BY LOW DOSE PULSATILE GnRH TREATMENT
Authors: STANHOPE R. , PRINGLE P. J. , BROOK C. G. D.
Published: March 2008

We have used GnRH administered in a pulsatile fashion to treat 26 patients (12M:14F) with delayed puberty. Treatment was for a mean of 1.05 years (range, 0.3‐1.6). Mean age at the onset of treatment was 16.4 years in the girls (range, 12.7‐28.2) and 15.8 years in the boys (range, 13.8‐17.8). At different stages of sexual maturation, overnight serum samples for growth hormone (GH) were taken at 15 min intervals between 2000 h and 0600 h. The girls had a peak growth velocity which occurred between breast stages 2 and stage 3 (B2/3). GH secretion (both sum of the GH peaks and area under the GH pulse) increased at B2 and reached a peak at B3. Growth acceleration in the boys started at the attainment of a 9‐10 ml testicular volume and reached a peak at 11‐15 ml. The boys demonstrated an initial fall in GH secretion with the onset of treatment until the attainment of 9‐10 ml testicular volume; peak GH secretion occurred at the attainment of 11‐12 ml testicular volume. There was no change in GH pulse frequency during treatment in either sex. These observations and the maintenance of the normal relationship of the growth spurts to the appearance of secondary sexual characteristics are relevant to the mechanisms and timing of the adolescent growth spurts in normal girls and boys.
THE RESPONSE OF PLASMA OXYTOCIN TO SURGICAL STRESS
Authors: NUSSEY S. S. , PAGE S. R. , ANG V. T. Y. , JENKINS J. S.
Published: March 2008

Recent evidence suggests that oxytocin (OXT) and arginine vasopressin (AVP) are involved in the response to stress. We have examined the changes in peripheral plasma OXT during abdominal surgery Hhin eight patients (six males, two female; ages 60‐82 years) undergoing hemicolectomy and compared the results with those for AVP to the same stimulus. There was no significant change in systolic blood pressure, blood haematocrit or plasma sodium, osmolality or glucose. AVP rose significantly after premedication (from 1‐8 ±0‐3 pmol/1 to 5‐5 ±2‐3 pmol/1; P<0‐05) but the greatest increase (to 35‐8 ±6‐6 pmol/1) occurred after gut manipulation. Plasma OXT concentrations fell slightly with premedication (from 5‐7 ± 2‐0 pmol/1 to 3‐3 ± 0‐9 pmol/1; .P<0‐05) but rose markedly (to a peak of 33‐5 ± 11‐4 pmol/1) after gut manipulation. The data support the concept that OXT like AVP may play a role in the neuroendocrine response to surgery. The stimulus to OXT release and its function remain to be determined.
RESPONSES OF PLASMA OXYTOCIN AND ARGININE VASOPRESSIN TO NAUSEA INDUCED BY APOMORPHINE AND IPECACUANHA
Authors: NUSSEY S. S. , HAWTHORN J. , PAGE S. R. , ANG V. T. Y. , JENKINS J. S.
Published: March 2008

Apomorphine, a centrally‐acting emetic, was administered subcutaneously (50 /μg/kg) to nine normal subjects (four male, five female; aged 22‐36 years) and four patients with idiopathic diabetes insipidus (DI) (one male, three female; aged 24‐49 years). In the normal subjects this stimulus caused nausea (and vomiting in seven of nine) with a latency of 9‐5 ± 0‐9 min which was followed by a large increase in plasma arginine vasopressin (AVP) concentration (from 0‐9 ± 0‐2 pmol/1 to 249 ± 104 pmol/1 at 15 min after the onset of symptoms; mean ± SEM, P<001). There was a small but significant increase in plasma oxytocin (OXT) concentration (from 1‐6 ± 0‐4 pmol/1 to 6‐2 ± 3‐4 pmol/1; P<005). Mean arterial pressure (MAP) fell slightly (from 87±1‐9 mm Hg to 71±4‐4 mm Hg; P < 005) 15 min after the onset of nausea; there was no change in blood haematocrit or plasma osmolality and sodium concentration. In the DI patients apomorphine produced nausea (with vomiting in three of four) with a latency of 100±1 ‐4 min but failed to cause an increase in either plasma AVP or OXT. In the DI patients the fall in MAP did not reach statistical significance (83 ± 4 mm Hg to 71 ± 11 mm Hg); there was also no change in haematocrit, osmolality or sodium concentration. Ipecacuanha, an emetic with both peripheral and central actions, was administered orally to seven normal subjects (three male, four female; aged 22‐36 years) six of whom also underwent apomorphine tests. Nausea followed with a latency of 16‐9 ± 3‐2 min (with vomiting in five of seven). However, despite producing symptoms considered by the subjects to be as severe as those caused by apomorphine there was no increase in plasma AVP or OXT. In contrast to apomorphine, ipecacuanha produced a significant increase in MAP (from 82 ± 2 mm Hg to 11101+7 mm Hg; P<0‐05) and pulse rate (62 ± 3 min‐1 to 76 ± 4 mm‐1; P<0‐05); there was no change in haematocrit, osmolality or sodium concentration.

The results provide evidence that OXT neurones are affected by the pathological process involved in the aetiology of idiopathic DI in some patients. They indicate that while nausea (and vomiting) produce elevations of plasma OXT and AVP these sequelae are not essential to these physiological processes. Finally, we interpret the failure of ipecacuanha‐induced nausea to increase plasma AVP and OXT concentrations as evidence that the neuroendocrine response to nausea, in the human, may depend on the site of action of the emetic stimulus.
A SPECIFIC CARRIER SUBSTANCE FOR HUMAN CORTICOTROPHIN RELEASING FACTOR IN LATE GESTATIONAL MATERNAL PLASMA WHICH COULD MASK THE ACTH‐RELEASING ACTIVITY
Authors: LINTON E. A. , WOLFE C. D. A. , BEHAN D. P. , LOWRY P. J.
Published: March 2008

Late gestational maternal plasma contains a carrier substance for corticotrophin releasing factor (CRF‐41) with a molecular weight in the region of 40000. Using gel chromatography and CRF‐41 immunoradiometric assay (IRMA), we show that binding of the peptide to its plasma carrier can be disrupted by treatment with urea. The binding capacity of the carrier substance is not saturated, since time‐dependent incorporation of synthetic CRF‐41 occurs at 4°C. The carrier substance is also present in normal male plasma. It is specific for human CRF‐41, not binding to ACTH, GnRH, vasopressin or ovine CRF‐41. Most of the high concentration of CRF‐41 in late gestational maternal plasma is bound to the carrier. Dilutions of pooled fractions containing carrier‐bound CRF‐41 after chromatography of maternal plasma had ACTH‐releasing activity as did the synthetic peptide. However, the more concentrated chromatographic fractions at the apex of the carrier‐bound CRF‐41 peak showed reduced bioactivity, indicating that the higher concentrations of carrier in the original maternal plasma could mask the ACTH‐releasing activity of CRF‐41.
GONADOTROPHINS, OESTRADIOL AND PROGESTERONE DURING THE MENSTRUAL CYCLE IN BULIMIA NERVOSA
Authors: PIRKE K. M. , DOGS M. , FICHTER M. M. , TUSCHL R. J.
Published: March 2008

Gonadotrophins and gonadal hormones were studied during the menstrual cycle or during 5 weeks when no cycles occurred in 15 patients who were diagnosed as having bulimia by DSM III criteria. Nine healthy age‐matched women served as controls. Based on plasma oestradiol (E2) values patients were divided into two groups. Group I (n= 8) did not show E2 increases greater than 444 pmol/l indicating that no follicular development took place. Group II showed normal follicular hormone production during the follicular phase but impaired progesterone (P4) levels during the luteal phase. Studies of episodic gonadotrophin secretion during the follicular phase revealed low average LH and FSH values and reduced amplitude but no significant changes of frequency in group I. Our data indicate that impaired follicular maturation as seen in about half of the bulimic patients is caused by impaired gonadotrophin secretion.
HIGHER THAN CONVENTIONAL DOSES OF CARBIMAZOLE IN THE TREATMENT OF THYROTOXICOSIS
Authors: O'MALLEY B. P. , ROSENTHAL F. D. , NORTHOVER B. J. , JENNINGS P. E. , WOODS K. L.
Published: March 2008

In order to ascertain whether higher than conventional doses of carbimazole achieve more rapid control of thyrotoxicosis, 30 thyrotoxic patients were alternately allocated into two groups, group 1 (15 subjects) receiving a conventional starting dose of 45 mg orally daily and group 2(15 subjects) a dose of 100 mg orally. In addition to weekly estimations of serum T4, T3, free T4, free T3 and TSH, the systolic time intervals ratio (STI), a measure of left ventricular contractility, was calculated as an accurate measure of peripheral thyroid hormone activity, the study end‐point being a normal STI (0.26‐0.32). None of the individuals studied experienced side‐effects during the study period. Mean pre‐treatment STI values for the two treatment groups were the same at entry (0.20). The mean recovery times for STI was 4‐4 weeks (SE 0.3) in the high dose group and 5.9 weeks (SE 0.4) in the low dose group (P=0.0037). There was a definite trend towards a shorter recovery time for free T3 in the higher dose group (P=0.057) but no apparent differences for T4, T3 and free T4. Higher than conventional doses of carbimazole may be advisable in the initial treatment of severe thyrotoxicosis.
HYPERMINERALOCORTICISM WITHOUT ELEVATION OF PLASMA ALDOSTERONE: DEOXYCORTICOSTERONE‐PRODUCING ADRENAL ADENOMA AND HYPERPLASIA
Authors: ISHIKAWA SAN‐E , SAITO TOSHIKAZU , KANEKO KENZO , OKADA KOJI , FUKUDA SHUICHI , KUZUYA TAKESHI
Published: March 2008

Two female patients were admitted for evaluation of hypertension and hypokalaemia. Plasma renin activity was suppressed and plasma aldosterone levels were within the normal value in a 52‐year‐old woman and below the normal value in the other patient, a 62‐year‐old woman. Plasma 11 ‐deoxycorticosterone (DOC) levels were as high as 113 and 1–47 nmol/1, respectively. Adrenal scintigram and abdominal CT scan clearly showed a right adrenal tumour in the 52‐year‐old woman. After adrenalectomy plasma DOC level decreased to the normal level of 0–12 nmol/1, and her blood pressure and serum potassium became normal. Abdominal CT scan revealed no finding of adrenal tumour in the older woman. These results indicate that these two patients had hypermineralocorticism with elevation of plasma DOC. One patient had a DOC‐producing adrenal adenoma, and the other probably had bilateral adrenal hyperplasia.
CHARACTERIZATION OF HUMAN PLATELET VASOPRESSIN RECEPTOR AND THE RELATION BETWEEN VASOPRESSIN‐INDUCED PLATELET AGGREGATION AND VASOPRESSIN BINDING TO PLATELETS
Authors: INABA KIYOSHI , UMEDA YUKIHISA , YAMANE YOKO , URAKAMI MASAYA , INADA MITSUO
Published: March 2008

Immunoreactive AVP was found to be much higher in platelets than in platelet‐free plasma (PFP) in normal subjects (12–8 ± 6–3 versus 1 –7 ± 0–8 fmol/ml). AVP levels in PFP were appreciably elevated in parallel with the elevation of plasma osmolality induced by the acute osmotic stimulation, while the AVP levels in platelets did not change before and after the stimulation.

Binding studies on intact platelets demonstrated specific binding sites for [3H]AVP. The specific binding was time, temperature and concentration–dependent, saturable and reversible, with the maximal binding capacity (Bmax) of 169–9 ± 14–4 sites/platelet and affinity of 4–84±115 × 108m−1. The affinity constants for unlabelled AVP, lysine vasopressin (LVP), oxytocin (OT) and dDAVP were 9–0, 8–5, 7–4 and 6–6, respectively, and the inhibition constant for d(CH2)5Tyr(Me)AVP (V1‐antagonist) was 7–7. There was a highly significant correlation between the affinity constants of AVP analogues and their relative vasopressor activities in vivo, whereas no such correlation was found between the affinity constants and antidiuretic activities.

AVP caused platelet aggregation with the maximal aggregation of 48–0 ± 25–1 % at 230 nm of AVP. A significant correlation was observed between the maximal percentage aggregation and Bmax of [3H]AVP to intact platelets. These results suggest that the platelet vasopressin receptor belongs to the V1 vascular subtype and mediates platelet aggregation.
INCREASED PRODUCTION OF α‐MELANOCYTE‐STIMULATING HORMONE IN THE PITUITARY GLAND OF PATIENTS WITH UNTREATED ADDISON'S DISEASE
Authors: COATES P. J. , McNICOL A. M. , DONIACH I. , REES L. H.
Published: March 2008

There is evidence that peptides related to α‐melanocyte‐stimulating hormone (α‐MSH) are involved in regulating the zona glomerulosa of the adrenal cortex in certain species. We have investigated the amount of immunoreactive (IR)‐ α‐MSH in the human pituitary gland of patients suffering from Addison's disease. We show increased numbers of cells containing demonstrable IR‐α‐MSH in the anterior lobe in these patients. Using an antiserum with specificity for the acetylated N‐terminus of α‐MSH we suggest that the major form present is desacetyl‐α‐MSH. These findings are in keeping with a role for anterior lobe derived desacetyl‐α‐MSH in the regulation of the human adrenal cortex.
A MULTIPLE TIMEPOINT STUDY OF N‐TERMINAL PRO‐OPIOMELANOCORTIN IN DEPRESSION USING A TWO‐SITE RECOGNITION IMMUNORADIOMETRIC ASSAY
Authors: CHARLTON B. G. , FERRIER I. N. , LEAKE A. , EDWARDSON J. A. , ECCLESTON D. , CROWCOMBE K. , McLEAN J. , JACKSON S. , LOWRY P.
Published: March 2008

N‐pro‐opiomelanocortin (N‐POMC) is secreted from the same precursor as ACTH and β‐endorphin. Elevated plasma ACTH and β‐endorphin β‐lipotro‐phin concentrations have been reported in depression, however there have been no previous studies of N‐POMC. Twenty‐five patients with major depression and 18 control subjects were studied at five timepoints to examine diurnal rhythm and the effect of a dexamethasone suppression test. N‐POMC was measured using a newly developed two‐site recognition immunoradiometric assay (IRMA). This demonstrated advantages of sensitivity, specificity and simplicity compared with existing radioimmunoassays. N‐POMC exhibited a pattern of diurnal rhythm and suppression in response to dexamethasone as described for other POMC derived peptides. Depressed subjects had higher levels of N‐POMC at 0900 h post‐dexamethasone than did control subjects. In conclusion, the results of this study are consistent with a hypothesis of cosecretion of POMC‐derived peptides. N‐POMC has a similar pattern of abnormal concentrations to ACTH and β‐endorphin /β‐Iipotrophin in depression. This constitutes probable evidence of POMC‐derived peptide resistance to glucocorticoid feedback in this condition.