bluuebunny/crossref_metadata_2025 huggingface dataset:
AN IMMUNOCHEMILUMINOMETRIC ASSAY FOR SERUM FREE THYROXINE
Authors: STURGESS M. L. , WEEKS I. , EVANS P. J. , MPOKO C. N. , LAING I. , WOODHEAD J. S.
Published: March 2008

An immunochemiluminometric assay has been developed for the measurement of free T4 concentrations in serum. The assay uses chemiluminescent acridinium ester labelled monoclonal antibodies which react with free T4 in the sample. A T4‐rabbit immunoglobulin G conjugate competes for antibody binding sites, immune‐complexes containing this being isolated using an anti‐immunoglobulin G antibody coupled to paramagnetic particles. Associated chemiluminescence intensity is thus dependent on the free T4 concentration. The assay distinguishes patients with primary thyroid disease from euthyroid subjects and is unaffected by abnormal binding proteins which compromise the diagnostic accuracy of radiolabelled analogue immunoassays. The test yields results which accurately reflect the clinical thyroid status of euthyroid patients with a variety of acute and chronic non‐thyroid illnesses. This is again in marked contrast to the aberrant results seen using certain radiolabelled analogue procedures.
THE SIGNIFICANCE OF ELEVATED LEVELS OF GASTRIN IN PATIENTS WITH PITUITARY ADENOMA
Authors: FONSECA M. E. , ZARATE A.
Published: March 2008

Six patients were studied with pituitary adenomas and elevated concentrations of gastrin similar to those found in cases of benign antral gastrinoma syndrome. Chromatography of the serum using Sephadex‐G50 revealed different molecular forms of gastrin according to the type of adenomas. In those cases of acromegaly and gonadotrophinoma, gastrin‐34 and unsulphated gastrins constitute the predominant forms. In contrast, in cases of Cushing's disease, gastrin‐17, sulphated as well as non‐sulphated were the predominant types; the chromatographic pattern was similar to that observed in two patients with antral gastrinoma syndrome who acted as controls. These findings demonstrate that pituitary adenomas might secrete gastrin. Taking into account that gastrin‐34 and unsulphated gastrins were the predominant forms in cases of acromegaly, gonadotrophinoma and non‐functioning adenoma, it is assumed that those molecular forms are mainly produced in the anterior lobe of the hypothysis. Conversely, gastrin‐17 was the principal molecular form in cases of Cushing's disease confirming the close relationship of the synthesis of gastrin and corticotrophin peptides. The cases with Cushing's disease exhibited a serum gastrin pattern similar to that observed in the two cases with antral syndrome in which the predominant immunoreactive form of gastrin in gastrin‐17 exhibiting a degree of sulphation corresponding to that of antral gastrin. It is concluded that the circulating excess of gastrin originated in the pituitary tumour tissue and the molecular form varied with the type of pituitary adenoma.
THYROTROPHIN RECEPTOR BLOCKING ANTIBODIES: INCIDENCE, CHARACTERIZATION AND IN‐VITRO SYNTHESIS
Authors: KRAIEM Z. , LAHAT N. , GLASER B. , BARON E. , SADEH O. , SHEINFELD M.
Published: March 2008

The prevalence and characteristics of TSH receptor blocking activity were examined in patients with different thyroid disorders. Studies were also performed on the in‐vitro synthesis and immunoregulation of the blocking antibody. Blocking activity was tested by measuring the inhibition of TSH‐stimulated cAMP production of cultured human thyroid cells by patient immunoglobulin (Ig) preparations. The following patients were investigated (number of cases in parentheses): Hashimoto's thyroiditis (33); primary myxoedema (17); euthyroid ophthalmopathy (8); active Graves’disease (19); cold nodule (5); non‐toxic goitre (14); toxic adenoma (8); toxic multinodular goitre (9) and 22 normal controls. TSH receptor blocking activity was only detected in primary hypothyroidism with the following characteristics: (i) Such activity was present in only 16% of the patients (both goitrous, i.e. Hashimoto's thyroiditis, and non‐goitrous, i.e. primary myxoedema), and in three patients with previously active Graves’hyperthyroidism who had become hypothyroid. (ii) Blocking activity seems to be associated with the Ig fraction of serum as indicated by protein A adsorption, (iii) The block‐positive samples did not bind l25I‐TSH, which seems to rule out an antibody directed against TSH. (iv) The specificity of the blocking activity seems to be directed towards the TSH‐(thyroid stimulating immunoglobulin, TSI) receptor‐mediated cAMP response since no inhibition of prostaglandin E1‐stimulated cAMP production was found. Moreover, all cases in which an inhibitory effect was demonstrated towards TSH also exhibited blocking of TSI‐stimulated cAMP, with a high correlation between the degree of inhibition of the TSH to that of the TSI response (r= 0.89, P<0.001, n= 11). The blocking activity may contribute to the pathogenesis of some cases of primary hypothyroid autoimmune thyroiditis, both goitrous and non‐goitrous, as well as in the evolution of hyper‐ to hypothyroidism. By culturing peripheral blood lymphocytes, as well as B/T lymphocyte co‐cultures isolated from three patients with blocking activity present in serum, the in‐vitro synthesis of the blocking antibody was demonstrated for the first time. Moreover, in‐vitro secretion of the antibody by patients B lymphocytes, as well as T cell regulation of autoantibody production, were also shown.
PREVENTION OF HYPOGLYCAEMIA IN A PATIENT WITH PANCREATIC MICROADENOMATOSIS BY A LONG‐ACTING SOMATOSTATIN ANALOGUE SMS 201‐995
Authors: KUNG A. W. C. , MA J. T. C. , WANG C. , FU K. H. , LAM K. S. L. , YEUNG R. T. T. , BOEY J.
Published: March 2008

Acute suppression of insulin secretion from pancreatic insulinomas by long‐acting somatostatin analogue SMS 201‐995 has been documented. We report the chronic use of the drug in a patient with persistent hypoglycaemia due to benign pancreatic microadenomatosis with satisfactory control of plasma glucose level and reduction of insulin production. There was no tachyphylaxis or untoward side‐effect noted during the 6‐month treatment period.
GROWTH HORMONE AND PROLACTIN SECRETION AFTER GROWTH HORMONE‐RELEASING HORMONE ADMINISTRATION, IN ANOREXIA NERVOSA PATIENTS, NORMAL CONTROLS AND TAMOXIFEN‐PRETREATED VOLUNTEERS
Authors: CASANUEVA F. F. , BORRAS C. G. , BURGUERA B. , LIMA L. , MURUAIS C. , TRESGUERRES J. A. F. , DEVESA J.
Published: March 2008

Anorexia nervosa is associated with several abnormalities in GH secretion elicited by different stimuli. To investigate the precise mechanism of this alteration, GHRH was administered to 14 women: a group of eight anorexia nervosa patients in the acute phase of their illness and a control group of six age‐matched volunteers. As patients with anorexia nervosa have chronic low oestrogen values, the volunteer women of the control group underwent a second GHRH test after pretreatment with the oestrogen receptor blocker tamoxifen. GHRH 1‐29 (1 μg/kg i.v.) induced a GH peak (mean±SEM) of 28.2 ±5.1 ng/ ml (GH ng/ml ± 2 = mU/l) at 30 min in the anorectic patients. This value was no different from the GHRH‐stimulated GH peak in the control women (28.1 ± 100 ng/ml). Tamoxifen pretreated women had a GH peak after GHRH of 35.6 ± 9.7 ng/ml, not significant versus control test. Compared with the control group, oestrogen levels were significantly lower in anorectic patients and higher in tamoxifen‐treated women. GHRH administration induced a small PRL peak at 15 min that was similar in the three groups tested. After this 15 min peak, PRL in both anorexic and tamoxifen‐treated women returned toward basal values steadily. However, in untreated control women a second PRL peak was evident at 60 min. In conclusion, GHRH‐induced GH secretion in anorexia nervosa patients was similar to that in control subjects and in controls under oestrogen receptor blockade.
EVALUATION OF A SENSITIVE CHEMILUMINESCENT ASSAY FOR TSH IN THE FOLLOW‐UP OF TREATED THYROTOXICOSIS
Authors: DAVIS J. R. E. , BLACK E. G. , SHEPPARD M. C.
Published: March 2008

We have studied 21 patients treated for thyrotoxicosis to evaluate a highly sensitive chemiluminescent thyrotrophin (TSH) assay in the assessment of changing thyroid status. Serum TSH was generally suppressed with high serum thyroid hormone concentrations and invariably rose when free T4 and T3 fell substantially below the normal range. However TSH values in 14 of the 21 patients remained undetectable or subnormal for variable periods despite normal or even slightly subnormal free T4 and T3 values. The level of free T4 and T3 at which TSH concentrations rose was highly variable, suggesting differing degrees of hypothalamo‐pituitary suppression. Sensitive T S H assays are likely to provide useful information regarding physiological regulation of TSH secretion in man, but our data indicate that in certain circumstances these assays used alone will be inadequate for biochemical assessment of thyroid status.
EFFECT OF BROMOCRIPTINE ON LH PULSATILITY IN THE POLYCYSTIC OVARY SYNDROME
Authors: CHAPMAN A. J. , WILSON M. D. , OBHRAI M. , SAWERS R. S. , LYNCH S. S. , ROYSTON J. P. , CLAYTON R. N.
Published: March 2008

The effects were studied of bromocriptine, 10 mg daily for 1 year, on luteinizing hormone (LH) pulse characteristics in patients with classical polycystic ovarian syndrome (PCOS). All patients were hirsute, had been oligomenorrhoeic since menarche, had LH: FSH ratios of > 3:1, and either elevated serum testosterone (T) or dehydroepiandrosterone sulphate (DHAS) concentrations. In 10 subjects who completed the study menstrual frequency increased from an average of 3‐6 to 8 per year but few of the cycles were ovulatory. Mean (SE) serum testosterone fell from 4‐4 (0‐5) nmol/1 pretreatment to 2‐8 (0‐3) nmol/1 (P<001) and DHAS from 7‐9 (1‐1) μmol/1 to 5‐4 (1‐1) μmol/1 (P<0‐05). Serum A4 androstenedione and oestradiol did not change with bromocriptine treatment. Mean serum LH fell from 17‐4 (2‐4) IU/l to 11‐2 (1‐8) IU/l (P<0‐03) after 12 months of bromocriptine. No pattern of LH pulsatility specific to PCOS was detected during 10 min sampling for an 8 h period prior to dopamine agonist treatment. LH interpeak interval (58 (5‐2) min) and peak amplitude (156 (7‐2%) of mean nadir) in untreated PCOS were similar to that of the mid‐follicular stage of ovulatory cycles, and bromocriptine for 1 year did not alter these variables. We conclude that while bromocriptine reduces serum androgen levels and increases menstrual frequency it has no effect centrally to modify hypothalamic GnRH secretion. The reduction in LH levels by bromocriptine may be the result of diminished gonadotroph sensitivity to GnRH or reduced pituitary stores of LH available for release. Despite the return towards normal of various hormonal characteristics of PCOS, bromocriptine has little place in the management of this condition.
CLINICAL EXPERIENCE WITH KETOCONAZOLE AS A THERAPY FOR PATIENTS WITH CUSHING'S SYNDROME
Authors: MCCANCE D. R. , HADDEN D. R. , KENNEDY L. , SHERIDAN B. , ATKINSON A. B.
Published: March 2008

Six consecutive patients with Cushing's disease were treated with the broad spectrum antifungal drug ketoconazole. Urinary Cortisol levels rapidly fell to within the normal range in five of the six patients. Acute hypoadrenalism occurred in one patient, and nausea and pyrexia in three. Our experience with hepatotoxicity was different from that reported by others in that reversible hepatotoxicity was demonstrated in three patients within 7 to 12 days of treatment. Further work is required before ketoconazole can be recommended as a standard primary therapy for patients with Cushing's syndrome. Continuing vigilance for both hypoadrenalism and hepatotoxicity is essential in any patient being treated with this drug either for hypercortisolism or for other reasons.
SIPPLE'S SYNDROME ASSOCIATED WITH A LARGE PROLACTINOMA
Authors: BERTRAND J.‐H. , RITZ P. , REZNIK Y. , GROLLIER G. , POTIER J.‐C. , EVRAD C. , MAHOUDEAU J. A.
Published: March 2008

A 26‐year‐old male presented with the symptoms and signs of acute congestive heart failure and hypertension. The left ventricle was shown to be thickened and displayed reversible hypokinesia. Further investigations revealed the underlying pathology of a phaeochromocytoma, bilateral medullary thyroid carcinoma (MTC), parathyroid adenoma and macro‐prolactinoma. There was a family history of MTC. The echocardiographic features of catecholamine‐induced cardiomyopathy were important in this diagnosis. Our research revealed no previous report of Sipple's syndrome associated with a macroprolactinoma. This case, along with the other 13 reports of mixed (type I and II) multiple endocrine neoplasia (MEN), are not within the classical subsets of MEN.
IN‐VITRO CONVERSION OF BLOCKING TYPE ANTI‐TSH RECEPTOR ANTIBODY TO THE STIMULATING TYPE BY ANTI‐HUMAN IgG ANTIBODIES
Authors: AMINO N. , WATANABE Y. , TAMAKI H. , IWATANI Y. , MIYAI K.
Published: March 2008

We examined the relationship between blocking type anti‐TSH receptor antibody (TRAb) and stimulating type TRAb by trying to convert blocking type TRAb to the stimulatory type in vitro. Immunoglobulins (IgGs) purified from sera of six patients with primary hypothyroidism blocked bovine TSH (100 μU/ml)‐induced cAMP production (58‐3‐82‐1% inhibition) in cultured porcine thyroid cells. None of these IgGs showed stimulating activity even after their dilution. In the conversion experiment, thyroid cells were first incubated with these IgGs at 34°C for 30 min and then washed with incubation buffer. They were then incubated with various kinds of anti‐human IgG antibodies first for 1 ‐5 h at 4°C and then for 18 h at 34°C, and the cAMP concentrations in the supernatants were measured. All six IgGs showed strong, dose‐dependent thyroid‐stimulating activity after addition of antibodies against human whole IgG, or Fab or Fc fragments of IgG. The Fab or F(ab')2 fragments of goat anti‐human IgG antibody also had these converting activities, although less than whole IgG. Addition of normal IgG in the first incubation or anti‐human IgG antibody alone had no thyroid‐stimulating activity. Anti‐human IgA or IgM antibodies did not have these converting activities. These results show that blocking type anti‐TSH receptor antibodies can be converted to the stimulating type by anti‐human IgG antibodies in vitro. The results suggest that the blocking and stimulating types bind to the same epitope(s) of TSH‐receptor related antigens. The same anti‐TSH receptor antibody may act as a stimulator or blocker by the influence of other factors, such as anti‐idiotype antibody.
EFFECTS OF LONG TERM DEXAMETHASONE TREATMENT IN ADULT PATIENTS WITH CONGENITAL ADRENAL HYPERPLASIA
Authors: HORROCKS P. M. , LONDON D. R.
Published: March 2008

We have followed nine adult patients with congenital adrenal hyperplasia (CAH) for between 7‐77 months on dexamethasone (DXM) 0.5 mg mane and 0.25 mg nocte, reducing to 0.5 mg mane. Twenty‐four hour profiles of ACTH, 17‐hydroxyprogesterone (17OHP), and androstenedione were performed; the areas under the curves (AUC) and the heights of the morning peaks were used to assess biochemical control. Comparisons were made between treatment before DXM (pre‐DXM), 0.75 mg for 2 weeks (DXM‐ST), 0.75 mg for at least 3 months (DXM‐LT), and 0.5 mg for at least 3 months (DXM‐0.5). None of the three males suffered any significant side‐effects. All women had menstrual disturbance but in three ovulation was induced. One female developed Cushing's syndrome and two developed hirsutism which resolved on stopping DXM. Overall there was no significant difference between DXM‐ST and DXM‐LT (mean AUCs for ACTH: DXM‐ST 660, DXM‐LT 383, for 170HP: DXM‐ST 1177, DXM‐LT 587, for androstenedione DXM‐ST 232, DXM‐LT 121). Reduction of the dose from 0‐75 mg to 0‐5 mg led to significant deterioration in control (Mean AUCs for ACTH DXM‐0 5,1123 (P < 0‐02), for 170HP DXM‐0‐5, 2068 (P < 0‐002), for androstenedione DXM‐05, 213 (P < 0‐5). We conclude that DXM is a satisfactory regime but the dose must be adjusted for each patient.
PLASMA AND CYST FLUID LEVELS OF A5 AND A4 STEROID HORMONES IN WOMEN WITH GROSS CYSTIC BREAST DISEASE
Authors: INAUDI P. , BERNABEI A. , GIOFFRÉ W. , FRANCHI F. , MAZZULLO G. , de LEO V. , D'ANTONA N.
Published: March 2008

Δ5 and Δ4 steroid levels were studied in the plasma and cyst fluid of women with gross cystic breast disease (GCBD). In luteal phase a significant increase in plasma levels (mean + SEM) of DHA (11.2 ± 2.4 ng/ml), DHAS (1.45 ± 0.6 fig/ ml) and Cortisol 277 ± 15.7 ng/ml) was found; in follicular phase the mean levels were 4.09 ± 0.47 ng/ml for DHA, 0.65 ± 0.08 μg/ml for DHAS and 190 ± 46.3 μg/ml for Cortisol. The DHA/DHAS and cortisol/androstenedione ratios were significantly higher in the plasma and lower in the cyst fluid of GCBD patients, than in the plasma of controls; the androstenedione/DHA ratio was higher in the cyst fluid than in the plasma of controls. The hormonal situation of the GCBD patients thus differed from that of the controls both in the plasma and cyst fluid, particularly as regards the Δ5 steroids.
SLEEP APNOEA AND DAYTIME SLEEPINESS IN ACROMEGALY: RELATIONSHIP TO ENDOCRINOLOGICAL FACTORS
Authors: PEKKARINEN T. , PARTINEN M. , PELKONEN R. , IIVANAINEN M.
Published: March 2008

Sleep history and pituitary function were studied and sleep polygraphy performed in 11 acromegalic patients before and after pituitary surgery. Excessive daytime sleepiness or habitual snoring or both together, as well as an elevated fasting level of serum GH occurred in all the patients. In five men but in none of the women an abnormal number of episodes of sleep apnoea were observed. Pituitary adenomectomy improved the apnoea frequency in one patient, whereas in the others the abnormality was still present 1 year later. After operation the fasting level of serum GH became normal in eight patients, two of them with persisting sleep apnoea. The sleep apnoea syndrome is common and clinically important in acromegaly. Its early diagnosis using polygraphic monitoring is emphasized, as it is a treatable disorder.
GROWTH HORMONE RESPONSES TO PYRIDOSTIGMINE IN NORMAL ADULTS AND IN NORMAL AND SHORT CHILDREN
Authors: GHIGO E. , MAZZA E. , IMPERIALE E. , MOLINATTI P. , BERTAGNA A. , CAMANNI F. , MASSARA F.
Published: March 2008

There is evidence indicating that the cholinergic system positively modulates GH release probably by inhibiting somatostatinergic tone. In the present study, the effects of cholinergic enhancement by pyridostigmine, (PD), a cholin‐esterases inhibitor, on GH release in normal adults (n= 14) (NA) and in both normal (n = 5) (NC) and short children (n = 19) (SC) with familial short stature (n =7) or constitutional growth delay (n= 12) were studied. In SC the insulin hypoglycaemia (IH)‐induced GH increase was also studied. In both NC and SC 60 mg orally PD induced a significant GH increase with mean peak at 90 min (mean ± SEM 11.0 ± 2.2 ng/ml in NC and 11.2 ± 2.3 ng/ml in SC). The GH areas under response curve (AUC) were 379.3 ± 76.6 and 327.8 ±43.2 ng/ml/h in NC and SC respectively. In NA 120 mg orally PD induced a significant GH increase with mean peak at 120 min (5.1 ± 11 ng/ml) which was significantly lower (P < 0.05) than that observed in both NC and SC. This statistical difference was strengthened by evaluating AUC (NA: 205.6 ± 33.7 ng/ml/h, P < 0.05 vs NC and SC). The correlation of drug dosage with body area ruled out that this difference could be related to the different PD dose in adults and children. In SC, IH induced a GH increase significantly lower than that observed after PD (GH peak 7.8 ± 0.6 vs 16.4 ± 1.9 ng/ml P<0.001). Our data show that cholinergic enhancement by PD induces a higher GH increase in both normal and short children than that observed in adults. This could be related to a variation of somatostatinergic tone. The higher PD‐induced GH response compared to the IH‐induced one indicates that PD test may be considered a more potent GH provocative stimulus than insulin hypoglycaemia.
GROWTH HORMONE RELEASING FACTOR STIMULATES and SOMATOSTATIN INHIBITS PROLACTIN RELEASE FROM HUMAN MIXED SOMATOTROPH‐LACTOTROPH ADENOMAS IN PERIFUSION
Authors: SERRI O.
Published: March 2008

The effects of human growth hormone‐releasing factor (hGRF) and somatostatin on growth hormone (GH) and prolactin (PRL) secretion in perifusion of dispersed cells of human GH‐secreting adenomas, obtained from seven acromegalic patients with hyperprolactinaemia, were examined. Six adenomas stained for both GH and PRL on immunohistochemical examination, and one contained only GH. GH release was consistently stimulated in a dose‐dependent manner by hGRF (0.01, 0.1 and 1.0 nM) in all seven adenomas studied. PRL release was undetectable in two adenomas. In the other five, hGRF stimulated PRL release and the response was dose related. Furthermore, the PRL response was significantly correlated with the GH response to hGRF. When cells were perifused with somatostatin (1 nM), GH and PRL secretion induced by hGRF was completely antagonized. We also evaluated the effect of hGRF pretreatment on the subsequent GH response to hGRF in two adenomas. hGRF pretreatment (1 nM) for 210 min reduced the GH response to a subsequent hGRF challenge (100 nM) in one tumour but not in the other. In conclusion, the PRL response is similar to the GH response in mixed GH and PRL‐secreting adenomas after exposure to GH release‐stimulating and inhibiting hormones. After prolonged exposure to hGRF, some adenomas remain responsive to further stimulation with hGRF, whereas others do not.
OVARIAN SUPPRESSION IN POLYCYSTIC OVARIAN DISEASE DURING 6 MONTH ADMINISTRATION OF A LUTEINIZING HORMONE‐RELEASING HORMONE (LH‐RH) AGONIST
Authors: FAURE N. , LEMAY A.
Published: March 2008

This study was designed to evaluate the long‐term effect (6 months) of the luteinizing hormone‐releasing hormone (LH‐RH) agonist buserelin on pituitary and ovarian function in a group of 14 patients presenting with the polycystic ovarian (PCO) syndrome. Buserelin was given subcutaneously 200 μg three times daily for the first 7 days followed by 500 μg once daily. Blood samples were taken weekly for the first month and then every month for radioimmunoassay of LH, FSH and sex steroids. While LH levels were stimulated during the first 2 weeks and then declined towards baseline, serum FSH levels were reduced after only 1 week (P < 0.05). Serum oestradiol levels were maximally suppressed to the menopausal range after 1 month and testosterone levels were also significantly inhibited (P < 0.05) after 2 weeks of therapy. Dehydroepiandrosterone (DHEA) sulphate did not show any significant change while 17‐hydroxyprogesterone was suppressed after the first month of buserelin administration (P < 0.01). The apparent divergent response of the gonadotrophins and the reduction of ovarian steroids in spite of a lack of suppression of LH levels can be explained by the marked inhibition of the bioactivity of LH assessed by dispersed mouse Leydig cells assay. The clinical evaluation of hirsutism did not detect any change during the 6 month period. No patient had any menstrual bleeding or spotting after the sixth week of buserelin. The monthly incidence of hot flushes varied between 50 to 66%. This study shows that LH‐RH agonist administration can selectively inhibit ovarian function and could be an interesting approach to evaluate the respective contribution of the ovary and adrenal on the pathophysiology of the polycystic ovarian disease.
(RAPID COMMUNICATION) PLASMA LEVELS OF ATRIAL NATRIURETIC PEPTIDE IN HYPERTHYROIDISM
Authors: WOOLF A. S. , MOULT P. J. A.
Published: March 2008

We measured plasma atrial natriuretic peptide (ANP) levels in 17 patients with newly diagnosed thyrotoxicosis. ANP was elevated compared to a group of healthy controls and fell to normal after treatment. Plasma cyclic guanosine monophosphate was also raised in untreated patients. Elevated circulating levels of ANP may play a part in the haemodynamic changes of hyperthyroidism.
EFFECTS OF ALPHA‐1 ADRENERGIC BLOCKADE ON THE HORMONAL RESPONSE TO HYPOGLYCAEMIC STRESS IN NORMAL MAN
Authors: CUNEO R. C. , LIVESEY J. H. , NICHOLLS M. G. , ESPINER E. A. , DONALD R. A.
Published: March 2008

In order to evaluate the effect of alpha‐1 adrenoreceptor regulation of ACTH release during insulin‐induced hypoglycaemia, we studied the response to hypoglycaemia with and without prazosin premedication in eight normal men. Prazosin pretreatment did not affect basal or peak plasma ACTH, Cortisol or GH during hypoglycaemic stress. However basal plasma levels of noradrenaline were increased (P < 0.02) as were responses of AVP, angiotensin II (P < 0.05) and noradrenaline (P < 0.05) to hypoglycaemia after prazosin. Though it is possible that these augmented responses masked an inhibitory effect of prazosin, we were unable to demonstrate a major role for alpha‐1 adrenergic receptors in mediating the ACTH response to hypoglycaemic stress in normal man.
INFLUENCE OF NIFEDIPINE AND ENALAPRIL ON OSMOREGULATION OF VASOPRESSIN
Authors: FAVRE L. , VALLOTTON M. B.
Published: March 2008

To determine whether calcium fluxes and angiotensin II influence osmoregulation of vasopressin (AVP) secretion, the effects of the calcium antagonist nifedipine and of the converting enzyme inhibitor enalapril on the AVP response to an osmotic load were compared to those of a placebo in seven normal female subjects. Plasma and urinary AVP were measured before and during a 3‐h infusion of 2.5% hypertonic saline. Nifedipine (10 mg orally 2 h before and 10 mg at the start of the infusion) increased heart rate but did not change blood pressure. The changes in free water clearance and in urinary AVP induced by hypertonic saline under nifedipine were greater than in the control test, but the slope and the intercept of the regression line of plasma AVP upon plasma osmolality were not significantly different. Enalapril (10 mg 3 h before the infusion) did not change heart rate or blood pressure. Free water clearance and urinary AVP did not differ from the control test, but the slope of the regression line was less steep. These slight modifications of the response to an osmotic load suggest that calcium fluxes and angiotensin II only exert a limited influence on AVP osmoregulation in normal females.
DURATION OF ANTITHYROID ACTION OF METHIMAZOLE ESTIMATED WITH AN INTRAVENOUS PERCHLORATE DISCHARGE TEST
Authors: McCRUDEN D. C. , HILDITCH T. E. , CONNELL J. M. C. , McLELLAN A. R. , ROBERTSON J. , ALEXANDER W. D.
Published: March 2008

We have used a method based on a perchlorate discharge test to estimate the duration of antithyroid effect of two doses of methimazole (MMI). Six patients with diffuse toxic goitre took 5 mg MMI twice daily and six took 20 mg twice daily over the study period of 12 weeks. Biochemical control of hyperthyroidism was achieved in all patients and thyroid hormone supplementation was required by all of the patients in the higher dose group to avoid hypothyroidism. Discharge of radioiodine from the thyroid by perchlorate diminished in both groups with time after MMI. After 5 mg MMI, perchlorate discharge as a percentage of the 30‐min uptake (mean ± SD), was 81.7 ± 3.3% at 2.2 h, 69.3 ± 18.9% at 5.9 h, 22.6–23.4% at 13.4 h and 2.7–6.7% at 25.1 h. After 20 mg MMI, the discharge was 92.5 ± 1.9% at 2.2 h, 84.3 ± 8.8% at 6.3 h, 64.8 ± 24.1 % at 13.3 h and 26.9–29.4% at 25.1 h. Only four patients (one in the lower dose group) showed a detectable discharge at 25 h and one of the patients treated with the lower dose showed no discharge at 13 h. These estimates of the effect of MMI on thyroidal iodide organification are not in keeping with published thyroidal MMI concentrations which do not show a fall between 3–6 h and 17–20 h after carbimazole. The explanation for this disparity is not clear but may be based on a redistribution of thioureylenes within the thyroid with time after dosage. The present data suggest that once daily is not the optimum dosage interval for MMI with respect to its effect on the organification of iodide.
RE‐EVALUATION OF THE CLINICAL VALUE OF THE 30 MIN ACTH TEST IN ASSESSING THE HYPOTHALAMIC‐PITUITARY‐ADRENOCORTICAL FUNCTION
Authors: LINDHOLM J. , KEHLET H.
Published: March 2008

The insulin hypoglycaemia test has been widely used for assessing the hypothalamic‐pituitary‐adrenocortical function. The outcome of this test has been compared to that of the 30 min ACTH test in 200 consecutive patients with proven or suspected hypothalamic‐pituitary disorder. A significant correlation (R= 0.83, P < 0.001) between the results of the two tests was found. In patients in whom blood glucose levels fell to 2.2 mmol/l (40 mg/dl) or below, the ratio between the peak plasma Cortisol concentration during hypoglycaemia and plasma Cortisol concentration 30 min after ACTH was 1.002. In patients in whom blood glucose concentration declined to 2.3–30 mmol/l (41–54 mg/dl) the ratio was significantly lower (0.828). In eight patients discordant results between the two tests were found. In two patients the ACTH test was normal despite impaired response to insulin. They were studied shortly after acute symptoms of a pituitary adenoma necrosis. Two patients had subnormal responses to insulin despite the fact that pituitary‐adrenal function appeared to be intact. In both cases relative insufficiency of the hypoglycaemic stimulus was the likely cause of the discrepancy. In the remaining four patients results of one test was marginally below, and that of the other test marginally above the lower limit of normal. It is concluded that the 30 min ACTH test is reliable for assessing integrated hypothalamic‐pituitary‐adrenal function (except shortly after acute ACTH deprivation).
ESCAPE FROM DEXAMETHASONE‐INDUCED ACTH AND CORTISOL SUPPRESSION BY CORTICOTROPHIN‐RELEASING HORMONE: MODULATORY EFFECT OF BASAL DEXAMETHASONE LEVELS
Authors: HERMUS A. R. M. M. , PIETERS G. F. F. M. , PESMAN G. J. , HOFMAN J. , SMALS A. G. H. , BENRAAD TH.J. , KLOPPENBORG P. W. C.
Published: March 2008

The response of ACTH and Cortisol to corticotrophin‐releasing hormone (CRH) after pretreatment with various doses of dexamethasone was investigated in five healthy subjects. The five subjects participated in six experiments. In each experiment 200 μg ovine CRH was administered as an i.v. bolus injection at 0900 h after pretreatment with respectively: (A) 1 mg dexamethasone orally at 2300 h in the evening before CRH injection, (B) 2 mg dexamethasone orally at 2300 h in the evening before CRH injection, (C) 4 mg dexamethasone orally at 2300 h in the evening before CRH injection, (D) 2 mg dexamethasone orally at 2300 h in the evening before CRH injection, followed by 2 mg dexamethasone orally 1 h before CRH, (E) no dexamethasone and (F) 1 mg dexamethasone orally 1 h before CRH injection. In spite of overnight suppression with a single dose of dexamethasone CRH elicited Cortisol rises in all individuals (experiments A‐C). Dexamethasone pretreatment in experiment D abolished the CRH‐induced stimulation of the pituitary‐adrenal axis. There was a significant and negative correlation between the basal dexamethasone levels (i.e. the dexamethasone levels immediately before CRH administration) in the experiments A‐D and the areas under the individual ACTH (R=−0.62; P < 0.01 by Spearman's rank correlation test) and Cortisol (R=−0.81; P < 0.001 by Spearman's test) curves, i.e. the lower the basal dexamethasone levels, the greater the rise in ACTH and Cortisol levels after CRH administration. Pretreatment with a single dose of 1 mg dexamethasone 1 h before CRH injection (experiment F) led to a significant inhibition of the CRH‐induced ACTH and Cortisol response, despite unsuppressed pre‐CRH ACTH and Cortisol levels. We conclude that CRH is able to overrule the inhibition of the pituitary‐adrenal axis by overnight suppression with pharmacological doses of dexamethasone. The strongly negative correlation between the basal dexamethasone levels and the CRH‐induced pituitary‐adrenal responses suggests that circulating glucocorticoid levels modulate the response of ACTH and Cortisol to CRH.
GROWTH HORMONE PRETREATMENT IN MAN BLOCKS THE RESPONSE TO GROWTH HORMONE‐RELEASING HORMONE; EVIDENCE FOR A DIRECT EFFECT OF GROWTH HORMONE
Authors: ROSS R. J. M. , BORGES F. , GROSSMAN A. , SMITH R. , NGAHFOONG L. , REES LESLEY H. , SAVAGE M. O. , BESSER G. M.
Published: March 2008

The effect of pretreatment with biosynthetic methionyl human GH (hGH) on the GH response to GHRH has been studied in normal subjects. Eight volunteers were given either 4IU hGH or placebo s.c. 12‐hourly for 72 h before a GHRH test, or a single s.c. dose of 4 IU hGH 12 h before a GHRH test. Somatomedin‐C (Sm‐C) levels at the time of the GHRH tests were significantly elevated after treatment with hGH compared to placebo, and the GH response to GHRH was significantly attenuated. A further six subjects were given 2 IU hGH or placebo i.v., and i.v. GHRH 3 h later; there was no rise in Sm‐C for the 5 h of the study after either treatment; nevertheless, the response to GHRH was completely abolished by pretreatment with hGH. These results demonstrate that GH can regulate its own secretion independently of changes in Sm‐C levels, through a mechanism other than the inhibition of GHRH release. The attenuated response to GHRH in the presence of elevated Sm‐C levels may be related to Sm‐C, or be a more direct effect of the recently elevated GH levels.
AN OPEN‐LABELLED STUDY OF THE SAFETY, ACUTE METABOLIC ACTIVITY AND PHARMACOKINETIC PROFILE OF A SHORT‐TERM COURSE OF RECOMBINANT HUMAN GROWTH HORMONE IN HEALTHY VOLUNTEERS
Authors: WILTON P. , SIETNIEKS ANNI
Published: March 2008

The safety and short‐term biological effects of recombinant human GH (Genotropin, KmbiVitrum AB, Stockholm, Sweden), given i.m. (8 IU/d) for 4 consecutive days to 10 healthy male volunteers, have been evaluated. No adverse reactions were detected by clinical investigation. Haematological parameters, clinical chemistry and the acute phase inflammatory profile showed no negative effects of the drug. The well‐known metabolic effects of GH were seen as an increase in free fatty acids and in the somatomedin level (IGF‐1). No antibodies to GH or periplasmic Escherichia coli peptides developed during the first month after treatment. The peak plasma level of hGH (62 ± 20 mU/1) occurred between 3.0 and 3.5 h. This study shows that recombinant hGH induces no toxic or other adverse reactions and that the acute metabolic effects and the pharmacokinetic profiles are comparable to those reported after injections of GH extracted from pituitary glands.
POSITIVE AND NEGATIVE FEED‐BACK EFFECT OF PROGESTERONE ON LUTEINIZING HORMONE SECRETION IN POST‐MENOPAUSAL WOMEN
Authors: STEELE P. A. , JUDD S. J.
Published: March 2008

Progesterone is known to exert a biphasic feedback effect on luteinizing hormone (LH) secretion in animals and it has been demonstrated that this effect is dependent upon both duration of exposure to progesterone and the dose administered. In this paper we sought to determine whether a similar biphasic effect exists in humans. The pattern of LH secretion was assessed in six healthy oestrogen treated post‐menopausal women before and after they were given progesterone (50 mg/day) for 1 and 7 days. Progesterone treatment for 1 day resulted in a significant elevation in the basal serum LH concentration and in individual LH pulse amplitude with no change in LH pulse frequency. In contrast, progesterone treatment for 7 days increased LH pulse amplitude with no change in basal serum LH concentrations and a significant reduction in LH pulse frequency. We concluded that firstly, progesterone does exert a biphasic feedback effect on LH secretion and that the nature of this effect is determined by the duration of exposure to the progesterone stimulus. Secondly, as LH pulsatility has been shown to be an accurate indicator of GnRH pulsatility, that the reduction in LH pulse frequency after a long exposure to progesterone is due to a hypothalamic effect of progesterone whereas the positive feedback effect may be the result of a pituitary or hypothalamic action.
A DIRECT ASSAY FOR PROINSULIN IN PLASMA AND ITS APPLICATIONS IN HYPOGLYCAEMIA
Authors: HAMPTON S. M. , BEYZAVI K. , TEALE D. , MARKS V.
Published: March 2008

A direct radioimmunoassay in unextracted plasma is described. The assay has a sensitivity of 4 pmol/l (2 standard deviation from zero). The proinsulin antiserum was immuno‐adsorbed against human C‐peptide and insulin coupled to glass beads. Cross‐reactivity of the antiserum was assessed and shown to be less than 0·01% with both peptides. In normal healthy fasting subjects the plasma proinsulin level was 6·7 ± 1·7 pmol/l (n=17) (mean ± SD). Fasting proinsulin levels in non‐insulin dependent diabetics were significantly elevated compared with non diabetics (14·2 ± 2 pmol/l (n=11) vs 6·7 ± 1·7 (n=17) P>0·005). The insulin/proinsulin ratio was 3·4:1 in the non‐insulin dependent diabetic compared with 6:1 in non‐diabetics. Samples from 21 insulinoma patients were assayed and mean fasting plasma proinsulin level was 255 pmol/l ± 479 when the patients were hypoglycaemic. The range in pro‐insulin levels was large (30–2300 pmol/l). Mean fasting proinsulin level in three hypoglycaemic subjects due to sulphonylurea overdose was 15·7 ± 2·3 pmol/l. The molar ratio of proinsulin to insulin was 1:6 in healthy subjects, 1:1 in insulinoma patients and 10:1 in sulphonylurea induced hypoglycaemic patients.
EXAGGERATED INSULIN SECRETORY RESPONSE IN PATIENTS WITH INSULINOMAS TO MIDAGLIZOLE, A DRUG WITH α2‐ADRENERGIC BLOCKING ACTIVITY
Authors: YAMADA Y. , KONO N. , HANAFUSA T. , MINEO I. , NAMBA M. , ITOH H. , KIYOKAWA H. , KAWACHI M. , YAMASAKI T. , TARUI S.
Published: March 2008

Midaglizole is a new α2‐adrenergic blocking agent which increases insulin release from normal pancreatic islets. We studied its effect in four patients with insulinomas. In three patients oral administration of 150 mg of midaglizole caused a large increase in serum insulin and a corresponding decrease in plasma glucose. The magnitude of the response cannot exclude the possibility that midaglizole has direct beta cell stimulatory activity. Two of the three patients had operations, and their insulin responses to midaglizole became normal after removing the tumours. In contrast, midaglizole did not stimulate insulin secretion in the fourth patient. A midaglizole stimulation test might be useful in screening patients with insulinomas.
BASAL AND STIMULATED INSULIN LEVELS RISE WITH ADVANCING PUBERTY
Authors: SMITH C. P. , ARCHIBALD H. R. , THOMAS J. M. , TARN A. C. , WILLIAMS A. J. K. , GALE E. A. M. , SAVAGE M. O.
Published: March 2008

We studied the effect of pubertal development on insulin secretion. Intravenous glucose tolerance tests were performed on 47 islet‐cell antibody negative siblings of diabetic children and on 16 normal adults. Puberty was staged using Tanner's criteria and subjects were grouped as follows: I, stage 1 (n= 16); II, stages 2 and 3 (n=15); III, stages 4 and 5 (n= 16); IV, adults (n= 16). Fasting insulin increased with advancing puberty (p= 0.59,P< 0.001). The stimulated insulin response also rose with increasing pubertal development: for the 0‐10 min insulin area, ρ= 0.46,P<0.001 and for the 10‐60 min area,ρ=0.68,P<0.00. There was a low positive correlation between insulin and age to 16 years but multiple regression analysis showed that this could be accounted for by puberty alone. Indeed prepubertal children and adults did not differ. There was no correlation between glucose (fasting and 0‐60 min area) and puberty or age. These findings suggest that insulin resistance increases during puberty, and this may contribute to the frequency of presentation or worsening control of insulin dependent diabetes at this time.
THE CORTISOL RESPONSE TO CORTICOTROPHIN‐RELEASING FACTOR IS BLUNTED IN OBESITY
Authors: KOPELMAN P. G. , GROSSMAN A. , LAVENDER P. , BESSER G. M. , REES L. H. , COY D.
Published: March 2008

Abnormalities of the adrenal cortex may be associated with extreme obesity but there is little information about hypothalamic‐pituitary function. We have investigated this by measuring plasma ACTH and Cortisol responses to ovine corticotrophin releasing factor (CRF‐41), 0.5 μg/kg/body weight, in 10 obese women and seven age‐matched normal weight women. The Cortisol response to insulin‐induced hypoglycaemia and intravenous synacthen (2.5 ng/kg/body weight) were also measured on different occasions in some of the subjects. The peak ACTH response to CRF was less in the obese but this was not significant (obese ACTH ± SEM, 31 ± 4 ng/l, controls 39 ± 4 ng/1) whereas the peak Cortisol was significantly reduced in the obese (obese Cortisol, 456 ± 21 nmol/l, controls 638 ± 50 nmol/l). Doubling the dose of CRF did not significantly alter either ACTH or Cortisol responses in six of the obese patients. The peak Cortisol response to symptomatic hypoglycaemia and following i.v. low dose synacthen stimulation was similar in the obese and normal weight women. We conclude that obese women have a normal Cortisol response to hypothalamic‐pituitary stimulation by hypoglycaemia and direct adrenal stimulation by synacthen but an impaired adrenal response to pituitary stimulation with CRF. Although the explanation for these findings is uncertain, our study underlines the importance of considering an individual's body weight when assessing the Cortisol response to CRF stimulation.
RADIOIMMUNOASSAY ARTIFACT ASSOCIATED WITH CIRCULATING ANTI‐RABBIT ANTIBODIES
Authors: JEFFCOATE W. J. , SELBY C. , POWELL R. J.
Published: March 2008

A 30 year old woman presenting with infertility was found to have elevated serum immunoreactive prolactin, TSH and total T3. These findings were eventually attributed to assay artifact when she was shown to have anti‐rabbit antibodies in her serum. The possibility of laboratory artifact should be considered in clinical practice when abnormal immunoassay results are unsupported by clinical or radiographic data.
THYROXINE‐BINDING GLOBULIN DEFICIENCY RE‐EXAMINED
Authors: And S. COPPING , BYFIELD P. G. H.
Published: March 2008

Seven sera, previously categorised as completely deficient in thyroxine‐binding globulin (TBG) by an immunoelectrophoretic technique, were re‐examined with a sensitive ELISA method. Only one of the sera was confirmed completely deficient by ELISA. The remaining six contained 0.08‐0.19 mg/1. The protein was immunologically identical with‘normal’TBG, could bind to thyroxine and had the correct mobility in reverse‐flow electrophoresis. Complete TBG deficiency may therefore be rare.
PROLACTIN RESPONSE TO METOCLOPRAMIDE DOES NOT DISTINGUISH PATIENTS WITH HYPOGONADOTROPHIC HYPOGONADISM FROM DELAYED PUBERTY
Authors: CRISTIANO A. M. , MUNABI A. , EL SABBAGH H. , CASSORLA F. , SHERINS R. J.
Published: March 2008

The prolactin response to metoclopramide (MCP) was studied in 23 sexually immature males, 14 with isolated hypogonadotrophic hypogonadism (IHH) and nine with constitutional delayed puberty. Six of the 14 IHH patients had not been treated prior to our study, whereas eight had received long term therapy with testosterone or hCG for variable periods ranging from 1 to 20 years. We also measured the prolactin response to chlorpromazine (CPZ) in the untreated IHH men. In these untreated subjects, we observed a greatly diminished prolactin response after CPZ by comparison to that measured following MCP administration (peak 15 ng/ml, areas 86 units vs peak 43 ng/ml, area 416 units, respectively) (P<0.01). Furthermore, prolactin levels following MCP were similar in untreated (peak 43 ng/ml, area 416 units) and treated (peak 55 ng/ml, area 545 units, NS) IHH males as well as in boys with constitutional delayed puberty (peak 50 ng/ml, area 532 units, NS). In addition, responses in the three groups of patients were about half (P<0‐01) those measured in normal men (peak 81 ng/ml, area 845 units). These data indicate that, unlike CPZ, MCP is not useful in distinguishing patients with hypogonadotrophic hypogonadism from boys with constitutional delayed puberty.
CIRCULATION OF A FRAGMENT OF HAEMOGLOBIN α‐CHAIN DURING A PENTAGASTRIN‐INDUCED FLUSH IN PATIENTS WITH METASTATIC CARCINOID TUMOURS
Authors: BALKS H. J. , THIM L. , CONLON J. M.
Published: March 2008

Intravenous injection of pentagastrin (0‐6 /μ g/kg body wt) into two patients with metastatic carcinoid tumours evoked a severe carcinoid flush. Analysis by reverse‐phase H P L C of acetone‐extracts of peripheral blood taken from the patients during the flush indicated the presence of a peptide identified as the residues (1‐33) fragment of the α‐chain of haemoglobin. The peptide was not detected in blood taken from the patients immediately before stimulation of the flush or in the blood of healthy subjects after pentagastrin injection. The observation is interpreted as evidence that the pentagastrin‐induce carcinoid flush is associated with the activation and possible release of a tumour protease that result in damage to erythrocytes.
EFFECTS OF LOW DOSE ORAL IODIDE SUPPLEMENTATION ON THYROID FUNCTION IN NORMAL MEN
Authors: GARDNER D. F. , CENTOR R. M. , UTIGER R. D.
Published: March 2008

Previous studies have demonstrated that short‐term oral iodide administration, in doses ranging from 1500 μg to 250 mg/day, has an inhibitory effect on thyroid hormone secretion in normal men. As iodide intake in the USA may be as high as 800 μ/d, we investigated the effects of very low dose iodide supplementation on thyroid function. Thirty normal men aged 22‐40 years were randomly assigned to receive 500, 1500, and 4500 μg iodide/day for 2 weeks. Blood was obtained on days 1 and 15 for measurement of serum T4, T3, T3‐charcoal uptake, TSH, protein‐bound iodide (PBI) and total iodide, and 24 h urine samples were collected on these days for measurement of urinary iodide excretion. TRH tests were performed before and at the end of the period of iodide administration. Serum inorganic iodide was calculated by subtracting the PBI from the serum total iodide. We found significant dose‐related increases in serum total and inorganic iodide concentrations, as well as urinary iodide excretion. The mean serum T4 concentration and free T4 index values decreased significantly at the 1500 μg/day and 4500 μg/day doses. No changes in T3‐charcoal uptake or serum T3 concentration occurred at any dose. Administration of 500 μg iodide/day resulted in a significant increase (P<0.005) in the serum TSH response to TRH, and the two larger iodide doses resulted in increases in both basal and TRH‐stimulated serum TSH concentrations. Thus, iodide supplementation within the range of normal daily intake in the USA has a significant inhibitory effect on thyroid hormone secretion in normal men.
COMPARISON OF METHIMAZOLE, METHIMAZOLE AND SODIUM IPODATE, AND METHIMAZOLE AND SATURATED SOLUTION OF POTASSIUM IODIDE IN THE EARLY TREATMENT OF HYPERTHYROID GRAVES’DISEASE
Authors: ROTI E. , ROBUSCHI G. , GARDINI E. , MONTERMINI M. , SALVI M. , MANFREDI A. , GNUDI A. , BRAVERMAN L. E.
Published: March 2008

We have evaluated three regimens for the rapid control (10 days’therapy) of thyrotoxicosis in hyperthyroid Graves’disease: methimazole (MMI, 40 mg/ day), MMI and sodium ipodate (MMI + Na Ipodate, 1 g/day and MMI and saturated solution of potassium iodide (MMI + SSKI, 6 drops twice daily). When serum T4 and T3 concentrations were analysed as the percent change from pre‐treatment values, the following results were observed. Serum T4 concentration decreased in the three treatment groups and the decrease was similar in the MMI and MMI + SSKI groups but significantly lower than in the MMI + Na ipodate group. The serum T3 concentration decreased to the normal range in all seven MMI + Na Ipodate treated patients by the fourth day of treatment and the per cent decrease in serum T3 from pre‐treatment values was significantly greater than in the MMI and MMI + SSKI treated patients. The decrease in serum T3 was similar in the latter two groups. Heart rate decreased in all three groups, but the decrease was significantly more in the MMI+Na ipodate treated patients. The present findings suggest that the rapid control of hyperthyroid Graves’disease is similar in patients treated with MMI and MMI + SSKI and that the combination of MMI + Na Ipodate is more efficacious since the decrease in serum T3 concentrations and heart rate was significantly greater in the MMI + Na ipodate‐treated patients.