bluuebunny/crossref_metadata_2025 huggingface dataset:
CORTICOTROPHIN, CORTISOL, PROLACTIN AND GROWTH HORMONE RESPONSES TO INSULIN‐INDUCED HYPOGLYCAEMIA IN NORMAL SUBJECTS GIVEN SODIUM VALPROATE
Authors: ABRAHAM R. R. , DORNHORST A. , WYNN V. , ALTAHER A. R. H. , CAMPBELL E. A. , BECKFORD U. , WATTS S. M. , NICHOLSON S. A. , GILLHAM B. , THODY A. , JONES M. T.
Published: March 2008

Plasma corticotrophin (ACTH), cortisol, prolactin and growth hormone (GH) responses to insulin‐induced hypoglycaemia were measured in normal healthy subjects of both sexes before and after three weeks' treatment with sodium valproate (Epilim, 200 mg three times a day). The drug had no effect on fasting plasma glucose levels, or the extent of hypoglycaemia induced by insulin (0·15 U/kg). There was no significant difference between pre‐ and post‐treatment values for basal or stress‐induced concentrations of ACTH and cortisol (n= 12), prolactin (n= 7) or GH (n= 9). The results suggest that treatment of normal subjects with sodium valproate has no effect on the response of the hypothalamo‐pituitary‐adrenocortical axis to hypoglycaemia, which is in contrast to its inhibitory effects on ACTH secretion in patients suffering from Nelson's syndrome. This implies that in the disease state, there may be a unique sensitivity to GABA‐ergic manipulation.
THE EFFECT OF DOPAMINE AGONIST THERAPY ON LARGE FUNCTIONLESS PITUITARY TUMOURS
Authors: GROSSMAN A. , ROSS R. , CHARLESWORTH M. , ADAMS C. B. T. , WASS J. A. H. , DONIACH I. , BESSER G. M.
Published: March 2008

Fifteen patients (12 male) with large pituitary tumours and serum prolactin levels below 1000 mU/1 were given dopamine agonist therapy (bromocriptine, mesulergine or pergolide) for a mean of 9 months (range 3–36 months). Serum prolactin became undetectable in all. Despite this, significant suprasellar extensions and any associated neurological defect remained in 14 patients, who therefore were referred for surgery. In one patient there was evidence of spontaneous pituitary infarction unrelated to dopamine agonist therapy. At operation 12 patients had apparently functionless pituitary adenomas which failed to immunostain for prolactin, one had an epidermoid cyst and one a Rathke's pouch cyst. We conclude that patients with large pituitary tumours and only a mildly elevated serum prolactin are unlikely to have prolactinomas, and that such tumours are not likely to show significant tumour shrinkage with medical treatment with dopamine agonists.
SERUM CONCENTRATION OF UNSATURATED THYROXINE‐BINDING GLOBULIN IN HYPER‐ AND HYPOTHYROIDISM
Authors: KONNO N. , KAKINOKI A. , MIURA K. , HAGIWARA K. , TAGUCHI H. , MINAMI R.
Published: March 2008

The concentration of serum thyroxine (T4)‐binding globulin (TBG) not binding T4 (unsaturated TBG, u‐TBG) was determined in hyper‐ and hypothyroidism. u‐TBG was expressed as the product of TBG concentration and the ratio of free TBG capacity to maximal TBG capacity as determined by reverse‐flow electrophoresis. u‐TBG concentration in normal sera (n= 40) was 15.5 ± 2.3 mg/l (mean ± SD), or 257 ± 38 nmol/l for a molecular weight of TBG of 60 000 daltons. u‐TBG levels were significantly lower in hyperthyroidism (7.1 ± 2.3 mg/l, n= 16, P<0.001) and higher in hypothyroidism (21.7 ± 5.0 mg/l, n= 22, P<0.001). Based on partial correlation analysis, u‐TBG was inversely correlated to serum T4 (r=−0.586, P<0.001), but not correlated to triiodothyronine (T3) (r=−0.180, NS). There was a reciprocal correlation between u‐TBG concentration and the T3 uptake value (r= 0.748, P<0.001). There was also a reciprocal correlation of u‐TBG with both % free T4 (r= 0.425, P<0.00 1) and % free T3 (r=0.377, P<0.001), when the data were subjected to partial correlation analysis. These results provide the values for u‐TBG concentration in hyper‐ and hypothyroidism, and support the concept that the free fractions of serum thyroid hormones may be determined by the number of binding sites of the TBG molecule that are not saturated with T4 in hyper‐ and hypothyroidism.
HIGH FREQUENCY OF GOITRE IN CIGARETTE SMOKERS
Authors: HEGEDÜS L. , KARSTRUP S. , VEIERGANG DAGMAR , JACOBSEN B. , SKOVSTED LIS , FELDT–RASMUSSEN ULLA
Published: March 2008

Thyroid function, the clinical occurrence of goitre and ultrasonically determined thyroid gland volume were investigated in 219 healthy subjects randomly chosen from hospital employees. Thirty‐five subjects (16%) had a clinically detectable goitre. The frequency of goitre among smokers was higher (32 of 107, 30%) than among non‐smokers (3 of 112, 3%), (P<0.001). Median thyroid volume was significantly higher in smokers, 26 ml (range 11–55 ml), compared with non‐smokers, 15 ml (range 8–37 ml), (P<0.001). The median serum thyroglobulin levels were significantly higher and median serum thyrotropin levels lower in smokers compared with non‐smokers. There were no differences between the groups regarding serum levels of T4, T3, rT3, free T4 index, free T3 index, thyroglobulin antibodies and 131I uptake (24 h) in the thyroid gland. It is suggested that these findings could partly be due to inhaled thiocyanate and/or increased adrenergic stimulation of the thyroid gland in smokers.
DETERMINATION OF THE FREQUENCY OF PULSATILE LUTEINIZING HORMONE SECRETION BY TIME SERIES ANALYSIS
Authors: MURDOCH A. P. , DIGGLE P. J. , DUNLOP W. , KENDALL‐TAYLOR P.
Published: March 2008

Statistical methods of time series analysis, in particular, spectral analysis, have been used to determine the pulse frequency of LH secretion. This method can detect significant harmonic variation within the data. Six normal women in the early follicular phase of the menstrual cycle were studied at 5 and 15 min sampling intervals and significant dominant pulse frequencies were revealed in five subjects (51–120 min). In addition, a low frequency variation (>6 h) was revealed in four subjects and more rapid frequencies (20 and 13.3 min) were seen clearly in one subject. Comparison of repeat studies on four individuals at the same stage of different menstrual cycles and on two individuals in the same cycle failed to demonstrate differences in five of the six subjects. This method of analysis offers a new approach to the analysis of LH pulse frequency. Realistic comparisons of this frequency between and within individuals can now be made. A new observation of superimposed harmonic components of LH pulsatility has also been recorded.
THE INTERACTION OF GROWTH HORMONE RELEASING HORMONE WITH OTHER HYPOTHALAMIC HORMONES ON THE RELEASE OF ANTERIOR PITUITARY HORMONES
Authors: LOOIJ B. J. , KRUSEMAN A. C. NIEUWENHUIJZEN , MUDDE A. H. , FRÖLICH M. , PIADITIS G. P. , HODGKINSON S. C. , MCLEAN C. , GROSSMAN A. , COY D. H. , REES L. H. , LOWRY P. J. , BESSER G. M.
Published: March 2008

To determine whether the 29 amino‐acid fragment of growth hormone releasing hormone (GHRH) can be combined with other hypothalamic releasing hormones in a single test of anterior pituitary reserve, the responses of anterior pituitary hormones to combinations of an i.v. bolus of GHRH(1–29)NH2 or saline with an i.v. bolus of either LH releasing hormone (LHRH) plus TRH, ovine CRH(oCRH) or saline were studied. Each infusion of GHRH(1–29)NH2 resulted in a rapid increment of the plasma GH value. Infusion of GHRH(1–29)NH2 also caused a small and transient rise in plasma PRL, but no change in the integrated PRL response. The combination of GHRH(1–29)NH2 with LHRH plus TRH caused a larger increment of peak and integrated plasma TSH levels than LHRH plus TRH alone. GHRH(1–29)NH2 did not affect the release of other anterior pituitary hormones after infusion with oCRH or LHRH plus TRH. Because of the finding of potentiation of the TSH‐releasing activity of LHRH plus TRH by GHRH(1–29)NH2, the study was extended to the investigation of TSH release after infusion of TRH in combination with either GHRH(1–29)NH2 or GHRH(1–40). In this study the combination of TRH with both GHRH preparations also caused a larger increment of the peak and integrated plasma TSH levels than TRH alone. It is concluded that GHRH(1–29)NH2 possesses moderate PRL‐releasing activity apart from GH‐releasing activity. In addition, GHRH potentiates the TSH‐releasing activity of TRH. Since sequential administration of GHRH(1–29)NH2
GROWTH HORMONE RESPONSE TO LOW DOSE INTRAVENOUS INJECTIONS OF GROWTH HORMONE RELEASING FACTOR IN OBESE AND NORMAL WEIGHT WOMEN
Authors: KOPELMAN P. G. , NOONAN K.
Published: March 2008

We have recently reported an impaired growth hormone (GH) response to a single i.v. bolus dose of growth hormone releasing factor (1 μg/kg body weight) in obese women. We have now investigated whether the i.v. administration of low dose GHRF(1–29)NH2 (0·33 μg/kg/h) by 15 min pulsed injections for 3 h followed by an i.v. bolus (1 μg/kg) to four normal weight women and six obese women results in an enhancement of GH release. In the control women low dose GHRF, given either as a single 10 μg injection or in pulses of equivalent total dosage, produced a GH response identical to that seen after a single bolus of 60 μg (mean peak GH low dose 30 ± 2 mU/1, peak GH large dose 30 ± 0·5 mU/1). In the obese women GH release was significantly less than the controls after low doses of GHRF (P < 0·01) and the peak was delayed compared to that following a single large bolus dose (peak GH 7±1·2 mU/1). However, three of the obese women who previously showed no response to a large dose of GHRF did release GH after low dose pulsed injections. The final bolus of GHRF after 3 h of pulsed injections did not elicit any additional GH release in the subjects irrespective of body weight. We conclude that obesity may be characterized by impaired GH release to i.v. GHRF. The finding that some obese women do not respond to a single large dose injection of GHRF but do release GH after low dose pulsed injections supports the hypothesis of a hypothalamic disorder in these women. Further studies are needed to determine the clinical efficacy of low dose GHRF.
PARADOXICAL EFFECTS OF THE ANTI‐ANDROGEN CYPROTERONE ACETATE ON LIPID AND LIPOPROTEIN METABOLISM
Authors: WYNN V. , GODSLAND I. F. , SEED M. , JACOBS H. S.
Published: March 2008

The effects on fasting serum lipids of the potent anti‐androgen, cyproterone acetate (CA) and the oestrogen, ethinyl oestradiol (EO) given both alone and in combination were examined in women acting as their own controls. Cyproterone acetate alone caused significant reductions in total cholesterol, high density lipoprotein subfraction 2 cholesterol (HDL2) and low density lipoprotein cholesterol (LDL). Ethinyl oestradiol alone significantly increased triglycerides, HDL and HDL2 and reduced LDL, and there was also a significant increase in the HDL/LDL and HDL2/LDL ratios. The two steroids were administered in combination according to a reverse sequential regime. The 28‐day treatment cycle thus included Phase A during which both drugs were given followed by Phase B when EO alone was given. Triglycerides rose significantly in Phases A and B to the same extent as for the group taking EO alone. High density lipoprotein cholesterol was unchanged but HDL2 was reduced in both phases and this effect could not be overcome by increasing the dose of oestrogen. Low density lipoprotein cholesterol fell and the HDL/LDL ratio rose during the two Phases and these changes were significant during Phase A. The effects of EO demonstrated in this study are consistent with previous reports. Cyproterone acetate, however, has properties conventionally ascribed to both synthetic androgens (e.g. lowering of HDL2) and oestrogens (e.g. lowering of LDL). The limitations of the terms androgenic and oestrogenic activity in relation to their conventional associations with changes in lipid and lipoprotein levels are discussed.
INAPPROPRIATE THYROTROPHIN SECRETION, INCREASED DOPAMINERGIC TONE AND PRESERVATION OF THE DIURNAL RHYTHM IN SERUM TSH
Authors: MAGEE B. , SHERIDAN B. , SCANLON M. F. , ATKINSON A. B.
Published: March 2008

A patient presented with mild hyperthyroidism, elevated serum T4 and T3, and an inappropriately raised serum thyrotrophin (TSH). There was no evidence of pituitary tumour (alpha‐subunit secretion and CT scan of the pituitary were normal). The TSH response to TRH was greater than normal. The elevated TSH was suppressed by oral triiodothyronine (100 μg daily for 10 d). The normal diurnal variation of TSH was preserved. Intravenous injection of the dopamine receptor blocking agent domperidone led to a greater than normal elevation in TSH (maximum increments 18‐20 mU/1). This increased dopaminergic tone was similar in studies carried out in the morning and late evening. The dopamine agonist bromocriptine (2·5 mg twice daily) failed to suppress serum TSH either acutely or over 6 weeks. The circadian rhythm was unaltered by this treatment. Basal serum prolactin levels were normal, and responded appropriately to TRH, domperidone and bromocriptine. These observations indicate that dopamine does not control the diurnal variation of TSH in nontumoral TSH‐mediated hyperthyroidism. The increased dopaminergic tone demonstrated may be secondary to the primary failure of pituitary‐thyroid feedback in the condition.
DEPOT‐BROMOCRIPTINE TREATMENT FOR PROLACTINOMAS AND ACROMEGALY
Authors: GROSSMAN A. , ROSS R. , WASS J. A. H. , BESSER G. M.
Published: March 2008

Fifteen patients with hyperprolactinaemia and pituitary macroadenomas (5 patients), microadenomas (6 patients), or acromegaly (4 patients) were given a single intramuscular injection of 50 mg bromocriptine bound to polylactic acid microspheres, depot‐bromocriptine. None of the patients had any short‐term or long‐term discomfort from the injection. In the 11 patients with prolactinomas, serum prolactin fell to minimum levels 12–72 h post‐injection; nine patients were highly responsive to depot‐bromocriptine, with a mean serum prolactin of 12·9% of basal levels 24 h post‐injection, rising to 19% at 28 days. Two patients with prolactinomas were resistant to both depot‐bromocriptine, and large doses of oral dopamine agonists. Initiating side‐effects (nausea, vomiting, symptomatic postural hypotension) were seen in five patients in the first 24 h post‐injection, but were minimal or absent thereafter. Five of six patients previously intolerant of oral dopamine agonists were able to be transferred successfully to bromocriptine 5 mg daily at 4 weeks. Of the four patients with acromegaly, raised prolactin levels were successfully lowered to normal for 4 weeks after injection; serum GH was also partially lowered, but returned to baseline levels at 2–4 weeks. In one patient serum GH was resistant to suppression by both depot bromocriptine and high doses of oral bromocriptine. One patient with a large tumour and visual field defects showed a rapid and maintained improvement in visual fields and acuity after depot‐bromocriptine, and was successfully transferred to high‐dose oral bromocriptine at 4 weeks. In the total group of 15 patients, computed tomography (CT) scans showed clear tumour shrinkage in seven patients 4 weeks post‐injection. It is concluded that depot‐bromocriptine is a significant improvement in the initiation of treatment for hyperprolactinaemia and acromegaly. It allows the rapid diagnosis of bromocriptine resistance, and the initiation onto oral dopamine agonist therapy of some patients said to be intolerant of such therapy. Furthermore, it may well be the treatment of choice for rapid shrinkage of large pituitary tumours sensitive to dopamine agonist therapy.
DEVELOPMENT AND APPLICATION OF A MID‐REGION SPECIFIC ASSAY FOR HUMAN PARATHYROID HORMONE
Authors: GLEED J. H. , HENDY G. N. , NUSSBAUM S. R. , ROSENBLATT M. , O'RIORDAN J. L. H.
Published: March 2008

A new peptide spanning residues 28–54 of human parathyroid hormone (PTH) was synthesized and used to develop a homologous immunoradiometric assay specific for the mid‐region of human PTH. The peptide was coupled to cellulose and used to adsorb mid‐region antibodies from a goat antiserum against intact human PTH. This assay has been applied to the measurement of circulating PTH in man: in normal subjects the concentration in serum ranged from undetectable (> 40 pg/ml) to 70 pg/ml, the reference standard being the human PTH 28–54 peptide. In patients with primary hyperparathyroidism concentrations ranged from 120 to 1800 pg/ml. Hormone was not detected in patients with hypoparathyroidism. In normal subjects and in patients with primary hyperparathyroidism the mid‐region PTH concentrations were similar to those obtained in an aminoterminal specific assay. By contrast, carboxy‐terminal PTH concentrations were markedly higher being 10‐fold greater in both groups studied. In patients with primary hyperparathyroidism undergoing parathyroidectomy and in chronic renal failure patients who were infused with calcium, mid‐region and aminoterminal PTH disappeared much more rapidly than carboxy‐terminal PTH. However, although mid‐region PTH was initially cleared as quickly as aminoterminal PTH, it then reached a plateau and remained at a higher level. Thus the mid‐region specific assay described here is proving to be of value in the study of the secretion and metabolism of PTH.
DEVELOPMENT OF A CYTOCHEMICAL ASSAY FOR PLASMA VASOPRESSIN: APPLICATION TO STUDIES ON WATER LOADING NORMAL MAN
Authors: BAYLIS P. H. , PIPPARD C. , GILL G. V. , BURD J.
Published: March 2008

A cytochemical assay has been developed to measure human plasma arginine vasopressin. It is based on the stimulation of Na+‐K+, ATPase activity located in the outer medulla of the rat kidney, and is capable of detecting very low plasma arginine vasopressin concentrations, limit of detection 0·01 pmol/l. Specificity for vasopressin stimulation of the enzyme is conferred on the assay by the use of specific vasopressin antiserum. Index of precision of the assay is 0·21. Degradation of arginine vasopressin in plasma in inhibited by phenanthro‐line. Samples may be stored up to 8 weeks at ‐ 70°C. Intra‐ and inter‐assay coefficients of variation were 22% (n= 8) and 104% (n=12), respectively. A sustained water load in eight healthy male adults caused a fall in plasma osmolality from a basal of 286·5±2·0 (mean±SEM) to 279·2 ± 2·4 mmol/kg after the load (P> 0.001), which was associated with a reduction in urine osmolality from 867 ± 54 to 69 ± 3 mmol/kg. Plasma immunoreactive arginine vasopressin fell from 1·3 ± 0·3 pmol/l to become undetectable (<0.3 pmol/l), but plasma cytochemical arginine vasopressin decreased from 0·96 ± 0·14 to 0.07 ± 0.02 pmol/l. There was a curvilinear relationship between plasma osmolality and plasma cytochemical arginine vasopressin, which militated against the concept of an osmotic threshold for vasopressin release.
HUMAN PANCREATIC GROWTH HORMONE RELEASING HORMONE FAILS TO STIMULATE HUMAN GROWTH HORMONE BOTH IN CUSHING'S DISEASE AND IN CUSHING'S SYNDROME DUE TO ADRENOCORTICAL ADENOMA
Authors: SMALS A. E. M. , PIETERS G. F. F. M. , SMALS A. G. H. , BENRAAD TH. J. , KLOPPENBORG P. W. C.
Published: March 2008

An absent or severely blunted hGH response to an i.v. bolus injection (100 μg) of human pancreatic growth hormone releasing hormone (hpGRF1–44) was found in seven female patients with Cushing's syndrome (five with pituitary dependent Cushing's disease and two due to an adrenal adenoma) and four men with pituitary dependent Cushing's disease. Three of the female and three of the male patients had an adequate hypoglycaemia after insulin administration. All these patients showed an absent or blunted hGH response after insulin induced hypoglycaemia. The GHRH data in these patients are in agreement with those in older literature on hGH responsiveness to stimuli such as L‐dopa, arginine and insulin induced hypoglycaemia. It is concluded that hypercortisolism inhibits hGH release to various stimuli at the pituitary level.
HUMAN PLATELET ARGININE VASOPRESSIN
Authors: NUSSEY S. S. , ANG V. T. Y. , BEVAN D. H. , JENKINS J. S.
Published: March 2008

Approximately 90% of arginine vasopressin circulating in blood is associated with the platelets. Studies in six patients with cranial diabetes insipidus indicate that the platelet vasopressin originates in the hypothalamus and is taken up from plasma. Extracted platelet vasopressin is chromatographically identical to the posterior pituitary peptide and biologically active. Infusion of low‐doses of exogenous vasopressin into 10 normal male subjects caused a marked rise in both plasma and platelet hormone concentrations. Stimulation of endogenous vasopressin release by hypertonic saline (0·51 mol/l) infusion for 135 min in five male subjects also caused a rise in platelet and plasma peptide concentrations. In seven male smokers, the deep inhalation of two consecutively smoked unfiltered cigarettes caused a significant rise in both platelet and plasma vasopressin. Baseline platelet vasopressin concentrations in the smokers were higher than in the non‐smoking males even after 10 hours abstinence.
COMPARATIVE EVALUATION OF CYCLIC AMP AND IODIDE ACCUMULATION RESPONSES TO THYROID‐STIMULATING IMMUNOGLOBULINS IN CULTURED FRTL‐5 CELLS
Authors: BIDEY S. P. , EKINS R. P.
Published: March 2008

The rat thyroid cell strain FRTL‐5 was used to investigate the relationship between cyclic AMP and iodide accumulation responses to thyroid‐stimulating immunoglobulins (TSIg). Immunoglobulin G‐enriched precipitates of sera from 19 of 21 (90%) newly‐diagnosed Graves' disease patients gave significant (P > 0.01) accumulation of iodide (125I), and 16 of these also stimulated intracellular cyclic AMP. Correlation was poor however, with certain TSIg preparations giving widely divergent responses. After initiation of antithyroid treatment, 40% of sera investigated contained TSIg detectable in both bioassay systems, and all but one of the remainder were stimulatory in one of the two bioassays. All patients in remission were devoid of detectable TSIg as determined by iodide accumulation, although a single preparation stimulated cyclic AMP accumulation. LATS‐B, a lyophilized reference serum preparation containing high TSIg activity, enhanced iodide accumulation, which showed evidence of correlation with intracellular cyclic AMP at doses above 0.5 mU/ml. At lower doses, iodide accumulation was observed in the absence of detectable cyclic AMP accumulation. TSH and LATS‐B‐induced iodide accumulation were enhanced, and iodide efflux reduced, by the anion channel blocker 4–4 diisothiocyanate stilbene 2,2′ disulphonic acid (DIDS). In contrast, Ig‐enriched fractions of normal sera decreased both basal and stimulated iodide accumulation, but were without effect on efflux. TSIg from untreated Graves' sera gave widely‐differing iodide accumulation responses which showed poor correlation with both intracellular cyclic AMP and cyclic‐AMP‐ independent iodide efflux. This clear dissociation of responses to serum Ig preparations suggests that iodide uptake in FRTL‐5 cells, which do not organify iodide, may be subject to variable effects of non‐TSIg components of Graves' sera, on both iodide uptake itself, and as inhibitors of TSIg‐induced accumulation of intracellular cyclic AMP.
SERUM IMMUNOREACTIVE SOMATOMEDIN‐C LEVELS IN GROWTH FAILURE AND DELAYED PUBERTY ASSOCIATED WITH CHRONIC HEPATOSPLENIC SCHISTOSOMIASIS
Authors: CAVALIERE H. , LEITE Z. , MEDEIROS‐NETO G.
Published: March 2008

Eleven patients, five males, six females, aged 14–20 years with hepatosplenic schistosomiasis (HSS), growth failure and delayed puberty were submitted to endocrine evaluation. All patients had well preserved parenchymal liver function although several changes were present in the portal system, showing a poorly vascularized liver. Bone age was retarded, thyroid function was normal, the human growth hormone response to hypoglycaemia was within the normal limits and the prolactin response to TRH was normal. LH and FSH basal levels were normal and a normal rise was observed after a provocative test with LHRH. Gonadal function, expressed as serum testosterone or oestradiol levels, was abnormally low for the chronological age. Serum somatomedin‐C levels were also low (range 0·11–2·10 U/ml) for the respective Tanner stage or bone age of each individual patient. One year after a splenorenal shunting in the three patients that returned for follow‐up, it was observed that sexual maturation reached Tanner stage III, linear growth increment ranged from 9·0 to 11·5 cm and serum somatomedin‐C levels increased to 4·3–5·6 U/ml. We concluded that a combination of undernutrition and marked vascular changes in the liver, present in HSS, are associated with decreased serum sex steroids and somatomedin‐C concentrations, resulting in growth failure and delayed puberty in these patients.
EFFECTS OF HIGH DOSE KETOCONAZOLE THERAPY ON THE MAIN PLASMA TESTICULAR AND ADRENAL STEROIDS IN PREVIOUSLY UNTREATED PROSTATIC CANCER PATIENTS
Authors: DE COSTER R. , CAERS I. , COENE M.‐C. , AMERY W. , BEERENS D. , HAELTERMAN C.
Published: March 2008

In vitro, ketoconazole has been shown to block testicular and adrenal 17,20‐lyase, which converts progestins to androgens. At higher concentrations, it also inhibits 11β‐hydroxylase, 20,22‐desmolase and 17α‐hydroxylase. To determine the differential hormonal effects of a 2‐week ketoconazole high‐dose therapy, the plasma levels of 10 major androgens, gluco‐ and mineralocorticoids were measured in 14 previously untreated patients with metastatic prostate cancer. Within 24 h, plasma testosterone fell from 14·6 ± 1·4 nmol/l (mean ± SEM) to 3·7 ± 0·7 nmol/l. Thereafter, it decreased to about 2·5 nmol/l and remained at that level. Plasma androstenedione and dehydroepiandrosterone decreased more gradually, respectively from 3·1 ± 0·4 nmol/l to 0·64 ± 0·17 nmol/l and from 6·6 ± 1·0 nmol/l to 2·82 ± 0·55 nmol/l (on day 14). In contrast, 17α‐hydroxyprogesterone and progesterone rose respectively 2‐ and 5‐fold. Plasma cortisol and aldosterone levels remained unchanged whereas 11‐deoxycorticosterone and 11‐deoxycortisol rose by factors of 14 and 6·7 respectively. Plasma corticosterone also increased, but to a much lesser extent (3‐fold). These results demonstrate that ketoconazole high dose therapy blocks mainly the 17,20‐lyase of both adrenal and testis. In addition it inhibits mitochondrial 11β‐hydroxylase to a lesser extent. The inhibition of 20,22‐desmolase also seems to be of little clinical relevance. However, since clinical or laboratory symptoms suggestive of hypo‐adrenalism have been reported in a small minority of patients, replacement therapy should be considered in such cases.
EFFECTS OF SOMATOSTATIN ANALOGUE SMS 201–995 IN NORMAL MAN
Authors: DAVIES R. R. , MILLER MARGARET , TURNER S. J. , GOODSHIP T. H. J. , COOK D. B. , WATSON M. , McGILL A. , ØRSKOV H. , ALBERTI K. G. M. M. , JOHNSTON D. G.
Published: March 2008

Long‐acting somatostatin analogues may be of benefit in certain hypersecretory endocrine and gastrointestinal disorders. The 24 h hormonal and metabolic profiles of six normal male subjects receiving a twice daily subcutaneous injection of one such analogue SMS 201–995, 50 μg, has been compared to that obtained following placebo injection. Spontaneous daytime peaks of GH secretion were delayed until 1400 h following SMS 201–995 but nocturnal and total 24 h GH secretion were unaffected. The nocturnal rise in thyrotrophin was abolished by SMS 201–995 but thyroid function was unaffected. Insulin levels were suppressed following SMS 201–995 and the response to meals was inhibited. Glucose intolerance followed main meals. Glucagon levels were suppressed for up to 6 h. Circulating alanine levels were raised between 1200 h and 0600 h and there were intermittent elevations in lactate, pyruvate, glycerol and 3‐hydroxybutyrate. Amino acid levels, including branched chain amino acids, were also increased. All six subjects suffered gastrointestinal side‐effects. SMS 201–995, 50 μg, given twice daily shortly before meals does not suppress 24 h GH secretion, but demonstrates significant effects on metabolism and causes side effects in normal subjects.
THE LONG‐TERM EFFECTS OF MEGAVOLTAGE RADIOTHERAPY AS SOLE OR COMBINED THERAPY FOR LARGE PROLACTINOMAS: STUDIES WITH HIGH DEFINITION COMPUTERIZED TOMOGRAPHY
Authors: JOHNSTON D. G. , HALL K. , KENDALL‐TAYLOR P. , ROSS W. M. , CROMBIE A. L. , COOK D. B. , WATSON M. J.
Published: March 2008

The long‐term sequelae of external pituitary irradiation alone or in combination with surgery and/or bromocriptine therapy have been studied in 14 patients with large prolactinomas over an observation period of 6–22 years (mean 13 years). Galactorrhoea was abolished in four of the five females with this symptom, but menstrual disturbance persisted in five of six patients. Sexual function was normal without sex hormone replacement in only one of the eight males after treatment. Neurological deficits were abolished or improved by treatment in all 9 patients with this presentation. Serum prolactin levels declined after treatment (P > 0·001) and fell to within the normal range off bromocriptine therapy in six of the 14 patients at a mean of 9 years (range 5–17 years) after radiotherapy. All patients had anterior pituitary deficiency of some degree at reassessment, and 13 required replacement treatment. Serial skull radiographs revealed remineralization of the fossa floor in five patients and a decrease in fossa size in three. All five patients who did not also have surgery had evidence of tumour shrinkage without bromocriptine treatment (on CT scan or metrizamide cisternography). Fourth generation CT scans on completion of the study revealed a decrease in tumour mass in all patients, with varying degrees of empty sella in 13 and a cystic intrasellar tumour in the remaining one. Residual tumour was demonstrated in 10 patients, three of whom had normal serum prolactin levels, while one patient without visible tumour had persistent hyperprolactinaemia. Radiotherapy, alone or in combination with surgery and bromocriptine, effectively decreases prolactin secretion and tumour size in patients with large prolactinomas at the expense of other anterior pituitary function. Circulating prolactin levels are a poor marker of residual tumour volume.
A STUDY OF CORTICOTROPH ADENOMAS IN CUSHING'S DISEASE: NO EVIDENCE OF INTERMEDIATE LOBE ORIGIN
Authors: McNICOL ANNE M. , TEASDALE G. M. , BEASTALL G. H.
Published: March 2008

There is little evidence for a separate functional or anatomical intermediate lobe in the adult human pituitary gland. Nevertheless, Lamberts et al. (1982) proposed that a subgroup of corticotroph adenomas in Cushing's disease arise in that lobe and can be identified by the presence of argyrophil (? neural) fibres, and that these tumours are more often associated with corticotroph hyperplasia and hyperprolactinaemia than those arising in the anterior lobe. We have examined a series of corticotroph adenomas from patients with Cushing's disease for evidence of argyrophil fibres, and have correlated this with tumour site, corticotroph distribution in the para‐adenomatous gland, serum PRL levels and PRL immunoreactive cells in the tumour. Argyrophil fibres were identified not only in tumours adjacent to the posterior lobe, but also in tumours situated deep in the anterior lobe. There was no correlation between the presence of fibres or the site of the tumour and corticotroph hyperplasia. Whilst the two patients with the highest serum PRL levels did have argyrophil fibres they also had a subpopulation of PRL immunoreactive cells in the tumour. On the basis of these results, we propose that the ‘intermediate lobe’ hypothesis as outlined above should not be accepted.
STUDIES OF HYPOTHALAMIC PITUITARY STRUCTURE AND FUNCTION IN PATIENTS PREVIOUSLY TREATED WITH BILATERAL ADRENALECTOMY ALONE FOR CUSHING'S DISEASE
Authors: BEACOM R. , ATKINSON A. B. , KENNEDY A. L. , SHERIDAN B. , HADDEN D. R. , MERRETT J. D. , McILRATH E.
Published: March 2008

A controversy still exists in regard to hypothalamic pituitary function long‐term after cure of hypercortisolism due to Cushing's disease. In an attempt to resolve this controversy, we have studied 15 patients, treated at least 6 years previously, by bilateral adrenalectomy. None of these patients had had pituitary‐directed therapy. The maximum increment response of serum TSH in response to TRH was < 5 mU/l in 13 of the 15. Serum PRL response to TRH, GH response to insulin‐induced hypoglycaemia, gonadotrophin responses to LHRH and nocturnal PRL secretion were normal in all patients studied. When nocturnal GH secretion was corrected for age, body mass index and menopausal status it was definitely abnormal in only two patients. The mean nocturnal GH secretion did not differ from that measured in a control group of Addisonian patients. The series of patients also did not differ significantly from the Addisonian patients in relation to the pattern of changes in plasma ACTH, over 24 h after an 0800 h oral dose of hydrocortisone. There was a significant rise in plasma ACTH between 2200 h and 0600 h in both groups of patients. The plasma ACTH concentrations were significantly higher in post‐adrenalectomy patients. Hypothalamic pituitary function is normal in the long‐term in the majority of patients treated by bilateral adrenalectomy for Cushing's disease.
PITUITARY PRO‐OPIOMELANOCORTIN‐CELL CARCINOMA OCCURRING IN CONJUNCTION WITH A GLIOBLASTOMA IN A PATIENT WITH CUSHING'S DISEASE AND SUBSEQUENT NELSON'S SYNDROME
Authors: GABRILOVE J. L. , ANDERSON P. J. , HALMI N. S.
Published: March 2008

Pituitary carcinoma is defined as a malignant pituitary tumour associated with blood‐ or lymph‐borne metastases. Cushing's disease is frequently present in patients with this condition. After adrenalectomy for Cushing's disease, a 37‐year‐old man developed Nelson's syndrome resulting from a pituitary carcinoma with metastases to the spinal cord, cauda equina, heart, liver, and pancreas. The primary tumour and its metastases showed immunocytochemical staining for ACTH, β‐lipotrophin, and variably for β‐endorphin and α‐melanocyte stimulating hormone (α‐MSH). A coincidental glioblastoma was also present. Nine cases of Cushing's disease associated with pituitary carcinoma, including the present patient, are documented in the literature. The case reported is only the second in which immunohistochemical staining of the primary pituitary tumour and its metastases was performed, and the first in which ACTH‐related peptides, in addition to ACTH itself, were demonstrated in the carcinoma cells.
EFFECT OF THE ANTI‐THYROID DRUG METHIMAZOLE ON INTERLEUKIN‐1 AND INTERLEUKIN‐2 LEVELS IN VITRO
Authors: WEETMAN A. P.
Published: March 2008

There is now good evidence that anti‐thyroid drugs such as methimazole have immunomodulatory effects which may be important in the treatment of patients with Graves' disease, but the immunological mechanisms by which these agents act are not clear. This study has examined the effect of methimazole on four important soluble mediators of the immune response, interleukin‐1 (IL‐1), interleukin‐2 (IL‐2), γ‐interferon (γ‐IFN) and B‐cell differentiation factor (BCDF). When peripheral blood mononuclear cells from normal subjects were stimulated with mitogens (phytohaemagglutinin, concanavalin A or pokeweed mitogen) in the presence of 10–100 μmol/l methimazole, there was an increase in IL‐2 activity in the culture supernatants. This effect was apparent between 24 and 60 h: enhanced proliferation of T‐cells was also seen in methimazole‐supplemented cultures. There was no effect of the drug on IL‐2 receptor expression or on IL‐1 and γ‐IFN production. BCDF was increased by methimazole in one of three experiments with pokeweed mitogen but not in three experiments with concanavalin A. These results suggest that the enhancement of mitogen‐stimulated T‐cell proliferation in vitro with methimazole is due to an increase in the IL‐2 available to the T‐cells in these cultures. Thus the in‐vivo immunological effects of these drugs are likely to be complex since they may have at least two, possibly related, actions on the intrathyroidal lymphoid infiltrate, namely inhibiting oxygen radical generation and increasing IL‐2 levels.
POSTOPERATIVE PLASMA GH LEVELS AND RESTORATION OF GH DYNAMICS IN ACROMEGALIC PATIENTS SURGICALLY TREATED BY THE TRANSSPHENOIDAL APPROACH
Authors: KARASHIMA T. , KATO K. , NAWATA H. , IKUYAMA S. , IBAYASHI H. , NAKAGAKI H. , KITAMURA K.
Published: March 2008

In 44 patients with acromegaly treated by transsphenoidal pituitary microsurgery, the relationship between changes in pre‐ and post‐operative GH dynamics and postoperative fasting plasma GH levels was examined to clarify which is the optimal approach for evaluating postoperative removal of the tumour. TRH, LHRH and bromocriptine tests, which act directly on the pituitary somatotroph, and the oral glucose tolerance test (oGTT) and insulin tolerance test (ITT), which act via hypothalamus, were carried out pre‐ and post‐operatively. Abnormal responses postoperatively were found in most patients with fasting postoperative plasma GH over 5 ng/ml. In 24 patients with postoperative fasting plasma GH level of 5 ng/ml or below, 7 of 17 (41%) showed abnormal responses in the TRH test, 2 of 5 (40%) in the LHRH test and 3 of 13 (23%) patients in the bromocriptine test. All patients with a fasting plasma GH level less than 10 ng/ml, except for those with panhypopituitarism, showed normal responses to ITT and the paradoxical increases with the oGTT were absent. These results indicate that abnormal responses caused by a direct action on adenoma cells do not necessarily disappear even when the fasting plasma GH level is below 5 ng/ml. Abnormal responses caused by indirect actions, through the hypothalamus, disappear when the level is less than 10 ng/ml.
GROWTH HORMONE SECRETING PITUITARY ADENOMAS ARE HETEROGENEOUS IN CELL CULTURE AND COMMONLY SECRETE GLYCOPROTEIN HORMONE α‐SUBUNIT
Authors: WHITE M. C. , NEWLAND P. , DANIELS M. , TURNER S. J. , MATHIAS D. , TEASDALE G. , KENDALL‐TAYLOR P.
Published: March 2008

Cell culture methods were used to assess whether human pituitary adenomas secreting GH and associated with clinical acromegaly also secreted the structurally unrelated glycoprotein hormone α‐subunit. Thirty‐two tumours, together with peri‐adenomatous tissue from two of them and three normal pituitaries were studied. Anterior pituitary hormones were measured by radioimmunoassay and included PRL, TSH, LH, FSH, and ACTH, as well as GH and α‐subunit. Normal pituitary tissues secreted all hormones assayed. All 32 tumours secreted GH ranging from 241 to 5556 ng/2 × 105 cells/24 h and 12 (37·5%) secreted α‐subunit in amounts which could not be accounted for by cross‐reaction of other hormones or contamination by normal pituitary tissue, and which ranged from 10·3 to 73·5 ng/2 × 105 cells/24 h. Ten other tumours also secreted α‐subunit but in very small amounts, not exceeding 1·8 ng/2 × 105 cells/ 24 h. PRL was secreted from 21 tumours (6679, and small amounts of other hormones, chiefly LH and TSH, were occasionally secreted from tumours. These cell culture studies would suggest that pituitary adenomas causing acromegaly are hormonally heterogeneous and that PRL and glycoprotein a‐subunit are commonly detected in addition to GH.
α‐HUMAN ATRIAL NATRIURETIC POLYPEPTIDE REDUCES THE PLASMA ARGININE VASOPRESSIN CONCENTRATION IN HUMAN SUBJECTS
Authors: FUJIO N. , OHASHI M. , NAWATA H. , KATO K. , IBAYASHI H. , KANGAWA K. , MATSUO H.
Published: March 2008

The synthetic α‐human atrial natriuretic polypeptide (α‐hANP) was infused into six normotensive, euvolaemic, healthy volunteers to examine the effect on the plasma arginine vasopressin (AVP) concentration. The intravenous administration of α‐hANP (0·1 μg/kg/min, 20 min) led to a remarkable reduction in mean blood pressure (‐10 mmHg, P>0·05), and there was an increase in pulse rate (+ 10 bpm, P>0·05), in each subject. The urinary volume, sodium excretion and cyclic 3′, 5′‐guanosine monophosphate (cyclic‐GMP) excretion were increased to 3·5 (P>0·05), 2·5 (P>0·05) and eight‐fold (P>0·01), respectively, during the α‐hANP infusion. The dose and duration of the synthetic α‐hANP in the present study was sufficient to induce these cardiovascular and renal effects. The plasma AVP concentrations decreased from 0·39 ± 0·09 pg/ml to the undetectable level during the α‐hANP administration. After infusion, the plasma concentrations of the AVP promptly returned to preinfusion levels (0·46 ± 0·14 pg/ml). However, there was no significant change in plasma AVP concentration during placebo infusion. The marked suppression in plasma AVP concentration may account for the remarkable diuresis, in addition of the direct renal effects of the synthetic α‐hANP.
ANTIPYRINE CLEARANCE IN CONGENITAL ADRENAL HYPERPLASIA
Authors: LOCHE S. , RIFKIND ARLEEN B. , STONER ELIZABETH , CONNEY A. H. , NEW MARIA I.
Published: March 2008

Antipyrine (AP) metabolism was studied in four adult patients with congenital adrenal hyperplasia (CAH) due to classical 21‐hydroxylase deficiency and in four (adult) patients with CAH due to non‐classical 21‐hydroxylase deficiency. This investigation was prompted by the known biochemical and functional similarities between drug‐ and steroid‐metabolizing enzymes. We hypothesized that a common genetic mechanism may regulate the expression and activity of both the adrenal and hepatic cytochrome P450 enzymes. AP half‐lives (T1/2, mean ± SD) were 10·7 ± 2·1 h in classical CAH patients, 10·1 ± 0·4 h in the non‐classical CAH patients and 10·9 ± 2·2 h in the control group, suggesting that there was no significant difference in AP metabolism among the three groups. Similarly, no significant differences were found in the AP apparent volume of distribution (aVd) and metabolic clearance rate (MCR) among the three groups. These results indicate that despite the deficiency of adrenal cytochrome P450 in patients with 21‐hydroxylase deficiency CAH, these individuals have normal hepatic drug metabolizing activity for the biotransformation of AP.
NURSING BEHAVIOUR, PROLACTIN AND POSTPARTUM AMENORRHOEA DURING PROLONGED LACTATION IN AMERICAN AND KUNG MOTHERS
Authors: STERN JUDITH M. , KONNER M. , HERMAN TALIA N. , † S. REICHLIN
Published: March 2008

In order to determine the effects of protracted nursing in American women, blood was collected hourly for 24 h and nursing periods recorded in 20 mothers, 10 amenorrhoeic, 3 3/4 to 17 1/4 months postpartum (PP), and 10 menstruating, 5 1/4 to 46 months PP. These data were compared to the daytime nursing behaviour and 1000–1100 h PRL of women among Kung hunter‐gatherers of Botswana, a non‐contraceptive using population with a birth space interval of < 3 years. Intense nursing behaviour maintained amenorrhoea and hyperprolactinaemia for 1 to nearly 2 years PP in both American and Kung mothers. Among Americans, 80 min of nursing per day, in conjunction with a minimum of six nursing episodes, was highly predictive of remaining amenorrhoeic up to 18 months PP. Amenorrhoea was always accompanied by hyperprolactinaemia, but delay in the onset of menses was related more to nursing behaviour than to a particular 24 h PRL level. The 1000–1100 h sample is equivalent to and about half of the 24 h mean in high and low intensity nursers, respectively. The Kung women were similar to the high intensity nursing American women in 1000–1100 h PRL, percent amenorrhoeic, and the number of minutes of daytime nursing.
TRANSIENT HYPOGONADOTROPHIC HYPOGONADISM AFTER HEAD TRAUMA: EFFECTS ON STEROID PRECURSORS AND CORRELATION WITH SYMPATHETIC NERVOUS SYSTEM ACTIVITY
Authors: WOOLF P. D. , HAMILL R. W. , McDONALD J. V. , LEE LOUYSE A. , KELLY MARY
Published: March 2008

Transient hypogonadotrophic hypogonadism commonly occurs after major medical insults. Because data on testosterone precursors are sparse and because little is known about the aetiology of these changes, we studied the interactions of traumatic brain injury with gonadal steroidogenesis and with sympathetic nervous system activation. Patients were divided into two groups based upon the severity of neurological dysfunction using the Glasgow Coma Score (GCS); Group 1 > 8, Group 2 ≥ 8. Group 1 was further divided into those patients treated (Group 1b) and those not treated with dexamethasone (Group 1a). Plasma levels of testosterone, androstenedione, 17‐hydroxyprogesterone, DHEA sulphate, cortisol, LH, FSH, and the catecholamines noradrenaline (NE), adrenaline (EPI) and dopamine were measured in 31 acutely brain injured men, aged 18–95, shortly after their accident and 4 days later. In all patients, NE and EPI were elevated on admission (NE: 841 ± 105 (SEM) pg/ml; EPI: 191 ± 32 pg/ml and there were highly significant inverse correlations between admission NE (r=−0·52, P > 0·003) and EPI (r=0·44, P > 0·02) levels and day 4 testosterone concentrations. Testosterone fell 53% (P>0·001) in 13 Group la men, but only 25% (P=NS) in the less severely injured. Similar reductions occurred in cortisol and the steroid precursors. However, only testosterone, 17‐hydroxyprogesterone, and DHEA sulphate levels were significantly lower than normal on day 4. LH and FSH levels were also significantly reduced from elevated admission levels. In the eight men treated with dexamethasone (8–40 mg/ml) (Group 1b), the decrease in testosterone, LH and FSH concentrations were similar to those present in Group 1a. Thus, severe traumatic brain injury leads to hypogonadotrophic hypogonadism which affects testosterone and its precursors. The magnitude of the hormonal dysfunction is dependent upon the severity of the neurological insult. Finally, the decrease in testosterone is significantly correlated with admission catecholamine levels, which may suggest a role for the sympathetic nervous system (SNS) in mediating this response in men.
CHARACTERIZATION OF TSH ANTAGONIST ACTIVITY IN THE SERUM OF PATIENTS WITH THYROID DISEASE
Authors: HASHIM F. A. , CREAGH F. M. , EL HAWRANI A. , PARKES A. B. , BUCKLAND P. R. , SMITH B. REES
Published: March 2008

The ability of sera from patients with thyroid disease to block TSH stimulation of cyclic AMP release from isolated porcine thyroid cells has been assessed and the blocking activity characterized. TSH receptor binding activity was also measured. No blocking or receptor binding activity was detectable in patients with primary myxoedema (n= 23), Hashimoto's disease (n= 11), multinodular goitre (n= 6), or rheumatoid arthritis (n= 10). However, analysis of sera from 23 patients (out of an initial screen of 110 patients) with treated Graves' disease which did not stimulate cyclic AMP production in the bioassay showed that two of these sera contained powerful blocking and receptor binding activity. Both these patients had been treated with 131I, Analysis of the two sera by gel filtration on Sephadex G‐200 indicated that blocking and TSH receptor binding activity were associated only with the IgG fraction. Digestion of the IgG with pepsin followed by reduction showed that both (Fab)2 and Fab fragments contained high levels of blocking and binding activity. Antibody divalency was not necessary therefore for TSH antagonist activity. However, our studies suggest that autoantibodies of this type with TSH antagonist activity do not occur frequently in patients from the Cardiff region with primary myxoedema, Hashimoto's or treated Graves' disease.