bluuebunny/crossref_metadata_2025 huggingface dataset:
THYROID STIMULATING ANTIBODIES: AN AID TO THE STRATEGY OF TREATMENT OF GRAVES' DISEASE?
Authors: MADEC A. M. , LAURENT M. C. , LORCY Y. , GUERRIER A. M. LE , ROSTAGNAT‐STEFANUTTI A. , ORGIAZZI J. , ALLANNIC H.
Published: March 2008

In 1976 we initiated a prospective study to specify the usefulness of thyroid stimulating antibody (TSAb) determinations in predicting the outcome of post‐antithyroid drug treatment for Graves' disease. This study was carried out on 55 patients, who were either treated for six (n= 16) or 18 months (n= 39) and followed up for an additional two‐year period. TSAb was determined on whole serum in 29 patients before and at the end of treatment, and in 26 patients at the end of treatment only. These determinations were carried out using a sensitive and reproducible microassay based on cAMP accumulation in human thyroid cell cultures. Before treatment, TSAb ranging from 170 to 1529% was present in 28/29 patients and reached significantly low levels at the end of treatment whatever its duration. TSAb was undetectable in 24/55 patients at the end of treatment. 8/16 'short‐treated’ and 18/39‘long‐treated’ patients remained in remission. As expected, initial TSAb levels had no predictive value. End‐treatment TSAb values, when low (±350%) or negative did not correlate with later evolution: in these 39 patients, relapse rate was 41%. In contrast, 13/16 patients with end‐treatment TSAb ± 350% relapsed. Relapses tended to occur earlier in patients with the highest TSAb levels. TSAb determined again during follow‐up was negative in each of the 18 patients in remission, and positive in 8/10 patients at the time of relapse, whatever its level at the end of the drug course. This study confirms that only high end‐treatment TSAb levels are predictive of relapse. In the other cases, TSAb had no prognostic value. Overall, it was shown that TSAb levels appear to reflect only partially, the activity of the underlying disturbances of Graves' disease.
LACK OF THIRST, OSMORECEPTOR DYSFUNCTION, EARLY PUBERTY AND ABNORMALLY AGGRESSIVE BEHAVIOUR IN TWO BOYS
Authors: DUNGER D. B. , LIGHTMAN S. , WILLIAMS M. , PREECE M. A. , GRANT D. B.
Published: March 2008

Two unrelated boys (C.C. 13 years; J. W. 18 years) presenting with early puberty and episodes of aggressive behaviour were found to have hypernatraemia and hypodipsia. Plasma vasopressin (AVP) levels were inappropriately low in relation to plasma osmolality, but the patients did not have diabetes insipidus since 24 h urinary volumes were < 1 litre and the maximal urinary osmolality was 1232 in C.C. and 950 in J.W. Plasma renin activity was elevated (> 2000 mg AI/1/h) although aldosterone concentrations were normal. Excretion of a water load (20 ml/kg) was delayed, but plasma renin and aldosterone fell with increased naturesis. An infusion of 0±85 mol/l saline produced a rise in AVP in C.C. but not in J.W. Insulin and hypotension resulted in the release of AVP in both boys suggesting a selective defect of osmoreceptor function. Hyperprolactinaemia and an exaggerated PRL response to TRH were also noted but no intracranial lesion was demonstrable on CT scan. These boys appear to have a hypothalamic syndrome with early puberty, hyperprolactinaemia, hypodipsia and osmoreceptor dysfunction which may be associated with aggressive behaviour.
IMMUNOPRECIPITATION OF TSH‐TSH RECEPTOR COMPLEXES
Authors: PARKES A. B. , KAJITA Y. , BUCKLAND P. R. , HOWELLS R. D. , RICKARDS CAROLE R. , CREAGH FIONUALA M. , SMITH B. REES
Published: March 2008

The ability of Graves' sera to interact with the TSH receptor crosslinked to a 125I‐labelled photoactive derivative of TSH has been investigated. Crosslinked complexes were prepared using non‐purified detergent solubilized human thyroid and guinea pig fat TSH receptors. Affinity purified porcine TSH receptor preparations were also used. After crosslinking, the crosslinked TSH‐TSH receptor complexes were separated from aggregates and free TSH on Sephacryl S‐300, incubated with test sera followed by immunoprecipitation using anti‐IgG or Protein A. Using non‐purified human TSH receptors crosslinked to TSH, a mean ± SD of 12±· 4·9% of the crosslinked complex was immunoprecipitated with Graves' sera (n= 7) compared with 10·3 · 2·6% with Hashimoto sera (n= 6; P > 0±4) and 3·8 · 1·0% with normal sera (n= 6; P < 0·004). These values were markedly reduced when TSH receptor preparations free of other thyroid autoantigens (guinea pig fat TSH receptors) were used. Under these conditions immunoprecipitation with Graves' sera (n= 24) was 1·6 · 1·3% compared with 0·8 · 0·6% for Hashimoto sera (n= 13) and 0·8 · 0·4% for normal sera (n= 2; P= 0·003). In addition complexes formed between TSH and affinity purified porcine TSH receptors gave low immunoprecipitation values for Graves' (1·44 · 0·73%; n= 20) and Hashimoto sera (1·7 · 0·94; n= 11) which were not significantly different (P= 0·4). Overall, therefore, the effects of Graves' and Hashimoto sera were similar and the amounts of material immunoprecipitated were markedly reduced when TSH receptor preparations containing reduced amounts of other autoantigens were used. Consequently the Graves' sera did not appear to interact specifically with crosslinked TSH‐TSH receptor complexes. However the Graves' sera studied did contain TSH receptor antibodies which could inhibit the binding of labelled TSH to TSH receptors in the preparations used and our results suggest that the binding of TSH and these antibodies to the receptor is mutually exclusive.
CONGENITAL 11β‐HYDROXYSTEROID DEHYDROGENASE DEFICIENCY ASSOCIATED WITH JUVENILE HYPERTENSION: CORTICOSTEROID METABOLITE PROFILES OF FOUR PATIENTS AND THEIR FAMILIES
Authors: SHACKLETON C. H. L. , RODRIGUEZ J. , ARTEAGA E. , LOPEZ J. M. , WINTER J. S. D.
Published: March 2008

Four children with 11bT‐hydroxysteroid dehydrogenase deficiency are described. All patients had severe hypertension, hypokalaemia, and low plasma aldosterone and renin activities. Two of the patients were siblings and two were unrelated. The most noticeable biochemical feature of these individuals was the extremely low excretion of cortisol metabolites containing an 11‐carbonyl group compared to the excretion of the 11β‐hydroxyl containing metabolites. Although this condition is readily diagnosed in affected individuals by urinary steroid analysis, carriers of the defect do not differ from normal in their urinary steroids. Both parents of the affected siblings had normal 11‐oxo‐steroid/11bT‐hydroxysteroid ratios under baseline conditions and the lesions could not be revealed by ACTH administration.
ACTH AND CORTISOL RESPONSES TO OVINE CORTICOTROPHIN‐RELEASING FACTOR IN PATIENTS WITH PRIMARY AND SECONDARY ADRENAL FAILURE
Authors: HERMUS A. R. M. M. , PIETERS G. F. F. M. , PESMAN G. J. , SMALS A. G. H. , BENRAAD T. J. , KLOPPENBORG P. W. C.
Published: March 2008

The ACTH and cortisol responses to an intravenous bolus injection of 100 μg ovine CRF were studied in 19 patients with adrenal failure. In all eight patients with primary adrenal failure, plasma ACTH levels increased from a mean basal level of 1494·431 (SEM) pg/ml to a peak value of 2601±220 pg/ml at 10 min. In comparison with healthy subjects absolute ACTH increments after ovine CRF were significantly augmented in the patients with Addison's disease (P* > 0.001), and the absolute ACTH responses after ovine CRF were positively correlated with the basal plasma ACTH levels. The 11 patients with secondary adrenal insufficiency could be subdivided into two groups: (A) those having little or no ACTH and cortisol response to ovine CRF (five patients) and (B) those having prolonged and pronounced ACTH responses with a biphasic pattern and a delayed second peak (six patients), followed in all patients by a marked cortisol increase. These data demonstrate that the CRF‐test can discriminate between hypothalamic and pituitary causes of secondary adrenal failure.
THE TREATMENT OF HIRSUTISM WITH A COMBINATION OF DESOGESTREL AND ETHINYL OESTRADIOL
Authors: DEWIS P. , PETSOS P. , NEWMAN M. , ANDERSON D. C.
Published: March 2008

Some available oral contraceptive agents are unsuitable for the treatment of hirsutism since, although they suppress endogenous gonadotrophins and so ovarian androgen production, they contain a progestogen which is itself androgenic. The combination of 30 μg ethinyl oestradiol (EE2) and 150 μg desogestrel (Marvelon) does not suffer from this drawback. We have therefore assessed its value in 15 hirsute women treated for one year. Mean±SE androgen‐dependent hair growth, assessed photographically fell from 0·31 ± 0·01 to 0·23 ± 0·01 mm/d at 1 year (P< 0·001). Ten of the fifteen patients reported definite subjective improvement. Treatment was associated with a marked rise in SHBG concentration identical to that seen with 30 μg EE2 alone. By four months there were significant falls in serum levels of androstenedione and LH throughout the cycle, but not for testosterone, dihydrotestosterone or 5α‐androstane 3α, β17 ‐diol. Calculated free testosterone levels were significantly suppressed. All the biochemical changes were maintained after seven months of treatment. We conclude that this preparation is a suitable oral contraceptive for the treatment of hirsute women.
HORMONAL CHANGES IN POSTMENOPAUSAL WOMEN WITH BREAST CANCER TREATED WITH TRILOSTANE AND DEXAMETHASONE
Authors: BEARDWELL C. G. , HINDLEY A. C. , WILKINSON P. M. , ST JOHN JUDY , BU'LOCK DENISE
Published: March 2008

Postmenopausal women with metastatic breast cancer were treated with trilostane, initially 240 mg daily increasing after 3 days to 480 mg daily and after a further three days to 960 mg daily. After 3 days at this dose dexamethasone 1 mg daily was added and this combination was continued until disease progression occurred. Partial remission was seen in 26% and stabilization of previously progressive disease in a further 13% of the first twenty‐three patients studied. During therapy with trilostane alone significant increases in DHEAS, androstene‐dione, 17‐hydroxypregnenolone, progesterone, testosterone and oestradiol were seen. A significant fall in oestrone concentration occurred at the same time. After dexamethasone was added the elevated steroid concentrations fell back to the baseline while oestrone remained depressed below this and testosterone was also significantly lowered. No change was seen in cortisol or ACTH concentration while patients were on trilostane alone but cortisol levels were undetectable after dexamethasone was added though, in most patients, ACTH remained detectable. There was no change in the ratio of Δ5: Δ4 steroids at any stage of therapy but a highly significant increase in the androstenedione: oestrone ratio was seen. We conclude that in long‐term use in vivo it is difficult to demonstrate that trilostane inhibits 3β‐hydroxysteroid dehydrogenase but it may produce inhibition of aromatase.
RELATIONSHIPS BETWEEN THE CIRCADIAN RHYTHMS OF TSH, PROLACTIN AND CORTISOL IN SURGICALLY TREATED MICROPROLACTINOMA PATIENTS
Authors: SALVADOR J. , WILSON D. W. , HARRIS P. E. , PETERS J. R. , EDWARDS C. , FOORD S. M. , DIEGUEZ C. , HALL R. , SCANLON M. F.
Published: March 2008

Pharmacological doses of glucocorticoids inhibit TSH release both in vivo and in vitro and since the circadian rhythms of TSH and cortisol show a reciprocal relationship, the hypothesis has been advanced that changes in cortisol levels may be a primary determinant of circadian TSH changes. We have tested this hypothesis by studying the relationship between circadian cortisol and TSH rhythms in subjects before and during blockade with metyrapone. Seven patients were studied during their routine post‐operative assessment following selective transethmoidal adenomectomy for microprolactinomas. PRL levels were restored to normal (<420 mU/l) in all patients by surgery (pre‐op: 930–2752 mU/1, post‐op: 33–376 mU/1) and the patients also had normal pituitary function in other respects. Blood was sampled hourly for 24 h before and on the third day of treatment with metyrapone (250 mg, 2 hourly). In order to compare circadian rhythms, hormonal data were subjected to cosinor analysis which involved fitting of the data with a cosine function using the method of least squares. The 6% cross reactivity of the Cortisol antibody with 11‐deoxycortisol was taken into account during the calculation of results. All subjects showed a normal Cortisol rhythm which was strikingly blunted during metyrapone treatment. Group mean (± SD) TSH mesors, amplitudes and acrophases for control and metyrapone treated subjects were 1.5 ± 0.26, 1.29 ± 0.48; 0.46 ± 0.26, 0.23 ± 0.13 and −49°± 9.8°; −62°± 2.7° respectively. Based on paired t‐testing of these data there was a small but significant reduction in the amplitude (P<0.05) and acrophase (P<0.05) of the TSH rhythm during metyrapone administration but no alteration in the circadian pattern of change. The normal circadian change in PRL levels which we observed in these patients was not altered by metyrapone treatment. It appears therefore that variation in endogenous cortisol is not the sole factor involved in the determination of the circadian TSH rhythm and that it does not influence circadian PRL changes in this group of subjects.
FAILURE OF PROPHYLACTIC SURGERY TO AVERT MASSIVE PITUITARY EXPANSION IN PREGNANCY
Authors: BELCHETZ P. E. , CARTY A. , CLEARKIN L. G. , DAVIS J. C. , JEFFREYS R. V. , RAE P. G.
Published: March 2008

Macroprolactinomas have a well‐recognized potential for marked expansion during pregnancy. Measures advocated to minimize this risk include prior treatment with dopamine agonists, radiotherapy and pituitary surgery. We describe a patient who underwent transsphenoidal surgery with the removal of an histologically proven prolactin‐secreting adenoma with the intention of rendering subsequent pregnancy safe. The patient remained hyperprolactinaemic and received prolonged therapy with metergoline and bromocriptine which suppressed prolactin to normal and she conceived after induction of ovulation with human menopausal gonadotrophin and human chorionic gonadotrophin. At 3 months gestation she developed headaches, vomiting, reduced visual acuity and bitemporal hemianopia caused by massive pituitary expansion. Reintroduction of bromocriptine rapidly abolished features of tumour expansion and after delivery of a full‐term normal female infant, repeat CT scan documented tumour shrinkage.
IgG THYROTROPHIN RECEPTOR ANTIBODY ACTIVITY IN GRAVES' DISEASE; A STUDY OF TSH AGONIST AND ANTAGONIST ACTIVITIES BY ISOELECTRIC FOCUSING
Authors: CREAGH FIONUALA M. , HOWELLS R. D. , WILLIAMS SUSAN , DIDCOTE SUZANNE , HASHIM F. A. , PETERSEN V. B. , SMITH B. REES
Published: March 2008

The distribution of TSH receptor antibody activity in the 7S and 19S fractions of Graves' sera has been re‐evaluated. Serum fractions were obtained by gel filtration from 12 Graves' sera and assayed for TSH receptor binding activity in a radioreceptor assay. Thyroid stimulating activity was determined in a cultured porcine thyroid cell bioassay. In apparent contrast to the findings of Baker et al. (1983) TSH receptor binding activity was confined to the 7S gel filtration fraction, containing IgG, and was not detected in the 19S fraction, containing IgM. Similarly thyroid stimulating activity was detected only in the 7S fraction. 7S fractions from seven Graves' sera were fractionated by isoelectric focusing and the fractions analysed for TSH receptor binding activity and TSH agonist and antagonist activities. Five of the IgGs showed TSH agonist activity and in all five, the peak thyroid stimulating activity (measured by stimulation of cyclic AMP release from isolated porcine thyroid cells) was in fractions with a pI of between 8.0 and 9.5. In four of these five IgGs, TSH receptor binding activity showed similar isoelectric distribution to the thyroid stimulating activities. High levels of TSH receptor binding activity without associated TSH agonist or antagonist activity were however observed in some isoelectric fractions of the fifth stimulating Graves’IgG studied. All the isoelectric fractions from the fifth IgG with thyroid stimulating activities contained TSH receptor binding activity. Two of the Graves' IgGs showed TSH antagonist activity and both the TSH receptor binding and TSH antagonist activities of these IgGs showed similar isoelectric distribution with the peak activities at a pI of around 9.0. Consequently, it was not possible to separate TSH agonist or TSH antagonist activities from TSH receptor binding activity in seven Graves' sera by isoelectric focusing although in one IgG several isoelectric fractions contained isolated receptor binding activity. These findings are in keeping with the hypothesis that the biological activities of Graves' IgGs are intimately related to their ability to bind to the TSH receptor.
GENETIC FACTORS IN GRAVES' OPHTHALMOPATHY
Authors: FRECKER MAXINE , STENSZKY VALERIA , BALAZS C. , KOZMA L. , KRASZITS E. , FARID N. R.
Published: March 2008

We investigated the distribution of HLA and immunoglobulin G heavy chain markers (Gm) in 117 patients with Graves' disease, 62 with ophthalmopathy and 55 without. With Graves' disease per se, there is a closer association with HLA‐DR3 than with B8. The opposite was true for Graves' patients with ophthalmopathy (odds ratio for ophthalmopathy associated with B8 was 12.4 and with DR3 was 7.7, both with P < 00005). HLA‐DR7 interacts with B8 in modifying the risk for eye disease; using the phenotype B8‐ DR7‐ as reference, the odds ratios were 16.7 for B8+ DR7 +, 8.7 for B8 + DR7‐ and 0.26 for B8‐ DR7 +. Thus, DR7 enhanced the risk for ophthalmopathy in the presence of B8+ but had a protective influence in its absence. Although Gm showed no association with eye disease, it modified the risk for ophthalmopathy associated with HLA‐B8; the odds ratios were 20.9 for B8+ Gmfb homozygo‐zity (fb +), 15.3 for B8+ fb‐ and 1.7 for B8‐ fb+ (B8‐ fb‐ =1.00). We conclude that the genetic factors contributing to Graves ‘ophthalmopathy are different from those related to liability for Graves’ hyperthyroidism.
POSTURAL SUPPRESSION OF PLASMA ATRIAL NATRIURETIC POLYPEPTIDE CONCENTRATIONS IN MAN
Authors: SAKURAI H. , NARUSE M. , NARUSE K. , OBANA K. , HIGASHIDA T. , KURIMOTO F. , DEMURA H. , INAGAMI T. , SHIZUME K.
Published: March 2008

The effects of sequential changes in posture, from recumbency, to sitting and then to the upright position, each for 60 min, respectively, on the levels of plasma immunoreactive atrial natriuretic polypeptide (ANP) in healthy human subjects were studied using a radioimmunoassay (RIA) method. At the end of each change in posture, plasma ANP levels were respectively 150±16‐4 pg/ml (recumbent), 103±11‐2 pg/ml (sitting), and 78‐1±7–90 pg/ml (upright). In contrast, plasma renin concentration (PRC) and plasma aldosterone concentration (PAC) determined concomitantly with ANP showed a significant increase in response to the sitting and upright postures. Plasma ANP levels determined in normal subjects who remained in the recumbent posture for the same period did not show any significant change. This suggests that ANP is involved in the maintenance of haemodynamic homeostasis under physiological conditions and emphasizes that postural factors must be taken into account and controlled in order to evaluate plasma ANP levels properly, as well as those of PRC and PAC.
GONADOTROPHIN RESPONSES TO GnRH PULSES IN HYPOGONADOTROPHIC HYPOGONADISM: LH RESPONSIVENESS IS MAINTAINED IN THE PRESENCE OF LUTEAL PHASE CONCENTRATIONS OF OESTROGEN AND PROGESTERONE
Authors: NIPPOLDT T. B. , KHOURY S. , BARKAN A. , KELCH R. P. , MARSHALL J. C.
Published: March 2008

LH pulse secretion changes during the menstrual cycle from a rapid regular pattern in the follicular phase to a slower and irregular pattern in the luteal phase. To determine whether the irregular LH pulse pattern in the luteal phase reflects altered GnRH secretion or altered pituitary responsiveness to GnRH, we gave low dose GnRH pulses (25 ng/kg i.v.) every 2 h or every hour for 10 or 12 d to three women with isolated GnRH deficiency. After 4 d of GnRH alone, oestradiol (E2) was given and after 6 d progesterone (P) was added to mimic the hormonal milieu of the luteal phase. LH and FSH were measured every 4 h throughout and also every 20 min for 6 or 12 h, before and after GnRH alone (day 0 and day 4), after E2 (day 6), and after E2+ P (day 10 and day 12). Both GnRH pulse frequencies resulted in a rapid increase in plasma FSH to peaks on day 4 (every 2 h) and day 2 and 3 (every hour). FSH concentrations then declined as plasma E2 rose to 50–80 pg/ml reflecting the selective inhibitory effect of E2 on FSH release. Plasma LH was also increased after the hourly GnRH injections and this regimen was associated with a more rapid rise in E2 reflecting follicular maturation. In contrast to the differences in mean hormone concentrations, administration of GnRH at both frequencies resulted in sustained one‐on‐one responsiveness of LH that was maintained in the presence of both oestrogen and progesterone at mid‐luteal phase concentrations. We conclude that the slow frequency of LH pulses observed during the luteal phase reflects decreased GnRH pulse frequency rather than impaired pituitary responsiveness to GnRH.
ADDITIVE EFFECTS OF GROWTH HORMONE RELEASING FACTOR AND INSULIN HYPOGLYCAEMIA ON GROWTH HORMONE RELEASE IN MAN
Authors: PAGE M. D. , KOPPESCHAAR H. P. F. , EDWARDS C. A. , DIEGUEZ C. , SCANLON M. F.
Published: March 2008

We have measured GH and PRL changes following separate and combined administration of insulin and GH releasing factor (GRF) in six normal males. Peak GH responses to separate administration of insulin and GRF were comparable (71 4 ± 10.2 vs 70.1 ± 27.7 mU/1; mean ± SEM). However, the peak GH response following combined administration was significantly higher (120.8 ± 29.7, P < 0.05) as was the total GH released as calculated by measuring the area under the curve (P <005). In contrast the PRL response to hypoglycaemia was not altered by the combined administration of insulin and GRF. This effect was not due to any direct action of hypoglycaemia or insulin at pituitary level since basal and 10−8 M GRF stimulated GH release from rat anterior pituitary cells in vitro was not influenced by varying glucose and insulin levels. Our findings support the hypothesis that GRF and insulin‐induced hypoglycaemia release GH via different pathways which are, at least in part, additive.
CUSHING'S SYNDROME IN PREGNANCY: THE TIMING OF DEFINITIVE TREATMENT
Authors: BEVAN J. S. , GOUGH M. H. , GILLMER M. D. G. , BURKE C. W.
Published: March 2008

Cushing's syndrome in pregnancy is rare but associated with a high fetal loss rate, premature labour and excessive maternal morbidity. There has been controversy regarding the safety and efficacy of surgical treatment during pregnancy. We describe two further cases, both due to adrenal adenomas, in whom the diagnosis was made at 28 and 31 weeks gestation. Both cases suffered from severe myopathy. The first case was not treated during pregnancy and developed wound and urinary infections after caesarean section and subsequent adrenalectomy. An incisional hernia in the caesarean section scar has been repaired twice. The second had an adrenalectomy when 29 weeks pregnant with rapid resolution of the features of Cushing's syndrome, particularly the myopathy, and had an uneventful vaginal delivery. The second case, and a review of those previously described, indicates that surgical treatment during pregnancy is safe and significantly reduces fetal losses, premature labour and maternal morbidity.
AMIODARONE AND THYROID HORMONE EFFECTS ON ANTERIOR PITUITARY HORMONE GENE EXPRESSION
Authors: FRANKLYN J A. , GAMMAGE M. D. , SHEPPARD M. C.
Published: March 2008

Amiodarone therapy results in marked changes in circulating thyroid hormone and TSH concentrations in man. In the present study we have demonstrated that amiodarone treatment of the rat increases serum TSH and pituitary cytoplasmic concentrations of TSH β and a subunit messenger RNAs (mRNAs) and reduces PRL mRNA as measured by cytoplasmic dot hybridization with specific complementary (c) DNA probes. The fall in circulating TSH and TSH mRNA resulting from thyroid hormone treatment was less marked in animals receiving amiodarone in addition to T3 and T4. In contrast, in the hypothyroid state, increases in serum TSH, TSH β and α mRNA, and reductions in PRL and GH mRNA were less marked in rats treated with amiodarone. In studies of rat anterior pituitary cells in primary monolayer culture we demonstrated a direct effect of amiodarone on PRL gene expression which was antagonized by T3. Changes in circulating thyroid hormone concentrations and deiodination of T4 and T3 induced by amiodarone in vivo may be important in the regulation of pituitary hormone gene expression but we have, in addition, shown a direct interaction between amiodarone and T3 effects on the anterior pituitary cell.
ULTRASENSITIVE ASSAY OF THYROID STIMULATING HORMONE IN PATIENTS WITH ACUTE NON‐THYROIDAL ILLNESS
Authors: BOLES J.‐M. , MORIN J.‐F. , GARRE M. A.
Published: March 2008

Serum TSH in critically ill euthyroid patients is generally within the normal range when measured with conventional radioimmunoassays. Sensitive immunoradiometric assays allow detection of low levels of serum TSH. We assessed this method in a prospective study of 34 euthyroid patients admitted to our critical care unit. Serum TSH ranged from 0.12 to 3.60 mU/1 and was significantly lower for the whole group than in the controls (P< 0‐001), as also were serum total T4 and T3 values (P<0.001). However, 21 patients had a serum TSH within the normal range (group 1) and 13 patients (33%) had a serum TSH < 0.40 mU/1 (group 2). The two groups did not differ in age, sex, type and severity of illness, outcome, and serum T4 and T3 levels. However, the magnitude of TSH increase from the baseline value after the i.v. injection of 200 μg of TRH, assessed by the 30 min TSH/basal TSH ratio was significantly higher in group 2 (P< 005). These results suggest that a substantial proportion of patients with acute illness have a clearly low serum TSH, unaccounted for by age, sex, type or quantified severity of illness, serum T4 and T3 levels. In addition, the secretory capacity of the pituitary to exogeneous TRH is significantly enhanced in those patients with low basal TSH.
GROWTH HORMONE SECRETION IN CHILDREN DETERMINED BY TIME SERIES ANALYSIS
Authors: HINDMARSH P. C. , MATTHEWS D. R. , BROOK C. G. D.
Published: March 2008

Mid childhood growth has been studied in 26 short children (18M;8F) aged between 5·2 and 11·9 years growing with height velocity standard deviation score (SDS) between 0 and — 0·8 and 24 short children (17M;7F) growing with height velocity SDS >0·8. Twenty‐four hour GH profiles were analysed by an iterative method of pulse detection and subjected to time series analysis to determine dominant periodicity within the data arrays. Children aged >7 years displayed no dominant periodicity but after this age a periodicity of 200 min emerged. In the whole sample, differences between growth rate could be explained entirely by pulse amplitude. Nevertheless, the normal decline in height velocity over this age period occurred despite a significant shift in periodicity and an increase in GH pulse amplitude. This modulation of childhood growth by GH pulse amplitude perisisted into puberty and the pubertal growth spurt of 14 tall girls was shown to be amplitude modulated with the periodicity unchanged. We conclude that mid childhood and pubertal growth is GH pulse amplitude modulated with a periodicity of approximately 200 min.
GROWTH HORMONE FACILITATES OVULATION INDUCTION BY GONADOTROPHINS
Authors: HOMBURG R. , ESHEL A. , ABDALLA H. I. , JACOBS H. S.
Published: March 2008

The addition of biosynthetic human growth hormone (GH) to treatment with human menopausal gonadotrophin (hMG) significantly augmented the ovarian response in four patients treated for in‐vivo and three patients treated for in‐vitro fertilization who had previously been resistant to hMG. The amount, duration of treatment and daily effective dose of hMG were all reduced by growth hormone. This action of growth hormone offers a new approach to ovulation induction.
VERTEBRAL BONE DENSITY IN NON‐AMENORRHOEIC HYPERPROLACTINAEMIC WOMEN
Authors: CICCARELLI E. , SAVINO L. , CARLEVATTO V. , BERTAGNA A. , ISAIA G.C. , CAMANNI F.
Published: March 2008

Recently, a decrease in bone mineral content (BMC) in hyperprolactinaemic women with long‐lasting amenorrhoea has been reported, and attributed either to a direct effect of PRL on bone or secondary to the oestrogen deficiency. To verify if PRL by itself has a direct effect on bone, we have studied BMC at the lumbar level by double‐photon absorptiometry in 22 patients with hyperprolac‐tinaemia, selected on the basis of normal or near‐normal oestradiol levels. The results were compared with those obtained in 28 healthy closely‐matched women, and seven hyperprolactinaemic patients with long‐lasting amenorrhoea and oestrogen deficiency. No significant difference in BMC was observed between hyperprolactinaemic patients with normal oestrogen levels (mean ± SEM = 3.87 ± 0.10 gHA/cm) and normal subjects (mean ± SEM = 3.76±0.10 gHA/cm). Moreover, no significant change was observed during a 6 month follow‐up in 13 patients. On the other hand, a significant difference (P < 0.05) was detected in BMC between the hyperprolactinaemic patients with normal oestradiol levels and those with long‐lasting amenorrhoea and oestrogen deficiency (mean ± SEM = 3.39 ± 0.18). These results suggest that hyperprolac‐tinaemia by itself is not a risk factor for the development of osteoporosis.
EFFECT OF A NEW SOMATOSTATIN ANALOGUE SMS 201‐995 (SANDOSTATIN) ON THE RENIN‐ALDOSTERONE AXIS
Authors: SIEBER C. , GNÄDINGER M. , DEL POZO E. , SHAW S. , WEIDMANN P.
Published: March 2008

The effects of a new somatostatin analogue SMS 201‐995 (H‐D‐Phe‐Cys‐Phe‐D‐Trp‐Lys‐Thr‐Cys‐Thr(ol), Sandostatin) on the orthostatic stimulation of plasma renin activity (PRA) following head‐up tilting and on angiotensin II (Ang‐II) induced aldosterone (PA) release were studied under placebo controlled conditions in separate groups of healthy volunteers consisting of six and 10 subjects, respectively. Head‐up tilting (by 60°) produced the characteristic increases in PRA and PA. Administration of SMS 201‐995 significantly (P < 0.05) inhibited this PRA elevation from 30 min on. Throughout the study period, PA levels were not consistently altered by this analogue. Furthermore, SMS 201‐995 failed to inhibit the stimulation of PA secretion induced by exogenous angiotension‐II (2‐10 ng/kg/min). Results presented here are at variance with data collected with natural somatostatin showing an inhibitory effect on stimulated PA. This discrepancy can be explained by the recently described absence of SMS 201‐995 binding sites in primate adrenal cortex and in human aldosteronomas.
PLASMA GROWTH HORMONE HALF‐LIFE AFTER SELECTIVE REMOVAL OF ADENOMA IN ACROMEGALICS DETERMINES THE OUTCOME OF SURGERY
Authors: ROELFSEMA F. , VAN DER HEIDE D. , LOWRY P. J. , VAN DULKEN H. , SCHRÖDER‐VAN DER ELST J.
Published: March 2008

We measured plasma GH levels during transsphenoidal surgery in eight patients with acromegaly. After removal of the adenoma GH levels fell monoexponen‐tially in six subjects while they were still under general anaesthesia, but no decrease was noted for two other subjects. Normal postoperative GH and Somatomedin‐C levels were found for those patients who exhibited a reduction in GH during surgery. During follow‐up studies one patient with a normal GH level exhibited a paradoxical reaction to TRH, attributed to tumour remnants. The plasma half‐life found for five patients was 18‐33 min; for another cured subject it was longer, i.e. 58 min. The major fraction of the circulating GH, as determined by gel‐chromatography, was mol. wt 22000; this applied for six subjects, while the patient with the long plasma half‐life appeared to have a mol. wt 33 000 variant. From this study we conclude that a clear drop in the plasma GH level after removal of the adenoma predicts a favourable outcome of surgery; however, if some tumour remnants are left behind, paradoxical reactions may occur despite normal basal GH levels.
CELL KINETICS, DNA CONTENT AND TSH RECEPTOR‐ADENYLATE CYCLASE SYSTEM IN DIFFERENTIATED THYROID CANCER
Authors: CHANG T. C. , KUO S. H. , LIAW K. Y. , CHANG C. C. , CHEN F. W.
Published: March 2008

The purpose of this study was to elucidate the changes of the TSH receptor‐adenylate cyclase system in differentiated thyroid carcinomas, and their relationships with nuclear DNA content, cell kinetics and clinical stage. The results showed that the papillary carcinomas had an impaired TSH receptor‐adenylate cyclase system. The production of cAMP stimulated by TSH was decreased when compared with non‐cancerous tissue and high‐affinity TSH receptors were reduced in number or even completely lost (nine in 24 cases). Follicular carcinomas also showed a reduction in, or even complete loss, of high‐affinity TSH receptor (one in five cases). However, the responses to the stimulation of TSH, Gpp (NH)p and forskoiin were not different from those in non‐cancerous tissue. Papillary and follicular cancer cells showed more proliferative activity than those in non‐cancerous tissue. Follicular carcinomas contained more hyperploid cells (DNA content >2.5 C) than papillary carcinomas. There were no differences in cell kinetics, DNA content or the effects of Gpp (NH)p or forskoiin on adenylate cyclase activity between those papillary carcinomas with high‐affinity TSH receptor and those without. However, the presence of high‐affinity TSH receptors had higher cAMP generation stimulated by TSH. The patients having papillary carcinomas in the absence of high‐affinity TSH receptors were all in clinical stage'III. These studies suggest that TSH receptors are the major sites influenced in the TSH receptor‐adenylate cyclase system in papillary carcinomas. The TSH receptor‐adenylate cyclase system of papillary carcinomas differs more from normal than does that of follicular carcinomas. That follicular carcinomas are usually more aggressive than papillary carcinomas may be partly explained by more hyperploid cells in follicular carcinomas. The absence of high‐affinity TSH receptor in papillary carcinomas may mean a more advanced clinical stage and poorer prognosis.
CHARACTERIZATION OF HUMAN CORTICOTROPHIN‐RELEASING HORMONE AND PRO‐OPIOMELANOCORTIN‐RELATED PEPTIDES IN A THYMIC CARCINOID TUMOUR RESPONSIBLE FOR CUSHING'S SYNDROME
Authors: DEMAY M. C. RAUX , PROESCHEL M. F. , DE KEYZER Y. , BERTAGNA X. , LUTON J. P. , GIRARD F.
Published: March 2008

Severe Cushing's syndrome developed in a man of 35 years. Plasma ACTH and lipotrophin hormone levels were supranormal, and dexamethasone failed to stop their production. An ACTH‐producing thymic carcinoid tumour was found to be responsible for the Cushing's syndrome. The tumour tissue contained pro‐opiomelanocortin (POMC)‐mRNA and POMC‐related peptides. In addition, human corticotrophin‐releasing hormone (h‐CRH) (0.25 ng/ mg wet tissue) was identified in the tumour extract. Among a series of extracts from two normal and three tumoral (Nelson's syndrome) pituitary glands, six non‐pituitary POMC‐producing tumours and five normal thymuses examined, only the extract from the thymic tumour of our patient contained h‐CRH. The molecule isolated had the same properties as synthetic h‐CRH (dilution, Sephadex G 50 chromatography). Circulating h‐CRH levels, however, were normal. The possible involvement of such ectopic CRH production in the aetiology of Cushing's syndrome remains uncertain.
LOW SERUM TSH WITH NORMAL TOTAL THYROID HORMONE LEVELS: AN INDICATOR OF FREE T4 EXCESS
Authors: O'MALLEY B. P. , ROSENTHAL F. D. , EXLEY A. , FALCONER‐SMITH J. F. , MAHABIR J. , WOODS K. L.
Published: March 2008

We have studied 18 patients with low serum thyrotrophin (TSH) levels accompanied by normal thyroxine (T4) and triiodothyronine (T3) levels in order to clarify whether or not they are thyrotoxic. Serum T4, T3, free T3, free T4 and TSH were estimated three times weekly for 3–4 weeks. Thyroxine binding globulin (TBG) levels were estimated on one occasion only. Thyroid hormone data were expressed as the cumulative probability of having at least one result above the relevant normal range by the nth sample (Pn). For free T4 this probability was 61% by the 10th sample. Free T4 values were confined to the upper half of the normal range or above throughout the study. In contrast, free T3 values were distributed evenly within the normal range (P10= 12%). For total T4 and total T3, P10 was 34 and 11% respectively. Thus, subjects with subnormal TSH levels but normal T4 and T3 levels have been shown to have elevated serum free T4 levels, an indicator of biochemical hyperthyroidism.
THE PHARMACOKINETICS, SAFETY AND ENDOCRINE EFFECTS OF AUTHENTIC BIOSYNTHETIC HUMAN GROWTH HORMONE IN NORMAL SUBJECTS
Authors: HO K. Y. , WEISSBERGER A. J. , STUART M. C. , DAY R. O. , LAZARUS L.
Published: March 2008

The pharmacokinetics, safety and endocrine effects of an authentic human growth hormone (bio‐hGH), produced by the expression of genomic hGH in a mammalian cell line, were studied in six healthy young men who were administered 0.2 U/kg/day subcutaneously for five consecutive days. Changes in sodium balance and in thyroid function were studied during the week of bio‐hGH administration and safety parameters were monitored over a 3‐week period. Growth hormone levels reached a mean (±SD) peak of 106 ± 10 mIU/1 at 3.3 ± 0.5 h following the first dose and resulted in a significant rise of somatomedin C, free fatty acids, fasting blood glucose and insulin concentrations. Bio‐hGH administration resulted in a significant increase in body weight (80.0± 4.5 to 81.1 ± 4.3 kg; P<0.01) which was associated with a marked reduction in urinary sodium excretion (196 ± 38 to 45 ± 20 mmol/day; P<0.025). Serum T3 increased during bio‐hGH administration and was asssociated with reciprocal changes in free thyroxine and TSH concentrations. Cardiac, hepatic, renal, biochemical, haematological, endocrinological and immunological functions remained normal throughout the study. No antibodies to hGH or to host cell protein developed during the study. The results show that bio‐hGH is safe in the short term, well tolerated, possesses pharmacokinetic and biological properties similar to pituitary hGH, and has distinct effects on sodium balance and on thyroid function. This study stresses the need to monitor patients for effects on sodium retention, carbohydrate metabolism and thyroid function when using hGH doses of 1.0 U/kg/week (40U/m2/week) or more in patients with GH responsive short stature.
INCREASED GH RESPONSE TO GHRH IN NORMAL TALL MEN
Authors: BATRINOS M. , GEORGIADIS E. , PANITSA‐FAFLIA CH. , STRATIGOPOULOS S.
Published: March 2008

The importance of growth hormone secretion to the growth of an individual raises the question of the role that the secretory capacity of this hormone may play in defining the variations of height within the population. To investigate this problem we studied the response of GH to GHRH in 20 normal tall (mean ± SD height 190.8 ± 2.4 cm, range 187–196 cm) adult males of the third decade and in 17 age‐matched controls of average height (mean ± SD height 173.8 ± 1.6 cm, range 171.177 cm). Synthetic GHRH (1.29) NH2 (Kabi, Vitrum, Sweden) was administered at 0800 h after an overnight fast and blood was drawn for GH assay. In the tall subjects basal GH concentrations at – 15 and 0 min were not significantly different from those of the controls. However, the tendency to higher basal GH levels and spontaneous peaks was evident in tall individuals. Only three basal GH values were below 1 pg/1 (0.8–0.9 μg/1; μg/l = 2mU/l) in the tall individuals while 24 of 33 basal GH values in the controls ranged between 0.25 and 0.87 μg/l. At +15 and +30 min after GHRH the rise in GH was significantly greater in the tall subjects. Moreover, the integrated area under the response curves was significantly greater in the tall subjects than the controls (P<0.01). No differences in the mean serum testosterone and prolactin levels were found in the two groups.

It is postulated that if this enhanced pituitary responsiveness is constant and chronic in tall individuals a definite relation of their stature to the GH secretion is to be anticipated.
CORTICOSTEROID‐BINDING GLOBULIN IN DEPRESSION
Authors: LEAKE A. , GRIFFITHS H. W. , PASCUAL J. A. , FERRIER I. N.
Published: March 2008

We undertook this study to evaluate the role of plasma free and total Cortisol, and corticosteroid‐binding globulin (CBG) in depression. Plasma was collected from 15 drug‐free depressed patients and 15 age and sex‐matched control subjects at 0900 and 2300 and at 1600 following an oral dose of dexamethasone. Depressed patients had elevated concentrations of both free and total Cortisol at all time points studied. The binding capacity and affinity of plasma CBG for Cortisol was similar in both groups at all times studied. No differences in CBG measures were noted if the depressed subjects were divided into elderly or younger subjects and dexamethasone suppression test (DST) suppressors or non‐suppressors.
LEUCOCYTE SODIUM CONTENT AND SODIUM PUMP ACTIVITY IN OVERWEIGHT AND LEAN HYPERTENSIVES
Authors: NG L. L. , HARKER M. , ABEL E. D.
Published: March 2008

Leucocyte sodium content and sodium pump activity was studied in overweight and lean hypertensive subjects and normotensive controls, all in the fasting state. In lean subjects (body mass index < 27 kg m−2), hypertensives did not have altered leucocyte sodium content or pump activity. In the overweight (mostly obese) subjects, the leucocyte sodium content was higher in hypertensive than in normotensive subjects (median (range) 56.1 (42.0–84.1) vs 320 (18.2–59.4) mmol kg−1, P< 0.001). This raised sodium content in overweight hypertensives was associated with a lower (ouabain‐sensitive) 22Na efflux rate constant (2.25 (1.15–3.01) vs 2.64 (1.98–3.61) h −1, P < 0.05) and a higher passive (or ouabain‐insensitive) 22Na efflux rate constant (0.90 (0.53–1.18) vs 0.63 (0.21–1.09) h−1, (P < 0.01). The systolic and diastolic blood pressures were significantly correlated to intracellular Na+ in the overweight group (r=0.41 and 0.56, P< 0.02 and 0.001 respectively). Thus, hypertension in the overweight subjects is associated with accumulation of intracellular sodium that may be due to abnormalities of the active sodium pump, though changes in ouabain‐insensitive mechanisms also occur.
GONADOTROPHIN‐RELEASING HORMONE AND HUMAN CHORIONIC GONADOTROPHIN TESTS REVEAL THAT BOTH HYPOTHALAMIC AND TESTICULAR ENDOCRINE FUNCTIONS ARE SUPPRESSED DURING ACUTE PROLONGED PHYSICAL EXERCISE
Authors: KUJALA URHO M. , ALEN MARKKU , HUHTANIEMI ILPO T.
Published: March 2008

The mechanism of suppression of gonadotrophins and; testosterone during prolonged exercise was studied. Fourteen healthy males were injected immediately before an exhaustive bicycle run for 4 h, and; before a control period without exercise, with one of the following substances: (1) 1 ml of saline, (2) 100 μg of a GnRH agonist (buserelin), and; (3) 50 IU/kg of hCG. Each test was repeated for each subject 2 weeks apart, in a randomized single‐blind fashion. Blood samples were taken before the injections (sample A), 6 h after the injections (sample B), and; the following morning (sample C). During placebo treatment testosterone concentration decreased from A samples to B samples more in the exercise trial than in rest trial (31 vs 8%, P =0.02). This exercise‐associated decrease was reversed by both the GnRH agonist and; hCG treatments. Serum gonadotrophin concentrations responded identically to GnRH agonist injections during exercise and rest trials. hCG resulted in a greater increase of serum testosterone from A to C samples at rest than during the exercise trial (52 vs 33%, P=0.04). In conclusion, the exercise‐induced suppression of serum testosterone is associated with two effects: suppressed endogenous GnRH stimulation of gonadotrophin release during exercise, and decreased testicular capacity to secrete testosterone during recovery period.
SUBCUTANEOUS GROWTH HORMONE‐RELEASING HORMONE AUGMENTS PULSATILE NOCTURNAL GH RELEASE IN GH‐INSUFFICIENT CHILDREN, BUT MAY ALSO RAISE BASAL GH SECRETION
Authors: ROSS R. J. M. , KIRK J. M. W. , TSAGARAKIS S. , TRAINER P. J. , CICCARELLI E. , TOUZEL R. , GROSSMAN A. , SAVAGE M. O. , BESSER G. M.
Published: March 2008

Growth hormone‐releasing hormone (GHRH) when given s. c. to GH‐insufficient children either as pulses, or once or twice daily, promotes linear growth. These treatment regimens, however, are not ideal as they require frequent drug administration and a significant proportion of patients do not show improved growth. We have now investigated the GH response to a nocturnal s. c. infusion of GHRH(1–29)NH2, at two dosages, 5 and 10 μg/kg/h, in a group of five GH‐insufficient children. The s. c. infusion of GHRH between 2100 h and 0600 h augmented nocturnal pulsatile GH release in all five children. There was a dose‐dependent response for the GH area under the curve (AUC), and mean total GH concentration. The AUC for GH was significantly greater after the 10 than 5 μg/kg/h GHRH which in turn was greater than that after placebo; mean (SD) AUC: 14816 (3978), 8125 (1931), 3032 (1582) mU min/1 respectively (P < 0.01 and P < 0.05). There was no significant change in the number of GH pulses during the 9‐h infusions when the subjects were infused with GHRH 10 or 5 pg/kg/h compared to placebo, and they occurred at similar times although the number of pulses tended to be greater after GHRH; the mean (SD) numbers of GH pulses were 5.0 (0‐7), 3.8 (0.8), 3.2 (0.8), respectively. There was however a significant rise in the mean baseline GH concentration in all patients during the infusion of GHRH 10 or 5 μg/kg/h compared to placebo, but not with 5 μg/kg/h. Thus, GHRH(1–29)NH2 given s. c. augmented nocturnal pulsatile GH release in GH‐insufficient children but it also increased baseline GH secretion. These results suggest that a sustained release preparation of GHRH could be a potential treatment for GH‐insufficient children, and that a dose of 5 μg/kg/h would promote pulsatile GH release, but that at higher dosage it may also raise basal GH secretion.
THE INTERACTION BETWEEN CLONIDINE AND GROWTH HORMONE RELEASING HORMONE IN THE STIMULATION OF GROWTH HORMONE SECRETION IN MAN
Authors: SURI D. , HINDMARSH P. C. , BRAIN C. E. , PRINGLE P. J. , BROOK C. G. D.
Published: March 2008

Six normal adult males were given clonidine and GHRH either separately, or in combination, in random order. The peak serum GH concentrations elicited by clonidine or GHRH were variable but one factor influencing the GH response to GHRH was the GH secretory status in the hour prior to the administration of the GHRH. Peak serum GH concentrations attained were significantly greater when serum GH concentrations were rising (mean 52.9 mU/l, SD 17.2) than if they were falling (mean 27.5 mU/l, SD 13.3) or unchanged/undetectable (mean 20.6 mU/l, SD 9.8) (one‐way ANOVA, F=8.77; P= 0.004). The GH response to clonidine was not influenced by the secretory status in the hour prior to administration of clonidine. Pretreatment with clonidine did not augment the peak serum GH response to GHRH but the direction of response was more predictable than when GHRH was administered separately or repeatedly. Prior treatment with GHRH(1–29)‐NH2 led to a marked attenuation of the peak serum GH response to clonidine. These results suggest that the alpha‐2 adrenergic agonists probably stimulate GH secretion through pathways other than just GHRH.