bluuebunny/crossref_metadata_2025 huggingface dataset:
Influence of sex, age and adrenergic pathways on the growth hormone response to GHRP‐6
Authors: Peñalva A. , Pombo M. , Carballo A. , Barreiro J. , Casanueva F. F. , Dieguez C.
Published: March 2008

OBJECTIVE His‐dTrp‐Ala‐Trp‐dPhe‐Lys‐NH2 (GHRP‐6) is a synthetic compound that releases GH in a dose‐related and specific manner in several species including man. To further characterize the effects of GHRP‐6 on GH secretion in normal human subjects, we assessed plasma GH levels following GHRP‐6 administration in normal male adult subjects, normal female adult subjects at different stages of their menstrual cycle and in normal prepubertal male and female children. We also studied the influence of adrenergic pathways on GHRP‐6 induced GH secretion in normal adult male subjects.

DESIGN In a group of eight volunteers the following tests were carried out: GHRP‐6 alone (1 μg/kg i.v. at 0 minutes); propranolol(40 mg p.o. at −30 minutes) plus GHRP‐6; and (3 mg p.o. at −120 minutes) plus GHRP‐6. Another group of eight volunteers were studied with GHRP‐6 as above; clonidine alone (300 mg p.o. at −60 minutes); and clonidine plus GHRP‐6. A group of nine women were studied with 1 μg/kg i.v. of GHRP‐6 at 0 minutes, at different stages of their menstrual cycle. Finally, 12 children were studied with GHRP‐6 using the same dose and methods as above.

PATIENTS Twenty‐five normal adult subjects (16 male and nine female) and 12 normal prepubertal children (six male and six female) wer studied after giving informed consent.

EASUREMENTS Plasma GH levels were measured by radioimmunoassay.

RESULTS No differences in GH responses to GHRP‐6 were found between children and normal adult male or female Subjects at different stages of their menstrual cycle. Administration of propranolol and clonidine did not modify the GH responses to GHRP‐6 in male adults. In contrast, prazosin administration induced an increase in plasma GH levels that was statistically different from that of GHRP‐6 alone (P>0.05 between area under curve).

CONCLUSIONS GHRP‐6 exerts a potent stimulatory effect on GH secretion in adults and children. Its effects, at least at the dose studied, are Independent of sex and age. Noradrenergic pathways through α2 adrenergic receptors are unlikely to influence this response.
The relationship between peripheral immunoactive inhibin, human chorionic gonadotrophin, oestradiol and progesterone during human pregnancy
Authors: Tovanabutra S. , Illingworth P. J. , Ledger W. L. , Glasier A. F. , Baird D. T.
Published: March 2008

OBJECTIVE The objective of this study was to investigate serial changes in the plasma concentration of inhibin in both the very early days of pregnancy following implantation and in late pregnancy. The timing of the changes in inhibin concentration relative to changes in the concentrations of other hormones of pregnancy was also investigated.

DESIGN Serial observations of the peripheral concentrations of inhibin and other hormones in two groups of healthy volunteers in (a) early pregnancy and (b) late pregnancy.

PATIENTS (a) Four healthy women recruited on cessation of contraception prior to conception. (b) Nine healthy women recruited at the antenatal clinic.

MEASUREMENTS In the early pregnancy subjects, the concentrations of inhibin, progesterone, oestradiol and hCG were measured in plasma samples obtained three times per week from day 8 to day 10 of each menstrual cycle until 11 weeks after the last menstrual period in the conception cycle. In the late pregnancy subjects, plasma samples were obtained at 4‐week intervals from 12 weeks until term.

RESULTS The concentration of inhibin, progesterone and oestradiol in conception cycles were similar to those in the preceding cycles until the mid/ to late‐luteal phase of the cycle when hCG was first measurable. By day 12 of the luteal phase the concentration of inhibin was significantly higher in the pregnancy cycle than in the non‐pregnancy cycle (P > 0.05) and progressively increased after the time of the missed menstrual period. The concentration of inhibin reached a peak (513.0 U/I, CI 442.1–595.3) by day 47 when the concentration of hCG was maximal. In early pregnancy the concentration of inhibin was correlated with that of hCG (r= 0.361; P>0.01) as well as progesterone (r= 0.584, P>0.001) and oestradiol (r= 0.602. P>0.001). After 12 weeks there was no significant correlation between hCG and lnhibin although significant correlations persisted with progesterone (r= 0.553, P>0.001) and oestradiol (r= 0.361, P>0.01).

CONCLUSIONS The corpus luteum makes a significant contribution to the production of inhibin in early pregnancy while after 12 weeks the placenta is the major source.
Pituitary apoplexy and sudden blindness following the administration of gonadotrophin releasing hormone
Authors: Masson Ewan A. , Atkin Stephen L. , Diver Michael , White Michael C.
Published: March 2008

Pituitary apoplexy has been reported as a rare complication of combined tests and of TRH administration in prolactinomas. A 54‐year‐old man with a pituitary macro‐adenoma had a single injection of 100 μg GnRH. Twenty minutes later he complained of increasing headache and vomited. These symptoms settled spontaneously and were attributed to the pharmacological effects of GnRH. Five hours later he was found to be blind and disorientated without spontaneous complaint. Emergency CT showed a large adenoma with central necrosis, consistent with pituitary apoplexy. An urgent surgical decompression was carried out and necrotic haemorrhagic debris removed. Baseline bloods revealed non‐pulsatile FSH of 40 U/I with LH 0.3 U/I with no hormonal response to GnRH administration, but the sequence of events strongly suggests a causal relationship between this and pituitary apoplexy. To our knowledge this is the first time that GnRH administration has been associated with pituitary apoplexy of a glycoprotein secreting pituitary adenoma.
Five‐year follow‐up of growth hormone antibodies in growth hormone deficient children treated with recombinant human growth hormone
Authors: Massa Guy , Vanderschueren‐Lodeweyckx Magda , Bouillon Roger
Published: March 2008

OBJECTIVE The aim was to investigate the long‐term evolution of circulating growth hormone antibodies (GH‐AB) during and after treatment with methionyl‐recombinant human growth hormone (met‐rhGH).

DESIGN AND PATIENTS The investigation was performed on serum samples of 46 growth hormone deficient children, treated for at least 12 months with met‐rhGH. Twenty patients had never been treated with hGH (previously untreated patients, Group I). Twenty‐six subjects were previously treated with pituitary extracted hGH (treated patients, Group II).

MEASUREMENTS Serum levels of GH‐AB were measured by radioimmunoassay using charcoal precipitation of free ligand.

RESULTS Fifteen patients (75%) of Group I and three patients (12%) of Group II developed GH‐AB. In 15 GH‐AB positive patients the antibodies became detectable during the first year of treatment with met‐rhGH. In three patients, however, the GH‐AB appeared during the second year. Once present, the GH‐AB remained detectable throughout the period of treatment with met‐rhGH. In six patients in whom treatment with met‐rhGH was stopped, GH‐AB levels decreased rapidly. In nine patients in whom treatment with met‐rhGH was changed to rhGH, the levels of GH‐AB decreased and ultimately became undetectable. In two patients GH‐AB remained present during administration of rhGH. No effect of GH‐AB on the growth‐promoting effect of met‐rhGH could be documented, either during the first or during the second year of treatment.

CONCLUSIONS This study confirms the high immunogenicity of met‐rhGH, especially in patients not treated earlier with hGH. Once present, the GH‐AB remain detectable throughout the period of treatment with met‐rhGH. After stopping met‐rhGH treatment or changing to rhGH the GH‐AB disappear rapidly in most patients. No effect of GH‐AB on the growth‐promoting effect of rhGH could be documented.
Different modes of growth hormone (GH) administration do not change GH binding protein activity in man
Authors: Ho Ken K. Y. , Jorgensen Jens O. L. , Valiontis Erefili , Waters Michael J. , Rajkovic Ivan A. , Christiansen Jens S.
Published: March 2008

OBJECTIVE Studies in rodents have shown GH binding protein (GHBP) levels to be dependent on the mode of GH administration. The aim is to determine whether GHBP levels in man are also modulated by the pattern of GH administration.

PATIENTS Six GH deficient subjects participated in a randomized study in which 2 IU GH were administered either as (i) a continuous 24‐hour infusion, (ii) two intravenous boluses or (iii) eight intravenous boluses every 3 hours. In a second study, six normal men received a single subcutaneous injection of 0 2 U/kg GH and GHBP activity was measured over 24 hours. Control data were obtained from an untreated group of six age‐matched normal men.

MEASUREMENTS GHBP activity was measured by immunoprecipitation using a monoclonal antibody that recognizes the human GHBP, and expressed as percentage specific binding of 125I‐GH in 50 μl of serum.

RESULTS GHBP activity was not significantly different between the GH deficient and normal subjects. GHBP activity did not rise significantly during GH administration with each of the three intravenous patterns of delivery nor were there any significant differences between treatments. in the second study, GHBP activity did not change significantly following subcutaneous GH injection nor did results differ from untreated normal controls.

CONCLUSIONS The level of GHBP in man is not dependent on GH secretory status or altered by short‐term GH treatment or the mode of administration. These findings stand in contrast to GH treatment effects in rodents and suggest that GH regulation of GHBP may be different between species.
Changes in pituitary response to GnRH during the luteal‐follicular transition of the human menstrual cycle
Authors: Messinis I. E. , Koutsoyiannis D. , Milingos S. , Tsahallna E. , Seferiadis K. , Lolis D. , Templeton A. A.
Published: March 2008

OBJECTIVE We studied changes in pituitary response to GnRH during the luteal‐follicular transition of the human menstrual cycle.

DESIGN Normally cycling women were investigated during two consecutive menstrual cycles. In each woman, GnRH tests were performed during the two LH surges and several times during the luteal‐follicular transition. Data for analysis were available in all women on days −8, −6, −4, −2, −1,1, 2, 3, 4, 5 and 7 in relation to the onset of second menstruation (day 1).

PATIENTS Five normally ovulating parous women were studied.

MEASUREMENTS Pituitary response to GnRH was calculated as the net increase in LH and FSH at 30 minutes (ΔLH and ΔFSH) above the basal value.

RESULTS ΔLH and ΔFSH showed a similar pattern of significant changes during the luteal‐follicular transition. They decreased progressively from days −8 to 1 and increased on day 2. ΔLH and ΔFSH then decreased on days 3 and 4 and showed a further increase on days 5 and 7. In contrast to these changes, basal FSH levels increased from days −2 to 1 and remained high up to day 5, while basal LH levels showed a trend to increase only after the onset of menses.

CONCLUSIONS These results demonstrate that the increase In basal FSH secretion during the luteal‐follicular transition is GnRH independent. It is suggested that LH and FSH release under the stimulation by GnRH is regulated by a common mechanism.
Control of prolactin‐secreting macroadenomas with parenteral, long‐acting bromocriptine in 30 patients treated for up to 3 years
Authors: Haase Roland , Jaspers Christian , Schulte Heinrich Maria , Lancranjan Ioana , Pfingsten Henrich , Orri‐Fend Miguel , Reinwein Dankwart , Benker Georg
Published: March 2008

OBJECTIVE We investigated the effect of intramuscular injections of long‐acting bromocriptine in patients with macroadenomas.

STUDY DESIGN AND PATIENTS Thirty patients with PRL‐secreting pituitary macroadenomas were treated with repeated 4‐weekly intramuscular injections of 50 or 100 mg of a long‐acting, repeatable bromocriptine formulation for six to 37 injections, amounting to a total of 473 injections. Twenty patients received parenteral bromocriptine as primary therapy, ten had persisting hyperprolactinemia after previous therapies including pituitary surgery (n= 7), oral bromocriptine (7), and pituitary Irradiation (2).

MEASUREMENTS A PRL day profile was obtained and the patients' clinical status and history were documented, at intervals. Detailed clinical, laboratory, and radiological (pituitary nuclear magnetic resonance or computed tomography scan) evaluations were performed at baseline, after 1 injection and every 6th injection therafter.

RESULTS In all patients PRL was suppressed from a mean ± SEM pretreatment level of 32 620 ± 8680 to 4480 ± 1140 mU/l on the third day after the first injection. In 12 patients PRL levels normalized (< 400 mU/l) with the first to fourth injection, in three additional patients PRL levels normalized after 8–15 months. In 19 patients PRL was suppressed to less than 1000 mU/l. In three patients PRL did not decrease to less than 50% of pretreatment; in two of them on oral bromocriptine prior to this study there had been a comparable low efficacy. Of 28 patients with macroadenomas (median height 22 mm) tumour shrinkage was evident in 15 by nuclear magnetic resonance or computed tomography scan 28 days after the first injection, and in three additional patients after 6 months. There was further regression in seven cases after 12, 18 or 24 injections. Adenoma size (mean SEM) decreased to 66 ± 7% of the pretreatment value. The 40 adverse events noted in 20 of 30 patients during 24 hours after the first injection were similar to known side‐effects of oral bromocriptine, nausea and postural hypotension being the most frequent. With repeated injections, on average 0 6 adverse events were noted per injection (mostly mild asthenia). There were no local adverse reactions at the injection site.

CONCLUSION We conclude that long‐acting repeatable bromocriptine in patients with macroprolactinomas offers a safe and efficacious primary treatment that ensures compliance and gives long‐term control. Adverse reactions are comparable to oral bromocriptine but subside with repeated injections.
Pharmacokinetics of 1‐deamino‐8‐d‐arginine vasopressin after various routes of administration in healthy volunteers
Authors: Fjellestad‐Paulsen A. , Höglund P. , Lundin S. , Paulsen O.
Published: March 2008

OBJECTIVE We investigated the pharmacokinetics and biological effects of 1‐deamino‐8‐d‐arginine vasopressin (dDAVP) in healthy adults after intravenous, subcutaneous, intranasal, peroral, sublingual and intrarectal administration.

DESIGN Eight normal volunteers were studied over an 8‐hour period after each drug administration, separated by at least one week. For intravenous and subcutaneous administration, the subjects received 2 μg of dDAVP. The intranasal and sublingual doses were 20 μg and the rectal dose was 50 μ. Oral administration of dDAVP was effected with a 200‐μg tablet.

MEASUREMENTS Plasma and urinary levels of dDAVP were measured using a specific and sensitive radioimmunoassay.

RESULTS A significant increase of urine osmolality was observed after all routes of administration, except the sublingual and intrarectal for up to 8 hours after administration. After intravenous administration, the half‐life of elimination (t) of dDVAP was 78 ± 10 minutes. An extensive adsorption of dDAVP to the plastic syringe was found with intravenous but not with subcutaneous administration. Using the area under the curve of dDAVP from the subcutaneous administration as a reference, bioavailability was found to be 3.4% after intranasal administration and 0.1% after oral administration. After sublingual and intrarectal routes of administration no detectable dDAVP was found in the blood; however, low amounts were found in the total 24‐hour urine.

CONCLUSION The bioavailability of dDAVP seems lower than previously reported after intranasal and oral administration.
Atrial natriuretic factor reduces vasopressin and angiotensin II but not the ACTH response to acute hypoglycaemic stress in normal men
Authors: Wittert G. A. , Espiner E. A. , Richards A. M. , Donald R. A. , Livesey J. H. , Yandle T. G.
Published: March 2008

OBJECTIVE We determined the effects of physiological (non‐hypotensive) increments of plasma atrial natriuretic factor (ANF) on the vasopressin and hypothalamic‐pituitary‐adrenal response to insulin induced hypoglycaemia. DESIGN Single blind, placebo controlled, randomized study of the effect of vehicle alone or ANF (2.5 pmol/kg/min for 120 minutes) commencing 30 minutes before bolus administration of insulin (0 15 U/kg body weight).

RESULTS ANF infusion raised venous plasma ANF levels four to five‐fold (mean level 32 ± 0.3 pmol/l at time of insulin injection) without affecting resting blood pressure or heart rate. After insulin, the fall in plasma glucose and rise in plasma adrenaline and noradrenaline were similar in both studies. In contrast, the responses in plasma arginine vasopressin (P < 0.02) and in plasma angiotensin II (P<0.05) were inhibited by ANF. Plasma corticotrophin releasing factor, ACTH and Cortisol responses to hypoglycaemic stress did not differ significantly in the presence and absence of ANF.

CONCLUSION We conclude that four to five‐fold acute increase in plasma ANF, while attenuating vasopressin and angiotensin II responses to hypoglycaemia, does not inhibit the hypothalamic, pituitary and adrenal responses or inhibit sympathetic nervous activation in normal men.
Self‐administered subcutaneous human menopausal gonadotrophin for the stimulation of testicular growth and the initiation of spermatogenesis in hypogonadotrophic hypogonadism
Authors: Jones T. H. , Darne J. F.
Published: March 2008

OBJECTIVE We determined whether or not self‐administered subcutaneous human menopausal gonadotrophin (hMG) therapy is safe and effective in the stimulation of testicular growth and initiation of spermatogenesis In men with hypogonadotrophic hypogonadism where human chorionic gonadotrophin alone had failed.

DESIGN Human menopausal gonadotrophin was self‐administered subcutaneously in two dosage regimens to patients requiring (a) fertility (Group I), 37.5 IU twice daily (total weekly dose 525 IU) (n= 7) and (b) increased testicular size (Group II) 37.5 IU once daily (total weekly dose 265.5 IU) (n=2). Patients were assessed on a monthly basis.

PATIENTS Nine patients with hypogonadotrophic hypogonadism were studied. Six patients had Idiopathic isolated hypogonadotrophic hypogonadism, one Kallman's syndrome, one idiopathic isolated hypogonadotrophic hypogonadism secondary to trauma and one with panhypopituitarism secondary to radiotherapy for a hypothalamic pituitary tumour. Five of these patients had a history of unilateral or bilateral cryptorchidism.

MEASUREMENTS Semen analysis and serum testosterone. Testicular size was assessed by use of a Prader orchidometer.

RESULTS Six of seven patients (four with a history of cryptorchidism) requesting fertility attained sperm counts of < 10 million/ml. Three pregnancies have been achieved so far. One failure occurred in a patient with a previous history of cryptorchidism. In Group I patients (a) with an initial testicular volume of 4 ml or less (n= 4), mean size increased from 3.25·0.9 (SD) ml to 12.2·3.8 ml, (b) an initial testicular volume of <4 ml mean size (n= 3) increased from 9.2 ± 3.9 ml to 10.3 ± 4 ml. In Group II (n= 2) testis size increased from a mean of 3.0 ± 1.4 ml to 9.0 ± 1.4 ml over a 6‐months treatment period.

CONCLUSION Self‐administered subcutaneous human menopausal gonadotrophin is a safe and effective mode of therapy in increasing testicular size and inducing spermatogenesis in males with hypogonadotrophic hypogonadism.
Molecular forms of parathyroid hormone‐related protein in tumours and biological fluids
Authors: Bowden S. J. , Hughes S. V. , Ratcliffe W. A.
Published: March 2008

OBJECTIVE We investigated the content and compared the molecular forms of parathyroid hormone‐related protein in tumour tissue, plasma and pleural fluid.

DESIGN Measurement of parathyroid hormone‐related protein in tumour extracts and biological fluids and comparison of the elution profiles of parathyroid hormone‐related protein (PTHRP) immunoreactivity following gel filtration chromatography on Bio‐gel P100.

PATIENTS Tumours and plasma from patients with humoral hypercalcaemia of malignancy were studied, together with tumours and pleural fluids from patients who were normocalcaemic.

MEASUREMENTS Immunoreactivity in column fractions, plasma and tumour extracts was measured by a highly sensitive immunoradiometric assay for PTHRP 1–86 with specificity directed at the 17–61 region of PTHRP.

RESULTS Similar levels of PTHRP immunoreactivity were measured in tumours from normocalcaemic and hyper‐calcaemic patients. PTHRP 1–86 (28–4630 fmol/g) was detected in eight of the nine tumours studied. Immunoreactivity in tumour extracts eluted as major peaks in the range 22–33 kDa with an additional peak of 15 kOa in three out of six tumours studied. In contrast, immunoreactivity in plasma and pleural fluid eluted within the range 7–14 kDa.

CONCLUSIONS The major species of parathyroid hormone‐related protein in plasma and pleural fluids was consistently smaller than that in tumour tissue (22–33 kOa) suggesting that tumour‐derived parathyroid hormone‐related protein is processed at the COOH‐terminus to form a species of approximately 10 kDa which circulates in patients with humoral hypercalcaemia of malignancy.
Inhibin and follicle‐stimulating hormone levels in gonadotroph adenomas: evidence of a positive correlation with tumour volume in men
Authors: Lahlou Najiba , Le Nestour Elisabeth , Chanson Philippe , Seret‐Bégué Dominique , Bouchard Philippe , Roger Marc , Warnet André
Published: March 2008

OBJECTIVE Gonadotroph adenomas are generally revealed by symptoms of mass effect at the stage of macroadenoma. Most of them hypersecrete FSH and/or gonadotrophin subunits. Rarely they hypersecrete LH, which could induce endocrinological symptoms. As the glycoprotein inhibin is secreted by the gonads under FSH control, we have evaluated whether high immunoreactive inhibin (IINH) levels correlated with FSH hypersecretion and whether IINH and FSH levels were related to tumour volume in subjects with gonadotroph adenomas.

PATIENTS Forty‐five patients (30 men, 15 women) were retrospectively selected on the basis of immunostaining technique using specific antibodies raised against FSH‐beta, LH‐beta and glycoprotein alpha‐subunit.

MEASUREMENTS Immunoreactive inhibin (IINH) was measured by radioimmunoassay using antiserum 1989 raised to bovine inhibin. Tumour volume index was the product in cm3 of length, width and height of the adenoma as assessed by computerized tomography.

RESULTS In men (age 21–61 years), IINH levels were positively correlated with FSH levels (Spearman's r=0.67, P < 0.001), and both IINH and FSH levels were significantly correlated with tumour volume index (Spearman's r= 0.38, P<0.05 and r=0.39, P<0.05 respectively). In the subgroup of men with normal FSH levels (n= 17), the correlation of FSH with tumour volume index was high: Spearman's r= 0.56, P< 0.05. In the post‐menopausal women (n= 8, age < 55 years), IINH levels were undetectable or below the follicular phase range regardless of FSH values. In the premenopausal women (n= 7, age 22–49 years, follicular phase or amenorrhoea) IINH levels were above follicular phase range in three women including one who had very high FSH levels.

CONCLUSIONS These data show that in men with gonadotroph adenoma FSH levels are related to tumour mass and suggest that a significant part of circulating FSH in patients with normal FSH levels arises from the tumour. The significant correlation between IINH and FSH levels demonstrates that tumoral FSH is bioactive and that high IINH levels do not exert any feedback control on tumoral FSH secretion. Therefore the coexistence of high FSH levels with high IINH levels is strongly suggestive of a gonadotroph adenoma. Gonadotroph adenomas seem to represent a unique model of long‐term FSH stimulation of Inhibin‐producing cells, in some way analogous to that created by repetitive administration of exogenous FSH.
Prevalence of subclinical hyperthyroidism and relationship between thyroid hormonal status and thyroid ultrasonographic parameters in patients with non‐toxic nodular goitre
Authors: Rieu Max , Bekka Saïd , Sambor Boris , Berrod Jean‐Louis , Fombeur Jean‐Pierre
Published: March 2008

OBJECTIVE Basal plasma T4, T3 and TSH concentrations are usually normal in patients presenting with non‐toxic nodular goitre. Using the evaluation of TSH response to TRH in a large series of such patients living In an area with normal iodine intake, we evaluated the prevalence of subclinical hyperthyroidism and the relationship between thyroid hormonal status and ultrasonographic parameters.

PATIENTS A prospective study of 242 consecutive patients (group I), referred with non‐autoimmune nodular goitre, normal plasma free T4, total T3 and TSH levels, without (subgroup IA, 222 patients) or with (subgroup IB, 20 patients) clear‐cut autonomous area(s) on scintigraphy. These patients were compared to 135 controls (group II).

MEASUREMENTS Plasma free T4 (FT4), total T3 (T3T) and TSH measurements. Evaluation of TSH response to TRH (A level of increased TSH = peak TSH level during TRH test‐basal TSH level), thyroid scintigraphy and morphological characteristics (number and total volume of nodule(s) and volume of extranodular tissue) determined by ultrasonography.

RESULTS In subgroup IA, (1) the mean (± SEM) basal TSH level (0.94± 0.04 μ/l) and the mean value of increased TSH after TRH (4.92 ± 0.34 μ/l) were lower (P<0.001) than in group II (1.28 ± 0.05 μ/l and 7.24 ± 0.25 μ/l, respectively). The prevalence of SH (Δ level of increased TSH below the mean – 3 SD in controls) was 17.2%; (2) the mean FT4 level and the mean T3T value were not different (P>0 05) from those of group II. In subgroup IB, (1) the mean basal TSH level (0.57 ± 0.11 μ/l) and the mean Increment of TSH after TRH (2.81 ± 0.62 μ/l) were lower (P < 0001) than in subgroup IA. The prevalence of subclinical hyperthyroidism was 750%; (2) the mean FT4 level (17.2± 0.9 pmol/l) was not different from that in group II. However, the mean T3T value (1.99 ± 0.01 nmol/l) was higher (P< 0.001) than in group II (1.65 ± 0.05). In group I, subgroup IA and IB, there were significant (P< 0.05, at least) correlations between the numbers of nodules and both basal TSH levels and Δ values of increased TSH or FT4 levels or T3T values. No correlations were found between other ultrasonographic data and plasma thyroid parameters.

CONCLUSIONS This study demonstrates a high prevalence of subclinical hyperthyroidism in patients presenting with non‐toxic nodular goitres and suggests that the number of nodules, but not their total volume, is an important factor in the development of this condition.
Serious, prolonged hypoglycaemia with glibenclamide in a patient with Mendenhall's syndrome
Authors: Kumar S. , Boulton A. J. M.
Published: March 2008

Mendenhall's syndrome, characterized by familial insulin resistant diabetes, pineal hyperplasia and multiple somatic abnormalities, is associated with defects involving the a‐subunit of the insulin receptor. The associated insulin‐resistant diabetes is extremely difficult to treat; insulin is required in very large doses to control hyperglycaemia and oral hypoglycaemic agents are ineffective. We report a case of severe, prolonged hypoglycaemia that occurred in a 24‐year‐old patient with Mendenhall's syndrome following therapy with glibenclamide. He had glibenclamide 10 mg daily for 1 week following which he was admitted to hospital in hypoglycaemic coma with blood glucose levels < 1 0 mmol/l. This subject had undergone hypophysectomy at the age of 11 years. Prior to pituitary ablation, oral hypoglycaemic agents did not improve glycaemic control. Thus, previous hypophysectomy in this patient appears to have made it possible for glibenclamide to exert its hypoglycaemic effect. The occurrence of hypoglycaemia in this patient suggests alternative mechanisms for insulin action in conditions characterized by severe insulin resistance due to insulin receptor defects.
17‐Hydroxyprogesterone response to buserelin testing in the polycystic ovary syndrome
Authors: Şahin Yilmaz , Keleştimur Fahrettin
Published: March 2008

OBJECTIVE We determined the 17‐hydroxyprogesterone (17‐OH P) response to buserelin, a GnRH agonist, and its relation to ovarian volume in the patients with polycystic ovary syndrome (PCOS).

DESIGN We compared 17‐OH P response to buserelin in a large group of patients with that In a control group of healthy women. We also investigated whether there is any relation between LH‐induced 17‐OH P production in response to buserelin and ovarian volume.

PATIENTS Ten normal women and 31 women with PCOS were included in the study.

MEASUREMENT Pelvic ultrasound examination by abdominal or vaginal transducer was performed. Serum basal levels of LH, FSH, free testosterone and 17‐OH P were measured by radioimmunoassay. 17‐OH P responses to both ACTH and buserelin were detected. Cortisol levels were measured before and after dexamethasone suppression.

RESULTS The subcutaneous administration of 1 mg buserelin produced an increase in serum 17‐OH P, which peaked within 24 hours in all groups. The mean ±SEM level of 17‐OH P, 24 hours after buserelin stimulation in the women with PCOS (15.94 ±1.31 nmol/l) was significantly higher (P<0001) than in the control group (6 75±0 69 nmol/l). The women with PCOS had increases in 17‐OH P levels exceeding 10.15 nmol/l 24 hours after buserelin testing. The increased 17‐OH P responses to buserelin were unchanged by pretreatment with dexamethasone to suppress adrenal function. The 17‐OH P response was significantly related to ovarian volume (r= 0.53, P<0.01).

CONCLUSIONS Our findings suggest that the serum 17‐OH P response to a 1‐mg subcutaneous test dose of buserelin may be a diagnostic and practical test for PCOS. Increased ovarian volume in PCOS may be responsible for the elevated 17‐OH P response to buserelin, a GnRH agonist, at least in some patients.
Circadian variation in serum free and non‐SHBG‐bound testosterone in normal men: measurements, and simulation using a mass action model
Authors: Cooke R. R. , McIntosh J. E. A. , McIntosh R. P.
Published: March 2008

OBJECTIVE We measured the changes in testosterone fractions in serum of normal men over a 24‐hour period, and determined whether they could be simulated on the basis of current understanding of the interactions betwen steroids and binding proteins in the blood.

DESIGN Starting from between 0830 and 0930 h, blood samples were taken every 45 minutes for 25 5 hours.

PATIENTS Five healthy males aged 26‐45 years. All participants worked on a hospital campus and while being sampled carried out their normal activities during waking hours.

MEASUREMENTS The concentrations of testosterone (RIA) and albumin, and the percentage non‐sex hormone binding globulin‐bound testosterone (ammonium sulphate precipitation) and percentage free testosterone (rate dialysis), were measured on each sample. Cortisol (RIA) and sex hormone‐binding globulin (SHBG) (IRMA) concentrations were measured on every second sample, and that of corticosteroid‐binding globulin on two samples from each series.

RESULTS In all participants the levels of free and non‐SHBG‐bound testosterone in early morning samples (near 0530 h) were significantly different from those taken before midnight (P< 0 0005). Significant circadian rhythms (P<0 05) in the concentration of testosterone and in the level of the free fraction were detected in all participants, and in four of the five participants for the non‐SHBG‐bound fraction. The amplitude of the free testosterone rhythm (34 ± 2% of basal) was greater than that for testosterone itself (24 ± 3% of basal). The 24‐hour rhythm of the non‐SHBG‐bound fraction was similar to the total and free fractions except for the period 0330‐0900 h when the level of this fraction declined by 15‐45% over 1 5‐3 hours. This decline was coincident with the initial rise in the concentration of Cortisol. A decline of 10 5 ± SEM 1 0% in the concentration of albumin, and 12 0 ± 1 1 % in that of SHBG occurred when the mean ambulant and supine levels were compared; analysis indicated significant circadian rhythms in the concentrations of these proteins. Simulation was used to investigate possible causes for the circadian rhythms in free and non‐SHBG‐bound testosterone. Simulation results matched the measured data well in qualitative terms, but quantitatively there were differences.

CONCLUSIONS Increasing saturation of the binding proteins following rises in testosterone production, and the small but significant changes in protein concentration, probably related to postural changes, were implicated as the major factors in the rhythm amplitude. However, the early morning decline in the non‐SHBG‐bound fraction was not explained by these factors. The rise in Cortisol concentration at this time is a probable cause. Alternatively, simulation suggests that a substance appearing in the early morning and competing with testosterone for albumin binding sites may be responsible.
Molecular heterogeneity of serum follicle‐stimulating hormone in hypogonadal patients before and during androgen replacement therapy and in normal men
Authors: Harsch Igor A. , Simoni Manuela , Nieschlag Eberhard
Published: March 2008

OBJECTIVE The present study was performed to characterize the molecular heterogeneity of serum FSH in normal males and to investigate the possible influence of testosterone on serum FSH in androgen‐deficient men before and during testosterone administration.

DESIGN AND PATIENTS Serum samples were taken at 10‐minute intervals between 0730 and 0830 h from nine healthy, eugonadal men and from eight men with primary hypogonadism (Klinefelter's syndrome). In the hypogonadal patients, sampling was performed before treatment (n= 8), 4‐5 days after the first and the third injection of 250 mg testosterone enanthate given intramuscularly at three‐weekly intervals (n= 6), as well as 3 months after the onset of therapy (n= 3). Sampling was repeated 7 days apart in two of the nine healthy volunteers.

MEASUREMENTS Aliquots from the individual serum samples were pooled and fractionated by chromatofocusing in the pH range 6‐3. Immunoreactive FSH was measured by immunofluorimetric assay (IFMA) in each fraction and the individual serum samples. In each serum pool, bioactive FSH was determined by in‐vitro bioassay (rat Sertoli cell aromatase bioassay), testosterone by RIA and LH by IFMA.

RESULTS After grouping the percentage of immunoreactive FSH recovered in the individual fractions into intervals of 0 5 pH units, significant differences between controls and patients were observed in the pH regions 4‐4.5, 5.5‐6 and 6‐6.5. No statistically significant changes in the isoform distribution of FSH were detected during therapy in the Klinefelter patients. A high degree of variability, which did not follow a common pattern, was observed in the isoform distribution of FSH within the same individuals, both in the hypogonadal patients during treatment and in the two normal men whose blood samples were taken on two different occasions.

CONCLUSIONS Serum FSH is highly heterogeneous in normal and hypogonadal men. There is a spontaneous intra‐individual variability in the relative abundance of the different FSH isoforms in serum that may most probably be related to metabolic deglycosylation of FSH. Minor but significant differences in the molecular heterogeneity of serum FSH could be demonstrated in Klinefelter patients compared to normal men. These differences are not modified by administration of testosterone enanthate at doses achieving normal androgenization, suggesting that factors different from testosterone may modulate FSH pleomorphism.
Evening administration of melatonin enhances the pulsatile secretion of prolactin but not of LH and TSH in normally cycling women
Authors: Terzolo Massimo , Revelli Alberto , Guidetti Daniela , Piovesan Alessandro , Cassoni Paola , Paccotti Piero , Angeli Alberto , Massobrio Marco
Published: March 2008

OBJECTIVE The aim of the study was to evaluate the effects of exogenous melatonin on the spontaneous pulsatile release of PRL, TSH and LH in normal women.

DESIGN A double blind placebo‐controlled protocol was designed to study seven subjects in the mid follicular phase of two non‐consecutive cycles. Two mg of exogenous melatonin or placebo were given at 1600 and 2000 h, and blood samples were collected every 10 minutes from 1800 to 2400 h for hormone determination.

RESULTS Melatonin treatment caused a significant upward resetting of the pulsatile pattern of PRL in six out of seven subjects. Average maximal peak height was significantly increased (median 716 mlU/l (range 198‐1433) on melatonin vs 324 mlU/l (212‐688) on placebo, P<0.001), nadir value (572 mlU/l (148‐1084) vs 216 mlU/l (54‐580), P < 0 001) and area under the peak (26352 mlU/l min (5904‐93672) vs 12096 mlU/l min (2340‐33552), P<0 001), whereas peak number, amplitude and interpeak interval did not change significantly. TSH pulsatility was unaffected by melatonin administration in four out of six subjects. Distribution of LH patterns after melatonin was inhomoge‐neous: level of pulsatility was higher in two cases and reduced in three; group analysis did not therefore show significant variation of pulsatility parameters.

CONCLUSIONS Exogenous melatonin has a stimulatory effect on PRL release without affecting the temporal pattern of its pulsatile secretion in normal women. Melatonin has minor, if any, effect on TSH secretion whereas the effect on LH may depend on individual sensitivity.
Enhanced prolactin responsiveness to galanin in patients with Cushing's disease
Authors: Invitti C. , Giraldi F. Pecori , Tagliaferri A. , Scacchi M. , Dubini A. , Cavagnini F.
Published: March 2008

OBJECTIVE Galanin is believed to play a role in the control of prolactin (PRL) secretion in the rat. Such a role is uncertain in humans where the neuropeptide is expressed by the corticotrophs. However, in clinical conditions of enhanced ACTH secretion, increased PRL levels are often observed. Therefore, we evaluated the effect of galanin infusion on serum PRL levels in patients with Cushing's disease and in control subjects. For comparison, the PRL responses to TRH and metoclopramide were also investigated in the same patients.

DESIGN Four tests were performed: (a) 40‐minute infusion of 0–3 μg/kg/min of galanin; (b) infusion of normal saline only; (c) metoclopramide test (10 mg as i.v. bolus); (d) TRH test (200 mg as i.v. bolus).

PATIENTS Twenty‐four normal subjects and nine patients suffering from active Cushing's disease were investigated.

MEASUREMENTS Serum concentrations of PRL were measured by radioimmunoassay on blood samples collected before and for 90 minutes after drug or saline administration.

RESULTS Serum baseline PRL levels were superimposable in normal subjects and in patients with Cushing's disease. In normal subjects, infusion of galanin induced a distinct PRL increase compared to saline (mean ±SEM incremental areas 6514 ±2572 vs 540 ±571 μ/l/90 min, P= 005, respectively).

In patients with Cushing's disease, galanin evoked a remarkable PRL rise with hormone levels which were significantly greater (P < 0.001) than those observed in the same patients after infusion of saline (21908 ± 4180 vs 534 ± 1556 mU/l/90 min) or after galanin administration in controls (P<0.01). The PRL response to TRH and, much more so, to metoclopramide was significantly lower in patients with Cushing's disease than in normal subjects (42125± 8000 vs 73181 ± 7246 mU/l/90 min, P<0.01 after TRH and 79095 ± 27265 vs 229049 ± 10602 mU/l/90 min, P < 001 after metoclopramide).

CONCLUSIONS Galanin appears to be a specific, though weak, PRL secretagogue in normal subjects. The galanin‐induced PRL release was significantly increased in patients with Cushing's disease. A number of hypothetical mechanisms may underlie the enhanced PRL reactivity to galanin in Cushing's disease. This finding together with the impaired PRL responsiveness to TRH and metoclopramide, also observed in this study, is a further example of a dysregulation of PRL secretion in patients with Cushing's disease.
Protein intake during aggressive calorie restriction in obesity determines growth hormone response to growth hormone‐releasing hormone after weight loss
Authors: Megia Ana , Herranz Lucrecia , Luna Reyes , Gómez‐Candela Carmen , Pallardo Felipe , Gonzalez‐Gancedo Pilar
Published: March 2008

OBJECTIVE We evaluated the influence of two types of calorie restriction, total fast or very low calorie diet, on GH responsiveness to GHRH in severely obese patients.

DESIGN Twenty patients with massive obesity underwent one of two types of calorie restriction, total fast (10 patients) or very low calorie diet (10 patients).

MEASUREMENTS Fasting GH, IGF‐I, glucose, insulin and GH secretion after GHRH (100 ug i.v.) were assessed in all patients before and after diet therapy.

RESULTS Both types of diet produced similar weight reduction (total fast, 5.6 ± 1.6 kg/m2vs very low calorie diet, 5.6 ± 1.5 kg/m2 mean ± SD). A significant increase in the integrated GH secretion was observed after weight‐loss with very low calorie diet (17 ± 9 vs27 ± 12mU/l min; P < 0.05). However, no change was found in GH response after weight loss with total fast (13 ± 5 vs 15 ± 7 μ/l min). Glucose, insulin and IGF‐I levels showed a significant decrease with weight reduction which was similar for both groups.

CONCLUSION These findings suggest that the type of dietary manipulation during calorie restriction in obese patients may influence the changes in GH response to GHRH after weight loss.
Relationships between insulin‐like growth factor‐1 levels and growth hormone concentrations during diurnal profiles and following oral glucose in acromegaly
Authors: Dobrashian R. D. , O'Halloran D. J. , Hunt A. , Beardwell C. G. , Shalet S. M.
Published: March 2008

OBJECTIVE The aim of this study was to refine the biochemical definition of disease activity in acromegaly by comparing serum growth hormone (GH) measurements during a 10‐hour day profile with serum GH values during an oral glucose tolerance test.

DESIGN Using plasma insulin‐like growth factor‐1 (IGF‐1) levels as a measure of disease activity, serum GH data from a day profile and from an oral glucose tolerance test were compared.

PATIENTS Thirty‐five acromegalic patients were studied, 13 of whom had serum GH measured during a day profile and 22 during an oral glucose tolerance test. In addition, basal plasma IGF‐1 levels were estimated in all acromegalic patients, and in 24 normal subjects.

MEASUREMENTS Following acid‐ethanol extraction of the plasma samples, IGF‐1 levels were measured by radioimmunoassay using a polyclonal antibody. In a day profile, six to eight blood samples for serum GH estimation were taken at hourly intervals during the day; during an oral glucose tolerance test samples for serum GH estimation were taken in the fasting state and every 30 minutes for 2 hours and measured by a two‐site IRMA for GH. RESULTS Ninety‐four per cent of acromegalic patients with raised plasma IGF‐1 levels had serum GH concentrations <10 mU/l whilst 98% of acromegalic patients with plasma IGF‐1 levels in the normal range had serum GH concentrations lt;6 mU/l. A highly significant positive correlation was found between the mean serum GH concentrations (r=0 67), the minimum serum GH concentration (r = 0 65) and the area under the GH curve (r = 0–66) estimated during an oral glucose tolerance test and plasma IGF‐1 concentrations. The relations between identical indices of serum GH concentration measured during a day profile and plasma IGF‐1 levels, although significant, show a less powerful correlation. The relation between serum GH and plasma IGF‐1 levels describes a curvilinear model, plasma IGF‐1 levels exhibiting a plateau at serum GH concentrations >40 mU/l but maintaining a linear relationship with serum GH levels <20 mU/l.

CONCLUSIONS A highly significant correlation exists between plasma IGF‐1 levels and various parameters of serum GH levels in acromegalic patients. Hormonal assessment of disease activity in acromegaly is more accurately reflected by the serum GH concentration during an oral glucose tolerance test rather than by the serum GH level during a day profile. Normalization of plasma IGF‐1 levels is rarely achieved unless the mean serum GH level is reduced to <6 mU/l.
High prolactin levels in patients with Cushing's disease without pathological evidence of pituitary adenoma
Authors: Comtois Ronald , Beauregard Hugues , Hardy Jules , Robert Françoise , Somma Maurice
Published: March 2008

OBJECTIVE This study was designed to compare the clinical and biochemical features of patients with Cushing's disease without pathological evidence of pituitary adenoma (n= 11) to those in whom a pituitary ACTH adenoma was documented (n= 11).

DESIGN The clinical and biochemical features of 11 patients with Cushing's disease without pathological evidence of pituitary adenomas were compared to 11 subjects with ACTH‐secreting adenomas. The patients underwent transsphenoidal microsurgery between 1979 and 1989. During surgery, when an adenoma was not visualized, a partial hypophysectomy of the central mucoid wedge was performed.

MEASUREMENTS Cushing's disease was established by the clinical features of hypercortisolism and the high levels of 24‐hour free urinary Cortisol with no suppression in response to low, but with suppression in response to high, doses of dexamethasone. Basal and post TRH‐GnRH plasma prolactin, FSH and LH levels were assessed in each patient before transsphenoidal microsurgery.

RESULTS Similar results were observed in patients with and without ACTH‐secreting adenomas regarding cure rate, and free urinary Cortisol levels both basal and after 2 days of dexamethasone, 8 mg daily. After surgery, plasma Cortisol levels in cured patients were lower in subjects with ACTH‐secreting adenomas than in those without pituitary tumours (P < 0.05). Areas under the curve of PRL (P<0.002) and LH (P< 0.04) were significantly higher in patients without pituitary adenoma after TRH‐GnRH administration. Compared to controls, the peak prolactin level after TRH‐GnRH administration was higher in patients without pituitary adenoma (P < 0005) and lower in those with ACTH adenoma (P< 0.05). Furthermore, a peak prolactin level equal to or greater than 1410 mU/l during the TRH‐GnRH test was found in 11/11 patients without ACTH adenoma and 3/11 patients in the other group (P < 0 001), while the CT‐scan findings were suggestive of pituitary adenoma in six patients of each group. CONCLUSION This study suggests that patients with Cushing's disease without pituitary adenomas can be distinguished from those with ACTH‐secreting adenomas by their high prolactin levels after TRH‐GnRH administration.