bluuebunny/crossref_metadata_2025 huggingface dataset:
Hyperprolactinaemia is associated with a higher prevalence of pituitary–adrenal dysfunction in non-functioning pituitary macroadenoma
Authors: Tjeerdsma Geert , Sluiter Wim J , Hew Joffre M , Molenaar Willemina M , de Lange Willem E , Dullaart Robin PF
Published: December 2008

Tjeerdsma G, Sluiter WJ, Hew JM, Molenaar WM, de Lange WE, Dullaart RPF. Hyperprolactinaemia is associated with a higher prevalence of pituitary—adrenal dysfunction in non-functioning pituitary macroadenoma. Eur J Endocrinol 1996;135:299—308. ISSN 0804–4643

In non-functioning pituitary macroadenoma (NFMA), hyperprolactinaemia (hyperPRL) is considered to be a sign of hypothalamic—pituitary dysregulation, but it is unknown whether hyperPRL is associated with an increased frequency of pituitary hormone deficiencies. Forty consecutive patients with histology-proven NFMA were studied and hyperPRL was defined as serum prolactin (PRL) >200 mIU/l in men and >600 mIU/l in women. The pituitary—adrenal axis was evaluated by measurement of urinary free cortisol (N = 38), peak cortisol to insulin-induced hypoglycaemia (IIH, N = 36) and to human corticotrophin-releasing hormone (hCRF, N = 40) and by urinary tetrahydro11-deoxycortisol (H4S, N = 39), plasma androstenedione increment (N = 39) and serum 11-deoxycortisol (N = 1) after metyrapone. Central hypothyroidism, gonadotrophin deficiency and growth hormone (GH) reserve were also assessed. Twenty patients had hyperPRL (serum PRL 331 (2231120)mIU/l (median, range) in men and 932 (660–3927)mIU/l in women); urinary free cortisol excretion (p < 0.03) and peak serum cortisol in response to IIH (p < 0.02) were lower in hyperPRL than in normoPRL patients; peak serum cortisol after hCRF was not different between groups but occurred later in hyperPRL patients (at 60 vs 30 min, p < 0.03); urinary H4S excretion and androstenedione response after metyrapone were lower in hyperPRL than in normoPRL patients (p < 0.05 for both); 60% of hyperPRL patients and 15% of normoPRL patients had an abnormal H4S response (p < 0.025); central hypothyroidism (overt + subclinical) was present in 74% of hyperPRL and in 60% of normoPRL patients (NS); 78% of hyperPRL and 55% of normoPRL patients had gonadotrophin deficiency (NS); growth hormone (GH) deficiency was present in 83% of hyperPRL and in 89% of normoPRL patients (NS); 73.3% of 75 evaluable pituitary hormone axes were abnormal in hyperPRL patients compared to 5 3.8% of 78 hormone axes in normoPRL patients (by metyrapone test to examine adrenal function, p < 0.025); and no significant differences in tumour grade and stage distribution were found between hyperPRL and normoPRL patients. It is concluded that hyperprolactinaemia in NFMA is associated with a higher prevalence of pituitary–adrenal dysfunction, which is likely to be explained at least in part by functional hypothalamic–pituitary interruption.

RPF Dullaart. Department of Endocrinology, University Hospital Groningen, PO Box 30.001, 9700 RB Groningen, The Netherlands
Hormonal changes related to eating behavior in oligomenorrheic women
Authors: Dumoulin Sonia C , de Glisezinski Isabelle , Saint-Martin Françoise , Jamrozik Sylvie I , Barbe Pierre , Thouvenot Jean-Paul , Plantavid Monique M , Bennet Antoine P , Louvet Jean-Pierre
Published: December 2008

Dumoulin SC, de Glisezinski I, Saint-Martin F, Jamrozik SI, Barbe P, Thouvenot J-P, Plantavid MM. Bennet AP, Louvet J-P Hormonal changes related to eating behavior in oligomenorrheic women. Eur J Endocrinol 1996;135:328–34. ISSN 0804–4643

The aim of this study was to determine those hormonal alterations in the gonadotropin-ovarian axis that are related to eating behavior in oligomenorrheic patients. We studied 74 oligomenorrheic women aged 26.2 ± 0.8 years, divided into group IA (N = 13) with eating disorders, group IB (N = 61) without eating disorders and 18 normally cycling controls aged 29.2 ± 1.6 years (group II). No subject had ovarian failure, pituitary disease, thyroid dysfunction or was taking any drug. Blood samples were taken on days 3–6 after the last menses. Luteinizing hormone (LH) was measured in two plasma pools, each made up of three samples taken at 30-min intervals, starting at 15.00 h (LH-1 5 h) and 09.00 h (LH-9 h), which allowed the mean LH (mLH) and variability in LH (V-LH: percentage increase from the lower to the higher of the two LH values) to be calculated. Follicle-stimulating hormone (FSH), sex steroids, and gonadotropin-releasing hormone-stimulated LH (sLH) and -FSH (sFSH) were also evaluated. Eating behavior was evaluated with the EAT questionnaire; the EAT 26 score, the dieting score (DS) and bulimia score (BS) were calculated. Dietary intake was evaluated in 35 group IB patients based on food diaries analyzed with the REGAL program, to evaluate daily calorie intake (Cal) and calories provided by carbohydrates (Carb), lipids (Lip) and proteins (Prot). Comparisons between groups were done by analysis of variance (followed by the Fisher PLSD test) and the KruskalWallis test. Groups IA. IB and II did not differ regarding age, body mass index, LH-9 h, LH-15 h, mLH, FSH, sLH, sFSH, estradiol or dehydroepiandrosterone sulfate; group IA had a higher V-LH than group II (p < 0.02) and a higher testosterone level than groups IB and II (p < 0.05). Positive correlations were found between V-LH and DS (p < 0.01) and BS (p < 0.05), and between testosterone and BS (p < 0.02) and DS (p < 0.05). The V-LH was negatively correlated with Cal and Carb, and testosterone was positively correlated with Cal and Lip. In patients referred for oligomenorrhea, it is concluded that testosterone levels and variability of LH levels are related to eating behavior.

Antoine P Bennet, Service d'Endocrinologie, Hôpital Purpan, Place du Dr Baylac, 31059 Toulouse-Cedex, France
Role of progesterone deficiency in the development of luteinizing hormone and androgen abnormalities in polycystic ovary syndrome
Authors: Fiad Tarek M , Cunningham Sean K , McKenna T Joseph
Published: December 2008

Fiad TM, Cunningham SK, McKenna TJ. Role of progesterone deficiency in the development of luteinizing hormone and androgen abnormalities in polycystic ovary syndrome. Eur J Endocrinol 1996;135:335–9. ISSN 0804–4643

The aetiology of polycystic ovary syndrome (PCOS) is unknown. It is uniquely characterized by oligomenorrhoea or amenorrhoea associated with normal or high oestrogen levels. This prospective clinical study was designed to examine the possible role of the lack of cyclical exposure to progesterone in the development of gonadotrophin and androgen abnormalities in PCOS. Gonadotrophin, androgen and oestrogen levels were measured in 15 PCOS patients and 10 normal subjects untreated and following treatment with the progestogen medroxyprogesterone acetate (MPA). When compared to control subjects, PCOS patients had significantly higher luteinizing hormone (LH) pulse height, pulse amplitude, integrated LH levels, LH response to gonadotrophin-releasing hormone (GnRH) and LH/FSH ratio; LH pulse frequency was similar in the two groups. In addition, the testosterone/sex hormone binding globulin ratio (T/SHBG), androstenedione and oestrone concentrations in the plasma were significantly higher in PCOS than in control subjects. When PCOS patients were treated with MPA for 5 days, there were significant decreases (p < 0.02–0.001) to values no longer different from normal: from 8.7 ± 1.2 to 5.6 ± 0.8 IU/l for integrated LH levels (untreated and MPA-treated PCOS); from 31.2 ±3.5 to 12.9 ±1.5 IU/l for LH response to GnRH; from 2.4 ± 0.26 to 1.3 ± 0.2 for LH/FSH ratio; and from 10.4 ± 0.63 to 8.5 ± for androstenedione. Significant decreases (p < 0.05–0.005) to values that still remained significantly higher than in normal subjects occurred for: LH pulse height, 11.05 ± 1.3 to 6.88 ± 0.79 IU/l (untreated and MPA-treated PCOS); LH pulse amplitude, 2.8 ± 0.5 to 1.8 ± 0.2 IU/l; total testosterone, 2.5 ± 0.2 to 2.0± 0.2 nmol/l; T/SHBG ratio, 14.1 ± 1.7 to 11 ± 1.5; and oestrone, 265 ± 24 to 208 ± 29 pmol/l. These results are consistent with the concept that ovulation failure and progesterone deficiency play a facilitatory role in the development of the hypothalamic-pituitary abnormality giving rise to disordered LH secretion in PCOS.

TJ McKenna. Department of Investigative Endocrinology. St Vincent's Hospital, Elm Park. Dublin 4, Ireland
Immunoreactive brain natriuretic peptide in human adrenal glands and adrenal tumors
Authors: Totsune Kazuhito , Takahashi Kazuhiro , Murakami Osamu , Satoh Fumitoshi , Sone Masahiko , Ohneda Makoto , Miura Yukio , Mouri Toraichi
Published: December 2008

Totsune K, Takahashi K, Murakami O, Satoh F, Sone M, Ohneda M. Miura Y. Mouri T. Immunoreactive brain natriuretic peptide in human adrenal glands and adrenal tumors. Eur J Endocrinol 1996;135:352–6. ISSN 0804–4643

The presence of brain natriuretic peptide (BNP) in tissues of human adrenal glands and adrenal tumors was investigated by radioimmunoassay. Immunoreactive BNP concentrations were 0.203 ± 0.061 pmol/g wet tissue (mean ± sem) in normal parts of adrenal glands (cortex and medulla. N = 8), 0.205 ± 0.037 pmol/g wet tissue in pheochromocytomas (N = 8), 0.230 ± 0.062 pmol/g wet tissue in aldosteronomas (N = 11) and 0.180 ± 0.054 pmol/g wet tissue in adrenocortical adenomas with Cushing's syndrome (N = 4). Sephadex G-50 superfine column chromatography and reverse-phase high-performance liquid chromatography showed that most (> 70%) of the immunoreactive BNP in the normal part of adrenal glands was eluted in the position of human BNP-32. Sephadex G-50 superfine column chromatography of immunoreactive BNP in the pheochromocytoma and aldosteronoma showed four peaks: one in the position ofγ-BNP, one in the position of BNP-32, one between γ-BNP and BNP-32 and one in the smaller molecular weight region. The present study has shown that immunoreactive BNP is present both in normal human adrenal glands and in adrenal tumors. Multiple molecular forms of BNP were found to be present in the tumor tissues of pheochromocytoma and aldosteronoma.

Kazuhiro Takahashi. Department of Applied Physiology and Molecular Biology, Tohoku University School of Medicine, 2–1 Seiryo-machi, Aoba-ku. Sendai 980–77, Japan
In-frame exon 2 deletion in insulin receptor RNA in a family with extreme insulin resistance in association with defective insulin binding: a case report
Authors: Moritz Wolfgang , Böni-Schnetzler Marianne , Stevens Wayne , Froesch E Rudolf , Levy James R
Published: December 2008

Moritz W, Böni-Schnetzler M, Stevens W, Froesch ER, Levy JR. In-frame exon 2 deletion in insulin receptor RNA in a family with extreme insulin resistance in association with defective insulin binding. Eur J Endocrinol 1996;135:357–63. ISSN 0804–4643

The phenotype and allelic expression of the insulin receptor gene is presented in a family with a patient with type A insulin resistance. Compared to controls, insulin receptor binding in transformed lymphocytes was 100%, 33% and 13% in the father, mother and proband, respectively. Reduced insulin receptor binding co-segregated with altered insulin receptor mRNA expression; the mother and daughter expressed eight insulin receptor mRNA species, including a set of four normal sized and a set of four shorter mRNA transcripts. In the proband the levels of the normal sized mRNA transcripts were suppressed relative to the shorter transcripts. Reverse polymerase chain reaction (PCR) revealed that the shorter transcripts contained an in-frame deletion of exon 2. Sequencing of the entire insulin receptor coding region revealed a paternally inherited A to T substitution in nucleotide 3205, converting isoleucine 996 to phenylalanine. which does not co-segregate with reduced binding. Therefore, we hypothesize that two findings are necessary for the presentation of type A insulin resistance in this patient: an in-frame deletion of the insulin receptor exon 2 that codes for amino acids crucial for insulin binding; and an inhibition of expression of the paternal insulin receptor allele.

Marianne Böni-Schnetzler, Division of Endocrinology and Metabolism, Department of Internal Medicine, University Hospital, 8091 Zurich, Switzerland
Gender-specific changes in thyroid hormone-glucuronidating enzymes in rat liver during short-term fasting and long-term food restriction
Authors: Visser Theo J , van Haasteren Goedele AC , Linkels Esther , Kaptein Ellen , van Toor Hans , de Greef Wim J
Published: December 2008

Visser TJ, van Haasteren GAC, Linkels E, Kaptein E, van Toor H, de Greef WJ. Gender-specific changes in thyroid hormone-glucuronidating enzymes in rat liver during short-term fasting and long-term food restriction. Eur J Endocrinol 1996;135:489–97. ISSN 0804–4643

Glucuronidation is a major pathway of thyroid hormone metabolism in rats, involving at least three different hepatic UDP-glucuronyltransferases (UGTs): bilirubin UGT, phenol UGT and androsterone UGT. We have studied the effects of short-term (3 days) fasting and long-term (3 weeks) food restriction to one-third of normal intake (FR3 3) on hepatic UGT activities for thyroxine (T4), triiodothyronine (T3), bilirubin and androsterone in male and female Wistar rats with either a functional (high activity, HA) or a defective (low activity, LA) androsterone UGT gene. Because food deprivation is known to induce centrally mediated hypothyroidism in rats, results were compared with those obtained in methimazole (MMI)-induced hypothyroid rats. Both fasting and FR33 produced largely parallel increases in T4 and bilirubin UGT activities. These effects were greater in males than in females, and were reproduced in MMI-treated rats. In male and female HA rats, fasting induced insignificant increases in T3 UGT activity and had no effect on androsterone UGT activity. In male HA rats, FR33 was associated with an increase in T3 UGT activity, while androsterone UGT activity showed little change. However, in female HA rats both T3 and androsterone UGT activities were markedly decreased by FR33. Triiodothyronine UGT activity in LA rats was strongly decreased compared with HA rats, but was not further decreased by FR3 3 in female LA rats, supporting the importance of androsterone UGT for T3 glucuronidation. These results demonstrate different sex-dependent effects of food deprivation on hepatic T4 and T3 glucuronidation that are associated with changes in the expression of bilirubin UGT and androsterone UGT, respectively. For the increased T4 and bilirubin UGT activities at least, these effects appear to be mediated by the hypothyroid state of the (semi)starved animals.

Theo J Visser, Department of Internal Medicine III, Erasmus University Medical School, PO Box 1738, Room Bd 234, 3000 DR Rotterdam, The Netherlands
Autocrine and paracrine roles of polypeptide growth factors, cytokines and vasogenic substances in normal and tumorous pituitary function and growth: a review
Authors: Renner Ulrich , Pagotto Uberto , Arzt Eduardo , Stalla Günter Karl
Published: December 2008

Renner U, Pagotto U, Arzt E, Stalla GK. Autocrine and paracrine roles of polypeptide growth factors, cytokines and vasogenic substances in normal and tumorous pituitary function and growth: a review. Eur J Endocrinol 1996;135:515–32. ISSN 0804–4643

In addition to the classical hormones, the production of numerous polypeptide growth factors, cytokines, vasogenic substances and neuropeptides by pituitary cells has been demonstrated. Expression of the corresponding receptors on pituitary cells enables these factors to influence growth and function of the pituitary by auto- or paracrine mechanisms. Thus, in addition to the external endocrine control of pituitary growth and function, an intrinsic intercellular communication network seems to be involved in the control of pituitary homeostasis. The cell-to-cell communication may be of importance for the pre- and postnatal differentiation of the pituitary, for the regulation of the cellular composition of the gland (by balancing mitosis and apoptosis and controlling angiogenesis) and for the adaption of pituitary function to altered physiological conditions (i.e. stress, pregnancy and diseases). Differences in the expression of or the response to the above-mentioned factors in pituitary adenomas indicate that these substances are of importance for pituitary tumorigenesis. Disturbances of auto-/paracrine mechanisms may not necessarily be involved in the tumor initiation processes, but they may play a crucial role in tumor progression. After the initial transformation, the clonal expansion of the tumor cell is dependent on its ability to escape either from the inhibitory action of growth suppressing factors or to develop an autocrine mechanism that allows autonomous growth. In summary, therefore, this review outlines the potential role of polypeptide growth factors, cytokines and vasogenic peptides as auto-/paracrine-acting substances in normal pituitary and pituitary adenomas.

Ulrich Renner, Max-Planck-Institute of Psychiatry, Clinical Institute, Department of Endocrinology, Kraepelinstr. 10, D-80804 Munich, Germany
Chronic treatment with CV 205-502 restores the gonadal function in hyperprolactinemic males
Authors: Colao Annamaria , De Rosa Michele , Sarnacchiaro Francesca , Di Sarno Antonella , Landi Maria Luisa , Iervolino Emilia , Zarrilli Stefano , Merola Bartolomeo , Lombardi Gaetano
Published: December 2008

Colao A, De Rosa M, Sarnacchiaro F, Di Sarno A, Landi ML, Iervolino E, Zarrilli S, Merola B, Lombardi G. Chronic treatment with CV 205-502 restores the gonadal function in hyperprolactinemic males. Eur J Endocrinol 1996;135:548–52. ISSN 0804–4643

The aim of this study was to evaluate the effects of a chronic treatment with the non-ergot-derived dopamine agonist quinagolide (CV 205-502) on sexual and gonadal function in hyperprolactinemic males. Thirteen males with macroprolactinoma and one with microprolactinoma were treated with CV 205-502 at the dose of 0.15–0.6 mg/day for 6–24 months. Baseline prolactin (PRL) was 464 ± 75.7 μg/l. All the patients suffered from libido impairment, five of reduced sexual potency, six had infertility and in four bilateral induced galactorrhea was shown. The semen analysis revealed a severe oligoasthenospermia with reduced sperm count, motility and forward progression, with an abnormal morphology and decreased viability. A significant reduction of serum PRL levels (nadir PRL = 12.3 ± 5.4 μg/l) was obtained during the treatment. Normalization of prolactinemia was reached in 13 of the 14 patients after 3 months. After 1 year, a significant improvement of sperm parameters, in terms of increase of number (from 5600 ± 111 to 20 564 ± 587 mm3), motility at 1 h (from 24.8 ± 0.1 to 52.6 ± 0.5%), forward progression (from 24 ± 1.4 to 62.3 ± 2.9%) and normal morphology (from 53.8 ± 2.5 to 62.2 ± 2.4%), was recorded. In addition, a significant increase of serum follicle-stimulating hormone (from 5.3 ± 0.6 to 7.8 ± 0.4 U/l), luteinizing hormone (from 4.4 ± 0.5 to 7.7 ± 0.4 U/l) and testosterone (from 3.4 ± 0.4 to 4.7 ± 0.2 μg/l) was recorded. A significant increase of luteinizing hormone (9.4 ± 0.7 U/l) and testosterone (5.2 ± 0.4 μg/l), as well as a further improvement of sperm parameters, was found after 2 years of therapy. Sellar computed tomography and/or magnetic resonance showed a considerable shrinkage (⩾ 30%) of tumoral mass in 8 out of 13 patients with macroprolacinoma. Side effects were recorded in only one patient. In conclusion, the treatment with CV 205-502 normalizing PRL levels improves gonadal and sexual function and fertility in males with prolactinoma, providing good tolerability and excellent patient compliance to medical treatment. This result demonstrates that the impairment of gonadal function in hyperprolactinemic patients is a functional modification.

Annamaria Colao, Department of Molecular and Clinical Endocrinology and Oncology, "Federico II" University, via S. Pansini 5, 80131 Naples, Italy
Effects of four years' treatment with biosynthetic human growth hormone (GH) on body composition in GH-deficient hypopituitary adults
Authors: AI-Shoumer Kamal AS , Page Brian , Thomas Elizabeth , Murphy Margaret , Beshyah Salem A , Johnston Desmond G
Published: December 2008

Al-Shoumer KAS, Page B, Thomas E, Murphy M, Beshyah SA, Johnston DG. Effects of four years' treatment with biosynthetic human growth hormone (GH) on body composition in GH-deficient hypopituitary adults. Eur J Endocrinol 1996;135:559–67. ISSN 0804–4643

Short-term trials of growth hormone (GH) substitution in hypopituitary adults have shown beneficial effects on body composition. To evaluate the long-term effects on body composition, we followed thirteen GH-deficient adults (GH < 6 mU/l following standard provocative tests) for 4 years of GH replacement. At yearly intervals, serum insulin-like growth factor I (IGF-I), body weight, body mass index (BMI), waist, waist-to-hip circumference ratio (WHR) and resting systolic (SBP) and diastolic blood pressure (DBP) were determined, and body composition was assessed using three independent methods: total body potassium (TBK), bioelectrical impedance analysis (BIA) and dual-energy X-ray absorptiometry (DXA). Compared to baseline, IGF-I levels increased significantly at 1 (p = 0.0001), 2 (p = 0.0004), 3 (p = 0.006) and 4 years (p = 0.002). Body weight and BMI changed minimally at 1, 2 and 3 years and increased significantly only at the fourth year (p = 0.012 and p = 0.0009, respectively) of GH therapy. Waist and WHR decreased significantly at 1, 2 and 4 years (waist: p = 0.0009, p = 0.0004, p = 0.049; WHR: p = 0.0025, p = 0.012, p = 0.047, respectively). Neither resting SBP nor DBP changed significantly. Fat-free mass (FFM) derived from TBK and BIA increased significantly at 1 (p = 0.004; p = 0.004), 2 (p = 0.003; p = 0.05), 3 (p = 0.005; p = 0.04) and 4 years (p = 0.02; p = 0.002). Using DXA, the increase in FFM was significant at 1 (p = 0.007) and 2 years (p = 0.008) but not at 3 and 4 years. Percentage body fat measured by TBK, BIA and DXA decreased significantly at 1 (p = 0.008; p = 0.003; p = 0.03), 2 (p = 0.018; p = 0.06; p = 0.049) and 4 years (p = 0.03; p = 0.002; p = 0.04). A rise in total body water, calculated from BIA, was observed at 1 year (p = 0.004) and was maintained throughout the treatment period. These data demonstrate that 4 years of GH treatment in hypopituitary adults is associated with sustained improvement in body composition.

Kamal AS Al-Shoumer, Unit of Metabolic Medicine, Imperial College School of Medicine at St. Mary's Hospital, Norfolk Place, London W2 1PG, UK
22-kD Growth hormone exclusion assay: a new approach to measurement of non-22-kD growth hormone isoforms in human blood
Authors: Boguszewski Cesar L , Hynsjö Lars , Johannsson Gudmundur , Bengtsson Bengt-Åke , Carlsson Lena MS
Published: December 2008

Boguszewski CL, Hynsjö L, Johansson G, Bengtsson B-Å, Carlsson LMS. 22-kD Growth hormone exclusion assay: a new approach to measurement of non-22-kD growth hormone isoforms in human blood. Eur J Endocrinol 1996;135:573–82. ISSN 0804–4643

Human growth hormone (GH) exists in a variety of isoforms. In the pituitary, the most abundant isoform is 22-kD GH (22 K GH), while other isoforms (non-22 K GH) are present in variable amounts. In human plasma, the GH heterogeneity contributes to the wide variability in GH levels measured by different immunoassays. The physiological role of the non-22 K GH isoforms is poorly understood, but they may represent a spectrum of agonists or antagonists of the GH receptor. It is possible that increased amounts of non-22 K GH isoforms in the circulation contribute to the growth failure observed in some short children and may be involved in the pathophysiology of acromegaly and other unrelated diseases. Currently, there is no method available to evaluate the ratio of non-22 K GH isoforms to total GH in large sets of serum samples. In this report, a novel assay procedure is described in which monomeric and dimeric isoforms of 22 K GH are removed from serum and non-22 K GH isoforms are quantitated. The 22 K GH exclusion assay (22 K GHEA) was established as a screening method to identify conditions in which the ratio of non-22 K GH isoforms to total GH in human blood is altered. A 22 K GH-speciflc monoclonal antibody (MCB) is used for binding to 22 K GH in serum. Magnetic beads coated with rat anti-mouse immunoglobulin G and a magnetic device are used to remove the 22 K GH-MCB complexes from serum. The non-22 K GH isoforms are measured by a polyclonal antibody-based immunoradiometric assay (GH-IRMA). The assay procedure was optimized systematically by statistical experimental designs. In serum spiked with monomeric or dimeric 22 K GH, the 22 K GH extraction was efficient at GH levels up to 100 μg/l (range 96.3–100%). The intra- and interassay precision for non-22 K GH levels of 3.9 μg/l were 2.6% and 8.7%, respectively, while for levels of 0.6 μg/l, which were very close to the detection limits of the assay, the coefficients were 17.0% and 21.6%, respectively. The percentage of non-22 K GH isoforms determined in serum samples from three different groups of subjects showed clearly distinctive values. The 22 K GHEA is a new method for evaluation of non-22 K GH isoforms in human blood under different physiological and pathophysiological conditions.

Cesar L Boguszewski, RCEM, Sahlgrenska University Hospital, Bruna Stråket, 16 S-413 45 Göteborg, Sweden
Developmental changes and differential regulation by testosterone and estradiol of growth hormone receptor expression in the rabbit
Authors: Yu Yu M , Domené Horacio M , Sztein Jorge , Counts Debra R , Cassorla Fernando
Published: December 2008

Yu YM, Domené HM, Sztein J, Counts DR, Cassorla F. Developmental changes and differential regulation by testosterone and estradiol of growth hormone receptor expression in the rabbit. Eur J Endocrinol 1996;135:583–90. ISSN 0804–4643

To investigate the effects of testosterone and estradiol (E2) on growth hormone receptor (GH-R) gene expression, we measured GH-R mRNA levels in relation to the changes of sex steroid concentrations in the normal male rabbits aged 1–12 months and after administration of testosterone or E2 to castrated male rabbits. In the normal animals, E2 levels were below the detection limit in all age groups, and testosterone levels were below the detection limit at 1 month, increased at 2 months and reached the plateau of the adult levels after 4 months. Liver GH-R mRNA levels were low at 1 month, reached a peak at 2 months and then decreased slightly thereafter. In the castrated animals, liver and growth plate GH-R mRNA levels were increased in the testosterone-treated group (162.0 ± 12.0%, p < 0.025; 128.4 ± 7.6%; p < 0.025) and reduced in the E2-treated group (29.6 ± 6.2%, p < 0.005; 53.6 ± 11.3%, p < 0.025). Sex steroid administration did not result in any significant change in GH-R mRNA levels in striated muscle, kidney and heart. Serum GH concentrations were increased in E2 (15.3 ± 7.7 μg/l vs 4.8 ± 2.2 μg/l, p < 0.025) but the increase was not significant in testosterone-treated animals (8.4 ± 7.7 μg/l vs 4.8 ± 2.2 μg/l). Both testosterone and E2 treatment resulted in a reduction of mean serum growth hormone-binding protein (GHBP) levels compared to control animals (1077 ± 422 pmol/l, p < 0.01; 1137 ± 443 pmol/l, p < 0.01; 2308 ± 565 pmol/l). We conclude that in addition to their stimulatory effect on GH secretion, testosterone and E2 have opposite effects on GH-R gene expression in liver and growth plate in the rabbit. The modulation of GH-R expression by sex steroids may be important for growth during sexual maturation in mammals.

Yu M Yu, MD, 11600 Bootjack Court, Gaithersburg, MD 20878, USA
Water distribution in insulin-dependent diabetes mellitus in various states of metabolic control
Authors: Brizzolara A , Barbieri MP , Adezati L , Viviani GL
Published: December 2008

Brizzolara A, Barbieri MP, Adezati L, Viviani GL. Water distribution in insulin-dependent diabetes mellitus in various states of metabolic control. Eur J Endocrinol 1996;135:609–15. ISSN 0804–4643

Alterations in water compartments have been described in insulin-dependent diabetes mellitus (IDDM). Both insulin and lack of natriuretic counteracting response lead to water expansion, while hyperglycemica-induced osmotic diuresis leads to water depletion. Both total body water and water distribution in the extra-intracellular space, as well as their relationships to metabolic control, were investigated in 15 controls (30.1 ± 1.4 years) and in 26 IDDM patients (31.3 ± 1.6, diabetes duration 11.3 ± 1.4 years) who were neither hypertensive nor proteinuric. The amounts of total body water (TBW) and extracellular water (ECW) were predicted by impedance measurements at 100 KHz and at 1 KHz. The amount of intracellular water (ICW) was computed as the difference between the two. Water distribution was estimated by measuring the ratio between low- and high-frequency impedance and by computing the ratio between ECW and ICW. The IDDM patients were divided into four groups on the basis of reference HbA1c mean and sd: A ≤ mean +2 sd < B ≤ mean + 4 sd < C ≤ mean + 6sd < D. The groups were comparable with sodium intake, insulin dosage, fasting glycemia and laboratory hydration markers. As compared to controls, impedance values at 1, 5, 10, 50 and 100 KHz were significantly lower in diabetic patients and the difference within group D increased as the frequency increased: −3.9% at 1 KHz, −10.1% at 100 KHz. As compared to controls, groups A, B and C showed higher TBW, ECW and ICW while water distribution was normal, and group D showed higher TBW and ICW but normal ECW and a different water distribution. In all IDDM patients, HbA1c correlated with ECW (r = −0.49) and distribution ratios (r = 0.42, impedance; r = 0.40, ECW/ICW ratio). These observations suggest that good or moderate long-term control IDDM patients have proportionately normal distributions of ECW and ICW excess. However, water excess in poor control IDDM patients was only found in the ICW space.

Giorgio L Viviani, Department of Internal Medicine, Clinica Medica III, University of Genoa, Viale Benedetto XV, 6. 16132 Genoa, Italy
Regulation of obese mRNA expression by hormonal factors in primary cultures of rat adipocytes
Authors: Yoshida Tadashi , Hayashi Matsuhiko , Monkawa Toshiaki , Saruta Takao
Published: December 2008

Yoshida T, Hayashi M, Monkawa T, Saruta T. Regulation of obese mRNA expression by hormonal factors in primary cultures of rat adipocytes. Eur J Endocrinol 1996;135:619–25. ISSN 0804–4643

The obese (ob) gene has been cloned recently and its protein product is called "leptin". Leptin is an adipocyte-derived satiety factor that regulates body weight homeostasis. Several hormonal factors have been reported to regulate ob mRNA expression. To determine which factors are most important for regulation of ob mRNA expression, we examined the effects of insulin, dexamethasone, a β3-adrenergic agonist (CGP12177A), 8-bromo-cAMP, 8-bromo-cGMP and 1-methyl-3-isobutylxanthine (MIX) on primary cultured adipocytes. Rat adipocytes obtained from epididymal fat were cultured using the ceiling method. Total RNA was extracted and the expression of ob mRNA was measured by quantitative reverse transcription-polymerase chain reaction. After 24 h of incubation, 100 nmol/l insulin significantly increased the expression of ob mRNA (21.4-fold compared to control). Moreover, insulin increased ob mRNA expression in a dose-dependent manner over a range of 1–100 nmol/l. The effect of 100 nmol/l insulin was similar to that seen with 20% newborn calf serum. Dexamethasone (25–1000 nmol/l) also increased ob mRNA expression (2.5–2.9-fold). The effect of dexamethasone occurred more rapidly than insulin. CGP12177A (1–10 μmol/l) and 0.5 mmol/l 8-bromo-cAMP had no effects, whereas 0.5 mmol/l 8-bromo-cGMP and 0.5 mmol/l MIX had stimulatory effects (2.8- and 2.4-fold increase in ob mRNA, respectively). The combination of 250 nmol/l dexamethasone and 0.5 mmol/l MIX did not have an additive effect on ob mRNA levels. Our present data suggest that, of these agents, insulin is the most important factor regulating ob mRNA expression.

Matsuhiko Hayashi, Department of Internal Medicine, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo 160, Japan
Effects of glucocorticoids and of growth hormone on serum leptin concentrations in man
Authors: Berneis Kaspar , Vosmeer Susanne , Keller Ulrich
Published: December 2008

Berneis K, Vosmeer S, Keller U. Effects of glucocorticoids and of growth hormone on serum leptin concentrations in man. Eur J Endocrinol 1996;135:663–5. ISSN 0804–4643

Recent data suggest an involvement of the ob gene and its product leptin in the regulation of body fat. To assess the effects of glucocorticoids and growth hormone (GH) on serum leptin and body fat, 30 normal subjects received methylprednisolone (0.5 mg·kg−1·day−1) per os for 7days and 15 subjects received in addition sc injections of GH (0.15 IU·kg−1·day−1)−1) twice daily (combination group). Serum leptin levels increased both in the glucocorticoid group (p < 0.02) and in the combination group (p < 0.002). When body fat was estimated by bioelectrical impedance analysis it decreased during combined treatment and remained unchanged in the glucocorticoid group. Plasma insulin concentrations increased in both groups. Resting energy expenditure (indirect calorimetry) increased in the combination group and remained unchanged in the glucocorticoid group. The finding of increased serum leptin concentrations during treatment with glucocorticoid and GH suggests that serum leptin is regulated by glucocorticoids, possibly though changes in insulin secretion, independently of changes of body fat mass.

Ulrich Keller, Departments of Research and of Internal Medicine, University Hospital Basel, Petersgraben 4, 4031 Basel, Switzerland
Dose-dependent effects of recombinant human growth hormone on biochemical markers of bone and collagen metabolism in adult growth hormone deficiency
Authors: Bollerslev Jens , Møller Jens , Thomas Sian , Djøseland Ole , Christiansen Jens S
Published: December 2008

Bollerslev J, Møller J, Thomas S, Djøseland O, Christiansen JS. Dose-dependent effects of recombinant human growth hormone on biochemical markers of bone and collagen metabolism in adult growth hormone deficiency. Eur J Endocrinol 1996:135:666–71. ISSN 0804–4643

Administration of growth hormone (GH) to patients with growth hormone deficiency (GHD) has beneficial effects, but so far has been employed only empirically. We have, therefore, investigated the dose-dependent effect of GH on target tissue by studying biochemical markers of bone and collagen turnover in GHD. Then patients with GHD (nine males and one female aged 21–43 years, mean age 28 years) participated in the study. Growth hormone deficiency was defined as a peak serum GH response of less than 15 mU/l in two provocation tests. After a 4-week run-in period, the study population received increasing doses of GH at 4-week intervals (1,2 and 4U/m2). Blood samples were collected in the fasting state at 7.00 h on the last day of each period and assayed for serum levels of osteocalcin (S-BGP), bone alkaline phosphatase (B-ALP), C-terminal propeptide of type I collagen (S-PICP), carboxy-terminal pyridinoline cross-linked telopeptide of type I collagen (S-ICTP) and N-terminal propeptide of type III collagen (S-PIIINP). Following replacement therapy, serum insulin-like growth factor I and insulin-like growth factor binding protein 3 increased sequentially with time (p<0.001 and p<0.001, MANOVA) and the values were elevated significantly over baseline levels after treatment with 1 U/m2. Serum BGP values were below normal at the start of the study and increased gradually following GH treatment to levels in the low–normal range. Baseline values for serum bone alkaline phosphatase (B-ALP), PICP and PIIINP were within the normal range. The collagen parameters increased with GH replacement (p<0.001, MANOVA) to levels above normal, whereas B-ALP stayed within normal limits. Serum ICTP values were elevated above the normal range at baseline, indicating increased bone resorption in GHD. A linear increase in values was observed with GH treatment (p< 0.001, MANOVA). Serum ICTP did not correlate significantly with the bone formative parameters but was correlated positively to PIIINP. The sensitivity of S-ICTP as a bone resorptive marker is thus questioned. In conclusion, a dose-dependent increase in markers of growth hormone metabolism and in biochemical markers of both bone and non-bone collagen synthesis was seen following incremental doses of GH in GHD.

Jens Bollerslev, Department of Medical Endocrinology, National University Hospital, N-0027 Oslo, Norway
Somatotrope responsiveness to Hexarelin, a synthetic hexapeptide, is refractory to the inhibitory effect of glucose in obesity
Authors: Grottoli Silvia , Maccario Mauro , Procopio Massimo , Oleandri Salvatore Endrio , Arvat Emanuela , Gianotti Laura , Deghenghi Romano , Camanni Franco , Ghigo Ezio
Published: December 2008

Grottoli S, Maccario M, Procopio M, Oleandri SE, Arvat E, Gianotti L, Deghenghi R, Camanni F, Ghigo E. Somatotrope responsiveness to Hexarelin, a synthetic hexapeptide, is refractory to the inhibitory effect of glucose in obesity. Eur J Endocrinol 1996;135:678–82. ISSN 0804–4643

Both spontaneous and stimulated growth hormone (GH) secretion is reduced in obesity, in which state insensitivity to the inhibitory effect of hyperglycemiacemia also has been reported. To further investigate this point, in eight male obese (OB) patients (27–49 years old; body mass index = 39.5 ± 1.7 kg/m2) we studied the effect of oral glucose load (100 g) on the GH response to Hexarelin (HEX, 2 μg/kg iv), a synthetic hexapeptide belonging to the GH-releasing peptide family, which has been reported to be able to induce a marked GH rise even in obese patients. As a control group, six male age-matched normal subjects (NS) were studied (26–35 years old; body mass index = 22.3 ± 1.5 kg/m2). In all subjects the GH response to growth hormone-releasing hormone (GHRH, 1 μg/kg iv) was also studied. Basal GH and insulin-like growth factor I (IGF-I) levels in OB and NS were similar (0.3 ± 0.1 vs 0.5 ± 1.0 μg/l and 166.7 ± 12.3 vs 145.4 ± 6.9 μg/l, respectively). Hexarelin induced a clear GH rise in OB (peak: 20.0 ± 2.9 μg/l; AUC: 1193.0 ± 213.7 μg·l−1·120 min−1) but this response was clearly lower (p < 0.0002) than that observed in NS (62.6 ± 7.3 μg/l, 4587.5 ± 614.9 μg·l −1·120 min−1). The GHRH-induced GH rise was lower (p < 0.002) in OB (4.4 ± 1.2 μg/l, 331.0 ± 95.9 μg·l−1·120 min−1) than that in NS (20.2 ± 1.9 μg/l, 1281.0 ± 157.5 μg·l−1·120 min−1) and both were lower (p < 0.05) than those induced by HEX. In NS, glucose significantly blunted the GH response to HEX (38.4 ± 7.2 μg/l, 2236.5 ± 514.8 μg·l−1·120 min−1, p < 0.05) but failed to modify it in OB (19.4 ± 2.7 μg/l, 934.5 ± 151.3 μg·l−1·120 min−1). Plasma glucose peaks after oral glucose load in OB and NS were similar (164.5 ± 9.7 vs 145.8 ± 4.6 mg/dl). In conclusion, the present data demonstrate that, in contrast to normal subjects, in obese patients HEX has a reduced GH-releasing effect that is not inhibited by glucose. In OB patients as well as in normal subjects HEX releases more GH than GHRH. These findings strengthen the evidence that GH secretion in obesity is refractory either to stimulatory inputs or to the inhibitory effect of hyperglycemia.

E Ghigo, Divisione di Endocrinologia, Ospedale Molinette, C.so A.M. Dogliotti 14, 10126 Torino, Italy
Acute stress attenuates but does not abolish circadian rhythmicity of serum thyrotrophin and growth hormone in the rat
Authors: Martí Octavi , Gavaldà Amadeu , John Trinidad , Armario Antonio
Published: December 2008

Martí O, Gavaldà A, Jolín T, Armario A. Acute stress attenuates but does not abolish circadian rhythmicity of serum thyrotrophin and growth hormone in the rat. Eur J Endocrinol 1996;135:703–8. ISSN 0804–4643

The effects of acute immobilization (IMO) on daily rhythms of corticosterone, thyroid-stimulating hormone (TSH) and growth hormone (GH) were studied in adult male rats. Two hours of IMO increased serum corticosterone, this increase still being observed 3 h after finishing stress exposure. In the dark period corticosterone levels did not differ in control and IMO rats, but higher levels were observed again in the morning of the day after. Immobilization lowered serum GH and TSH levels throughout the 24-h period that followed exposure to the stressor. Such an effect was more marked in GH than in TSH. In addition, GH, but not TSH, levels were found to be reduced significantly by IMO at 08.30 h of the next day. None the less, daily rhythms of GH and TSH were still persistent and roughly similar to those of control rats. The daily rhythm of food intake was measured in a separate experiment and it was observed, as expected, that IMO reduced food intake only in the dark period of the lighting cycle. It appears therefore unlikely that IMO-induced anorexia was the major factor responsible for the inhibition of GH and TSH caused by IMO at 11.00 and 19.00 h, considering that the amount of food intake was very low and similar in control and IMO rats during this period. However, anorexia might have contributed to inhibition of GH and TSH secretion afterwards. Thus, in a third experiment we studied the contribution of IMO-induced anorexia to the changes in hormone levels observed 24 h after stress by introducing a group of pair-fed rats. It was found that IMO, but not pair-feeding, reduced TSH levels, whereas a similar reduction of GH was found in the two conditions. It might be concluded that acute stress transiently altered corticosterone secretion, the only long-lasting effect being a slight increase in its morning levels on the following stress. Immobilization also causes an inhibition of GH and TSH secretion in the rat that persists for several hours after finalization of exposure to the stressor, but daily rhythms were still apparent. It appears that the contribution of stress-induced anorexia is different in GH than in TSH. In conclusion, an acute severe stressor such as IMO, although modifying circulating levels of some hormones, particularly in the hours following exposure to the stressor, did not appear to interfere greatly with the expression of circadian rhythms of anterior pituitary hormones.

Octavi Martí, Unitat de Fisiologia Animal, Facultat de Ciències, Universitat Autònoma de Barcelona, 08193 Bellaterra, Barcelona, Spain
Post-transcriptional induction of β1-adrenergic receptor by retinoic acid, but not triiodothyronine, in C6 glioma cells expressing thyroid hormone receptors
Authors: López-Barahona Mònica , Iglesias Teresa , García-Higuera Irene , Mayor Federico , Zaballos Angel , Bernal Juan , Muñoz Alberto
Published: December 2008

López-Barahona M, Iglesias T, García-Higuera I, Mayor Jr F, Zaballos A, Bernal J, Muñoz A. Posttranscriptional induction of β1 -adrenergic receptor by retinoic acid, but not triiodothyronine, in C6 glioma cells expressing thyroid hormone receptors. Eur J Endocrinol 1996:135:709–15. ISSN 0804–4643

Thyroid hormone (triiodothyronine; T3) has been shown to control the expression of β1 -adrenergic receptors (β1-AR) in cardiac myocytes, but not in C6 glioma cells. This cell specificity has been attributed to low expression of T3 receptors and high expression of the c-erbAα2 splice variant that interferes with the action of T3. To check this hypothesis we have expressed the c-erbA/thyroid hormone receptor (TR) α1 gene in C6 glioma cells and investigated their response to thyroid hormone. Cells expressing TRα1, but not wild-type cells, were responsive to T3 as shown by increased expression of mitochrondrial hydroxymethylglutaryl CoA synthase after T3 exposure. However, T3 had no effect on β1-AR gene expression in either set of cells. The β1-AR mRNA concentrations were, however, altered by retinoic acid (RA) treatment. Retinoic acid caused a rapid up-regulation of β1-AR mRNA levels that was blocked by cycloheximide. Retinoic acid did not increase the β1-AR gene transcription rate in run-on experiments. These results indicate an indirect post-transcriptional effect of RA. Control of β1-AR expression in C6 cells is also exerted at the translational level, because there was no correlation between mRNA and protein induction, as determined by radioligand binding studies. We conclude that lack of responsiveness of the β1-AR gene in C6 cells to T3 is not due to high expression of c-erbAα2 but to undefined cell-specific factors.

Alberto Muñoz, Instituto Investigaciones Biomedicas, Arturo Duperier 4, 28029 Madrid, Spain
Dendritic cells and macrophages in the pituitary and the gonads. Evidence for their role in the fine regulation of the reproductive endocrine response
Authors: Hoek A , Allaerts W , Leenen PJM , Schoemaker J , Drexhage HA
Published: December 2008

Blood monocytes are able to mature into macrophages as well as into dendritic cells. Dendritic cells and macrophages have mainly been studied for their function in the immune response, e.g. in the presentation of antigens to lymphocytes and in the phagocytosis/degradation of unwanted material. The cells are also, however, important producers of a variety of signalling molecules and hormones and are thus involved in other physiological functions such as wound healing, the regulation of the microcirculation and the regulation of the function and growth of endocrine cells. This review summarizes the existing evidence for a regulatory role of dendritic cells and macrophages in the function and growth of hormone-producing cells of the pituitary–gonadal axis. It focusses on the presence, localization and phenotype of dendritic cells and macrophages in the anterior pituitary and the gonads, the endocrine regulatory role of cytokines produced by these cells and the existence of putative feedback mechanisms between endocrine cells of the pituitary–gonadal axis and dendritic cells and macrophages. The recognition of a 'floating endocrine-regulatory force' of monocyte-derived cells that also plays a role in the initiation of immune responses has implications for our understanding of the pathogenesis of gonadal and pituitary autoimmune reactions.

European Journal of Endocrinology 136 8–24
Chromogranin A and chromogranin B are sensitive circulating markers for phaeochromocytoma
Authors: Stridsberg Mats , Husebye Eystein S
Published: December 2008

Specific assays for measurements of circulating chromogranin (Cg) A, CgB, CgC and pancreastatin (Ps) have recently been developed. The aim of the present study was to investigate the usefulness of these markers in diagnosing and following the effects of treatment of patients with phaeochromocytoma, and to compare the results with those concerning other biochemical markers. CgA was elevated in 19/21 (90%), CgB in 17/21 (81%), Ps in 9/21 (43%) and neuropeptide Y in 9/21 (43%) of the patients. Urinary noradrenaline was increased in 19/21 (90%) and urinary adrenaline in 17/19 (89%) of the patients. All patients had increased levels of either urinary catecholamines or plasma chromogranins. In one patient levels of CgA, CgB and Ps were measured at frequent intervals before, during and after surgery. The CgA level fell to normal shortly after the tumour was removed, whereas the CgB level decreased towards normal over the course of several days. Significant correlation was observed between the contents of CgA and CgB in the tumour tissue and the plasma levels of CgA and CgB respectively. We conclude that CgA and CgB are sensitive circulating markers for phaeochromocytoma and that measurements of both urinary catecholamines and plasma chromogranins improve the diagnostic sensitivity. Furthermore, measurements of CgA may be useful in assessing the radicality of surgery in the early postoperative period.

European Journal of Endocrinology 136 67–73