bluuebunny/crossref_metadata_2025 huggingface dataset:
Amniotic fluid and plasma levels of parathyroid hormone-related protein and hormonal modulation of its secretion by amniotic fluid cells
Authors: Dvir Rina , Golander Avraham , Jaccard Niva , Yedwab Gideon , Otremski Itzhak , Spirer Zvi , Weisman Yosef
Published: December 2008

Dvir R, Golander A, Jaccard N, Yedwab G, Otremski I, Spirer Z, Weisman Y. Amniotic fluid and plasma levels of parathyroid hormone-related protein and hormonal modulation of its secretion by amniotic fluid cells. Eur J Endocrinol 1995;133:277–82. ISSN 0804–4643

Parathyroid hormone-related (PTHrP), the major mediator of humoral hypercalcemia of malignancy, may also regulate placental calcium flux, uterine contraction and fetal tissue development. In the present study, we demonstrated that the mean immunoreactive PTHrP concentrations in amniotic fluid at mid-gestation (21.2 ± 3.7 pmol/l) and at term (19.0 ± 2.7 pmol/l) were 13-16-fold higher than levels measured in either fetal (1.6 ± 0.1 pmol/l) or maternal plasma (1.4 ± 0.3 pmol/l) at term and equal to levels found in plasma of patients with humoral hypercalcemia of malignancy. In vitro studies pointed to three possible sources of PTHrP in amniotic fluid: cultured amniotic fluid cells, cells derived from the amniotic membrane overlying the placenta and placental villous core mesenchymal cells. Treatment of cultured amniotic fluid cells with human prolactin, human placental lactogen (hPL) or human growth hormone (100 μg/l) increased PTHrP secretion after 24 h by 43%, 109% and 90%, respectively. Insulin-like growth factors I and II(100 μg/l), insulin (100 μg/l) and epidermal growth factor (EGF) (10 μg/l) increased PTHrP secretion by 53%, 46%, 68% and 118%, respectively. The stimulation of PTHrP secretion by EGF or by hPL was both time- and dose-dependent. In contrast, calcitriol and dexamethasone (10 nmol/l) decreased PTHrP secretion by 32% and 75%, respectively. Estradiol, progesterone, dihydrotestosterone and human chorionic gonadotropin had no effect on PTHrP secretion. These findings support the notion that PTHrP may play a physiological role in the uteroplacental unit and demonstrate that human amniotic fluid cells could be a useful model for studying the regulation of PTHrP production and secretion by hormones and growth factors.

Y Weisman, Bone Disease Unit, Tel Aviv Medical Center, 6 Weizman Street, Tel Aviv 64239, Israel
Presence of heterogeneous thyroid-stimulating antibodies in sera from individual Graves' patients as shown by synthesized thyrotropin receptor peptide application: evidence showing two independent epitopes and a possible recognition of two epitopic regions by one antibody molecule
Authors: Sugawa Hideo , Akamizu Takashi , Kosugi Shinji , Ueda Yoshimichi , Ohta Chizuko , Okuda Jyoji , Mori Toru
Published: December 2008

Sugawa H, Akamizu T, Kosugi S, Ueda Y, Ohta C, Okuda J, Mori T. Presence of heterogeneous thyroidstimulating antibodies in sera from individual Graves' patients as shown by synthesized thyrotropin receptor peptide application: evidence showing two independent epitopes and a possible recognition of two epitopic regions by one antibody molecule. Eur J Endocrinol 1995;133:283–93. ISSN 0804–4643

To define the epitope(s) of stimulating thyrotropin receptor antibody (TSH-R-Sab), we synthesized 19 oligopeptides covering almost all amino acids of the extracellular domain of the human TSH-R and studied these effects on the inhibition of one TSH-R-Sab activity. Four of the 19 peptides encompassing residues 31–50 (P31-20), 91–119 (P91-29), 287–304 (P287-18) and 354–367 (P354-14) were found to show significant TSH-R-Sab inhibition and to have similar effects on the other three Graves' immunoglobulins. When these peptides were applied in combination with P354-14 only P287-18 revealed additional effects but the other two combinations did not. Furthermore, sequential addition of these peptide pairs confirmed the additional effects of P287-18 and P354-14. Sequential peptideaffinity gel studies were then performed. Most of the TSH-R-Sab activity in the unabsorbed fraction from P287-18 gel was absorbed to a subsequent P354-14 gel and the eluted fraction from P287-18 mostly remained unabsorbed by the P354-14 gel. On the other hand, most of the unabsorbed fraction from P91-29 gel remained unabsorbed even by the subsequent P354-14 gel. When a P354-14 affinity gel-purified TSH-R-Sab immunoglobulin was labeled and evaluated for its binding to FRTL-5 cells, additions of original immunoglobulin, P354-14 and P91-29 resulted in significant inhibition of the binding but P287-18 did not affect either. From these results, it was concluded that most of the individual Graves' immunoglobulins contain at least two heterogeneous moieties with TSH-R-Sab activity, one of which binds P354-14 and the other binds P287-18. Further, P354-14 and P91-29 were indicated to bind the same molecule of TSH-R-Sab immunoglobulin.

Toru Mori, Department of Laboratory Medicine, Kyoto University School of Medicine, 54 Shogoin Kawaharacho, Sakyo-ku, Kyoto 60601, Japan
Effect of galanin on basal and stimulated secretion of prolactin, gonadotropins, thyrotropin, adrenocorticotropin and cortisol in humans
Authors: Arvat Emanuela , Gianotti Laura , Ramunni Josefina , Grottoli Silvia , Brossa Pier Carlo , Bertagna Angela , Camanni Franco , Ghigo Ezio
Published: December 2008

Arvat E, Gianotti L, Ramunni J, Grottoli S, Brossa PC, Bertagna A, Camanni F, Ghigo E, Effect of galanin on basal and stimulated secretion of prolactin, gonadotropins, thyrotropin, adrenocorticotropin and cortisol in humans. Eur J Endocrinol 1995;133:300–4. ISSN 0804–4643.

Galanin enhances both baseline and growth hormone-releasing hormone (GHRH)-induced GH secretion both in animals and in man. Although galanin has a clear influence on the secretion of other anterior pituitary hormones in animals, in man it increases prolactin (PRL) slightly but does not affect spontaneous thyrotropin (TSH), luteinizing hormone (LH), follicle-stimulating hormone (FSH) or adrenocorticotropin (ACTH) secretion. The aim of our study was to verify the effect of galanin on basal and releasing hormone-stimulated release of gonadotropins, PRL, TSH, ACTH and cortisol secretion. As GH release has been shown to be inhibited by corticotropin-releasing hormone (CRH), we also studied the effect of CRH on galanin-stimulated GH increase. The effect of porcine galanin (15 μg/kg iv infused in 60 min) alone and in combination with thyrotropin-releasing hormone (TRH, 200 μg iv bolus), CRH (100 μg iv bolus) and gonadotropin-releasing hormone (GnRH, 100 μg iv bolus) on GH, PRL, TSH, ACTH, cortisol, FSH and LH secretion in seven normal young women (aged 25–30 years) was studied. Galanin infusion caused an increase in serum GH levels (p < 0.02) but failed to modify significantly the spontaneous PRL, LH, FSH, TSH, ACTH and cortisol secretion. The combined administration of TRH, GnRH and CRH caused a significant increase in PRL (p < 0.02), LH (p < 0.02), FSH (p < 0.02), TSH (p < 0.02), ACTH (p < 0.02) and cortisol (p < 0.05), but not in GH levels. Galanin infusion significantly enhanced the PRL response to TRH + GnRH + CRH administration (p < 0.05), while the releasing hormone-stimulated levels of LH, FSH, TSH, ACTH and cortisol were not influenced by galanin. The GH release after the combined administration of GAL, TRH, GnRH and CRH was similar to that observed after galanin alone. In conclusion, the present results support the view that galanin plays a role in the control of GH and PRL secretion in humans. On the other hand, galanin does not seem to have any influence on the secretion of the other pituitary hormones in humans. However, a role for galanin in the modulation of hypophysiotropic neurohormone function at the hypothalamic level cannot be ruled out.

Ezio Ghigo, Divisione di Endocrinologia, Ospedale Molinette. Corso Dogliotti 14, 10126 Torino, Italy
Long-distance and long-term follow-up of a patient with intermittent Cushing's disease by salivary cortisol measurements
Authors: Mosnier-Pudar H , Thomopoulos P , Bertagna X , Fournier C , Guiban D , Luton JP
Published: December 2008

Mosnier-Pudar H, Thomopoulos P, Bertagna X, Fournier C, Guiban D, Luton JP. Long-distance and long-term follow-up of a patient with intermittent Cushing's disease by salivary cortisol measurements. Eur J Endocrinol 1995;133:313–6. ISSN 0804–4643

Salivary cortisol is an excellent indicator of the plasma free cortisol concentration in normal and pathological situations. We took advantage of its ease of sampling, allowing multiple collections at home, to follow the course of a patient with Cushing's disease living in North Africa. This 48-year-old woman presented with a clinically moderate hypercortisolism caused by a large basophilic pituitary adenoma. Bilateral extension to the cavernous sinuses precluded surgical therapy. She went into spontaneous remission based on clinical signs as well as biochemical findings. During the following 2 years she demonstrated intermittent relapses that were treated by radiotherapy (50 Gy), followed by ketoconazole and then o-paraprime-dichloro-diphenyl-dichloroethane (Op′DDD). After a prolonged clinical remission, Cushing's syndrome again became active. Bromocriptine was started without effect and a new treatment with Op′DDD was began. Evaluation and follow-up were performed during hospitalizations and mainly through the measurements of salivary cortisol in more than 100 samples sent from North Africa by air mail to our department in Paris. Thus we were able to demonstrate intermittent overproduction of cortisol before any treatment, with periods of normal and even low values, and to follow the efficacy of therapy and to detect the relapses. We conclude that measurement of salivary cortisol is a valuable tool in difficult clinical situations such as intermittent hypercortisolism and remoteness between the patient and hospital.

H Mosnier-Pudar, Clinique des Maladies Endocriniennes et Metaboliques, Hôpital Cochin, 27 rue du Faubourg Saint Jacques, 75014 Paris, France
A case of cyclical Cushing's disease associated with corticosteroidbinding globulin deficiency: a rare pitfall in the diagnosis of Cushing's disease
Authors: Watanobe Hajime , Nigawara Takeshi , Nasushita Ryo , Sasaki Shinsuke , Takebe Kazuo
Published: December 2008

Watanobe H, Nigawara T, Nasushita R, Sasaki S, Takebe K. A case of cyclical Cushing's disease associated with corticosteroid-binding globulin deficiency: a rare pitfall in the diagnosis of Cushing's disease. Eur J Endocrinol 1995;133:317–9. ISSN 0804–4643

We experienced an extremely unusual combination of Cushing's disease and corticosteroid-binding globulin (CBG) deficiency that has been reported in only one similar case to date. A 53-year-old woman presented at a medical clinic with clinical Cushing's disease. However, her plasma levels of adrenocorticotropin (ACTH) and cortisol were in the normal range. Six months later, during a second visit, a high urinary excretion of 17-hydroxycorticosteroids was found, but plasma ACTH and cortisol levels were normal again. Further investigation revealed a decreased CBG concentration. Free plasma cortisol levels were clearly elevated. Furthermore, the Cushing's disease of our patient was complicated by periodic secretion of ACTH and cortisol, with high or normal outputs of corticosteroids occurring alternately every 1–3 days, which explained the occasionally normal plasma ACTH and cortisol levels. A combination of a decreased serum CBG concentration and periodic secretion of ACTH can be an important pitfall in the diagnosis of Cushing's disease.

Hajime Watanobe, Third Department of Internal Medicine, Hirosaki University School of Medicine, 5 Zaifu-cho, Hirosaki, Aomori 036, Japan
Subcutaneous octreotide treatment of a growth hormone-releasing hormone-secreting bronchial carcinoid: superiority of continuous versus intermittent administration to control hormonal secretion
Authors: Lefebvre Sophie , De Paepe Lutgarde , Abs Roger , Rahier Jacques , Selvais Philippe , Maiter Dominique
Published: December 2008

Lefebvre S, De Paepe L, Abs R, Rahier J, Selvais P, Maiter D. Subcutaneous octreotide treatment of a growth hormone-releasing hormone-secreting bronchial carcinoid: superiority of continuous versus intermittent administration to control hormonal secretion. Eur J Endocrinol 1995;133:320–4. ISSN 0804–4643

Diagnosis of ectopic acromegaly was made in a 21-year-old female patient who 3 years before had undergone a right pneumectomy for a disseminated bronchial carcinoid. Plasma growth hormonereleasing hormone (GHRH) concentrations were markedly elevated (6440 ng/l; normal value <100 ng/l), as were serum GH (187 μg/l; normal <5 μg/l) and plasma insulin-like growth factor I (IGF-I) levels (6.7 U/ml; normal <2 U/ml). Retrospective immunohistochemical examination of the carcinoid tumor was positive for GHRH and the tumoral content of GHRH was 2130 ng/g wet weight. Subcutaneous treatment with octreotide was begun and first resulted in a profound inhibition of GH hypersecretion, normalization of plasma IGF-I and only partial reduction of GHRH concentrations. However, the initial dose of 3 × 100 μg had to be increased gradually to 4 × 750 μg because of a progressive deterioration of the hormonal control. After 15 months of intermittent therapy, octreotide was administered by continuous sc infusion. This treatment improved compliance, allowed the daily dose of octreotide to be reduced to 1500 μg and normalized serum GH levels. A near-normalization of the plasma IGF-I concentrations was also obtained, whereas the suppression of plasma GHRH concentrations remained incomplete. Despite favorable evolution of the endocrine parameters, intramedullar metastases were diagnosed and required radiation therapy. This observation emphasizes the superiority of continuous over intermittent administration of octreotide in the treatment of ectopic acromegaly. It also shows that the somatostatin analog acts more at the pituitary level to inhibit GH secretion than at the site of the neuroendocrine tumor.

S Lefebvre, Division of Rheumatology, Clinique du Refuge, Rue du Couvent 39, B-7700 Mouscron, Belgium
Expression of sex hormone-binding globulin mRNA in human ovarian cancers
Authors: Misao Ryou , Nakanishi Yoshihito , Fujimoto Jiro , Hori Masashi , Ichigo Satoshi , Tamaya Teruhiko
Published: December 2008

Misao R, Nakanishi Y, Fujimoto J. Hori M, Ichigo S, Tamaya T. Expression of sex hormone-binding globulin mRNA in human ovarian cancers. Eur J Endocrinol 1995;133:327–34. ISSN 0804–4643

To know the role of sex hormone-binding globulin (SHBG) in the intracellular steroidal actions in human ovarian cancers, the expression of SHBG mRNA as a substitute for intracellular SHBG expression was investigated in normal ovarian tissues and ovarian tumors. In the present study, we used competitive reverse transcription–polymerase chain reaction–Southern blot analysis to evaluate SHBG mRNA levels. The expression of SHBG mRNA was detected in all normal ovaries and benign and malignant ovarian tumors analyzed. There were no significant differences in the mean SHBG mRNA levels among the three types of tissue. The expression in normal ovaries was significantly higher (p < 0.01) in premenopause, suggesting the predominance of a sex steroid hormone effect on ovarian SHBG synthesis. Relative overexpression of SHBG mRNA was observed in six out of 22 cases (27%) of ovarian cancer (three cases of endometrioid adenocarcinoma, two cases of serous cystadenocarcinoma and one case of mucinous cystadenocarcinoma) in comparison with normal ovaries and benign ovarian tumors. There was no difference in expression among the clinical stages of ovarian cancers. These data suggest that normal human ovaries and ovarian tumors might synthesize SHBG intracellularly, ovarian cancers might conserve an estrogen-associated property via SHBG and the regulation of intracellular SHBG expression might be changed in some cancers.

Ryou Misao, Department of Obstetrics and Gynecology, Gifu University School of Medicine, 40 Tsukasamachi, Gifu 500, Japan
Alterations in atrial natriuretic peptide gene expression during endurance training in rats
Authors: Azizi Chafik , Bouissou Philippe , Galen François-Xavier , Lattion Anne-Laure , Lartigue Martine , Carayon Alain
Published: December 2008

Azizi C, Bouissou P. Galen F-X, Lattion A-L, Lartigue M, Carayon A. Alterations in atrial natriuretic peptide expression during endurance training in rats. Eur J Endocrinol 1995;133:361–5. ISSN 0804–4643

Spontaneous and experimental rises of intracardiac pressure and/or volume increase the level of atrial natriuretic (ANP) mRNA in rat atrial tissue. There is expanding evidence that ANP synthesis is increased in the ventricle under such conditions. However, little is known with regard to the myocardial ANP synthesis response to physical training. In this study, plasma and atrial immunoreactive ANP concentrations were measured in Sprague-Dawley rats trained on a treadmill and compared to sedentary controls. Atrial natriuretic peptide mRNA was detected in the heart cavities of each group by dot-blot hybridization analysis. Physical training reduced the mean immunoreactive ANP plasma levels from 405 ± 99 to 303 ± 45 ng/l (p < 0.05). Immunoreactive ANP in the left atrium was depleted after endurance training, while immunoreactive ANP concentration in the right atrium was unaffected. Physical training resulted in a 70% (p < 0.01) rise in ANP mRNA of the right atrium, while no changes in the other compartments were found. These data indicate that during physical training: ANP mRNA does not increase in ventricles; despite depletion of immunoreactive ANP in the left atrium, no corresponding changes of ANP mRNA are detected; and ANP mRNA increases in the right atrium while its immunoreactive ANP does not. These findings suggest that during chronic exercise the ratio between immunoreactive ANP and ANP gene expression in the atria may be altered.

C Azizi, Service de Biochimie, CHU Pitré-Salpêtrière. 91 boulevard de l'Hôpital, 75634 Paris Cedex 13. France
Plasma testosterone surge and luteinizing hormone beta (LH-β) following parturition: lack of association in the male rat
Authors: McGivern Robert F , Hermans Ralph HM , Handa Robert J , Longo Lawrence D
Published: December 2008

McGivern RF, Hermans RHM, Handa RJ, Longo LD. Plasma testosterone surge and luteinizing hormone beta (LH-β) following parturition: lack of association in the male rat. Eur J Endocrinol 1995; 133:366–74. ISSN 0804–4643

Studies examining the role of luteinizing hormone (LH) in the initiation of the postnatal surge of testosterone in the male rat have produced ambiguous results. We examined the pattern of postnatal LH secretion in the newborn male rat, coincident with plasma testosterone levels, using a specific monoclonal antibody for LH-β. In some males, we attempted to block LH secretion and the postnatal testosterone surge by injecting males with a gonadotropin-releasing hormone (GnRH) antagonist, an LH antibody or progesterone immediately after delivery by cesarean section on day 22. Following injection, animals were immediately sacrificed (time 0) or housed in a humidified incubator maintained at 30°C until sacrifice at 60, 120, 240, 360 or 480 min after delivery. Plasma from individual animals was measured subsequently for LH-β and testosterone by radioimmunoassay. Results revealed a postnatal surge of testosterone which peaked at 2 h after delivery in males from all treatment groups. This testosterone surge was not accompanied by a postnatal rise in plasma LH-β in any group. Administration of the GnRH antagonist or the ethanol vehicle produced a transient drop of approximately 25% in LH-β levels at 60 min but did not decrease the postnatal testosterone surge in the same animals. Additional studies in untreated males and females born by cesarean section or natural birth also failed to reveal a postnatal rise in plasma LH-β during the first 3 h after birth. Plasma levels in both sexes were significantly lower in animals delivered by cesarean section compared to natural birth. Overall, these results indicate that the postnatal surge of testosterone occurs without a corresponding surge of detectable LH-β in the male rat.

Robert F McGivern, 6363 Alvarado Ct, Suite 200H. San Diego, CA 92120, USA
Thyroid hormones and brain development
Authors: Bernal Juan , Nunez Jacques
Published: December 2008

Bernal J, Nunez J. Thyroid hormones and brain development. Eur J Endocrinol 1995;133:390–8. ISSN 0804–4643

Thyroid hormone is a major physiological regulator of mammalian brain development. Cell differentiation, migration and gene expression are altered as a consequence of thyroid hormone deficiency or excess. The physiological role of thyroid hormone can perhaps be defined so as to ensure the timed coordination of different developmental events through specific effects on the rate of cell differentiation and gene expression. All triiodothyronine (T3) receptor isoforms are expressed in the brain and their spatial and temporal patterns of expression suggest unique and complementary functions for the different isoforms. Cell biology studies suggest a role for T3 and its receptors in oligodendroglial and neuronal differentiation and the control of cell death. Some of the effects on neuronal differentiation might be due to an action of thyroid hormone on the production of neurotropins and their receptors. In recent years a number of T3-dependent genes have been identified in the rat brain, such as myelin protein-encoding genes or specific neuronal genes, and thyroid hormone-responsive elements have been demonstrated in some of these genes. The identification of the gene network regulated by thyroid hormone during brain development, the elucidation of the mechanism of regulation and the clarification of the physiological roles of the regulated genes remain major goals for future studies.

Jacques Nunez, INSERM U282. Hôpital Henri Mondor, 94010 Créteil, France
Early polycystic ovary-like syndrome in girls with central precocious puberty and exaggerated adrenal response
Authors: Lazar Liora , Kauli Rivka , Bruchis Celia , Nordenberg Jardena , Galatzer Avinoam , Pertzelan Athalia
Published: December 2008

Lazar L, Kauli R, Bruchis C, Nordenberg J, Galatzer A, Pertzelan A. Early polycystic ovary-like syndrome in girls with central precocious puberty and exaggerated adrenal response. Eur J Endocrinol 1995;133:403–6. ISSN 0804–4643

Exaggerated adrenal response (ExAR), i.e. hypersecretion of both 17-hydroxypregnenolone (170HPreg) and 17-hydroxyprogesterone(17OHP) in response to adrenocorticotropic hormone (ACTH) stimulation, is frequently found in women with polycystic ovary (PCO) syndrome who had precocious adrenarche. In an earlier study we found an abnormal adrenal response in girls with idiopathic true central precocious puberty (CPP) at early stages of puberty. On follow-up it was noted that a significant number of girls with CPP develop PCO-like syndrome at a relatively young age. The aim of the present study was to determine if there is an association between ExAR and early PCO in girls with a history of CPP. Included were 49 girls with a history of CPP, 34 of whom were treated with gonadotropin-releasing hormone (GnRH) analog. All 49 were evaluated at full maturity, at ages 12.5–14 years, 0.5–4 years after menarche or resumption of menses. Of the 49 girls, 20 had at least 3/4 clinical signs of PCO (irregular menses, hirsutism, acne and obesity) and were defined as PCOlike+, whereas 29 did not fulfil the criteria and were considered PCO-like -. Girls with a definite enzyme deficiency were excluded from the study. All participants underwent a combined iv ACTHGnRH test at early follicular phase. The PCO-like + girls all revealed ExAR, i.e. an elevated stimulated 17OHPreg of 63.4 ± 9.6 nmol/l (normal 28.6 ± 9.2 nmol/l) and a normal stimulated 17OHPreg/ 17OHP ratio of 7.1 ± 1.8 (normal 6.2 ± 2.7), whereas all the PCO-like – had a normal adrenal response (30.0 ±8.7 and 5.3 ± 2.0 nmol/l, respectively). Compared to the PCO-like – girls, those with PCO-like± had significantly higher levels of testosterone (1.8 ± 0.7 vs 1.0 ± 0.5 nmol/l; p < 0.001), androstenedione (6.6 ±3.2 vs 4.7 ± 1.8 nmol/l; p < 0.02) and dehydroepiandrosterone sulfate (7.8 ± 4.7 vs 4.2 ± 2.5 μmol/l; p < 0.004), and a trend toward inappropriate luteinizing hormone secretion. The prevalence of ExAR (40.8%) in the mature CPP girls (confined to only PCO-like ±) was similar to that previously found by us in another group of girls with CPP at early puberty (44.6%). In conclusion, our findings indicate that the pattern of adrenal response remains unchanged from early puberty to adulthood and is probably inherent. As only the girls with CPP who developed early PCO syndrome showed ExAR, it is suggested that ExAR in early puberty may serve as a predictive marker for the eventual development of PCO.

A Pertzelan, Institute of Pediatric and Adolescent Endocrinology, Children's Medical Center of Israel, Beilinson Medical Campus, Kaplan Street, Petah Tiqva 49202, Israel
Growth hormone-releasing effect of oral growth hormone-releasing peptide 6 (GHRP-6) administration in children with short stature
Authors: Bellone J , Ghizzoni L , Aimaretti G , Volta C , Boghen MF , Bernasconi S , Ghigo E
Published: December 2008

Bellone J, Ghizzoni L, Aimaretti G, Volta C, Boghen MF, Bernasconi S, Ghigo E. Growth hormonereleasing effect of oral growth hormone-releasing peptide 6 (GHRP-6) administration in children with short stature. Eur J Endocrinol 1995;133:425–9. ISSN 0804–4643

Growth hormone-releasing peptide 6 (GHRP-6) is a synthetic hexapeptide with a potent GH-releasing activity after intravenous, subcutaneous, Intranasal and oral administration in man. Previous data showed its activity also in some patients with GH deficiency. The aim of our study was to verify the GH-releasing activity of oral GHRP-6 administration on GH secretion in children with normal short stature. The effect of oral GHRP-6 (300 μg/kg) was compared with that of the maximally effective dose of intravenous GH-releasing hormone (GHRH-29, 1 μg/kg). As the GHRH-induced GH rise in children is potentiated by arginine (ARG), even when administered by oral route at low dose (4 g), we studied also the interaction of oral GHRP-6 and ARG administration. We studied 13 children (nine boys and four girls aged 6.2–10.5 years, pubertal stage I) with normal short stature (height less than –2 sd score; height velocity more than –2 sd score; normal bone age; insulin-like growth factor I > 70 μg/l), In a first group of children (N = 7), oral GHRP-6 administration induced a GH response (mean ± sem, peak at 60 min vs baseline: 18.8 ±3.0 vs 1.1 ± 0.3 μg/l, p < 0.0006; area under curve: 1527.3 ± 263.9 μgl−1 h) which was similar to that elicited by GHRH (peak at 45 min vs baseline: 20.8 ±4.5 vs 2.2±0.9 μg/l, p <0.007; area under curve: 1429.4 ± 248.2 μgl−1 h−1). In a second group of children (N = 6), the GH response to oral GHRP-6 administration (peak at 75 min vs baseline: 18.5 ±5.1 vs 1.5 ± 0.6 μg/l, p < 0.01; area under curve: 1598.5 ± 289.3 μgl−1 h−1) was not modified by co-administration of oral ARG (peak at 90 min vs baseline: 15.2 ±5.6 vs 0.9±0.3 μg/l, p < 0.002; area under curve: 1327.8 ± 193.2 μgl−1 h−1). The amount of GH released and the timing of the somatotrope response after the oral administration of GHRP-6 were similar in the two groups. In conclusion, the present data show that in normal short children the oral administration of GHRP-6 is able to increase GH secretion to an extent similar to that observed after intravenous administration of the maximally effective GHRH dose. Moreover, in contrast to GHRH, the effect of GHRP-6 is not enhanced by low-dose oral ARG. As this amino acid likely acts via inhibition of hypothalamic somatostatin release, our data suggest that a decrease in the somatostatinergic activity does not improve the GH-releasing effect of GHRP-6 in childhood, at variance with that observed after GHRH. Our results suggest that GHRP-6 could be clinically useful to stimulate GH secretion in short children.

E Ghigo, Divisione di Endocrinologia, Ospedale Molinette, C. so. AM Dogliotti 14, 10126 Torino, Italy
Insulin-like growth factor binding proteins in prepubertal children with insulin-dependent diabetes mellitus
Authors: Knip Mikael , Tapanainen Päivi , Pekonen Fredrika , Blum Werner F
Published: December 2008

Knip M, Tapanainen P, Pekonen F, Blum WF. Insulin-like growth factor binding proteins in prepubertal children with insulin-dependent diabetes mellitus. Eur J Endocrinol 1995:133:440–4. ISSN 0804–4643

To study the possible role of insulin-like growth factor binding proteins (IGFBPs) in the discrepancy between normal or only slightly retarded growth and substantially reduced concentrations of insulin-like growth factor I (IGF-I) in prepubertal children with insulin-dependent diabetes mellitus (IDDM), we measured the plasma concentrations of IGF-I, IGFBP-1, IGFBP-2 and IGFBP-3 and free insulin in 24 prepubertal diabetic subjects and 12 control children. In addition, the growth hormone response to exercise was evaluated. The diabetic children had significantly decreased peripheral IGF-I levels (8.2 + 1.1 (sem) vs 16.7 + 2.5 nmol/l; p < 0.001), whereas the concentrations of free insulin were increased (217 + 14 vs 103 + 21 pmol/l; p < 0.001). The concentrations of IGFBP-1 and IGFBP-3 were of the same magnitude in both groups. The diabetic children had significantly increased levels of IGFBP-2 (465 + 13 vs 416 + 14 μg/l; p = 0.029), which were inversely related to the circulating IGF-I levels (r = −0.35; p = 0.034). The diabetic and control children had comparable growth hormone responses to exercise. Diabetic children with poor glucose control had even lower IGF-I levels than those with moderate metabolic control (6.0 + 0.8 vs 10.3 + 1.7 nmol/l; p = 0.037). No differences could be observed in the plasma concentrations of various IGFBPs between these two groups of diabetic subjects. The absence in prepubertal diabetic children of increased IGFBP-1 levels observed in adolescent and adult patients with IDDM may contribute to their maintained linear growth, despite definitely decreased IGF-I concentrations. The role of increased IGFBP-2 levels in prepubertal children with IDDM remains open, but the inverse relationship between IGF-I levels and IGFBP-2 concentrations suggests that IGF-I may be involved in the regulation of IGFBP-2.

Mikael Knip, Department of Pediatrics, University of Oulu, FIN-90220 Oulu, Finland
Resting metabolic rate, body composition and related hormonal parameters in growth hormone-deficient adults before and after growth hormone replacement therapy
Authors: Snel Yvonne EM , Doerga Manorath E , Brummer Robert-Jan M , Zelissen Pierre MJ , Zonderland Maria L , Koppeschaar Hans PF
Published: December 2008

Snel YEM, Doerga ME, Brummer R-JM, Zelissen PMJ, Zonderland ML, Koppeschaar HPF. Resting metabolic rate, body composition and related hormonal parameters in growth hormone-deficient adults before and after growth hormone replacement therapy. Eur J Endocrinol 1995;133:445–50. ISSN 0804–4643

The resting metabolic rate (RMR), and body composition were assessed in 30 growth hormone-deficient (GHD) adults before and after 3 and 6 months of replacement therapy with recombinant human growth hormone (rhGH). In addition, insulin-like growth factor I (IGF-I), IGF binding proteins (IGFBPs) and plasma insulin were measured at baseline and at 6 months in relation to RMR. During 6 months of rhGH replacement therapy, body fat decreased from 18.2 ± 1.5 (mean±sem) to 14.3 ± 1.6 kg (p < 0.0001), whereas fat-free mass (FFM) increased from 53.5 ± 3.3 to 56.3 ± 3.6 kg (p < 0.0001), RMR increased from 1246 ± 92 to 1539 ± 102 kcal/24 h (p < 0.0001) and RMR per kilogram of FFM increased from 23.2 ± 0.6 to 27.4 ± 0.5 (p < 0.0001). When RMR data were adjusted for the differences in FFM, it appeared that apart from the increase in FFM, other factors may play a role in the increase in RMR. During rhGH replacement therapy, IGF-I (p < 0.0001) and IGFBP-3 (p = 0.003) levels increased, whereas IGFBP-1 levels decreased significantly (p = 0.004). The FFM explained for about 80% of the variance in RMR. In addition, waist/hip ratio and plasma IGF-I contributed significantly to the explained variance of RMR. This study shows that in GHD adults FFM is the main determinant of RMR and that, next to the increase in FFM, changes in metabolic and hormonal parameters contribute to the increase in RMR during rhGH replacement therapy.

HPF Koppeschaar, Department of Endocrinology, University Hospital Utrecht, PO Box 85500, 3508 GA Utrecht, The Netherlands
Familial acromegaly: a specific clinical entity—Further evidence from the genetic study of a three-generation family
Authors: Benlian Pascale , Giraud Sophie , Lahlou Najiba , Roger Marc , Blin Christian , Holler Colette , Lenoir Gilbert , Sallandre Janine , Calender Alain , Turpin Gérard
Published: December 2008

Benlian P, Giraud S, Lahlou N, Roger M, Blin C, Holler C, Lenoir G, Sallandre J, Calender A, Turpin G. Familial acromegaly: a specific clinical entity. Eur J Endocrinol 1995;133:451–6. ISSN 0804–4643

Familial acromegaly is a very rare inherited disorder, characterized by the clustering within a single family of several related cases with somatotroph adenomas and acromegaly. The causes of these dominantly inherited pituitary tumours remain unknown. Although these families have a clinical presentation distinct from that of multiple endocrine neoplasia type 1 (MEN-1), the question of this syndrome as being linked to the MEN-1 locus has remained open. Our aim was to study a three-generation family with cases of acromegaly in a mother and her son, to explore better the clinical presentation of the disease, its pattern of inheritance and to test the hypothesis of a genetic linkage to the MEN-1 locus using closely linked polymorphic genetic markers. The refined analysis of 15 unaffected relatives revealed miscellaneous non-specific endocrine dysfunctions and the presence of multiple lipomata, as noted previously in some cases. Moreover, the notion of acromegalo-gigantism in the maternal grandmother and an incomplete penetrance appeared even more typical, suggesting that familial acromegaly is a specific clinical entity. Finally, under the hypotheses assumed for segregation analysis, no clinical, biological or genetic evidence of linkage to the MEN-1 locus could be retained in this family. However, these conclusions were limited because of incomplete penetrance and uncertain definition of the carrier status. Therefore, we conclude that further identification of the genetic predisposition to familial acromegaly might be obtained from the combined molecular genetic analysis of several families presenting with the same clinical features.

Pascale Benlian, Service d'Endocrinologie Métabolisme, Groupe Hospitalier Pitié Salpétrière, 83 Boulevard de l'Hôpital, 75651 Paris cedex 13, France
Distinct effects of ovarian transplantation and exogenous 17 β-oestradiol on cancellous bone of osteopenic ovariectomized rats
Authors: Gallagher Andrea C , Chambers Timothy J , Tobias Jonathan H
Published: December 2008

Gallagher AC, Chambers TJ, Tobias JH. Distinct effects of ovarian transplantation and exogenous 17 β-oestradiol on cancellous bone of osteopenic ovariectomized rats. Eur J Endocrinol 1995;133:483–8. ISSN 0804–4643

Although 17 β-oestradiol (E2) is known to prevent bone loss, prolonged administration of E2 is unable to reverse this in female rats rendered osteopenic by ovariectomy. To determine whether this reflects a failure to replace other components of ovarian function involved in bone metabolism, we compared the effects of administering E2 to osteopenic ovariectomized (ovx) rats with those of ovarian transplantation. Ovariectomy was performed in female rats. After 13 weeks, by which time marked bone loss had occurred, one group of ovx animals received ovaries from donor rats, and, after a delay of 2 weeks to allow oestrus cycles to return, a further group received E2 5 μg · kg−1 · day−1 for 9 weeks. The dose of E2 was chosen as that which in preliminary studies restored mean serum E2 levels to that of intact female rats. The study was terminated 24 weeks after ovariectomy. Both E2 and ovarian transplantation largely restored indices of oestrogenic exposure in ovx rats to those of sham-ovx animals. Animals receiving ovarian transplants also showed a small increase in serum progesterone and full restoration of serum testosterone. However, while ovarian transplantation also returned indices of cancellous bone metabolism to those of sham-ovx animals, there was little increase in bone volume. Interestingly, exogenous E2 caused a greater increase in cancellous bone volume than ovarian transplantation but also caused more marked suppression of bone formation, as assessed at the end of the study. In conclusion, exogenous E2 and ovarian transplantation exerted distinct effects on skeletal metabolism in osteopenic ovx rats, although the basis for this difference is currently unclear.

JH Tobias, Department of Histopathology, St George's Hospital Medical School, London SW17 ORE, UK
Molecular defects in thyroid carcinomas: Role of the RET oncogene in thyroid neoplastic transformation
Authors: Santoro Massimo , Grieco Michele , Melillo Rosa Marina , Fusco Alfredo , Vecchio Giancarlo
Published: December 2008

Santoro M, Grieco M, Melillo RM, Fusco A, Vecchio G. Molecular defects in thyroid carcinomas. Role of the RET oncogene in thyroid neoplastic transformation. Eur J Endocrinol 1995;133:513–22. ISSN 0804–4643

Tumors are believed to arise as a result of an accumulation of mutations in critical genes involved in the control of cell proliferation. Thyroid neoplasms represent a good model for studying the role of these mutations in epithelial cell multistep carcinogenesis because they comprise a broad spectrum of lesions with different degrees of malignancy. Recent reports have described the involvement of specific genetic alterations in different types of thyroid neoplasms. Papillary carcinomas are characterized by the activation of the receptor tyrosine kinases RET and TRK-A proto-oncogenes. Ras point mutations are frequently observed in tumors with follicular histology and a high prevalence of p53 point mutations have been found in anaplastic carcinomas. A definition of molecular defects characterizing thyroid tumors will be helpful in establishing sensitive and specific detection strategies and, in addition, to define genetic and environmental factors important for their pathogenesis.

Giancarlo Vecchio, Dipartimento di Biologia e Patologia Cellulare e Molecolare "L, Califano", Facoltà di Medicina e Chirurgia, Università degli Studi di Napoli "Federico II", via S Pansini 5, 80131 Napoli, Italy
Plasma neurotensin levels in humans: relation to hormone levels in diseases involving the hypothalamo-pituitary-thyroid axis
Authors: Schimpff Rose-Marie , Gourmelen Micheline , Scarcériaux Valérie , Lhiaubet Anne-Marie , Rostène William
Published: December 2008

Schimpff R-M, Gourmelen M, Scarcériaux V, Lhiaubet A-M, Rostène W. Plasma neurotensin levels in humans: relation to hormone levels in diseases involving the hypothalamo-pituitary-thyroid axis. Eur J Endocrinol 1995;133:534–8. ISSN 0804–4643

This study was aimed to investigate, in humans, the possible relationship between plasma neurotensin (NT) levels and the activity of the hypothalamo-pituitary-thyroid axis. Neurotensin was measured by radioimmunoassay in 14 healthy adult volunteers and in 41 patients among whom 10 were considered as controls and 31 had thyroid dysfunction according to free thyroxine and thyrotropin plasma values. Basal NT levels were not significantly different in healthy adults and in control patients: 9.7 ± 1.1 fmol/ml (mean±sem) vs 13.3 ± 2.9fmol/ml, respectively. In patients with central hypothyroidism the NT level was significantly lower (5.7 ± 1.2 vs healthy volunteers and controls; p < 0.05) and in patients with peripheral hypothyroidism and hyperthyroidism the NT level was significantly higher (35.9 ± 12.8 and 29.9 ± 9.5 fmol/ml, respectively, vs healthy adults (p < 0.01) and vs controls (p < 0.05)). After thyrotropin-releasing hormone (TRH) injection (250 μg iv) in nine subjects (two control patients, five patients with hypothyroidism and two patients with hyperthyroidism), NT levels decreased independently of the endocrine status from mean values of 13.4 ± 8.4 at basal level to 7.3 ± 0.8 fmol/ml 30 min after injection (p < 0.01 on paired percentage decrease values). These data suggest that plasma NT levels in humans depend upon the pituitary-thyroid status and indicate that TRH could exert a negative regulation on circulating NT levels.

R-M Schimpff, INSERM U 339. Hôpital St Antoine, 184 rue du Faubourg, St Antoine, Paris 75012, France
Transmission of thyrotoxicosis of autoimmune type by sibling allogeneic bone marrow transplant
Authors: Thomson John A , Wilson Rhoda M , Franklin Ian M
Published: December 2008

Thomson JA, Wilson RM, Franklin IM. Transmission of thyrotoxicosis of autoimmune type by sibling allogeneic bone marrow transplant. Eur J Endocrinol 1995;133:564–6. ISSN 0804–4643

This case report is on a 25-years-old male with acute myeloblastic leukaemia who achieved a remission after cytoxic therapy and whole-body irradiation. He received a bone marrow transplant from his human leucocyte antigen (HLA)-identical sister who had unsuspected autoimmune thyroid disease. Nine months later the bone marrow recipient developed thyrotoxicosis of autoimmune type at a time when his circulating lymphocytes were of 46XX karyotype. It is suspected that the thyrotoxicosis resulted from the transplantation of a clone of lymphocytes predisposed to the production of thyroid-stimulating autoantibodies.

JA Thomson, University Department of Medicine, Glasgow Royal Infirmary, Queen Elizabeth Building, 10 Alexandra Parade, Glasgow G31 2ER, UK
Hypothalamic multiunit activity and pulsatile luteinizing hormone release in the castrated male rat
Authors: Goubillon Marie-Laure , Kaufman Jean-Marc , Thalabard Jean-Christophe
Published: December 2008

Goubillon M-L, Kaufman J-M, Thalabard J-C. Hypothalamic multiunit activity and pulsatile luteinizing hormone release in the castrated male rat. Eur J Endocrinol 1995:133:585–90. ISSN 0804–4643

Using chronically implanted microelectrodes, multiunit electrical activity (MUA) was recorded from the arcuate nucleus of freely moving gonadectomized male rats. Intermittent increases in MUA activity (MUA volleys) closely associated with luteinizing hormone pulses measured in the peripheral circulation were observed, which confirms that this experimental approach can be used for monitoring the activity of the gonadotropin-releasing hormone-associated hypothalamic pulse generator in the male rat. The mean MUA volley frequency was 22.2 min (range 13–38 min), whereas the mean MUA volley duration was 2.7 ± 0.8 min (standard deviation). In addition to a large inter-individual variability, MUA volley intervals also showed an important intra-individual variability. This observation suggests that, beside the mean frequency of pulse generator activation, the degree of variability in gonadotropin-releasing hormone-associated pulse generator activity might be an additional relevant parameter in the characterization of the reproductive function in the male rat.

M-L Goubillon, Laboratoire d'Histologie et d'Embryologie, Faculté de Médecine, CNRS URA 1454, 69600 Oullins, France
Endothelin-induced phosphoinositide hydrolysis in the muscular layer of stem villi vessels of human term placenta
Authors: Mondon Françoise , Maka Florence Doualla-Bell Kotto , Sabry Sana , Ferré Françoise
Published: December 2008

Mondon F, Doualla-Bell Kotto Maka F, Sabry S, Ferré F. Endothelin-induced phosphoinositide hydrolysis in the muscular layer of stem villi vessels of human term placenta. Eur J Endocrinol 1995;133:606–12. ISSN 0804–4643

In the present study, we examined the relationship between endothelin receptors and phosphoinositide breakdown in muscle explants of placental stem villi vessels. All peptides examined, i.e. endothelin-1 (ET-1), ET-3, sarafotoxin 6b (S6b) and S6c, were able to induce phosphoinositide hydrolysis in a dosedependent manner; ET-1 was more potent than S6b and ET-3, with corresponding ec50 values of 44 ± 16 pmol/l, 18 ± 13 nmol/l and 33 ± 24 nmol/l, respectively. Sarafotoxin induced only moderate stimulation of inositol phosphate accumulation. Both ET-1- and S6b-induced accumulation of inositol phosphate was almost totally (90%) inhibited by 100 μmol/l BQ 123, while the S6c response was not affected by the ETA receptor antagonist. In contrast, the ETB receptor antagonist IRL 1038 inhibited S6c-induced inositol phosphate accumulation by more than 80%, whereas inhibition was only about 30% for ET-1 and S6b stimulations. This indicates that both ETA and ETB receptors were coupled to the phospholipase C transducing system in the muscular layer of placental stem villi vessels, and there is evidence that the phosphoinositide hydrolysis response is obtained predominantly via ETA receptor activation.

F Ferré. U.361 INSERM, Maternité Baudelocque, 123 Bid de Port-Royal, 75014 Paris, France
Impairment of lung volumes and respiratory muscle strength in adult patients with growth hormone deficiency
Authors: Merola Bartolomeo , Sofia Matteo , Longobardi Salvatore , Fazio Serafino , Micco Assunta , Esposito Vincenzo , Colao Annamaria , Biondi Bernadette , Lombardi Gaetano
Published: December 2008

Merola B, Sofia M, Longobardi S, Fazio S, Micco A, Esposito V, Colao A, Biondi B, Lombardi G. Impairment of lung volumes and respiratory muscle strength in adult patients with growth hormone deficiency. Eur J Endocrinol 1995;133:680–5. ISSN 0804–4643

Little is known of the respiratory function in patients with growth hormone (GH) deficiency. The aim of the present study was to evaluate lung volumes and respiratory muscle strength in patients diagnosed as GH deficient in childhood. Ten patients diagnosed as GH deficient in childhood and ten healthy subjects entered the study. For each subject the evaluation of respiratory function followed the same standard approach, consisting of respiratory muscle strength assessment, recording of flowvolume curves, measurement of static lung volumes and lung diffusing capacity. Both maximal inspiratory and expiratory mouth pressures were decreased in GH deficiency. Vital capacity, N2 functional residual capacity and total lung capacity were significantly reduced when compared to healthy subjects. Conversely, the residual volume and diffusing lung capacity to CO did not show any significant change. No significant change of percentage forced expiratory volume in 1 s/forced vital capacity ratio was observed. The decrease of respiratory mouth pressures was not correlated to the decrease of lung volumes. In conclusion, the results of this study show that adult patients affected with childhood onset GH deficiency suffer from impairment of ventilatory function and a decrease of respiratory muscle pressures, probably due to reduction of respiratory muscle strength.

Gaetano Lombardi, Via G Santacroce 40/1, 80 129 Naples, Italy