Yearbook of Pediatric Endocrinology 2011
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The body of knowledge in most medical specialties is rapidly expanding, making it virtually impossible to follow all advances in clinical and basic sciences that are relevant to a given field. This is particularly true in pediatric endocrinology, at the cross-road of pediatrics, endocrinology, development and genetics. Providing abstracts of articles that report the year’s breakthrough developments in the basic sciences and evidence-based new knowledge in clinical research and clinical practice that are relevant to the field, the Yearbook of Pediatric Endocrinology 2011 keeps busy clinicians and scientists, pediatric endocrinologists, and also pediatricians and endocrinologists informed on new advances. Twelve Associate Editors and their co-authors selected from several thousand papers those that brought the most meaningful new information, summarized them and provided comments to put them into perspective. The papers are classified into those that identify new genes involved in diseases, new hormones, concepts revised or re-centered, important observations for clinical practice, large-scale clinical trials, new mechanisms, new paradigms, important review articles, new fears and new hopes. Because the Yearbook is endorsed by the European Society for Paediatric Endocrinology (ESPE), its publication is linked to the annual meeting of the ESPE. The Yearbook of Pediatric Endocrinology 2011 covers the medical and scientific literature from June 2010 through May 2011.



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Date de parution 14 septembre 2011
Nombre de lectures 0
EAN13 9783805598606
Langue English
Poids de l'ouvrage 1 Mo

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Yearbook of Pediatric Endocrinology 2011
Yearbook of Pediatric Endocrinology 2011
Endorsed by the European Society for Paediatric Endocrinology
Associate Editors
Jean-Claude Carel
Ze’ev Hochberg
Gary Butler
Evangelia Charmandari
Francesco Chiarelli
Stefano Cianfarani
Mehul Dattani
Nicolas De Roux
Outi Mäkitie
Ken Ong
Orit Pinhas-Hamiel
Michel Polak
Olle Söder
Martin Wabitsch
Sponsored by a grant from Pfi zer Endocrine Care
Disclaimer. The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publisher and the editor(s). The appearance of advertisements in the book is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
Drug Dosage. The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any change in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
© Copyright 2011 by S. Karger AG, P.O. Box, CH-4009 Basel (Switzerland)
Printed in Switzerland on acid-free and non-aging paper (ISO 9706) by Reinhardt Druck, Basel
ISBN 978-3-8055-9859-0
ISSN 1662-3391
Jean-Claude Carel
Pediatric Endocrinology and Diabetology, and INSERM U690, University Paris 7
Denis Diderot, Hôpital Robert Debré, 48, boulevard Sérurier
FR-75935 Paris cedex 19, France
Tel. +33 1 40 03 41 05; Fax +33 1 40 03 24 29; E-Mail
Ze‘ev Hochberg
Meyer Children's Hospital, Rambam Medical Center, Faculty of Medicine
Technion-Israel Institute of Technology, POB 9602
IL-31096 Haifa, Israel
Fax +972 (0) 4 854 21 57; E-Mail
Associate Editors
Gary E. Butler
Department of Paediatrics and Adolescents
University College London Hospital, 250 Euston Road
London NW1 2PQ, UK
Tel. +44 8451 555 000 ext. 5240
Evangelia Charmandari
Division of Endocrinology and Metabolism
Clinical Research Center
Biomedical Research Foundation of the Academy of Athens
4 Soranou tou Efessiou Street
GR-11527 Athens, Greece
Tel. +30 210 659 7196, Fax +30 210 659 7545, E-Mail
Francesco Chiarelli
Department of Pediatrics, University of Chieti, Via dei Vestini, 5
IT-66013 Chieti, Italy
Tel +39 0871 358015, Fax +39 0871 574831, E-Mail
Stefano Cianfarani
Department of Public Health and Cell Biology
Tor Vergata University
Room E178, Via Montpellier 1
IT-00133-Rome, Italy
Tel. +39 06 6859 3074, Fax +39 06 6859 2508, E-Mail
Mehul T. Dattani
Developmental Endocrine Research Group
Clinical and Molecular Genetics Unit, Institute for Child Health
University College London
London, WC1N 1EH, UK
Tel. +44 207 905 2657, Fax +44 207 404 6191, E-Mail:
Nicolas De Roux
INSERM U 690, Laboratoire d’Hormonologie, AP-HP
Hôpital Robert Debré, 48 Boulevard Sérurier
FR-75019 Paris, France
Tel. +33 1 40 03 19 85, Fax +33 1 40 40 91 95, E-Mail
Outi Mäkitie
Pediatric Endocrinology and Metabolic Bone Diseases
Children's Hospital
Helsinki University Central Hospital and University of Helsinki
FI-00029 HUS Helsinki, Finland
Tel. +358 9 4711, Fax +358 9 471 75888, E-Mail
Ken Ong
Medical Research Council Epidemiology Unit
Institute of Metabolic Science, Addenbrooke's Hospital, Box 285
Cambridge CB2 0QQ, UK
Tel. +44 1223 769207; Fax +44 1223 330316; E-Mail
Orit Pinhas-Hamiel
Pediatric Endocrine and Diabetes Unit
Safra Children's Hospital
Sheba Medical Center Ramat-Gan
IL-52621 Ramat-Gan, Israel
Tel. +972 3 5305015, Fax +972 3 5305055, E-Mail
Michel Polak
Service d’endocrinologie pédiatrique
Hôpital Necker-Enfants Malades
149, rue de Sèvres
FR- 75015 Paris, France
Tel. +33 1 44 49 48 03/02, +33 1 44 38 16 48,
Olle Söder
Pediatric Endocrinology Unit, Q2:08
Department of Woman and Child Health
Karolinska Institutet and University Hospital, Solna
SE-171 76 Stockholm, Sweden
Tel. +46 8 517 75124, Fax +46 8 517 75128, E-Mail
Martin Wabitsch
Pediatric Endocrinology, Diabetes and Obesity Unit
Department of Pediatrics and Adolescent Medicine
University of Ulm, Eythstrasse 24
DE-89075 Ulm, Germany
Tel. +49 731 5002 7715; +49 731 50027789; E-Mail
Table of Contents
Ze’ev Hochberg and Jean-Claude Carel
Lucie Chevrier, Lukas Huijbregts, Carine Villanueva and Nicolas De Roux
Evelien F. Gevers and Mehul T. Dattani
Michel Polak, Mireille Castanet, Aurore Carré and Gabor Szinnai
Growth and Growth Factors
Stefano Cianfarani
Bone, Growth Plate and Mineral Metabolism
Outi Mäkitie and Ola Nilsson
Reproductive Endocrinology 2011
Lena Sahlin and Olle Söder
Erica L.T. van den Akker and Evangelia Charmandari
Type 1 Diabetes: Clinical and Experimental
Francesco Chiarelli and M. Loredana Marcovecchio
Obesity and Weight Regulation
Martin Wabitsch, Daniel Tews, Michaela Keuper, Carsten Posovszky, Christian Denzer, Primoz Kotnik, Anja Moss, Julia von Schnurbein and Pamela Fischer-Posovszky
Type 2 Diabetes, the Metabolic Syndrome and Dyslipidemia in Children and Adolescents
Orit Pinhas-Hamiel
Population Genetics and Pharmacogenetics
Ken K. Ong
Evidence-Based Medicine in Pediatric Endocrinology
Gary Butler, Carrie Williams and Stephen O’Riordan
Editor's Choice
Jean-Claude Carel and Ze’ev Hochberg
Science and Medicine
Ze’ev Hochberg
Author Index
Subject Index
This was an exciting year (the Yearbook counts years from June to June, when we submit the manuscripts to the publisher): The Neanderthal genome was sequenced and compared to ours, H. sapiens, and it shows that Neanderthals shared more genetic variants with present-day humans in Eurasia than with present-day humans in sub-Saharan Africa; gene flow from Neanderthals into our ancestors of non-Africans occurred before the divergence of Eurasian groups from each other. This was also the year when the price of whole genome sequencing dropped such that it is now affordable by many investigators and clinicians. It was also the year when we learnt that the skeleton was part of the endocrine system beyond minerals regulating hormones: the skeleton controls reproductive and energy balance, while adipose tissue and insulin regulate bone metabolism.
The gargantuan advances of 2010-11 provide a new insight in pediatric endocrinology, and have been recapped by the Associate Editors of this 2010 Yearbook . These are based on discoveries in varied fields of genomics and genetics, molecular biology and systems biology, evolutionary biology, clinical trials and medical reports. As the complexity increases, the Yearbook becomes an essential reading for clinical scientists and practitioners who wish to update on the most recent developments in pediatric endocrinology and beyond.
In the Yearbook Preface we annually recognize a prize given in the field of endocrinology. Time and again, hormones are recognized as groundbreaking discoveries, and this year we salute Douglas Coleman and Jeffrey M. Friedman for their Lasker Award granted to them for the discovery of leptin.
We also mention annually important anniversaries: in 1911, Ernest Rutherford postulated that atoms have their positive charge concentrated in a very small nucleus, and thereby pioneered the Rutherford model, or planetary, model of the atom. Using isotopes in medicine reveals just some of the ways in which his work has been utilized.
These were labeled the four most deadliest words that will prevent progress on the personal but also at the scholar level: ‘ I already know that’ . Our twelve Associate Editors and their coauthors do not take anything for granted, and have once again done an enormous work to discern this year's advances. The European Society for Paediatric Endocrinology (ESPE) endorses the Yearbook in its 8th year, and we acknowledge the generous support of Pfizer that makes the Yearbook project possible. We thank again the Associate Editors who have contributed during these 8 years to the success of the Yearbook which has become a landmark in the yearly cycle of pediatric endocrinology. Our publisher, Karger, has also done a tremendous job to bring paperbacks on time to the ESPE meeting with so little time for preparation, thanks to the dedication of Mr. Hermann Frei. Several Associate Editors have come and gone, some of them might come back again. The same is true of the Editors and we welcome Ken Ong as the new Editor of the Yearbook with Ze’ev Hochberg for 2012.
Ze’ev Hochberg (Haifa) Jean-Claude Carel (Paris)
Lucie Chevrier, Lukas Huijbregts, Carine Villanueva and Nicolas De Roux
INSERM U676, Hôpital Robert Debré and Université Paris Diderot, Paris, France
New in-vivo model and revised concept
In the two following studies from the same group, the authors used an interesting and sophisticated design of genetically modified mice that express diphtheria toxin upon Cre recombination, the expression of which itself is driven by the endogenous regulatory sequences of a target gene. This strategy thereby results in specific ablation of an entire cellular population, like kisspeptin or KISS1R neurons. What is intriguing, and certainly more unexpected, is that instead of observing at least similar or even worse effects than in single gene knockout mice, the authors observed a much milder phenotype, suggesting a greater physiologic plasticity when a cell population is theoretically missing rather than a gene. Overall, these two studies bring very challenging results, which have to be cautiously interpreted and will need further confirmations.
Embryonic gonadotropin-releasing hormone signaling is necessary for maturation of the male reproductive axis
Wen S, Ai W, Alim Z, Boehm U
Institute for Neural Signal Transduction, Center for Molecular Neurobiology, Hamburg, Germany.
Proc Natl Acad Sci U S A 2010;107:16372-7.
Background: Gonadotropin-releasing hormone (GnRH) signaling regulates reproductive physiology in mammals by controlling synthesis and secretion of gonadotropins by gonadotrope cells. However, the role of GnRH signaling on embryonic gonadotrope cells development is not well established.
Methods: The authors developed transgenic mice in which GnRHR-expressing cells were selectively ablated by the expression of the diphtheria toxin. They developed another model in which diphtheria toxin gene was replaced by a gene encoding the yellow fluorescent protein (YFP) to study the timing of GnRHR expression.
Results: At embryonic day 16.75, GnRHR is only expressed in luteinizing hormone (LH)-expressing gonadotropes. The maturation of follicle-stimulating hormone (FSH)-expressing gonadotropes requires the increase of embryonic LH secretion. The lack of GnRHR-expressing cells does not alter migration of GnRH neurons toward the hypothalamus, but increases the number of GnRH neurons in the anterior hypothalamus.
Conclusion: Embryonic GnRH signaling is involved in the maturation of gonadotropes cells in males.
The central developmental control of reproduction by GnRH is now well established. The hypothalamo-pituitary-gonadal axis is functional during embryonic development. To study the precise role of GnRH signaling on the embryonic reproductive axis, the authors developed genetic strategies to ablate GnRHR-expressing cells in mice and to follow GnRHR expression with YFP. Their results show that GnRH signaling is required for gonadotrope cell maturation. At E16, only LH-expressing gonadotropes express GnRHR. LH secretion is increased in response to GnRH, inducing the development and maturation of FSH-expressing cells and LH receptor. These cells start to express GnRHR after E17. At E16, FSH cells transiently express thyroid-stimulating hormone (TSH), suggesting that they represent an intermediate gonadotrope cell type expressing TSH whose differentiation depends on GnRH signaling. Ablation of GnRHR cells did not affect migration of GnRH neurons, indicating that this phenomenon is independent of GnRH signaling. However, in mice lacking GnRHR cells, the number of GnRH neurons in the anterior hypothalamus increased by 30%. This observation is not in agreement with previous data showing that GnRH neurons expressed GnRHR and with analyses of mice expressing inactive GnRHR which are not associated with an increase in GnRH neurons. This set of data suggests that the number of GnRH neurons depends on GnRHR-expressing cells, but not on GnRH signaling. These differences could be due to the model used in the present study in which one cell population is abated.
Female reproductive maturation in the absence of kisspeptin/GPR54 signaling
Mayer C, Boehm U
Institute for Neural Signal Transduction, Center for Molecular Neurobiology, Hamburg, Germany.
Nat Neurosci 2011;14:704-10.
Background: The onset of puberty is triggered by an increase of GnRH secretion from a subpopulation of hypothalamic neurons. This reactivation of GnRH neurosecretion depends on the integration of several activating signals, but the neural network governing the timing of puberty remains largely unknown. The recent discovery of the kisspeptin neuropeptide as the most potent GnRH secretagogue suggests that kisspeptin neurons may be the key regulators of puberty onset.
Results: To test this hypothesis, the authors designed genetically modified female mice in which kisspeptin-expressing neurons are missing, and show that these animals undergo puberty at a normal age. They are also fertile although they have smaller ovaries. The complementary approach, consisting of ablating GPR54 neurons, also resulted in fertile animals. However, when kisspeptin neurons were ablated in adult mice, these became infertile, suggesting the existence of a time window during development when the kisspeptin/GPR54 system can be compensated.
Conclusion: Overall, these data indicate that puberty can be normally triggered and achieved in the absence of kisspeptin/GPR54 signaling.
In this surprising study, the authors show that in animals lacking kisspeptin or GPR54 neurons, puberty undergoes normally and adults are fertile, which is in contrast with knockout animals which are infertile. To explain this intriguing difference, the authors propose that a quiescent compensatory mechanism replaces the missing neural network, thereby driving normal reproductive function and that this mechanism would be under the influence of inhibitory signals coming from kisspeptin or GPR54 neurons. This interesting hypothesis is however challenged by the fact that contrary to knockout approaches, where kisspeptin neurons are present but the gene is not expressed, in the toxin strategy a few percent of kisspeptin or GPR54 neurons remain and could express some levels of a protein. With kisspeptin being by far the most potent GnRH secretagogue, it would not be unlikely that the few remaining cells could be sufficient to trigger puberty and maintain fertility. This hypothesis has to be tested because instead of undermining the importance of the kisspeptin/GPR54 system in puberty onset, it would highlight its extreme potency.
Using an alternative approach, the authors also acutely ablated kisspeptin or GPR54 neurons by injecting diphtheria toxin in adult animals expressing the diphtheria receptor instead of the toxin itself. Ablation of kisspeptin neurons in adults and in 20-day-old juvenile animals resulted in infertile and acyclic animals, suggesting that a compensatory network can only occur during a time-defined window during development. Very interestingly, the authors did not detect any kisspeptin-positive neurons, meaning that the inducible deletion of target neurons is more efficient than the genetic toxin strategy and may account for the loss of fertility in one case and not in the other. However, efficiently ablating GPR54 neurons resulted in a loss of 93% of GnRH neurons but did not totally impair fertility, suggesting that very few GnRH neurons are sufficient to maintain an active gonadotropic axis.
New concept How estradiol influences pubertal timing
Timing and completion of puberty in female mice depend on estrogen receptor-α signaling in kisspeptin neurons
Mayer C, Acosta-Martinez M, Dubois SL, Wolfe A, Radovick S, Boehm U, Levine JE
Institute for Neural Signal Transduction, Center for Molecular Neurobiology, Hamburg, Germany.
Proc Natl Acad Sci U S A 2010;107:22693-8.
Background: Although poorly known, the mechanisms that trigger puberty probably rely on a dynamic of both inhibitory and activating mechanisms of GnRH neurosecretion. These maintain low levels of GnRH during the juvenile period but then increase it in order to achieve puberty and sexual maturation of the brain. Estrogen receptor-α (ER) is known to participate to both signals, but the underlying neural network is poorly known.
Results: In this study, the authors hypothesized that kisspeptin-expressing neurons are the mediators of ERα signaling toward GnRH neurons. They designed a genetically modified mouse in which ERα expression is conditionally ablated in kisspeptin neurons, and show that it resulted in a dramatically advanced age of puberty onset in females. Although precautiously activated, the gonadotropic axis failed to reach full maturation as the animals could not acquire normal ovulatory cyclicity.
Conclusion: The authors propose that two different populations of kisspeptin neurons in the hypothalamus respond to estrogens and are responsible for both the juvenile restraint and the pubertal activation of GnRH neurosecretion.
Estrogen and ERα play a major role in the regulation of the gonadotropic axis but given the fact that GnRH neurons do not express ERα, there had to be interneurons as signaling intermediates. The discovery of kisspeptin as the most potent GnRH secretagogue and the fact that all kisspeptin neurons expressed ERα naturally led to the hypothesis that these interneurons were kisspeptin neurons. Here, the authors give compelling evidence that it actually is the case, at least in females, thereby confirming what was suspected for several years. Surprisingly, onset of puberty and sexual maturation in males was not as dramatically impaired by the selective invalidation of ERα in kisspeptin neurons as in female mice, which may suggest that androgen receptor may compensate for the loss of ERα. The authors confirm what was previously known from studies of gonadectomized animals that kisspeptin neurons are upregulated (positive feedback) by estradiol in the anteroventral periventricular nucleus (AVPV) and downregulated (negative feedback) in the arcuate nucleus (ARC). In the context of puberty, they therefore hypothesize that ARC neurons provide the juvenile restraint on GnRH neuro-secretion, which is supplanted by AVPV neurons at the end of the juvenile period. Overall, this study is extremely important because it shows the necessity of ERα expression within kisspeptin neurons for normal puberty onset in females.
Concept revised Leptin does not act on the reproduction via kisspeptin neurons
Leptin's effect on puberty in mice is relayed by the ventral premammillary nucleus and does not require signaling in Kiss1 neurons
Donato J, Jr, Cravo RM, Frazao R, Gautron L, Scott MM, Lachey J, Castro IA, Margatho LO, Lee S, Lee C, Richardson JA, Friedman J, Chua S, Jr, Coppari R, Zigman JM, Elmquist JK, Elias CF
Department of Internal Medicine, Division of Hypothalamic Research, University of Texas Southwestern Medical Center, Dallas, Tex.,USA.
J Clin Invest 2011;121:355-68.
Background: A minimum amount of stored energy is required for normal pubertal onset. Leptin is a key metabolic signal to the neuroendocrine reproductive axis. Humans and mice lacking leptin or the leptin receptor (LepR) fail to enter puberty. Leptin administration to leptin-deficient subjects and leptin-deficient mice (ob/ob) induces puberty and restores fertility, but the exact site of leptin action is unclear. Kisspeptins were recently described as the major regulator of GnRH secretion at the pubertal onset.
Methods and Results: In this study, the authors showed that selective invalidation of LepR in hypothalamic kisspeptin neurons in mice had no effect on puberty or fertility. Direct leptin signaling in kisspeptin neurons is therefore not required for these processes. However, bilateral lesions of the ventral premammillary nucleus (PMV) of ob/ob mice blunted the ability of exogenous leptin to induce sexual maturation but did not prevent leptin's effect on food intake. Moreover, unilateral re-expression of LepR in PMV neurons was sufficient to induce puberty and improve fertility in female LepR-null mice.
Conclusion: These data show that leptin does not directly act on kisspeptin neurons. They suggest that the PMV is a key site for leptin's permissive action at the onset of puberty and support the hypothesis that the multiple actions of leptin to control metabolism and reproduction are anatomically dissociated.
This article is interesting as it reports the first molecular study showing that leptin's function on reproduction differs from its function on metabolism. The role of leptin on pubertal onset and reproduction status has largely been described but the exact hypothalamic sites of action of this peripheral hormone were lacking. Since the description of kisspeptins in pubertal onset, leptin was proposed by several groups as a possible candidate to trigger activation of the kisspeptin system at the end of the juvenile period. As the leptin receptor is expressed in kisspeptin neurons, it was justified to test the hypothesis whether leptin receptor invalidation in these neurons interferes with reproduction status and pubertal onset. This paper clearly shows that this is not the case. Moreover, this paper reports that leptin action on the reproduction status is mediated through neurons located in the ventral premammillary nucleus. These PMV neurons do not relay leptin action on the metabolism. Additional work is now needed to determine how leptin-sensitive PMV neurons act on reproduction. The authors also have observed a sexual dimorphism of leptin action on PMV neurons that represents an additional complexity to the understanding of the link between nutrition and reproduction.
New concerns Brain differentiation and endocrine disruptors
Endocrine disruption of brain sexual differentiation by developmental PCB exposure
Dickerson SM, Cunningham SL, Patisaul HB, Woller MJ, Gore AC
Division of Pharmacology and Toxicology and Center for Molecular and Cellular Toxicology, The University of Texas at Austin, Tex.,USA.
Endocrinology 2011;152:581-94.
Background: Adult reproductive functions critically rely on the sexual differentiation of the hypothalamus, which depends on sexually dimorphic secretion of sex hormones during perinatal development. The authors tested the hypothesis that polychlorinated biphenyl (PCB) exposure during the perinatal period may lead to permanent impairment of the sexual differentiation of the rat preoptic area (POA) through disruption of hormonal pathways.
Results: In order to test this hypothesis, the authors injected 16- or 18-day pregnant rats with several PCB mixtures, estradiol or a vehicle. They then analyzed the expression of known sexual hormones targets in the POA of the adult offspring using immunohistochemistry and a PCR-based expression array. They also monitored somatic and reproductive development of the pups. Overall, their results show that pubertal onset was delayed in PCB-exposed males and advanced in females and led to anormal estrous cyclicity. Interestingly, PCB exposure induced in females a masculinization of the neuroen-docrine system, as shown by expression of kisspeptins and estrogen receptor-α in the sexually dimorphic anteroventral periventricular (AVPV) nucleus. Using a PCR-based array, the authors show that the expression of genes encoding IGF-1, NMDA receptor subunit NR2b, androgen receptor and TGF-ß1 is strongly reduced in the female POA, suggesting a major impact of PCB exposure on sexual maturation of the brain during development of female rats.
Conclusion: PCB exposure during the perinatal period in rats leads to severe and permanent dysregulation of genes involved in puberty onset and estrous cycle in female adults.
PCBs are environmental endocrine-disrupting chemicals which are suspected of causing numerous reproductive impairments. They are present in nearly all humans and can be transferred from the mother to the baby through the placental barrier and milk. This study is important because it brings molecular insight into the dramatic effect of perinatal PCB exposure on female sexual maturation and shows that kisspeptin and ERα expression are impaired in the AVPV. Furthermore, PCB exposure masculinizes the female brain and induces a female-specific decrease of IGF-1, AR, NR2b and TGF-ß1 expression in the POA, suggesting that these genes are of particular importance in the establishment of the neural circuitry that leads to the sexual differentiation of the brain.
New mechanism Nesfatin-1 and puberty onset
The anorexigenic neuropeptide, nesfatin-1, is indispensable for normal puberty onset in the female rat
Garcia-Galiano D, Navarro VM, Roa J, Ruiz-Pino F, Sanchez-Garrido MA, Pineda R, Castellano JM, Romero M, Aguilar E, Gaytan F, Dieguez C, Pinilla L, Tena-Sempere M
Department of Cell Biology, Physiology and Immunology, University of Cordoba, Cordoba, Spain.
J Neurosci 2010;30:7783-92.
Background: Nesfatin-1 is a peptide derived from the NEFA/nucleobindin 2 (NUCB2) precursor expressed in the hypothalamus. It was recently identified as an anorexigenic peptide, but other biological functions gated by body energy status remain unexplored. The authors studied the involvement of nesfatin-1 on the control of female puberty.
Methods and Results: ISH and ICC studies indicated that NUCB2/nesfatin mRNA and protein were detected at the hypothalamus of pubertal female rats, with prominent signal at lateral hypothalamus (LHA), paraventricular (PVN), and supraoptic (SON) nuclei. Quantitative analysis showed that expression of NUCB2/nesfatin increased threefold between late-infantile and peripubertal periods. 48 h fasting or sustained subnutrition of pubertal females induced a decrease in the expression of hypothalamic NUCB2 mRNA and/or protein levels. Central administration of nesfatin-1 induced an increase of circulating gonadotropins which was further enhanced upon food deprivation. Inhibition of NUCB2 in the hypothalamus by continuous intracerebroventricular infusion of antisense morpholino oligonucle-otides along pubertal maturation was associated with a delay of vaginal opening and a decrease of ovarian weight and serum luteinizing hormone levels. In contrast, suppression of hypothalamic NUCB2 in adult female rats had no effect on gonadotropins levels and did not alter preovulatory gonadotropin surges.
Conclusion: NUCB2/nesfatin-1 plays a role in the control of puberty in female rat, a function that may contribute to the functional coupling between reproduction and energy homeostasis.
The link between energy balance and reproduction is crucial. In negative energy balance, reproduction function is aborted, but the mechanisms coupling energy balance and reproduction remain unclear. This study reports the effect of the anorexigenic peptide NUCB2/nesfatin-1 on the onset of puberty in female rat. The authors provide a neuroanatomical characterization of NUCB2/nesfatin-1 neurons distribution in the hypothalamus at puberty. Two populations of NUCB2/nesfatin-1 neurons seem to be present and have a different sensibility to development and metabolic cues. However, no mature nesfatin-1 peptide has been detected in the hypothalamus.
The role of nesfatin-1 on puberty was studied by pharmacological studies and in-vivo gene invalidation. This peptide stimulates gonadotropin release, with an enhanced effect in negative energy balance conditions. It is also involved in the timing of puberty but has no effect in adult female rat. One surprising observation is that suppression of nesfatin-1 in the hypothalamus does not affect food intake and body weight in peripubertal and adult female rats. Several hypotheses could explain this result. First, redundant mechanisms of energy balance control could occur during puberty. Second, the anorexigenic effect of nesfatin-1 has been demonstrated in male rats, suggesting a possible sexual dimorphism of nesfatin-1 action. Third hypothesis, the decrease of hypothalamic nesfatin-1 expression by antisense morpholino oligonucleotides is not sufficient to abolish the anorexigenic effect of this peptide or another unknown source of peptide exists. Fourth, the hypothalamic sites of nesfatin-1 action differ between reproduction and regulation of food intake.
This study is the first to highlight the role of the anorexigenic peptide nesfatin-1 on the onset of puberty. It will be interesting to investigate the molecular mechanisms of nesfatin-1 action in order to have a better knowledge of the link between reproduction and energy balance.
New concept How maternal care influences estradiol receptor function in adulthood
Sex differences in epigenetic regulation of the estrogen receptor-« promoter within the developing preoptic area
Kurian JR, Olesen KM, Auger AP
Psychology Department, University of Wisconsin-Madison, Madison, Wisc.,USA.
Endocrinology 2010;151:2297-305.
Background: Sexual dimorphism of the central nervous system is mainly organized by a postnatal testicular hormone surge that is absent in females. Although very brief, this hormone surge induces permanent changes in terms of sexual behavior and brain sexual differences. Because these largely depend on the brain-derived testosterone metabolite estradiol, which acts via the receptor ERα, the authors have investigated the hypothesis that a difference in DNA methylation of the ERα gene promoter region exists between male and female mice.
Results: The authors show that ERα promoter methylation is higher in males than females in the preoptic area of the hypothalamus, thereby decreasing transcription of the ERα gene. Furthermore, they found that simulating grooming of the pups’ anogenital region by the mother resulted in an increase of ERα promoter methylation in females to reach the same level as in males. Finally, the authors show that females perinatally treated with estradiol have a male-like methylation pattern of the ERα gene promoter.
Conclusion: The authors show that the methylation level of the ERα gene promoter is sexually dimorphic and influenced by both the perinatal surge of male sexual hormone and maternal grooming.
Growing evidence is emerging from the literature that the sexual differentiation of the brain results, at least in part, from epigenetic modifications driven by environmental and social factors. Interestingly, this study strongly suggests that normal differences in maternal care, such as grooming of the ano-genital region, can induce extremely tight and precise molecular modification of certain CpG sites in the ERα gene promoter in the preoptic area of the hypothalamus (although the authors did not examine methylation levels in other brain regions). The perinatal surge of estradiol has a lasting impact on the brain that will drive sexual behaviors but the underlying molecular mechanisms are unclear. Part of this effect, as shown by the authors, may result from a sexually dimorphic methylation pattern of CpG sites of the ERα gene promoter region in the preoptic area of the hypothalamus that leads to local transcriptional variations. The molecular link between a somatosensory stimulus and the methylation of a very specific genomic region remains unknown, but overall, evidences that such early social interactions as well as early estradiol exposure can influence the methylation of ERα promoter gives a better understanding on how variations in maternal care can have permanent effects on the sexual behavior during adulthood. Entire methylome studies, which are becoming more and more available, will certainly help to get further insight on the fascinating influence of the environment on sexual behaviors.
Concept revised Sexual dimorphism of the GH network
Pituitary growth hormone network responses are sexually dimorphic and regulated by gonadal steroids in adulthood
Sanchez-Cardenas C, Fontanaud P, He Z, Lafont C, Meunier AC, Schaeffer M, Carmignac D, Molino F, Coutry N, Bonnefont X, Gouty-Colomer LA, Gavois E, Hodson DJ, Le Tissier P, Robinson IC, Mollard P Department of Endocrinology, Institute of Functional Genomics, Montpellier, France.
Proc Natl Acad Sci U S A 2010;107:21878-83.
Background: Sex-specific gonadal steroid imprinting generates sex differences in many pituitary endocrine axes, notably the somatotropic axis. The authors have previously shown that GH cells form functionally organized networks in the pituitary. In this study, they tested the hypothesis that the response of the GH pituitary network is sexually dimorphic.
Methods: Calcium spikes were monitored within GH cell networks in pituitary slices taken from 45-day-old male and female GH-eGFP transgenic mice after a GH-releasing hormone (GHRH) stimulus. These mice were sham-operated, gonadectomized or gonadectomized and treated with acute gonadal replacement. Experiments were carried out 15 days after surgery.
Results: GH cell network responses were sexually dimorphic: cell responses were higher in male mice. This sex difference was switched by postpubertal gonadectomy and reversed by hormone treatment.
Conclusion: The functional organization of the pituitary gland is involved in the sexually dimorphic responses in the GH axis and may explain some growth and metabolism differences between males and females.
GHRH exposure generates calcium spikes in the lateral wings of the pituitary, with significant differences in the proportion of GH-responsive cells between males (60%) and females (35%) in pituitary slices taken from male and female GH-eGFP transgenic mice. Repetitive waves of calcium spikes were observed in male pituitary slices whereas no waves were observed in female pituitary slices. These rhythmic calcium waves may influence a wide range of downstream processes. The authors did not observe any sexual dimorphism of the GHRH response when they tested isolated GH cells. They conclude that the difference in GHRH response between males and females is a property of the GH cell network in the pituitary.
The effects of these networks on GHRH responses seem to be regulated by gonadal steroid hormones in both adult females and males. After gonadectomy, steroid supplementation restored the proportion of GHRH-responsive cells back to what was seen in normal males and females. However, gonadectomy abolished the waves of activity in males after GHRH exposure and testosterone treatment did not restore it. Another interesting result is that masculinization of ovariectomized females increased to 60% the number of GHRH-responsive GH cells (instead of 80% in non-treated ovariectomized females), similar to the findings in intact males and generated repetitive waves of calcium spikes in lateral wings of the pituitary. Studies generally show that exposure to steroids during critical periods exert organizational effects on brain circuits. During the perinatal period, steroids permanently imprint a specific neuronal architecture that will drive behavioral and somatic traits. Gonadal steroid regulation of GH secretion has been largely attributed to their effect on the hypothalamic pulse generator: this study indicates that steroids also regulate GH response to GHRH at the pituitary level. The sexually dimorphic GH secretion observed in humans at puberty could therefore be related to hypothalamic and pituitary signals via steroid regulation.
New mechanism Hypothalamic inflammation and pancreas function
Melanocortin signaling in the CNS directly regulates circulating cholesterol
Perez-Tilve D, Hofmann SM, Basford J, Nogueiras R, Pfluger PT, Patterson JT, Grant E, Wilson-Perez HE, Granholm NA, Arnold M, Trevaskis JL, Butler AA, Davidson WS, Woods SC, Benoit SC, Sleeman MW, DiMarchi RD, Hui DY, Tschop MH
Metabolic Diseases Institute, Division of Endocrinology, Department of Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio,USA.
Nat Neurosci 2010;13:877-82.
Background: Metabolic syndrome comprises obesity, hypertension, impaired glucose metabolism and dyslipidemia. The gut hormone grhelin has been shown to increase adiposity and to promote hyperglycemia via brain circuits, the hypothalamic melanocortin system being the most important target. Melanocortin receptor mutations are strongly associated to human obesity and alterations in cholesterol transport are a common occurrence in the metabolic syndrome. In this study, the authors tested the hypothesis that a gut-brain axis regulates cholesterol metabolism via the central melanocortin system.
Methods and Results: Inhibition of the brain's melanocortin system by pharmacological, endocrine or genetic approaches reduced HDL uptake by the liver, resulting in an increase in circulating HDL cholesterol.
Conclusion: These data suggest that a neural circuit in the brain is directly involved in the control of cholesterol metabolism by the liver.
It is now well established that the gut hormone ghrelin is involved in the molecular energy balance regulation. This study indicates that a gut-brain axis including ghrelin and the melanocortin system directly regulates the HDL cholesterol level in rodents. The authors showed that the inhibition of the melanocortin system by antagonist treatment induced an increase of circulating HDL cholesterol associated with a decrease of its uptake by the liver. Peripheral administration of ghrelin had the same effect through an indirect inhibition of the melanocortin system. However, treatment with melanocortin receptor agonist or glucagon-like peptide 1 (GLP-1) had an opposite effect on circulating the HDL cholesterol level. This effect is mediated via melanocortin-4 receptor (MC4R) signaling and the vagal pathway, suggesting the involvement of the dorsal motor nucleus of the vagus and the lateral hypothalamus. The lack of MC4R signaling induces severe obesity, but is also associated with a decrease of HDL cholesterol uptake by the liver, leading to an increase of ‘good’ cholesterol. This paradox could be related to the fact that unlike in humans, in rodents the majority of circulating cholesterol is contained in HDL. The hypothalamic melanocortin system, which regulates the circulating cholesterol level, represents a new potent therapeutic target to treat hypercholesterolemia and metabolic syndrome.
Inflammation of the hypothalamus leads to defective pancreatic islet function
Calegari VC, Torsoni AS, Vanzela EC, Araujo EP, Morari J, Zoppi CC, Sbragia L, Boschero AC, Velloso LA Laboratory of Cell Signaling, of Campinas, São Paulo, Brazil.
J Biol Chem 2011;286:12870-80.
Background: The hypothalamus becomes inflamed and dysfunctional under diet-induced obesity and this could lead to type 2 diabetes. Because pancreatic function is partially regulated by the autonomic nervous system, the authors evaluated the role of hypothalamic inflammation in pancreatic islet function.
Methods: Intracerebroventricular injection of a low dose of tumor necrosis factor-α (TNF-α) was performed in two groups (control vs. 12-week high-fat diet) of 4-week-old rats. Alternatively, lean animals received stearic acid through intracerebroventricular injection, which activates inflammation through the tau-like receptor 4 and endoplasmic reticulum stress.
Results: TNF-α injection led to an increase of insulin secretion, whereas stearic acid produced an impairment of insulin secretion. Both TNF-α and stearic acid induced an increase of apoptosis marker expression in pancreatic islets. Insulin secretion after stearic acid injection was restored upon sympathectomy or inhibition by a specific antisense oligonucleotide of the peroxisome proliferator-activated receptor-γ coactivator-1, PGC-1α.
Conclusion: The present study provides evidence that the autonomic signals associated with hypothalamic inflammation induced by either TNF-α or a saturated fatty acid can impair pancreatic islet function. This phenomenon may explain the link between obesity and defective insulin secretion.
In animal models of obesity, the hypothalamus is one of the first affected tissues. Inflammation of the hypothalamus leads to its dysfunction associated with the development of leptin and insulin resistance as well as loss of coupling between energy expenditure and caloric intake. Insulinemia rises in proportion to the body mass. Then, with the appearance of type 2 diabetes onset, insulin production and secretion decline. The single injection of TNF-α in lean rats induces hypothalamic inflammation and an insulin-resistant phenotype. These functional changes observed in pancreatic islets and those observed in gene expression after intracerebroventricular TNF-α injection are similar to the ones found in obesity. Other studies have reported that some of the TNF-α upregulated genes are, at least in part, engaged in defective pancreatic islet function.
The authors suggest that the importance of sympathetic signals on the modulation of the pancreatic ß-cell function could be a way to modulate pancreatic ß-cell function via the classical cAMP or the alternative PGC-1α pathways. For the first time, this study shows that inflamed dysfunctional hypothalamic tissues are connected with the pancreatic islets and are responsible for apoptotic gene activation and peripheral insulin resistance, notably via the sympathetic pathway. Considering this new mechanism, new therapeutic targets could eventually be developed to treat obesity and prevent the onset of diabetes.
New concept Adolescents are more plastic to stress than adults
Stress vulnerability during adolescent development in rats
Jankord R, Solomon MB, Albertz J, Flak JN, Zhang R, Herman JP Department of Psychiatry, University of Cincinnati, Cincinnati, Ohio,USA.
Endocrinology 2011;152:629-38.
Background: Adolescence is a period of continued growth, sexual maturation, and behavioral and social development. The authors of this study therefore tested the hypothesis that adolescent development represents a time of increased susceptibility to stress.
Method: Male Sprague-Dawley rats were exposed (or not) to 14 days of chronic variable stress (CVS) paradigm at three different stages of life: early adolescence (35 days), late adolescence (50 days) and adulthood (80 days). Several items were analyzed to assess stress influence: depression-like behavior, somatic indices, hypothalamic-pituitary-adrenal axis activity, and hypothalamic neuropeptides expression.
Results: Increased immobility during the forced swim test, which is considered a depression-like behavior, was only observed in adult animals in response to CVS. Late adolescent animals however were selectively vulnerable to the somatic effects of stress, depicted by a disproportionate increase of corti-costerone, thymic involution, a loss of body fat, and a decreased expression of oxytocin, a stress-protective peptide, in the paraventricular nucleus.
Conclusion: Despite the enhanced susceptibility to somatic and central effects of chronic stress, late adolescence represents a time period with unique protection from the effect of chronic stress on depression-like behavior.
The authors propose that adolescence is a window of unique vulnerabilities and protections to the effects of chronic stress. Previous studies showed that basal stress hormones do not change during puberty. However, adolescence is a period of intense brain maturation but has received less research attention than pre- and postnatal or adult life. The authors studied the effect of chronic stress on early/late adolescent rats and adult rats. Although they observed somatic changes like increases in basal corticosterone, thymic involution, and loss of body fat in late-adolescent animals exposed to chronic stress, these animals were more resistant than adults to the effect of CVS on depression-like behavior. The mechanisms of this protection remain unknown. According to other studies, corticotrophin-releasing hormone (CRH) is also stress-sensitive, but no age differences of CRH hypothalamic expression were observed. On the contrary, vasopressin and oxytocin hypothalamic expression increased between early and late adolescence, suggesting an important role of these hormones. CVS during late adolescence prevents the normal increase of oxytocin, which is an important mediator of social behavior. This study shows the necessity to be more attentive to the possible link between unexplained somatic changes at the end of adolescence and a possible stress, considering that stress has major implications for health.
New mechanism The importance of the perinatal photoperiod
Perinatal photoperiod imprints the circadian clock
Ciarleglio CM, Axley JC, Strauss BR, Gamble KL, McMahon DG
Neuroscience Graduate Program, Vanderbilt University, Nashville, Tenn.,USA.
Nat Neurosci 2011;14:25-7.
Background: It is well known that seasonal light input largely influences the activity of the mature biological clock located in the suprachiasmatic nucleus (SCN) of the hypothalamus. However, the impact of seasonal photoperiods during development on mature circadian clock remains largely unknown. In this study, the authors sought to analyze whether the perinatal photoperiod has a lasting effect on adult mouse circadian rhythms and behavior.
Methods and Results: The authors compared three groups of mice exposed to different seasonal developmental photoperiods: short day light/dark (LD) 8:16, long day, 16:8 or equinox day, 12:12 until weaning followed by 4 weeks of matching or counterbalanced continuation seasonal photoperiod. At 7 weeks of age, they analyzed SCN circadian clock by ex-vivo imaging or recorded wheel-running behavior in constant darkness. Their results show that in response to the continuation photoperiod, long days elicited SCN waveform broadening whereas short days elicited an increased degree of neuronal synchrony. When results were analyzed regardless of the ensuing continuation photoperiod, it appeared that SCN and neuron properties were solely determined by the perinatal photoperiod. The developmental imprinting was also reflected in circadian behavior.
Conclusion: The perinatal photoperiod has lasting effects on the circadian rhythms expressed by clock neurons as well as on mouse behavior, and sets the responsiveness of the biological clock to subsequent changes in photoperiod. These developmental gene/environment interactions may contribute to the influence of season on neurobehavioral disorders.
The circadian clock in mammals is located in the suprachiasmatic nucleus of the hypothalamus; it entrains a light-dark cycle and determines the phases of circadian rhythms onto behavior and physiology. The SCN consists of a number of oscillating cells in the circadian domain, which are independent but coupled to each other to produce coherent SCN output rhythms. The intracellular molecular machinery of circadian oscillation consists of interlocked transcriptional and translational auto-feedback loops. It was well known that circadian rhythms in clock gene expression and their protein products change between long and short photoperiods. Differences in circadian activity of the SCN result in a change of the 24-hour hormonal profiles as well as behavior rhythms. The new finding reported in this paper is that the imprinting of the SCN circadian activity by perinatal photoperiods persists in mature mice. The molecular mechanism by which photoperiodic imprinting occurs and permanently modifies clock neuron activity is completely unknown. It may result from epigenetic effects of light on clock gene expression in the SCN. The medical application of such fundamental research is quite large and may be important to understand the link between perinatal environment and some psychiatric diseases. It may also be important for medical care and optimal environment of preterm babies in our NICU.
A new mechanism: the hypothalamic function of emotional tears
Human tears contain a chemosignal
Gelstein S, Yeshurun Y, Rozenkrantz L, Shushan S, Frumin I, Roth Y, Sobel N
Department of Neurobiology, Weizmann Institute of Science, Rehovot, Israel.
Science 2011;331:226-30.
Background: Although tearing has been described as an eye protection or a mechanism for expelling toxic substances, the functional significance of emotional tearing remains unknown. This behavior is uniquely considered in humans. Tears are drops of liquid which contain proteins, lipids, electrolytes and traces of drugs, but the composition of emotional tears differs from that of reflexive eye-protective tears. In this paper, the authors decided to test whether emotional tears may also serve as a chemical signal.
Methods and Results: To analyze whether tears contain a chemical signal, the authors set up a clinical assay by collecting negative-emotion tears from adult women who watched sad films in isolation. They then exposed tears in different ways to young adult men. In the first test, they showed the absence of discernable odor in emotional tears. Then they tested whether tears contained a signal indicating sadness or information related to sociosexual behavior by viewing on screen ambiguous pictures of women's faces. This second test demonstrated that tears may contain a chemical signal decreasing the sexual attraction and arousal when compared to saline control. This decrease is correlated with a decrease of salivary testosterone levels in men sniffing tears when compared to saline. Finally, the authors showed by functional resonance imaging that sniffing tears significantly decreased the activity normally provoked by a sad film in the hypothalamus.
Conclusion: Emotional tears are odorless but contain a chemosignal which induces reductions in sexual arousal.
Emotional tears are specific to humans. In contrast to reflexive eye-protective tears, emotional tears are considered as an emotional signal but no specific function has been reported. In this paper, the authors report that emotional tears from sad women convey a chemosignal which seems to have an emotional impact on men sniffing those tears. Their main result is the reduced self-rated sexual arousal of men associated with reduced levels of salivary testosterone and reduced brain activity in specific regions implicated in sexual arousal such as the hypothalamus. This work is an example of how emotions can be transmitted through a chemical signal between two individuals close enough to each other. It also is an additional example of how the hypothalamus may relay emotions to the hormonal system. The active compound involved in this emotional effect remains to be described and it will be interesting to compare this chemical signal with the one conveying the emotions of ‘tears of joy’.
Evelien F. Gevers a, b and Mehul T. Dattani a
a Developmental Endocrine Research Group, Clinical and Molecular Genetics Unit, Institute for Child Health b Great Ormond Street Hospital, Department of Endocrinology, London, UK
Transcription factors continue to be of major interest in the field of pituitary research. Interestingly, emphasis is not anymore just on the role of transcription factors in pituitary development, but also on their role in tumorigenesis. For example, we have selected a paper suggesting Pit-1 is involved in breast cancer and a paper on the gene NUMB , which is known to be involved in cancer development, and is now shown to play a role in pituitary homeostasis. Aryl hydrocarbon-interacting protein (AIP) is involved in the development of familial isolated pituitary adenomas and a beautiful paper of Chahal et al. tracks an AIP mutation back to a common ancestor that lived in Ireland approximately 66 generations ago, using DNA from a skeleton of an Irish giant exhibited in a museum. Clinically important papers relate to the treatment of prolactinomas, albeit in adults, and to diagnostic outcome in a huge series of patients undergoing pituitary MRIs for sellar/parasellar tumors. We chose the involvement of microRNA in pituitary development as the mechanism of the year. This work shows that deletion of microRNA in the pituitary results in abnormal pituitary development and dwarfism, adding a new dimension to the genetic regulation of growth. Other developments include the presence of PIT-1 antibodies as a cause for combined TSH, GH and prolactin deficiency. The ‘Food for thought’ section includes a paper suggesting an important role for pituitary adenylate cyclase-activating peptide (PACAP) in post-traumatic stress disorder.
Mechanism of the year - microRNA
MicroRNAs regulate pituitary development, and microRNA 26b specifically targets lymphoid enhancer factor 1 (Lef-1), which modulates pituitary transcription factor 1 (Pit-1) expression
Zhang Z, Florez S, Gutierrez-Hartmann A, Martin JF, Amendt BA
Center for Environmental and Genetic Medicine, Texas A&M University Health Science Center, Houston, Tex.,USA.
J Biol Chem 2010;285:34718-28.
Background: The authors hypothesized that microRNAs (miRNAs) play a role in pituitary development.
Methods: MicroRNA was isolated from pituitary stem cell lines and hybridized on miRNA arrays to identify pituitary-specific miRNAs. Dicer1 , an endonuclease essential for miRNA maturation, was conditionally knocked out using the Pitx2-Cre mouse, resulting in the loss of mature miRNAs in the anterior pituitary. ChIP assays were used to identify binding partners for lymphoid-enhancing factor 1 (Lef-1).
Results: The Pitx2-Cre/Dicer1 mutant mice demonstrate growth retardation, and the pituitaries are hypoplastic with an abnormal branching of the anterior lobe, thus revealing a role for miRNAs in pituitary development. Growth hormone, prolactin, and thyroid-stimulating hormone ß-subunit expression were decreased in the Dicer1 mutant mouse, whereas proopiomelanocortin and luteinizing hormone ß-sub-unit expression were normal. Pit-1 expression was decreased and Lef-1 expression increased in the mutant mouse pituitary, consistent with the repression of the Pit-1 promoter by Lef-1. Lef-1 directly targets and represses the Pit-1 promoter. MicroRNA-26b (miR-26b) was identified as targeting Lef-1 expression, and miR-26b represses Lef-1 in pituitary and non-pituitary cell lines. Furthermore, miR-26b upregulates Pit-1 and growth hormone expression by attenuating Lef-1 expression in GH3 cells.
Conclusion: MicroRNAs are critical for anterior pituitary development. miR-26b regulates Pit-1 expression by inhibiting Lef-1 expression and may promote Pit-1 lineage differentiation during pituitary development.
MicroRNAs (miRNAs) are short (usually 22 nucleotides), endogenous non-coding ribonucleic acids (RNAs) that post-transcriptionally regulate gene expression by targeting complement mRNA, either in the 3'-UTR, resulting in inhibition of protein production, or in other regions of the mRNA, resulting in mRNA degradation. MiRNAs were identified in the 1990s but their biological significance was not recognized until the 2000s. They are now known to be involved in many physiological and developmental processes, including endocrine processes [ 1 , 2 ]. Zhang et al. beautifully assessed the involvement of miRNA in pituitary development. In line with previous work in adult pituitary [ 3 ], expression of approximately 10 miRNA families was found in the anterior pituitary, including the miR-26 family. Pitx-2 (paired-like homeodomain transcription factor-2) is expressed at an early stage in pituitary development. Dicer is an endonuclease needed for miRNA maturation. Pitx-2-Cre mice and Dicer flox/ flox mice were therefore used to downregulate Dicer and thus mature miRNA in all anterior pituitary cell lines. This resulted in a 20% reduction in size of the mice and severely reduced GH, PRL and TSH-ß expression, suggesting suppressed Pit1 function. Indeed, further studies identified that miR26b represses lymphoid-enhancing factor 1 (Lef-1). Lef-1 represses Pit-1 directly and Lef-1 also binds ß-catenin, a master ‘on-off switch’ in organogenesis, resulting in activation of c-myc and cyclin D1 promoters and proliferation. Physiological reduction of Lef-1 expression by miR-26b may shift more ß-catenin to the Prop1-ß-catenin complex and increase Prop1-specific targets like Pit-1 leading to promotion of cell differentiation.
Regulation of Lef-1 and Pit1 expression by miR-26b adds further complexity to the regulation of pituitary development. miR-26 is only one of multiple miRNA families found in the pituitary, so we are far away from understanding pituitary development. The search is now for perturbations in miRNA expression in pituitary disease. Interestingly, downregulation of miR-26a expression is commonly found in nasopharyngeal tumors and increasing miR-26a expression inhibits their growth and tumorigenesis [ 4 ].
Not so new gene of the year
AIP mutation in pituitary adenomas in the 18th century and today
Chahal HS, Stals K, Unterlander M, Balding DJ, Thomas MG, Kumar AV, Besser GM, Atkinson AB, Morrison PJ,
Howlett TA, Levy MJ, Orme SM, Akker SA, Abel RL, Grossman AB, Burger J, Ellard S, Korbonits M
Department of Endocrinology, Barts and the London School of Medicine, London, UK
N Engl J Med 2011;364:43-50.
Background: Gigantism results when a growth hormone-secreting pituitary adenoma is present before epiphyseal fusion. Mutations in the aryl hydrocarbon-interacting protein (AIP) can be the underlying cause for such adenomas. In 1909, when Harvey Cushing examined the skeleton of an Irish patient who lived from 1761 to 1783, he noted an enlarged pituitary fossa.
Methods: DNA was extracted from the patient's skeleton's teeth and sequenced.
Results: A germline mutation in the aryl hydrocarbon-interacting protein was identified. The same mutation and associated haplotype was present in four contemporary Northern Irish families who presented with pituitary adenomas. Coalescent theory was used and it was inferred that these patients share a common ancestor approximately 57-66 generations ago.
Conclusion: A single mutation in AIP is responsible for the formation of pituitary adenoma in many Irish families. The mutation has been identified in DNA extracted from the tooth of a 200-year-old skeleton of an Irish giant.
Characterization of aryl hydrocarbon receptor-interacting protein (AIP) mutations in familial isolated pituitary adenoma families
Igreja S, Chahal HS, King P, Bolger GB, Srirangalingam U, Guasti L, Chapple JP, Trivellin G, Gueorguiev M, Guegan K, Stals K, Khoo B, Kumar AV, Ellard S, Grossman AB, Korbonits M
Department of Endocrinology, Barts and the London School of Medicine, London, UK.
Hum Mutat 2010;31:950-60.
Background: Familial isolated pituitary adenoma (FIPA) is an autosomal dominant disease with variable genetic background and incomplete penetrance. Germline mutations of the aryl hydrocarbon receptor-interacting protein (AIP) gene have been reported in 15-40% of FIPA patients. Limited data are available on the functional consequences of the mutations or the regulation of the AIP gene.
Methods: Mutations in a large cohort of FIPA families are described and all mutations are characterized using minigene constructs, luciferase and ß-galactosidase assays, as well as in silico predictions.
Results: A promoter showed reduced in vitro activity corresponding to lower mRNA expression in patient samples. Stimulation of the protein kinase A-pathway positively regulates the AIP promoter. Silent mutations led to abnormal splicing resulting in truncated protein or reduced AIP expression. A two-hybrid assay of protein-protein interaction of all missense variants showed variable disruption of AIP-phosphodiesterase-4A5 binding. In addition, it was found that patients with AIP mutations had a lower mean age at diagnosis (23.6 ± 11.2 years) than AIP mutation-negative patients (40.4 ± 14.5 years).
Conclusion: Exonic, promoter, splice-site, and large deletion mutations in AIP are implicated in 31% of families in this large FIPA cohort. Functional characterization of AIP changes is important to identify the functional impact of gene sequence variants.
AIP appears to act as a tumor suppressor gene and normally decreases cell proliferation. Heterozygous germline mutations are found in 15-40% of patients with familial pituitary adenomas, most often somatotroph or somatolactotroph adenomas. The first paper is very interesting from both a scientific and historic point. The skeleton of a 231-cm tall giant, originally from Ireland, is kept at the Huntarian Museum in London. William Harvey examined its skull many years ago and described that the pituitary sella was expanded, suggestive of an adenoma, and in the 1980s a bone age showed epiphyses had not fused, likely due to secondary hypogonadotrophic hypogonadism. Korbonits’ team extracted DNA from the tooth and found a mutation in AIP , which has also been found in other Irish families. Four contemporary acromegalic Irish families carried the same mutation. Microsatellite data and coalescent simulation are techniques that can be used as a retrospective model of genealogies for a sample from a population with a defined demographic history. The demography for the Irish families and the family of the giant were known and well defined. Using this technique it was inferred that a common ancestor that carried the mutation lived approximately 1,400-1,650 years ago.
The second paper is impressive because it examines the functional consequences of all mutations in AIP described so far, including promoter mutations and splicing mutations, and also describes six new mutations. Importantly, some missense mutations did not have functional consequences and may therefore not be related to the phenotype. This emphasizes the need to assess functional consequences of sequence variants before they can be assumed to be disease-causing mutations. Very little information is available about regulation of the promoter of AIP and these studies also revealed that cAMP-PKA signaling is a positive regulator of the promoter. The paper also highlights the need for Multiplex Ligation-dependent Probe Amplification (MLPA) analysis, used to detect copy number changes, to exclude AIP deletions in the work-up of families with GH adenoma. Some patients with familial adenomas may present in childhood, and this is therefore important knowledge for pediatric endocrinologists.
New paradigm - Pit-1 in breast cancer
Deregulation of the Pit-1 transcription factor in human breast cancer cells promotes tumor growth and metastasis
Ben-Batalla I, Seoane S, Garcia-Caballero T, Gallego R, Macia M, Gonzalez LO, Vizoso F, Perez-Fernandez R
Department of Physiology, University of Santiago de Compostela, Santiago de Compostela, Spain.
J Clin Invest 2010;120:4289-302.
Background: The transcription factor PIT-1 plays a critical role in cell differentiation during organogenesis of the anterior pituitary in mammals. Expression of PIT-1 however has also been reported in human breast cancer cells. Here the authors investigate the role of PIT-1 in breast cell tumorigenesis and metastasis.
Methods: Human breast cancer cell lines were used to overexpress and knock down PIT-1 to assess in vitro effect on cell migration, BrdU incorporation, apoptosis and epithelial-mesenchymal transition. SCID mice, injected with PIT-1-positive or PIT-1-negative breast cells, were used to assess the in vivo effect of PIT-1 on tumor growth and metastasis. Human breast cancer biopsies were rated for PIT-1 immunostaining to assess a correlation between PIT-1 expression and prognostic factors.
Results: PIT-1 overexpression or knock down in human breast cancer cells induced profound changes in the expression of proteins involved in cell proliferation, apoptosis, and invasion. Some of these protumorigenic effects of PIT-1 were mediated by upregulation of SNAI1, known to induce epithelial-mesenchymal transition. In immunodeficient mice, Pit-1 overexpression induced tumor growth and promoted pulmonary metastasis. In patients with invasive ductal carcinoma of the breast and lymph node-positive tumor, high expression of PIT-1 was significantly correlated with SNAI1 positivity. Notably, in these patients, elevated expression of PIT-1 was significantly and independently associated with the occurrence of distant metastasis.
Conclusion: PIT-1 is able to regulate tumorigenesis and metastasis of breast cancer cells. The findings may suggest that PIT-1 could be used as a marker to help define the prognosis in patients with node-positive breast cancer and may represent a new therapeutic target.
PIT-1 plays a vital role in the development of progenitor cells into GH-, PRL- and TSH-producing cells in the pituitary. PIT-1 however is also expressed in placenta, lymphoid tissue and breast tissue. It is not known whether PIT-1 also has a role in the development of progenitors in those tissues, either during physiological or pathological growth. Physiological embryonic organ growth and tumorigenesis/ metastasis have many features in common. For metastases to occur, epithelial cells need to break their intercellular adhesion complexes and change from immobile epithelial cells to mobile mesenchymal cells. Epithelial to mesenchymal transition (EMT) is a known mechanism for carcinoma progression, whereas EMT as well as mesenchymal to epithelial transition (MET) play physiological roles in organ development. Several transcription factors involved in EMT during embryonic development, like TWIST, SNAI1, GOOSECOID and SIX-1, are also involved in metastatic processes. The paper by Ben-Batilla et al. shows strong evidence that PIT-1 upregulation in breast cells promotes tumor growth and metastasis. The authors used multiple experimental designs to assess the role of PIT-1 in breast cell tumors. Overexpression and knock down of PIT-1 in the mammary adenocarcinoma cell line MCF-7 revealed that PIT-1 regulates cell proliferation and apoptosis, an increase in PIT-1 expression resulting in increased proliferation, reduced apoptosis and increased cell motility. Markers for adhesion, like E-cadherin, were decreased, and anti-apoptotic factors like BCL2 and cyclin D2 were increased after transfection with PIT-1 . Knock down of PIT-1 in a metastatic breast cancer cell line reduced invasion and migration by an impressive 90%. SCID mice, injected with PIT-1 overexpressing MC7 cells, but not mice injected with control MCF-7 cells, developed tumors and metastases, whereas reduction of Pit-1 expression in mice injected with metastatic breast cancer cells resulted in a reduction of metastasis.
The authors showed that PIT-1 expression is also of importance in human breast cancer since a strong correlation existed between the intensity of PIT-1 in tumor tissue and survival, as established with Kaplan-Meier curves.
This work is not only of interest because it relates an important transcription factor to both normal embryonic organ growth and abnormal tumor growth, but is also important for the care of patients with breast cancer as it may pave the way for the development of a new prognostic marker as well as a new therapeutic target. The possibility of directly targeting Pit-1 has been opened by a recent in vitro study, showing a direct inhibition of the DNA-binding activity of Pit-1 by a small molecule (DB293) [ 5 ].
New concept - important for clinical practice
Adult combined GH, prolactin, and TSH deficiency associated with circulating PIT-1 antibody in humans
Yamamoto M, Iguchi G, Takeno R, Okimura Y, Sano T, Takahashi M, Nishizawa H, Handayaningshi AE, Fukuoka H, Tobita M, Saitoh T, Tojo K, Mokubo A, Morinobu A, Iida K, Kaji H, Seino S, Chihara K, Takahashi Y
Division of Diabetes and Endocrinology, Kobe University Graduate School of Medicine, Kobe, Japan
J Clin Invest 2011;121:113-9.
Background: A genetic defect in the PIT-1 gene results in congenital growth hormone (GH)-, prolactin (PRL)-, and thyroid-stimulating hormone (TSH) deficiency but antibody-related combined GH, PRL and TSH deficiency has not been described.
Methods and Results: Three cases of adult-onset combined GH-, PRL-, and TSH deficiencies were investigated. The endocrine phenotype in each was linked to autoimmunity directed against the PIT-1 protein. Anti-PIT-1 antibody as well as other autoantibodies were detected in the patients’ sera. An ELISA-based screening revealed that the antibody was highly specific to the disease and absent in control subjects. Immunohistochemical analysis showed that PIT-1-, GH-, PRL-, and TSH-positive cells were absent in the pituitary of 1 of the patients, who also had a range of autoimmune endocrinopathies and fulfilled the criteria for autoimmune polyendocrine syndrome (APS). However, the main manifestations of APS-I - hypoparathyroidism and Candida infection - were not observed and the pituitary abnormalities were different from the hypophysitis associated with APS.
Conclusion: The patients described define a unique ‘anti-PIT-1 antibody syndrome’, related to APS.
Autoimmune polyendocrinopathy syndrome can be divided into three groups: (1) APS-I caused by defects in the AIRE gene, (2) X-linked IPEX syndrome (immune dysfunction, polyendocrinopathy, X-linked), due to FOXP3 mutations, and (3) APS-II, which includes overlapping groups of disorders. Hypophysitis can be part of the syndrome and several antigens including GH, α-enolase and tudor domain containing protein-6 (TDRD-6) have been proposed as candidate antigens. Three patients are described with GH, PRL and TSH deficiency and features of autoimmune disease including IDDM and atrophic gastritis, but without mutations in PIT-1, PROP1 and HESX1. When the sera of the patients were used as primary antibodies, a band the size of PIT-1 was detected in lysates from pituitary and GH3 cells, whereas control sera did not. Patient's sera also detected PIT1-positive cells in immunohistochemistry in pituitary slices. Autopsy in 1 of the patients shows typical lymphocytic infiltrates in multiple tissues including the pituitary and absence of specifically the GH-, PRL- and TSH-producing cells. The authors postulate that the pituitary pathology is different from the hypophysitis described in APS, partly because MRI did not show an enlarged pituitary. Antibodies against PIT-1 have not been described before and are unusual, since PIT-1 is a nuclear antigene, and further analysis is therefore needed to elucidate the mechanism. The authors propose that this is a novel anti-APS-related syndrome and have named it anti-PIT-1-antibody syndrome.
Pituitary magnetic resonance imaging for sellar and parasellar masses: 10-year experience in 2,598 patients
Famini P, Maya MM, Melmed S
Departments of Medicine and Imaging, Pituitary Center, Cedars Sinai Medical Center, Los Angeles, Calif.,USA.
J Clin Endocrinol Metab 2011;96:1633-41.
Background: The presentation of sellar and parasellar masses can vary enormously. Patients can be asymptomatic or present with symptoms resulting from mild hormone anomalies to local compression effects of the tumor mass. Pituitary masses are diagnosed with increased frequency due to increased availability and advances of magnetic resonance imaging (MRI), but indications and diagnostic outcomes of MRI screening for sellar lesions are not defined. Pituitary adenomas are the most frequently encountered sellar mass lesions in adults, but other etiologies should be considered in the differential diagnosis.
Methods: The study retrospectively reviewed 2,598 subjects that had had at least one pituitary MRI scan from 1999 to 2009 in a single tertiary pituitary center. Prevalence and diagnosis of specific sellar and parasellar masses as screened by pituitary MRI were assessed.
Results: Hyperprolactinemia and hypogonadism were the most common indications for pituitary imaging (excluding known mass follow-up). 47% of subjects had a normal pituitary gland. Prolactinoma (40%), non-functioning adenoma (37%), and GH adenoma (13%) were the most common pituitary adenomas initially identified by MRI. Non-adenomatous sellar masses accounted for 18% of visible lesions, of which the most common were Rathke's cleft cyst (19%), craniopharyngioma (15%), and meningioma (15%). Metastases accounted for 5% of non-pituitary lesions and breast cancer was the most common primary source.
Conclusions: Nearly half of all pituitary MRI scans performed in a large adult population were reported as normal. Non-adenomatous pituitary lesions should be considered in the diagnosis of sellar masses, and a high clinical suspicion is required to exclude the presence of a non-functioning pituitary adenoma.
The incidence of clinically active pituitary adenomas is 1:1,000-1,250, and in autopsies pituitary adenomas have been reported in as much as 1.5-27% of people. Over the last decade, the incidence of pituitary adenomas has increased substantially, at least partly due to an increase in incidental detection using advanced MRI techniques. This paper describes an enormous case series, likely the largest to date, of MRIs of patients with sellar and parasellar masses.
The most common indication for MRI was follow-up of a known mass, followed by endocrinological work-up (most commonly for hyperprolactinemia, suspected Cushing's disease or hypogonadism), followed by neurological symptoms (most commonly headaches and visual loss/blur). Approximately half the MRIs were normal. Of the identified sellar and parasellar masses, approximately 10% could not be diagnosed, and approximately 75% were pituitary prolactinomas and non-functioning adenomas (40% prolactinomas), The remaining 18% were mostly Rathke's cysts, craniopharyngiomas and meningiomas (19, 15 and 15% respectively) and the remainder was due to an extremely wide variety of rare abnormalities, including metastases and not further defined pituitary hyperplasia, apoplexy, lymphoma and even syphilis (see table 1 ). The 282 incidentalomas were most often nonfunctioning adenomas (117), followed by Rathke's cyst (22), craniopharyngioma (15) and meningiomas (18). Even though the incidence and etiology of sellar masses in children is different compared to adults, this study is of value for pediatricians. It will not be possible to build a similarly large patient cohort in children, and many of the rare pituitary abnormalities reported in this study, may be found in children. Sellar and parasellar masses are rare in children but like in adults, incidentalomas are becoming more common. Physiological pituitary enlargement during puberty complicates assessment of pathology and decisions regarding the need for intervention in children and young people with sellar masses. This paper may help with some of the diagnostic dilemmas.
Table 1. Diagnoses in 2,598 patients who underwent pituitary MRI [adapted from Famini et al.: J Clin Endocrinol Metab 2011;96:1633-1641]
Total number a
Pathological dx available b
Anterior pituitary tumors
Non-functioning adenoma
GH adenoma
ACTH adenoma
GH/prolactin mixed adenoma
Nelson's syndrome
Pituitary carcinoma
LH/FSH functioning adenoma
TSH adenoma
GH/TSH mixed adenoma
Rathke's cleft cyst
Pineal cyst
Non-adenomatous neoplasms
Pituitary lymphoma
Embryonal rhabdomyosarcoma
Granular cell tumor
Hemangiopericytoma, malignant
Mucoepidermoid carcinoma
Inflammatory and vasculitides
Lymphocytic hypophysitis
Hypophysitis, unspecified type
Lymphocytic infundibulitis
Amyloidosis, primary
Wegener's granulomatosis
Pseudomonas aeruginosa
CNS lymphoma, to pituitary stalk
Nasopharyngeal lymphoma
Liver epitheliod hemangioendothelioma
Lung, adenocarcinoma
Pineal germinoma/dysgerminoma
Prostate, adenocarcinoma
Sinusoidal squamous cell carcinoma
Apoplexy with masses
Carotid aneurysm
Hypothalamic cavernous angioma
Hypothalamic interpeduncular hematoma
Empty sella
Ectopic pituitary gland
Fibrous dysplasia
Undiagnosed masses
Normal pituitary
1, 242
a Number of patients.
b Number of histopathologically confirmed diagnosis.
Diagnosis and treatment of hyperprolactinemia: an Endocrine Society clinical practice guideline
Melmed S, Casaneuva FF, Hoffman AR, Kleinberg DL, Montori VM, Schlechte JA, Wass JAH
Cedars Sinai Medical Center, Los Angeles, Calif.,USA.
Background: The aim of this work was to formulate a practical guideline for the diagnosis and treatment of hyperprolactinemia in adults.
Methods: A Task Force developed the guideline using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system describing both the strength of recommendations and the quality of evidence.
Results: Consensus was met to present evidence-based approaches to assessing the cause of hyperprolactinemia, treating drug-induced hyperprolactinemia, and managing prolactinomas in pregnant and non-pregnant patients. Indications and side effects of drugs used in the treatment of prolactinoma are discussed.
Conclusion: Guidelines are presented for the diagnosis and treatment of patients with elevated prolactin concentrations.
This work was the joint effort of the Endocrine Society, European Society for Endocrinology and The Pituitary Society. The guideline is written and intended for adult patients and adult endocrinologists, but it contains interesting points for pediatric endocrinologists. The guideline recommends the use of dopamine agonist therapy to lower prolactin concentrations, decrease tumor size and restore gonadal function and specifically recommends cabergoline rather than bromocriptine because of its higher efficacy and fewer side effects. Follow-up should include regular prolactin measurements, a repeat MRI in 1 year (or in 3 months in patients with macroprolactinoma) and visual-field examinations. Cessation of treatment is a difficult issue, also in pediatric patients. The guideline suggests that with careful clinical follow-up, therapy may be tapered and stopped after 2 years of treatment if prolactin concentrations have normalized and no tumor remnant is visible on MRI. The guideline also recommends surgical intervention only for those that fail to respond to increased doses of cabergoline, and this may not be common practice in pediatrics. Interestingly, the guideline recommends first-line cabergoline treatment for all patients independent of tumor size or chiasmal impingement, factors that may be taken into consideration in pediatric prolactinomas. Radiotherapy is reserved for those who fail surgical treatment or harbor aggressive or malignant prolactinomas. Maybe this guideline can be used to assess and review the management of pediatric prolactinomas in various centers.
New genes - Usp39 and Numb in pituitary development
Zebrafish usp39 mutation leads to rb1 mRNA splicing defect and pituitary lineage expansion
Rios Y, Melmed S, Lin S, Liu NA
Department of Molecular, Cell, and Developmental Biology, UCLA, Los Angeles, Calif.,USA.,
PLoS Genet 2011;7:e1001271.
Background: Loss of retinoblastoma ( Rb ) tumor suppressor function is associated with human malignancies. Molecular and genetic mechanisms responsible for tumorigenic Rb downregulation are not fully defined.
Methods and Results: Forward genetic screening and positional cloning was used to search for genes involved in pituitary homeostasis in zebrafish. This led to the identification of ubiquitin-specific peptidase 39 ( usp39 ), the human homolog of which encodes a component of RNA splicing machinery. Zebrafish usp39 mutants exhibit microcephaly and adenohypophyseal cell lineage expansion of POMC cells without apparent changes in major hypothalamic signals. Gene expression profiling of usp39 mutants revealed decreased rb1 and increased e2f4, rbl2 (p130), and cdkn1a (p21) expression. Rb1 mRNA overexpression, or antisense morpholino knock down of e2f4 , partially reversed embryonic pituitary expansion in usp39 mutants. Analysis of pre-mRNA splicing status of critical cell cycle regulators showed misspliced Rb1 pre-mRNA resulting in a premature stop codon, likely due to abnormal RNA splicing machinery.
Conclusion: These studies unravel a novel mechanism for rb1 regulation by a neuronal mRNA splicing factor, usp39. Zebrafish usp39 regulates embryonic pituitary homeostasis by targeting rb1 and e2f4 expression, respectively, contributing to increased adenohypophyseal sensitivity to these altered cell cycle regulators. These results provide a mechanism for dysregulated rb1 and e2f4 pathways that may result in pituitary tumorigenesis.
Previous studies have shown that retinoblastoma ( Rb )+/- mice develop pituitary adenomas, however RB1 mutations have not been found in human pituitary tumors. In this study, a novel genetic pathway was uncovered that may lead to Rb downregulation through RNA splicing mediated by usp39 , a gene involved in assembly of the spliceosome. A forward genetic study in zebrafish, using ENU-induced mutagenesis, showed that loss of usp39 resulted in aberrant rb1 mRNA splicing, which likely caused elevated expression of its target e2f4 , a key regulator known to have oncogenic activity when overexpressed. The authors showed that e2f4 upregulation is a main factor responsible for the adenohypophyseal cell lineage hyperplasia observed in the zebrafish usp39 mutant. This work has revealed a new mechanism for the regulation of zebrafish rb1 by the mRNA splicing factor usp39 , specifically expressed in the brain, pituitary and eyes. Loss of usp39 results in dysregulation of rb1 and e2f4 leading to loss of pituitary cell homeostasis. Human USP39 may play a similar role in human pituitary development or tumorigenesis.
Numb deletion in POMC-expressing cells impairs pituitary intermediate lobe cell adhesion, progenitor cell localization, and neuro-intermediate lobe boundary formation
Moran TB, Goldberg LB, Serviss SL, Raetzman LT
University of Illinois at Urbana-Champaign, Urbana, Ill.,USA.
Mol Endocrinol 2011;25:117-27.
Background: Formation of pituitary hormone-secreting cells during development relies on Notch signaling to prevent progenitors from prematurely differentiating. Tight regulation of Notch activity is important for cell fate determination in progenitor cells, including, potentially, stem cells. The nature of the signal curtailing Notch signaling in the pituitary is unknown, but a good candidate is the endocytic adaptor protein NUMB, which acts as a Notch antagonist. The adaptor protein NUMB was first identified as a mediator of asymmetric cell division in Drosophila . NUMB targets Notch for proteolytic degradation, but it also has a broad range of actions, including stabilizing adherens junctions through interactions with cadherins and influencing cell proliferation by stabilizing expression of the tumor suppressor protein p53.
Methods: In situ hybridization on embryonic and adult mouse pituitaries was performed. Numb and its homolog Numblike were conditionally deleted using Pomc-Cre mice and Numb and Numblike floxed mice.
Results: NUMB and NUMBLIKE are expressed in undifferentiated cells during development and later in gonadotropes, and melanotropes in the intermediate lobe. Conditionally deleting Numb and Numblike in the intermediate lobe melanotropes with Pomc-Cre mice led to disruption of the border between the posterior and intermediate lobe and mixing of AVP-axon terminals and POMC cells. The mice also had disorganized progenitor cells, marked by SOX2, and impaired localization of adherens junction proteins. Interestingly, Notch signaling was unaffected.
Conclusion: Numb is critical for maintaining cell-cell interactions in the pituitary intermediate lobe that are essential for proper cell placement, at least partly independent of Notch.
This is an interesting study investigating the roles of the proteins NUMB and NUMBLIKE in pituitary development. The Notch signaling pathway is critical for early pituitary formation, but becomes largely undetectable after E14.5 in the mouse, and can only be found in isolated pituitary stem cells. NUMB is believed to play a role in the regulation of Notch signaling, however these studies also reveal a NOTCH-independent role for NUMB. In the postnatal pituitary, NUMB staining was observed in gonadotropes as well as sporadically in the intermediate lobe of the pituitary. The authors show that loss of NUMB in the mouse intermediate lobe melanotropes dramatically altered cell adhesion and progenitor cell localization, and results in posterior and intermediate lobe cell intermixing, identifying NUMB and NUMBLIKE as putative regulatory proteins during early pituitary development as well as during adulthood.
NUMB affects p53 degradation and can both promote and inhibit progenitor cell division, and also controls epithelial- to mesenchymal-like transitions and alters cell migration; it is therefore not surprising that loss of NUMB is associated with a number of cancers. Keeping in mind the role of Notch proteins in cancer and pituitary adult stem cell maintenance, studies such as these will illuminate further the increasing links between cancer and development.
New mutations - SOX3 and GLI2 in hypopituitarism
Increased transactivation associated with SOX3 polyalanine tract deletion in a patient with hypopituitarism
Alatzoglou KS, Kelberman D, Cowell CT, Palmer R, Arnhold IJ, Melo ME, Schnabel D, Grueters A, Dattani MT
Developmental Endocrinology Research Group, Clinical and Molecular Genetics Unit, University College London
Institute of Child Health, London, UK.
J Clin Endocrinol Metab 2011;96:E685-90.
Background: Correct gene dosage of SOX3 is critical for the development of the hypothalamo-pituitary axis. Previous studies have shown that overdosage of SOX3 , as a result of gene duplication, and loss of function resulting from expansion of the first polyalanine (PA) tract (p.A234_A235ins11, referred to as_+11PA; p.A240_A241ins7, +7PA) are associated with variable degrees of hypopituitarism, with or without mental retardation. A single in-frame deletion (p.A240_A248del9, del9PA) has been described in 2 brothers with mental retardation but without a clearly defined pituitary phenotype; the significance of this finding was unknown because functional studies were not performed and the deletion was also observed in the unaffected maternal grandfather. Sox3 null mutant animals have a variable phenotype, showing poor growth, craniofacial defects, and variable endocrine deficits. They have a small anterior pituitary with additional clefts and dysgenesis of the corpus callosum. The aim of this study was to further investigate the contribution of SOX3 in the etiology of hypopituitarism and the mechanisms involved in the phenotypic variability.
Methods: 154 patients with congenital hypopituitarism and an undescended posterior pituitary were screened for mutations in SOX3 and variability in the length of the first PA tract. In addition, 300 patients with variable septo-optic dysplasia were screened for variability of the PA tract.
Results: A novel 18-base-pair deletion (p.A243_A248del6, del6PA) was identified in a female patient with hypopituitarism resulting in a twofold increase in transcriptional activation in vitro, compared with wild-type SOX3; the del9PA was also associated with a similar increase in transcriptional activation. The paper also reports a previously identified 7-alanine expansion (p.A240_A241ins7, +7PA) in 2 male siblings with isolated GH deficiency and a distinct phenotype, in addition to the non-synonymous variant p.R5Q in an unrelated individual; this appears to have no functional effect on the protein. In contrast to +7PA, del6PA and del9PA maintained their ability to repress ß-catenin-mediated transcription in vitro.
Conclusion: This is the first study to report that PA tract deletions associated with hypopituitarism have functional consequences in vitro, possibly due to increased activation of SOX3 target genes. In addition, the phenotypic spectrum associated with PA tract expansion (+7PA) mutations has now expanded to include panhypopituitarism or isolated GH deficiency, with or without mental retardation.
This study describes a novel mechanism of hypopituitarism associated with SOX3 mutations, namely increased transcriptional activation associated with deletion within a polyalanine tract. The phenotype is also novel, with an enlarged anterior pituitary in association with a normally descended posterior pituitary; previous mutations have been associated with anterior pituitary hypoplasia in association with an undescended posterior pituitary. The increased transactivation may reflect a gain in function, which is reminiscent of the SOX3 duplications associated previously with hypopituitarism. The presence of a phenotype associated with an X-linked gene in a female patient is intriguing and counterintuitive; however, Rizzoti et al. [ 6 ] have previously shown the presence of structural defects in the hypothalamo-pituitary region and abnormal pouch morphology in 3 of 4 female adult XX; Sox3/gfp mice without growth failure, reflecting incomplete penetrance of a hypothalamo-pituitary phenotype in females. The paper also underlines the considerable phenotypic variability observed with SOX3 mutations, particularly with respect to the extent of hormonal deficiencies and learning difficulties.
Novel heterozygous nonsense GLI2 mutations in patients with hypopituitarism and ectopic posterior pituitary lobe without holoprosencephaly
Franca MM, Jorge AA, Carvalho LR, Costalonga EF, Vasques GA, Leite CC, Mendonca BB, Arnhold IJ
Laboratorio de Hormonios e Genetica Molecular, Disciplina de Endocrinologia, Hospital das Clinicas da Faculdade de
Medicina da Universidade de São Paulo, São Paulo, Brazil.
J Clin Endocrinol Metab 2010;95:E384-91.
Background: GLI2 is a transcription factor downstream in sonic hedgehog signaling, acting early in ventral forebrain and pituitary development. Previously, GLI2 mutations were reported in patients with holoprosencephaly and pituitary abnormalities. This paper reports three novel frameshift/nonsense GLI2 mutations and the phenotypic variability in the three families.
Methods: The GLI2 coding region of patients with isolated GH deficiency (IGHD) or combined pituitary hormone deficiency was amplified by PCR using intronic primers and was sequenced.
Results: Three novel heterozygous GLI2 mutations were identified: c.2362_2368del p.L788fsX794 (family 1), c.2081_2084del p.L694fsX722 (family 2), and c.1138 G>T p.E380X (family 3). All predict a truncated protein with loss of the C-terminal activator domain. The index case of family 1 had polydactyly, hypoglycemia with seizures, developmental delay, short stature and absence of puberty with GH, TSH, prolactin, ACTH, LH, and FSH deficiencies. Her mother and 7 relatives harboring the same mutation had polydactyly, including 2 uncles with IGHD and 1 cousin with GH, TSH, LH, and FSH deficiencies. In family 2, a boy had cryptorchidism, cleft lip and palate, and GH deficiency. In family 3, a girl had hypoglycemia, seizures with developmental delay, poor growth, excessive thirst and polyuria, and GH, ACTH, TSH, and antidiuretic hormone deficiencies. Magnetic resonance imaging of 4 patients with GLI2 mutations and hypopituitarism showed a hypoplastic anterior pituitary and an ectopic or undescended posterior pituitary lobe without holoprosencephaly. In family 3, MRI showed anterior pituitary hypoplasia with a non-visualized posterior pituitary.
Conclusion: Three novel heterozygous frameshift or nonsense GLI2 mutations, predicting truncated proteins lacking the activator domain, are partly penetrant and associated with IGHD or combined pituitary hormone deficiency and an ectopic/undescended posterior pituitary without holoprosencephaly.
Direct and indirect requirements of Shh/Gli signaling in early pituitary development
Wang Y, Martin JF, Bai CB
Department of Genetics, Case Western Reserve University, Cleveland, Ohio,USA.
Dev Biol 2010;348:199-209.
Background: Oral ectoderm-derived sonic hedgehog (Shh) is required for specification and/or proliferation of early pituitary progenitors. Shh signaling is mediated by the Gli transcription factors, Gli1, Gli2, and Gli3. Gli2 is the major activator of Shh signaling, and previous studies have revealed a variable loss of the pituitary in Gli2 mutants at E12.5 [ 7 ]. However, the mechanism of action whereby different Gli genes mediate Shh signaling to control pituitary progenitor development has not yet been determined.
Methods: Pituitary-specific Gli mutant embryos were generated, using either the FoxG1Cre or Pitx2Cre . FoxG1 is expressed initially in the anterior neural ridge and in the early telencephalon, whereas Pitx2 is largely expressed in the anterior pituitary. Gli2 mosaic mutant embryos were also generated.
Results: Gli2 is required for proliferation of specific groups of pituitary progenitors but not for initial dorsoventral patterning. Most Gli2 -/- embryos showed smaller pituitaries than the wild-type mice, with a reduction in corticotropes, somatotropes and lactotropes. Rathke's pouch and the infundibulum were morphologically normal but contained fewer cells, suggesting a requirement for Gli2 for cell proliferation in both anterior and posterior pituitary. Gli1 and Gli3 mutants had no pituitary phenotype, suggesting that Gli2 is the primary Gli transcription factor in the pituitary. Gli2/Gli3 double mutants, in which there is also loss of expression of Gli1, completely lack a pituitary. Conditional transgenesis using an active form of Smo resulted in an increase in cell proliferation in the anterior dorsal region of Rathke's pouch, and at E14.5, the pituitaries were much bigger than in WT controls, confirming a role for Shh in proliferation. Lastly, Shh/Gli2 signaling controlled the diencephalic expression of bone morphogenetic protein 4 (Bmp4) and fibroblast growth factor 8 (Fgf8), two genes known to play critical roles in patterning and growth of Rathke's pouch. In keeping with these data, all Gli2 mutants had no posterior pituitary.
Conclusion: The results suggest both cell-autonomous and non-cell-autonomous requirements for Gli2 in regulation of pituitary progenitor specification, proliferation and differentiation.
These two papers by Franca et al. and Wang et al. shed novel insights on the role of GLI2 in normal hypothalamo-pituitary development in mouse and human. Wang et al. report a series of murine mutants and show that Gli2 loss of function is associated with variable pituitary hypoplasia of the anterior pituitary with absence of the posterior pituitary. The patterning of the pituitary in the conditional mutants is normal, but there is a clear proliferation defect. Removal of Gli2 function at an early stage using the FoxG1Cre leads to an abnormal pituitary phenotype whereas later removal using Pitx2Cre does not affect the pituitary, suggesting a critical window of Shh/Gli2 signaling in the control of pituitary progenitors. Gli2 is also implicated in the development of the posterior pituitary and this effect is probably mediated via effects on Bmp4 and Fgf8 expression in the diencephalon, both of which are expressed at a markedly reduced level in Gli2 mutants. These data therefore indicate a requirement for Shh/Gli2 at two levels of hypothalamo-pituitary development, namely within Rathke's pouch to promote proliferation of pituitary progenitors, and secondly within the ventral diencephalon to control early patterning of Rathke's pouch by regulating Bmp4 and Fgf8 expression.
How can one reconcile the human phenotypes associated with GLI2 mutations with those observed in the mouse? Previous studies [ 8 ] have reported the association of hypopituitarism with complex midline abnormalities in the form of holoprosencephaly in patients with GLI2 mutations. Five patients with variable hypopituitarism ranging from isolated GHD to panhypopituitarism were described; of the 3 with panhypopituitarism, all had an absent pituitary although it is unclear whether this included both the anterior and posterior lobes. The endocrine phenotypes were variably penetrant and were not described in detail, and indeed, 2 patients were deceased and no genetic confirmation was possible. Franca et al. describe three families that have variably penetrant hypopituitary phenotypes. Interestingly, apart from a cleft palate in the proband in family 2, none of the other patients had midline defects although polydactyly, previously also reported by Roessler et al. [ 8 ], was present in family 1. Four of the 5 patients in this second study had an undescended or ectopic posterior pituitary, and 1 patient had an absent posterior pituitary. None had a completely absent pituitary. This is the first description of a patient with both anterior and posterior pituitary hormone deficiencies in the absence of any midline defects, confirming the findings of Wang et al. that Gli2/GLI2 is required for the formation of both the anterior and posterior pituitary. Interestingly, the parents of the probands in both family 2 and family 3 who transmitted the mutations were unaffected. The authors suggest that the variable penetrance may be due to the impact of environmental factors or possibly a digenic effect whereby mutations in other genes may be contributory to the phenotype.
These two papers add a new player to be considered when screening children with hypopituitarism for genetic mutations. The field of hypothalamo-pituitary development is becoming increasingly complex. Studies such as these help in putting together the jigsaw pieces.
Concept revised
Birth dating studies reshape models for pituitary gland cell specification
Davis SW, Mortensen AH, Camper SA
Department of Human Genetics, University of Michigan, Ann Arbor, Mich.,USA.
Dev Biol 2011;352:215-27.
Background: The intermediate and anterior lobes of the pituitary gland are derived from an invagination of oral ectoderm that forms Rathke's pouch at E9.5. The overlying neural ectoderm then evaginates to form the infundibulum, from which the posterior pituitary and pituitary stalk will derive, which comes into direct contact with Rathke's pouch. The juxtaposition of Rathke's pouch and the diencephalon is maintained throughout the early stages of pituitary organogenesis. This close relationship is required for tissue interactions between neural and oral ectoderm which are critical for the initial stages of pituitary specification. During gestation, proliferating progenitor cells are enriched around the pouch lumen, and they appear to delaminate as they exit the cell cycle and differentiate. During late mouse gestation and the postnatal period, anterior lobe progenitors re-enter the cell cycle and expand the populations of specialized, hormone-producing cells. At birth, all cell types are present, and their localization appears stratified based on cell type. Current models of cell specification in the anterior lobe suggest that opposing gradients of FGF and BMP signaling pattern the progenitor cells within Rathke's pouch before they move on to the anterior lobe where they differentiate.
Methods: The authors conducted a birth dating study of Rathke's pouch derivatives to determine whether the location of specialized cells at birth is correlated with the timing of cell cycle exit. Pregnant mice were injected with BrdU on each embryonic day of development between E9.5 and E17.5. All embryos were collected at E17.5, and immunohistochemistry performed on pituitary sections.
Results: The authors report that all of the anterior lobe cell types initiate differentiation concurrently with a peak between E11.5 and E13.5. Differentiation of intermediate lobe melanotropes is delayed relative to anterior lobe cell types. Specialized cell types were not grouped together based on birth date, and are dispersed throughout the anterior lobe.
Conclusion: The apparent stratification of specialized cells at birth is not correlated with cell cycle exit, thereby indicating that the currently popular model of cell specification, dependent upon timing of extrinsic, directional gradients of signaling molecules such as FGF8 and BMP4, needs revision. The authors propose that signals intrinsic to Rathke's pouch are necessary for cell specification between E11.5 and E13.5 and that cell-cell communication likely plays an important role in regulating this process.
This is an intriguing study that sets out to challenge the current dogma of pituitary cell specification, using simple yet elegant experiments. The authors show by using BrdU injections into mice, that the pattern of cell specification that results in the rostral location of gonadotropes, the caudal location for somatotropes and a more intermediate location for corticotropes and thyrotropes, does not appear to be the result of an ordered cell cycle exit. All anterior lobe cell types appear to begin the differentiation process concurrently (E11.5-E14.5), rather than in a temporally discrete manner. The authors put forward a persuasive argument against the currently held belief that opposing BMP and FGF gradients are responsible for specification and stratification of the various cell types within the anterior pituitary. Both Bmp2 and its intracellular transducers the phosphoSMAD proteins (pSMAD) are expressed throughout Rathke's pouch by E11.5. This expression pattern persists until E13.5, after which time there is a decrease in pSMAD intensity. Similarly, the phosphorylation status of MAPK (pMAPK), an intracellular mediator of FGF signaling, was used to examine FGF signaling within the pouch. Although pMAPK immunoreactivity was enriched on the dorsal side of the pouch at E10.5, adjacent to the developing infundibulum where Fgf8 and Fgf10 are expressed, by E11.5 pMAPK expression had decreased and was undetectable from E12.5 to E14.5. Hence, although gradients of Bmp and Fgf signaling are present at E10.5, thereafter, during the period when anterior lobe cell types exit the cell cycle between E11.5 and E13.5, BMP signaling is found throughout Rathke's pouch and FGF signaling cannot be detected.
This study challenges existing beliefs, but also raises the important question of what determines the formation of cell type-specific networks within the pituitary gland, which are increasingly important for normal function [ 9 , 10 ]. The authors of this study suggest that active movements of cells to preferred locations are necessary to establish cell type-specific networks.
Follow-up on Yearbook 2010 - HES1 in pituitary development
The Notch effector gene Hes1 regulates migration of hypothalamic neurons, neuropeptide content and axon targeting to the pituitary
Aujla PK, Bora A, Monahan P, Sweedler JV, Raetzman LT
University of Illinois at Urbana-Champaign, Urbana, Ill.,USA.
Dev Biol 2011;353:61-71.
Background: Proper development of the hypothalamic-pituitary axis requires precise neuronal signaling to establish a network that regulates homeostasis. The developing hypothalamus and pituitary utilize similar signaling pathways for differentiation in embryonic development. Magnocellular neurons located in the paraventricular nuclei (PVN) and the supraoptic nuclei (SON) release arginine vasopressin (AVP) and oxytocin (OT) from their axonal terminals within the posterior lobe of the pituitary. The hypothalamic anterior periventricular (aPV) nucleus contains parvocellular somatostatin (SS)-releasing neurons. Several signaling molecules and transcription factors have been implicated in the formation of hypothalamic neurons. The Notch signaling effector gene Hes1 is present in the developing hypothalamus and pituitary and is required for proper formation of the pituitary. In this paper, the authors hypothesized that Hes1 is necessary for the proper formation, migration and projection of AVP and SS neurons to the pituitary.
Methods: The hypothalamus and pituitary of Hes1 null mice were analyzed using immunohistochemistry, quantitative real-time PCR, and mass spectrometry.
Results: Hes1 null mice showed no significant difference in cell proliferation or death in the developing diencephalon during early development. By E16.5, AVP cell bodies were formed in the SON and PVN, but were abnormally placed and by E18.5 also exhibited abnormal axonal projection. GAD67 immunoreactivity was ectopically expressed, which may contribute to cell body misplacement. Hes1 null pituitaries also had aberrant SS peptide, which correlated with abnormal SS cells in the pituitary and misplaced SS axon tracts. Additionally, POMC and α-MSH were not detected in Hes1 null mutants, in accordance with previous data suggesting a lack of specification of POMC cells in the intermediate lobe.
Conclusion: The data indicate that Notch signaling and Hes1 facilitate the migration and guidance of hypothalamic neurons, as well as neuropeptide content.
Although much is known about pituitary development in the mouse and human, little is known about the events that lead to normal hypothalamic development. In this elegant study, Aujla et al. have examined the anatomy of the hypothalamus and pituitary in Hes1 null mice with particular emphasis on AVP neurons. Last year, we commented on the role of HES1 in maintaining a balance between proliferation and differentiation [ 11 , 12 ]. In Hes1 null mutants, AVP cell bodies are abnormally placed, POMC cells are not specified in the intermediate lobe, and SS cells in the pituitary are also abnormal with misplaced SS axon tracts at E18.5. The authors suggest a genetic interaction between the Notch signaling pathway and the extracellular matrix molecule Reelin, that then leads to the guidance of axons to the median eminence and pituitary. In Hes1 null animals, the median eminence is clearly misplaced within the head, which may contribute to the aberrant cluster of AVP axons and the reduced number of AVP axons within the posterior lobe. The authors suggest that Hes1 may be important for normal development of support cells such as tanycytes within the median eminence, and that these in turn modulate hypothalamic neurons that travel through it. Disruption of tanycytes indeed results in dysregulated axon guidance. Whatever the underlying mechanism, Notch signaling clearly plays a critical role in hypothalamo-pituitary development. Interestingly, deletion of Numb , which also can affect Notch signaling, also results in misplacement of posterior and intermediate lobe cells, as discussed earlier in this chapter. In the future, mutations in this complex pathway may well be identified in association with abnormal hypothalamo-pituitary development in humans.
Reviews - ion channels and pituitary stem cells
Ion channels and signaling in the pituitary gland
Stojilkovic SS, Tabak J, Bertram R
Program in Developmental Neuroscience, National Institutes of Health, Bethesda, Md.,USA.
Endocr Rev 2010;31:845-915.
Like neurons, hormone-producing pituitary cells express numerous voltage-gated channels enabling sodium, calcium, potassium, and chloride flux. Pituitary cells also fire action potentials spontaneously, like neurons, accompanied by a rise in intracellular calcium. In some cells, spontaneous electrical activity results in intracellular calcium concentration sufficiently high for hormone secretion or gene transcription to occur. In other cells, the function of such action potentials is to maintain the cells in a responsive state with cytosolic calcium concentration near, but below, the threshold level for hormone secretion. Some pituitary cells also express gap junction channels, which could be used for intercellular Ca signaling. Endocrine cells also express extracellular ligand-gated ion channels. Hypothalamic and intrapituitary hormones can activate ion channels and this results in amplification of the cell's pace-making activity and facilitation of calcium influx and hormone release. Pituitary endocrine cells also express numerous G-protein-coupled receptors, and these can stimulate or silence electrical activity and action potential-dependent calcium influx and hormone release. Other members of this receptor family can activate calcium channels in the endoplasmic reticulum, leading to a cell type-specific modulation of electrical activity. This review summarizes the current understanding of the relationship between voltage-gated ion channels, ligand-gated ion channels, gap junction channels, and G-protein-coupled receptors in pituitary cells.
This is an extremely comprehensive review, counting 72 pages and 761 references. Ion channels provide a basic signaling system for individual pituitary cells. This review discusses in great detail how this signaling system works and how it affects hormone release from individual cells. Like neurons, endocrine anterior pituitary cells express numerous voltage-gated ion channels, but also many other channels, like cation-conducting cyclic nucleotide-modulated channels (that translate a change in concentration of cyclic nucleotides to changes in membrane potential) and transient receptor potential channels (of which TRPV5 and 6, that play a role in bone formation, are members). Flux through these channels leads to altered membrane potential. As in neurons, a change in action potential allows for Ca influx through Ca channels. The pattern and frequency of electrical activity and Ca flux determines the coupling to hormone secretion in single cells. The review covers Na, K, Ca and Cl channels, cyclic nucleotide-modulated channels, voltage-gated and ligand-gated channels, gap junction channels (connexins and pannexins), receptor channels (acetylcholine receptor, 5-HT receptor, GABA receptor, glycine receptor, glutamate receptor, purinergic receptor (for ATP, ADP and adenosine)), transient receptor potential channels, and channels expressed in the endoplasmic reticulum (IP3 receptors, ryanodine receptors). It also discusses the regulation of electrical activity and Ca mobilization by G-protein-coupled receptors in pituitary cells, such as neuro-peptide receptors (ghrelin receptors, GnRH receptors) but also other G-protein-coupled receptors such as acetylcholine receptors, endothelin receptors and angiotensin receptors, to name a few. Ion channels, action potentials and calcium flux may not be on the forefront of the mind of many pediatric endocrinologists. This review may serve as a mini-textbook to remind ourselves how the system works, and how it regulates hormone release, which is on the forefront of our minds on a daily basis.
Pituitary stem cell update and potential implications for treating hypopituitarism
Castinetti F, Davis SW, Brue T, Camper SA
Department of Human Genetics, University of Michigan, Ann Arbor, Mich.,USA.
Endocr Rev 2011; doi: 10.1210/er.2010-0011.
Stem cells are characterized by the expression of key marker genes for undifferentiated cells, the ability to self-renew, and the ability to regenerate tissue after cell loss. Several recent reports have suggested the presence of pituitary stem cells in the form of either a SOX2+ cell population, GFRa2+ cells, a side population of cells, nestin+ cell population, or folliculostellate cells. In this paper, the authors give a critical review of the field and suggest studies that could resolve points of debate.
Recent studies have used SOX2, nestin, GFRa2, and SCA1 to identify pituitary stem cells and progenitors but future studies will be needed to resolve the relationships between cells expressing these markers. The authors hypothesize that there are two critical roles of stem cells: one in establishing the pituitary gland during development, and the other involved in maintenance of the mature pituitary gland in response to physiological challenges and normal cell turnover. The hypothesis of two different populations of stem cells, one involved in embryogenesis and one involved in maintenance function after birth, remains highly controversial. Members of the Sox family of transcription factors are likely involved in the earliest steps of pituitary stem cell proliferation and the earliest transitions to differentiation. The transcription factor PROP1 and the NOTCH signaling pathway may then regulate the transition to differentiation. Identification of the stem cell niche is important for several reasons and the authors suggest that the niche may be the marginal zone around the lumen of Rathke's pouch, between the anterior and intermediate lobes of mouse pituitary, since cells in this region are able to give birth to all five pituitary hormone cell lineages. Stem cells have been shown to play a role in tumorigenesis in some tissues, and their role in pituitary hyperplasia, pituitary adenomas, and tumors is an important area for future investigation. The ability to cultivate and grow stem cells in a pituitary pre-differentiation state might also be helpful for the long-term treatment of pituitary deficiencies.
This comprehensive review attempts to describe the current state of knowledge in what is a controversial and rapidly evolving field. A number of groups have described cells that demonstrate some of the characteristics associated with stem cells, namely pluripotency, self-renewal, ability to proliferate, and to differentiate into diverse cell types. However, considerable debate exists as to which of these cell types best reflects a true pituitary stem cell. This review dissects the characteristics of each of these cell types. The review also discusses the potential role of stem cells in the etiology of pituitary tumors, and looks forward to pituitary stem cell therapy for a number of conditions including congenital hypopituitarism, trauma and damage. The field of stem cells progresses rapidly and no doubt will the authors themselves generate new data that will make this review outdated.
Food for thought
Post-traumatic stress disorder is associated with PACAP and the PAC1 receptor
Ressler KJ, Mercer KB, Bradley B, Jovanovic T, Mahan A, Kerley K, Norrholm SD, Kilaru V, Smith AK, Myers AJ,
Ramirez M, Engel A, Hammack SE, Toufexis D, Braas KM, Binder EB, May V
Howard Hughes Medical Institute, Chevy Chase, Md.,USA.
Nature 2011;470:492-7.
Background: Pituitary adenylate cyclase-activating polypeptide (PACAP) is known to broadly regulate the cellular stress response. In contrast, it is unclear if the PACAP-PAC1 receptor pathway has a role in human psychological stress responses, such as post-traumatic stress disorder (PTSD).
Methods: Research interviews, SNP analysis of salivary DNA and radioimmunoassays for PACAP38 were used in more than 1,200 highly traumatized subjects with and without PTSD. Fear potentiation was assessed by measuring the ‘acoustic startle reflex’. A Human Methylation Bead Chip was used to assess methylation of the PAC1 receptor. Rats were used to assess estrogen-induced changes in PACAP and ADCYAP1R1 in the bed nucleus of stria terminalis.
Results: In heavily traumatized female but not male subjects, an association of PACAP blood concentration with fear physiology, PTSD diagnosis and symptoms was found. 44 single nucleotide polymorphisms (SNPs) spanning the PACAP and PAC1 genes, demonstrated a sex-specific association with PTSD. A single SNP in a putative estrogen response element within the PAC1 gene ( ADCYAP1R1 ), rs2267735, predicted PTSD diagnosis and symptoms in females and was associated with fear discrimination and with ADCYAP1R1 messenger mRNA expression in human brain. Methylation of ADCYAP1R1 in peripheral blood was also associated with PTSD. Complementing these human data, ADCYAP1R1 mRNA is induced with fear conditioning or estrogen replacement in rats and mice.
Conclusion: Perturbations in the PACAP-PAC1 pathway are involved in abnormal stress responses underlying PTSD in females. These sex-specific effects may occur via estrogen regulation of ADCYAP1R1 . PACAP blood concentration and ADCYAP1R1 SNPs may serve as useful biomarkers to further our understanding of PTSD.
Pituitary adenylate cyclase-activating polypeptide (PACAP) is produced in CNS neurons, especially in the hypothalamus and limbic structures, and peripheral neurons, for example in the gut. PACAP is co-produced with VIP, and PACAP and VIP share two receptors, but PACAP also has its own receptor PAC1 (encoded by ADCYAP1R1 ). PACAP was named after its ability to stimulate cyclic AMP production in the anterior pituitary. PACAP and PAC1 are known to function in the control of the stress response and PACAP is required for normal activation of the hypothalamo-sympatho-adrenal and hypothalamo-pituitary-adrenal axes in response to stressors. Indeed, mice deficient in PACAP or PAC1 display reduced anxiety and have blunted CRH and corticosterone responses to stress [ 13 ]. A role for PACAP in schizophrenia and chronic depression has also been suggested.
The group of May et al. hypothesized that PACAP-PAC1 is involved in post-traumatic stress disorder and analyzed PACAP concentration, SNPs in ADCYAP1 and its receptor ADCYAP1R1 , and methylation status of CpG island in ADCYAP1R1 in a large cohort of more than 1,200 traumatized patients with and without PTSD. They showed that their hypothesis was correct. SNPs in PACAP, in PAC1 and in a putative estrogen response element in PAC1 gene demonstrated a sex-specific association with PTSD. PACAP38 concentration was higher in females with vs. without PTSD and predicted PTSD symptoms like re-experiencing of trauma, avoidance and hyperarousal (assessed with the acoustic startle response). Female patients with a SNP in the putative estrogen response element within PAC1, had increased dark-enhanced startle, a measure of increased anxiety. Furthermore, methylation of PAC1 was significantly associated with PTSD symptoms, suggesting that environmental and epigenetic mechanism likely affect the long-term response to trauma.
This work suggests that PACAP-PAC1 is involved in both behavioral and hormonal responses to trauma and stress. The sex specificity of the relation between PACAP-PAC1 and PTSD is of interest since females are twice more likely to suffer from PTSD than males. Further work on the PACAP-PAC1 pathway may pave the way for the development of novel biomarkers and potential therapeutic targets for PTSD.
1. Lim LP, Lau NC, Garrett-Engele P, Grimson A, Schelter JM, Castle J, et al: Microarray analysis shows that some microRNAs downregulate large numbers of target mRNAs. Nature 2005;433:769-773.
2. Cuellar TL, McManus MT: MicroRNAs and endocrine biology. J Endocrinol 2005;187:327-332.
3. Bak M, Silahtaroglu A, Moller M, Christensen M, Rath MF, Skryabin B, et al: MicroRNA expression in the adult mouse central nervous system. RNA 2008;14:432-444.
4. Lu J, He ML, Wang L, Chen Y, Liu X, Dong Q, et al: MiR-26a inhibits cell growth and tumorigenesis of nasopharyngeal carcinoma through repression of EZH2. Cancer Res 2011;71:225-233.
5. Peixoto P, Liu Y, Depauw S, Hildebrand MP, Boykin DW, Bailly C, et al: Direct inhibition of the DNA-binding activity of POU transcription factors Pit-1 and Brn-3 by selective binding of a phenyl-furan-benzimidazole dication. Nucleic Acids Res 2008;36:3341-3353.
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7. Park HL, Bai C, Platt KA, Matise MP, Beeghly A, Hui CC, et al: Mouse Gli1 mutants are viable but have defects in SHH signaling in combination with a Gli2 mutation. Development 2000;127:1593-1605.
8. Roessler E, Du YZ, Mullor JL, Casas E, Allen WP, Gillessen-Kaesbach G, et al: Loss-of-function mutations in the human GLI2 gene are associated with pituitary anomalies and holoprosencephaly-like features. Proc Natl Acad Sci USA 2003;100:13424-13429.
9. Bonnefont X, Lacampagne A, Sanchez-Hormigo A, Fino E, Creff A, Mathieu MN, et al: Revealing the large-scale network organization of growth hormone-secreting cells. Proc Natl Acad Sci USA 2005;102:16880-16885.
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Michel Polak a , Mireille Castanet b , Aurore Carré c and Gabor Szinnai d
a Paediatric Endocrinology, Gynecology and Diabetology, Hôpital Necker Enfants Malades, AP-HP, INSERM U845, Université Paris Descartes, Paris b Paediatric Endocrinology, Hôpital Charles Nicolle, Rouen c UMR 8200 CNRS, Institut Gustave Roussy, Villejuif, France d Paediatric Endocrinology, University Children's Hospital Basel, and Department of Biomedicine, University Basel, Basel, Switzerland
In the last 12 months significant advances have been achieved in central areas of thyroid research - clinical outcome studies have increased our knowledge on the short- and long-term effects of congenital hypothyroidism as well as maternal thyroid disorders during pregnancy on the infant. Basic research has shed more light on the molecular mechanisms of the hypothalamic-pituitary-thyroid axis and thyroid hormone transporter and receptor function in development and disease. Further, the Fukushima accident in Japan prompted us to review some of the data generated after Chernobyl. This chapter aims at giving a representative overview of the key publications in thyroidology.
Important for clinical practice
Maternal thyroid function during early pregnancy and cognitive functioning in early childhood: the Generation R Study
Henrichs J, Bongers-Schokking JJ, Schenk JJ, Ghassabian A, Schmidt HG, Visser TJ, Hooijkaas H, de Muinck Keizer-Schrama SM, Hofman A, Jaddoe VV, Visser W, Steegers EA, Verhulst FC, de Rijke YB, Tiemeier H
The Generation R Study, Erasmus Medical University Center, Rotterdam, The Netherlands.
J Clin Endocrinol Metab 2010;95:4227-34.
Background: Thyroid hormones are known to be essential for neurodevelopment from early pregnancy onwards. Transfer of T 4 from the mother to the conceptus has even been demonstrated before placentation. Population-based data on the association between maternal thyroid function in early pregnancy and children's cognitive development are sparse. Therefore the objective of the authors was to study associations of maternal hypothyroxinemia and of early pregnancy maternal TSH and free T 4 (FT 4 ) levels across the entire range with cognitive functioning in early childhood.
Methods: They investigated a population-based cohort in the Netherlands. 3,659 children and their mothers were included in the study. In pregnant women with normal TSH levels around 13 weeks’ gestation, mild and severe maternal hypothyroxinemia were defined as FT 4 concentrations below the 10th and 5th percentile, respectively. Children's expressive vocabulary at 18 months was reported by mothers using the MacArthur Communicative Development Inventory. At 30 months, mothers completed the Language Development Survey and the Parent Report of Children's Abilities measuring verbal and nonverbal cognitive functioning.
Results: Maternal TSH was not related to the cognitive outcomes. An increase in maternal FT 4 predicted a lower risk of expressive language delay at 30 months only. However, both mild and severe maternal hypothyroxinemia was associated with a higher risk of expressive language delay across all ages (odds ratio (OR) = 1.44; 95% confidence interval (CI) = 1.09-1.91; p = 0.010 and OR = 1.80; 95% CI = 1.24-2.61; p = 0.002, respectively). Severe maternal hypothyroxinemia also predicted a higher risk of non-verbal cognitive delay (OR = 2.03; 95% CI = 1.22-3.39; p = 0.007).
Conclusion: Hypothyroxinemia of the mothers in early pregnancy is a risk factor for cognitive delay in early childhood.
Previous smaller studies have suggested that maternal hypothyroxinemia can negatively affect cognitive function of the children [ 1 - 3 ]. However the scale of the present study is much larger than any other before. This gives a power not only to test the consequences of low T 4 on the offspring cognition but also to correlate the whole range of FT 4 during early pregnancy with cognition in early childhood. One can be ’picky’ regarding the methodology, using questionnaires, with no direct access to the children, but the large scale of the study is certainly the reason for this. The question is how this should be applied to pregnancy in general. A first difficulty is the lack of trimester-specific range of FT 4 and TSH for pregnant women. The authors overcome this problem in their cohort by defining FT 4 levels below the 10th percentile as hypothyroxinemia. A second difficulty is the paucity of data providing evidence for beneficial outcome of infants of hypothyroxinemic mothers after iodine or T 4 supplementation. Therefore, intervention studies with iodine or thyroxine supplementation are needed to further justify general screening for hypothyroxinemia in early gestation. For the interested reader, further papers from this mother/child cohort from the Netherlands were published this year [ 4 , 5 ].
Association between thyroid autoantibodies and miscarriage and preterm birth: meta-analysis of evidence
Thangaratinam S, Tan A, Knox E, Kilby MD, Franklyn J, Coomarasamy A
Centre for Health Sciences, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
BMJ 2011;342:d2616.
Background: The authors wished (1) to evaluate the association between thyroid autoantibodies and miscarriage and preterm birth in women with normal thyroid function, and (2) to assess the effect of treatment with levothyroxine on pregnancy outcomes in the group of women having thyroid antibodies.
Methods: A meta-analysis was performed from Medline, Embase, Cochrane Library, and SCISEARCH (inception-2011) without any language restrictions. The studies that evaluated the association between thyroid autoantibodies and pregnancy outcomes were selected by two reviewers. Odds ratios from individual studies were pooled separately for cohort and case-control studies.
Results: Thirty articles with 31 studies (19 cohort and 12 case-control) involving 12,126 women assessed the association between thyroid autoantibodies and miscarriage. Five studies with 12,566 women evaluated the association with preterm birth. Twenty-eight of 31 studies evaluating miscarriage showed a positive association between thyroid autoantibodies and miscarriage. More than a tripling in the odds of miscarriage with the presence of thyroid autoantibodies was observed in the meta-analysis of the cohort studies (odds ratio 3.90, 95% confidence interval 2.48-6.12). For case-control studies the odds ratio for miscarriage was also statistically significant (1.80; 1.25-2.60). There was a significant doubling in the odds of preterm birth with the presence of thyroid autoantibodies (2.07; 1.17-3.68). Two randomized studies evaluated the effect of treatment with levothyroxine on miscarriage. Both showed a fall in miscarriage rates, and meta-analysis showed a significant 52% relative risk reduction in miscarriages with levothyroxine (relative risk 0.48, 0.25-0.92). A 69% relative risk reduction on the rate of preterm birth was noted in one study which reported on the effect of levothyroxine.
Conclusion: The presence of maternal thyroid autoantibodies is strongly associated with miscarriage and preterm delivery. There is evidence that treatment with levothyroxine can attenuate the risks.
The authors remind us that miscarriage affects up to 1 in 5 women who conceive, making it the commonest complication of pregnancy. Preterm birth occurs in 6-10% of pregnancies. Given the high prevalence of thyroid autoantibodies in women of the reproductive age group, the observed increased risk for miscarriage and preterm birth in these women is clinically highly relevant at the individual and population level.
The mechanism behind these findings is still speculative. Pregnancy is an inflammatory process involving a shift in the regulation of cytokine networks within the local placental-decidual environment. Dysregulation of local inflammatory processes can be associated with miscarriage and premature delivery. The presence of thyroid autoantibodies can reflect a generalized activation of the immune system and specifically a dysregulated activity of the immune system at the fetal-maternal interface. Furthermore, the presence of thyroid autoantibodies might be a marker of underlying subtle alteration in thyroid reserve. An argument for this hypothesis is that treatment with thyroxine improved the outcome. However, there have been only two small randomized trials involving a total of 187 women to assess the protective effect of L-T 4 for miscarriage or preterm birth. Therefore, and in anal-ogy with the publication on hypothyroxinemia in early pregnancy, a large placebo-controlled randomized trial is needed before general screening of thyroid autoantibodies can be advocated.
Congenital hypothyroidism with a delayed thyroid-stimulating hormone elevation in very premature infants: incidence and growth and developmental outcomes
Woo HC, Lizarda A, Tucker R, Mitchell ML, Vohr B, Oh W, Phornphutkul C
Department of Pediatrics, The Warren Alpert Medical School of Brown University, Providence, R.I.,USA.
J Pediatr 2011;158:538-42.
Background: The authors address the question of the detection of congenital hypothyroidism (CH) in babies with delayed TSH elevation after birth. Their hypothesis was that very low birth weight (VLBW) and extremely low birth weight (ELBW) infants have an increased incidence of CH with a delayed thyroid-stimulating hormone (TSH) elevation. They further evaluated the outcomes of these infants in comparison to control infants.
Methods: Retrospective analysis of newborn thyroid screening data for 92,800 live births in Rhode Island to identify CH with a delayed TSH elevation. Developmental, growth, and endocrine outcomes of the index cases were assessed at 18 months of corrected age.
Results: CH with a delayed TSH elevation occurred in 1 in 58 ELBW, 1 in 95 VLBW, and 1 in 30,329 infants weighing ≥1,500 g (p < 0.0001). The incidence of head circumference <10th percentile was higher in VLBW infants with CH associated with a delayed TSH elevation (p < 0.05), and the mean head circumferences, weights, lengths, and developmental scores were similar to matched control infants.
Conclusion: The incidence of CH with a delayed TSH elevation was higher in ELBW and VLBW infants compared with infants weighing ≥1,500 g. The outcomes of these infants were comparable with matched control infants at 18 months.
Delayed TSH rise is a non-classical screening result suggesting thyroid dysfunction and is particularly frequent in premature infants. It is only detected in newborn screening programs with a routine or physician-based second TSH-based screening test 2-6 weeks after birth in preterm infants with <1,500 g birth weight. The presented study was realized within the context of the Rhode Island Newborn Screening program, measuring both thyroxine and TSH at 48 h of age with repeated specimens collected in infants <1,500 g birth weight at 2, 6, and 10 weeks of age or until they reach 1,500 g. This study confirmed previous data showing highest incidence of congenital hypothyroidism with delayed TSH rise in extremely low birth weight infants (<1,000 g; 1:58) versus very low birth weight infants (1,000-1,499 g; 1:295) and neonates with a birth weight >1,500 g (1:30,329). Further, the authors showed for the first time that most untreated cases of congenital hypothyroidism with delayed TSH rise were transient, however the underlying mechanisms remained unclear. Finally, although clearly limited by sample size, the authors found no differences in psychomotor development of affected patients at 18 months of age compared to matched controls. However, 3 infants with congenital hypothyroidism and delayed TSH rise had a head circumference <10th percentile versus none in the controls. From this set of data, it remains unclear whether to treat these infants or not. As stated in the accompanying editorial, ‘it may rather be prudent to treat those until more data on the neurocognitive abilities of those children are available’ [ 6 ].
Subtle health impairment and socioeducational attainment in young adult patients with congenital hypothyroidism diagnosed by neonatal screening: a longitudinal population-based cohort study
Leger J, Ecosse E, Roussey M, Lanoe JL, Larroque B
Pediatric Endocrinology Department, Centre de Référence Maladies Endocriniennes Rares de la Croissance, Groupe Avenir, Institut National de la Santé et de la Recherche Médicale, Unite 676, Hôpital Robert Debré, Assistance Publique-Hôpitaux de Paris and University Paris, Paris; Association Française pour le Dépistage et la Prévention des Handicaps de l’Enfant, Paris; Pediatric Department, Hôpital Sud, University Rennes I, Rennes; INSERM U687, Villejuif, and Clinical Epidemiology and Research Unit, Hôpital Beaujon, Assistance Publique-Hôpitaux de Paris, and INSERM, Unité Mixte de Recherche S953, Epidemiological Research on Perinatal Health and Women's and Children's Health, University Pierre et Marie Curie Paris, Clichy, France.
J Clin Endocrinol Metab 2011;96:1771-82.
Background: Improved neurodevelopmental outcome has been documented with screening programs resulting in the early treatment of patients with congenital hypothyroidism (CH). However, knowledge about long-term health in those patients is scarce. The aim of the authors was to assess health status, and socioeconomic attainment, for a population-based registry of young adult patients.
Methods: The authors included 1,748 eligible patients diagnosed during the first decade after the introduction of the national neonatal screening program in France. Questionnaires were used and completed by 1,202 of the selected patients with a median age of 23.4 years. The comparison group included 5,817 subjects from the last French Decennial Health Survey. Measures of health status included medical conditions, hearing and visual status, sociodemographic characteristics, and quality of life.
Results: Patients with CH were significantly more likely than their peers to report associated chronic diseases (5.7 vs. 2.9%), hearing impairment (9.5 vs. 2.5%), visual problems (55.4 vs. 47.9%), and being overweight with a body mass index of at least 25 kg/m 2 (22.8 vs. 15.7%). Importantly, fewer patients attained the highest socioeconomic category (14.6 vs. 23.1%) and were in full-time employment (39.9 vs. 44.8%). They were more likely to still be living with their parents. A lower health-related quality of life than their healthy peers, particularly for mental dimensions, was documented. The main determinants of educational achievement and health-related quality of life scores were: (1) CH severity at diagnosis, (2) treatment adequacy, and (3) the presence of other chronic health conditions.
Conclusion: These findings highlight the need for careful monitoring of neurosensory functioning, weight, and long-term treatment adequacy throughout childhood and adulthood.
This unique population-based, large-scale study of young adults affected by congenital hypothyroidism provides important information on long-term health and socioeconomic status. The general health outcomes reveal important differences in comparison with a control group, with increased risk for both hypothyroidism-associated and -independent comorbidities. Of special concern is the fourfold increased rate of patients with hearing impairment. Interestingly, graduating from high school was associated with athyreosis, but not with older age or L-T 4 dose at the start of treatment. Later on, adequacy of long-term L-T 4 substitution was a major determinant for graduating from high school. About 20% of the subjects had serum TSH concentrations above the upper limit of the reference range at the last available examination, suggesting non-optimal follow-up or poor compliance with treatment in these young adults. However, from a public health standpoint, these impairments had little impact because most patients were well integrated into society, in education, or with at least some employment. The major limitation of the study is that the analyzed population was diagnosed and treated according to historical guidelines and therefore might not be representative for infants diagnosed today. Nevertheless, there remains room for improvement of monitoring of affected children, adolescents and young adults and care during transition from pediatric to adult follow-up.
Thyroid cancer and thyroid hormone receptors in cancer
Thyroid cancer risk in Belarus among children and adolescents exposed to radioiodine after the Chornobyl accident
Zablotska LB, Ron E, Rozhko AV, Hatch M, Polyanskaya ON, Brenner AV, Lubin J, Romanov GN, McConnell RJ, O’Kane P, Evseenko VV, Drozdovitch VV, Luckyanov N, Minenko VF, Bouville A, Masyakin VB
Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, Calif.,USA.
Br J Cancer 2011;104:181-7.
Background: Previous studies showed an increased risk of thyroid cancer among children and adolescents exposed to radioactive iodines released after the Chornobyl (Chernobyl) accident. However, the effects of factors influencing dose response, such as screening, iodine deficiency, and age at exposure, need to be clarified.
Methods: The authors screened 11,970 individuals in Belarus aged 18 years or younger at the time of the accident who had estimated 131 I thyroid doses based on individual thyroid activity measurements and dosimetric data from questionnaires. They obtained fine needle biopsy when needed and surgery was performed so that pathology established the final diagnosis. By statistical modeling the excess odds ratio per gray (EOR/Gy) for thyroid cancer was calculated.
Results: For thyroid doses <5 Gy, the dose-response was linear (n = 85; EOR/Gy = 2.15, 95% confidence interval: 0.81-5.47), but at higher doses the excess risk fell. The EOR/Gy varied significantly in several situations: (1) being increased among those with prior or screening-detected diffuse goiter, (2) being larger for men than women, and (3) with a non-significant trend for persons exposed before age 5 than those exposed between 5 and 18 years.
Conclusion: 10-15 years after the Chernobyl accident, thyroid cancer risk was significantly increased among individuals exposed to fallout as children or adolescents, but the risk appeared to be lower than in other Chernobyl studies and studies of childhood external irradiation.
Twenty-five years after the Chernobyl accident and months after the Fukushima accident in March this year, studies on thyroid carcinoma prevalence among children exposed to radioactive iodine have regained wide interest. Parallel studies in Ukraine and Belarus and sequential risk analyses in the same population are providing an increasing knowledge for more precise risk estimates depending on exposed 131 I doses and dose-response modifying factors.
The strength of the Belarus thyroid cancer screening program study are (1) the individual estimates of 131 I thyroid dose based on thyroid radioactivity measurements performed within 2 months after the accident as the key baseline parameter, (2) a standardized screening protocol in all included patients by physician blinded for the individual initial 131 I thyroid dose, and (3) a high compliance of the patients with FNA and surgery in case of suspected malignancy centralized in two hospitals. However, this extensive study underlies a possible non-participation bias: only 32.6% of the eligible and initially analyzed population could be screened.

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