Abnormalities in Puberty - part 1 pot

Delemarre-van de Waal Amsterdam 41 figures, 2 in color, and 11 tables, 2005 This is trial version www.adultpdf.com... Delemarre-van de Waal This is trial version www.adultpdf.com... The

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Abnormalities in Puberty

Scientific and Clinical Advances

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Endocrine Development

Vol 8

Series Editor

Martin O Savage London

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Abnormalities in

Puberty

Scientific and Clinical Advances

Basel · Freiburg · Paris · London · New York · Bangalore · Bangkok · Singapore · Tokyo · Sydney

Volume Editor

Henriette A Delemarre-van de Waal Amsterdam

41 figures, 2 in color, and 11 tables, 2005

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Prof Dr Henriette A Delemarre-van de Waal

VU University Medical Center

Paediatric Endocrinology

PO Box 7057

Amsterdam, The Netherlands

Bibliographic Indices This publication is listed in bibliographic services, including Current Contents ® and Index Medicus.

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.

www.karger.com

Printed in Switzerland on acid-free paper by Reinhardt Druck, Basel

ISSN 1421–7082

ISBN 3–8055–7867–9

Library of Congress Cataloging-in-Publication Data

Abnormalities in puberty : scientific and clinical advances / volume editor,

Henriette A Delemarre-van de Waal.

p ; cm – (Endocrine development, ISSN 1421-7082 ; v 8)

Includes bibliographical references and indexes.

ISBN 3-8055-7867-9 (hard cover : alk paper)

1 Pediatric endocrinology 2 Endocrine glands–Diseases 3 Precocious

puberty 4 Puberty.

[DNLM: 1 Puberty, Precocious 2 Gonadal Disorders 3 Puberty,

Delayed 4 Puberty WS 450 A153 2005] I Delemarre-van de Waal, H A.

(Henriette A.) II Series.

RJ418.A24 2005

618.92 ⬘4–dc22

2004026715

This is trial version

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Contents

VII Foreword

Savage, M.O (London)

IX Preface

Delemarre-van de Waal, H.A (Amsterdam)

1 Secular Trend of Timing of Puberty

15 Fetal Nutrition and Timing of Puberty

van Weissenbruch, M.M.; Engelbregt, M.J.T.; Veening, M.A.;

34 Adrenal Function of Low-Birthweight Children

Ong, K (Cambridge)

54 Puberty and Fertility in Congenital Adrenal Hyperplasia

Otten, B.J.; Stikkelbroeck, M.M.L.; Claahsen-van der Grinten, H.L.;

Hermus, A.R.M.M (Nijmegen)

67 Molecular Genetics of Isolated Hypogonadotropic Hypogonadism

and Kallmann Syndrome

Karges, B (Ulm); de Roux, N (Paris)

81 Hypothalamic Hamartoma: A Paradigm/Model for Studying

the Onset of Puberty

Jung, H.; Parent, A.-S.; Ojeda, S.R (Beaverton, Oreg.)

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94 Gonadotropin-Releasing Hormone Analogue Treatment for Precocious Puberty Twenty Years of Experience

Heger, S.; Sippell, W.G (Kiel); Partsch, C.-J (Esslingen)

126 Very Long-Term Follow-Up of Girls with Early and Late Menarche

Johansson, T.; Ritzén, E.M (Örebro)

137 Polycystic Ovary Syndrome in Adolescence.

New Insights in Pathophysiology and Treatment

Homburg, R (Amsterdam)

150 Reversing Sex Steroid Deficiency and Optimizing Skeletal Development

in the Adolescent with Gonadal Failure

Vanderschueren, D.; Vandenput, L.; Boonen, S (Leuven)

166 Present and Future Options for the Preservation of Fertility in

Female Adolescents with Cancer

Beerendonk, C.C.M.; Braat, D.D.M (Nijmegen)

176 Author Index

177 Subject Index

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the management of the child with too early onset of puberty, with delayed puberty and other pubertal disorders Not only the clinical aspects, but also the aspects related to their causes such as early growth, and genetic and develop-mental defects are discussed, which may have consequences on final height, bone development and reproduction

Henriette A Delemarre-van de Waal

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Delemarre-van de Waal 2

result of a developing negative feedback as well as due to central inhibiting influences on GnRH release [1]

Gonadotropin levels are low at birth, which is followed by a transient increase during the first months of life, the so-called postnatal peak Thereafter, levels return into a very low, often undetectable range during the prepubertal phase as a result of the instrinsic restraint This developmental pattern of the gonadotropin axis appears to be independent of the fetal and child’s own gonadal steroids, since a similar development can be observed in agonadal patients [2]

During the fetal period a sex dimorphism in gonadotropin concentrations

is manifest at both the pituitary and peripheral level with higher levels in the female fetus [3] The sex dimorphism maintains in later life The high inci-dence of idiopathic central precocious puberty in girls, and the easier response

of the pituitary to stimulation with GnRH in girls compared to boys are good examples of this phenomenon [4] It is assumed that the restraint of GnRH and gonadotropin release is more intense in boys than in girls The fact that GnRH

is not completely suppressed in girls has been confirmed in a study measuring estrogens using ultra-sensitive assays to measure estrogens, showing measur-able and bioactive estrogen levels in the prepubertal girl [5]

Timing of Puberty

The clinical signs of puberty are an increase of testicular volume above

3 ml (G2) in boys, and bud-shaped elevation of the areola and papilla (B2) in girls In girls, this stage is associated with an immediate increase of height velocity, whereas in boys the pubertal spurt occurs in the second half of puberty Girls experience menarche, a milestone of pubertal development, about 2.3 years after start of breast growth The appearance of axillary and pubic hair

is not a good measure of puberty since it depends on adrenal steroids in girls and at least initially in boys

Improvement of the socioeconomic status appears to advance and shorten pubertal development In the Netherlands, in the 16th to 18th centuries menar-che was reported to occur at 14–15 years of age and seldom before the age of

13 years [6] In 1928, a shift to a menarcheal age of 13.7 years was described, and in 1965 it was 13.4 years of age The growth survey of 1980 showed that most stages of sexual maturation were reached at a younger age and menarche was again advanced to 13.3 years and in 1997 to 13.2 years

In several European countries the trend to an earlier start of pubertal maturation seems to have come to a halt during the last decades In the Netherlands pubertal onset even tended to be slightly later In girls the start of

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Timing of Puberty 3

breast development started at mean ages of 10.5 and 10.7 in 1980 and in 1997, respectively, whereas in boys testicular development started at the ages of 11.3 and 11.4 years in the same studies [7]

In contrast to the Dutch data, investigations in the United States have shown an ongoing trend of earlier onset of breast development in girls and genital growth in boys, particularly in the black population [8, 9] These reports resulted in wide discussions, firstly on the methods used in these studies and secondly on whether we should adjust our criteria for the definitions of an abnormal puberty, especially for central precocious puberty

These studies described breast development at the age of 7 years in 5% of white American girls and as high as in 15% in African-American girls Menarche at a mean age of 12.7 years did not advance, indicating that with an earlier start but a similar menarcheal age, pubertal development in American girls progresses at a slower pace The earlier onset of puberty in these girls is associated with an increased body mass index, which is more pronounced in white than in black girls [10] The reason that overweight children often have

an early onset of puberty may be explained by the fact that estrogens are stored

in body fat resulting in increased bioactivity

Mechanisms

The underlying mechanism of the timing of puberty is the result of a genetic constitution and the influence of environmental forces on it Chronic malnutrition will not allow the body to spend energy in growth and puberty and fertility The different aspects of genetic background as well as of various envi-ronmental such as malnutrition, immigration and the effects of endocrine disrupters will be discussed

Genetics

It is well known that timing of puberty has a familial inheritance The identification of genetic factors involved is still insufficient Over the last decades, gene mutations playing a role in the puberty cascade are identified explaining abnormal pubertal development

Mutations in gonadotropin genes and gonadotropin receptors have been found [for review, see 11, 12] LH and FSH, together with TSH and hCG, are part of the family of glycoprotein hormones consisting of a common ␣-subunit and a hormone specific ␤-subunit The ␣-subunit consists of 92 amino acids and is encoded by one gene localized on chromosome 6q12.21 For the

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Delemarre-van de Waal 4

FSH ␤-subunit the gene is localized on 11p13 The gene encoding for the LH

␤-subunit is located on chromosome 19q13.32, where hCG ␤-subunit genes are identified as well

Glycoproteins bind to receptors with similar structures These receptors belong to the G protein-coupled receptors with a, for them, characteristic large extracellular hormone-binding domain at the N-terminus The LH receptor is encoded by a gene located at chromosome 2p21 The FSH receptor gene is located on the same chromosome 2p21–16 It is evident that mutations in the gonadotropin genes and their receptors can lead to a disturbed pubertal maturation

A mutation of the LH␤ gene has been reported in a 17-year-old boy with delayed puberty The history of his family revealed several male relatives with infertility The boy had low testosterone levels and increased serum LH levels, which lack LH bioactivity [13] Substitution with hCG resulted in appropriate testosterone levels, testicular growth and spermatogenesis The boy was homozygous for this mutation, while his mother, sister and three uncles appeared to be heterozygous The heterozygous individuals had less bioactive

LH activity related to its immunoreactivity as well

Polymorphisms as a genetic variation of the LH␤ gene are also described One of these polymorphisms leads to diminished levels of immunoreactive LH, while a bioassay measures appropriate activity The frequency of the

variant-LH␤ gene appears to be high worldwide with a high frequency in Northern European countries (allelic frequency 10%) and a low frequency in Asian populations and American Indians (2.5–5%) [14] A wide variety of pheno-types has been described, in women varying from no symptoms to recurrent miscarriages, menstrual irregularity and polycystic ovary syndrome, and in boys low testosterone levels associated with high LH levels with delayed puber-tal maturation [15] Another LH␤ gene polymorphism, whereby glycine has been replaced by serine at amino acid 102, appears to be associated with an increased risk to infertility in both males and females [16, 17]

For the FSH␤ gene different inactivating mutations have been described in males and females In males, azoospermia with and without pubertal delay has been described These men have low FSH, increased LH and low testos-terone levels DNA sequencing showed among others a homozygous 2-bp deletion in codon 61 [18] In females, a similar as well as a different homozy-gous genetic condition are reported associated with an absence of FSH, low estradiol levels, lack of development of secondary sex characteristics and primary amenorrhea [19]

For both LH and FSH receptors activating and inactivating mutations of the encoding genes have been identified A well-known activating mutation

of the LH receptor is seen in the clinical syndrome of testotoxicosis, a

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Timing of Puberty 5

gonadotropin-independent state of male precocious puberty characterized by slight testicular growth, virilization with increased testosterone levels and low gonadotropin levels This condition is male limited and has an autosomal-dominant pattern of inheritance [20] In addition to polymorphisms of the LH receptor, different kinds of inactivating mutations of the type of insertion, missense, deletion and nonsense, while for activating mutations only missense types have been described [for review, see 11]

The clinical picture of inactivating mutations of the LH receptor is different

in males and females It usually presents with a relatively mild phenotype in females with normal development of pubertal characteristics and amenorrhea, with increased LH and FSH, and low estradiol levels and no response to hCG

In contrast, males have incomplete male differentiation of external genitalia due to low testosterone levels during pregnancy The hCG test shows a blunted testosterone response The severity of ambiguity depends on the amount of LH receptor activity and may vary from micropenis to severe hypospadia to a complete female phenotype [21]

In contrast to the LH receptor, only a few FSH receptor mutations have been described All polymorphisms, inactivating mutations and the only activating FSH mutation described are of the missense type The female phenotype of homozygous FSH receptor mutation genotype consists of gonadal dysgenesis with lack of development of sex characteristics, high levels of LH and FSH, although the ovaries contain follicles [22] In men, the phenotype is characterized by impaired testicular growth, normal virilization and often oligospermia The gonadotropin levels are in the normal or elevated range [23] The only activating FSH receptor mutation has been described in a man with multiple pituitary hormone deficiencies including gonadotropins Under testos-terone treatment, he developed spermatogenesis Screening of the FSH receptor gene revealed a mutation in the transmembrane domain-encoding exon 10 [24]

At the hypothalamic level, GnRH release can be affected by genetic disor-ders as well The KAL1 gene located in the Xp22.3 region encodes for a protein anosmin that shares homology with molecules involved in neuronal migration and axonal path finding Mutations of the KAL1 gene will result in an arrest of migration of both the olfactory and GnRH neurons leading to the clinical picture of hypogonadotropic hypogonadism associated with anosmia, the Kallmann syndrome [25] Recently, autosomal inheritance has been described among others to be due to a mutation of the fibroblastic growth factor receptor gene [26]

Congenital adrenal hypoplasia can be associated with hypogonadotropic hypogonadism and caused by DAX-1 mutations at Xp21 The congenital adrenal hypoplasia presents already during infancy, while lack of pubertal onset will become clear at a pubertal age In some of the boys puberty can be induced

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