Delayed Puberty: What Parents Need to Know Fact Sheet
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Background Briefing Document from the Consortium of Sponsors for The
BRIEFING BOOK FOR Pediatric Advisory Committee (PAC) Prepared by Alan Rogol, M.D., Ph.D. Prepared for Consortium of Sponsors Meeting Date: April 8th, 2019 TABLE OF CONTENTS LIST OF FIGURES ................................................... ERROR! BOOKMARK NOT DEFINED. LIST OF TABLES ...........................................................................................................................4 1. INTRODUCTION AND BACKGROUND FOR THE MEETING .............................6 1.1. INDICATION AND USAGE .......................................................................................6 2. SPONSOR CONSORTIUM PARTICIPANTS ............................................................6 2.1. TIMELINE FOR SPONSOR ENGAGEMENT FOR PEDIATRIC ADVISORY COMMITTEE (PAC): ............................................................................6 3. BACKGROUND AND RATIONALE .........................................................................7 3.1. INTRODUCTION ........................................................................................................7 3.2. PHYSICAL CHANGES OF PUBERTY ......................................................................7 3.2.1. Boys ..............................................................................................................................7 3.2.2. Growth and Pubertal Development ..............................................................................8 3.3. AGE AT ONSET OF PUBERTY.................................................................................9 3.4. -
Hypogonadism in Adolescence 173:1 R15–R24 Review
A A Dwyer and others Hypogonadism in adolescence 173:1 R15–R24 Review TRANSITION IN ENDOCRINOLOGY Hypogonadism in adolescence Andrew A Dwyer1,2, Franziska Phan-Hug1,3, Michael Hauschild1,3, Eglantine Elowe-Gruau1,3 and Nelly Pitteloud1,2,3,4 1Center for Endocrinology and Metabolism in Young Adults (CEMjA), 2Endocrinology, Diabetes and Metabolism Correspondence Service and 3Division of Pediatric Endocrinology Diabetology and Obesity, Department of Pediatric Medicine and should be addressed Surgery, Centre Hospitalier Universitaire Vaudois (CHUV), Rue du Bugnon 46, 1011 Lausanne, Switzerland and to N Pitteloud 4Department of Physiology, Faculty of Biology and Medicine, University of Lausanne, Rue du Bugnon 7, Email 1005 Lausanne, Switzerland [email protected] Abstract Puberty is a remarkable developmental process with the activation of the hypothalamic–pituitary–gonadal axis culminating in reproductive capacity. It is accompanied by cognitive, psychological, emotional, and sociocultural changes. There is wide variation in the timing of pubertal onset, and this process is affected by genetic and environmental influences. Disrupted puberty (delayed or absent) leading to hypogonadism may be caused by congenital or acquired etiologies and can have significant impact on both physical and psychosocial well-being. While adolescence is a time of growing autonomy and independence, it is also a time of vulnerability and thus, the impact of hypogonadism can have lasting effects. This review highlights the various forms of hypogonadism in adolescence and the clinical challenges in differentiating normal variants of puberty from pathological states. In addition, hormonal treatment, concerns regarding fertility, emotional support, and effective transition to adult care are discussed. European Journal of Endocrinology (2015) 173, R15–R24 European Journal of Endocrinology Introduction Adolescence is generally defined as the transitional phase (FSH)) (1, 2). -
ANDROGEN INSENSITIVITY SYNDROME AMONG COUSIN SISTERS - a RARE ENTITY Sarah Ramamurthy *1, Aravindhan Karuppusamy 2
International Journal of Anatomy and Research, Int J Anat Res 2018, Vol 6(3.2):5564-67. ISSN 2321-4287 Case Study DOI: https://dx.doi.org/10.16965/ijar.2018.282 ANDROGEN INSENSITIVITY SYNDROME AMONG COUSIN SISTERS - A RARE ENTITY Sarah Ramamurthy *1, Aravindhan Karuppusamy 2. *1 Assistant Professor, Department of Anatomy, Pondicherry Institute of Medical Sciences, Kalapet, Pondicherry, India. 2 Additional Professor and Head, Department of Anatomy, JIPMER, Pondicherry, India. ABSTRACT Androgen insensitivity syndrome (AIS), is a X-linked disorder characterized by resistance to androgen caused by mutation of androgen receptor gene in which XY karyotype individuals exhibit female phenotype. AIS is characterised by evidence of feminization (under masculinization) of the external genitalia at birth, abnormal secondary sexual development at puberty, and infertility in individuals with 46 XY karyotype. We are presenting here a familial case of complete androgen insensitivity syndrome in south Indian Population. 46 XY karyotype was found in two subjects who were cousin sisters with female phenotype,who presented with primary amenorrhoea. Comet assay was done, which showed results comparable with normal males. In both girls’ inguinal gonads was present which was removed and hormonal therapy with estrogen was given to prevent osteoporosis. Androgen insensitivity syndrome can be inherited as an X linked disorder as evidenced by previous studies. KEY WORDS: testicular feminization syndrome, Androgen Receptor Deficiency, Primary amennorrhea, Comet -
Distinguishing Constitutional Delay of Growth and Puberty from Isolated Hypogonadotropic Hypogonadism: Critical Appraisal of Available Diagnostic Tests
SPECIAL FEATURE Clinical Review Distinguishing Constitutional Delay of Growth and Puberty from Isolated Hypogonadotropic Hypogonadism: Critical Appraisal of Available Diagnostic Tests Jennifer Harrington and Mark R. Palmert Division of Endocrinology, The Hospital for Sick Children and Department of Pediatrics, The University of Toronto, Toronto, Canada M5G1X8 Context: Determining the etiology of delayed puberty during initial evaluation can be challenging. Specifically, clinicians often cannot distinguish constitutional delay of growth and puberty (CDGP) from isolated hypogonadotropic hypogonadism (IHH), with definitive diagnosis of IHH awaiting lack of spontaneous puberty by age 18 yr. However, the ability to make a timely, correct diagnosis has important clinical implications. Objective: The aim was to describe and evaluate the literature regarding the ability of diagnostic tests to distinguish CDGP from IHH. Evidence Acquisition: A PubMed search was performed using key words “puberty, delayed” and “hypogonadotropic hypogonadism,” and citations within retrieved articles were reviewed to identify studies that assessed the utility of basal and stimulation tests in the diagnosis of delayed puberty. Emphasis was given to a test’s ability to distinguish prepubertal adolescents with CDGP from those with IHH. Evidence Synthesis: Basal gonadotropin and GnRH stimulation tests have limited diagnostic spec- ificity, with overlap in gonadotropin levels between adolescents with CDGP and IHH. Stimulation tests using more potent GnRH agonists and/or human chorionic gonadotropin may have better discriminatory value, but small study size, lack of replication of diagnostic thresholds, and pro- longed protocols limit clinical application. A single inhibin B level in two recent studies demon- strated good differentiation between groups. Conclusion: Distinguishing IHH from CDGP is an important clinical issue. -
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1 184 A B Hansen and others Sex steroids in adolescencel 184:1 R17–R28 Review DIAGNOSIS OF ENDOCRINE DISEASE Sex steroid action in adolescence: too much, too little; too early, too late A B Hansen 1, D Wøjdemann1, C H Renault1, A T Pedersen 2, K M Main1, L L Raket3,4, R B Jensen1 and A Juul 1 Correspondence 1Department of Growth and Reproduction, 2Department of Gynecology and Fertility Clinic, Rigshospitalet, University should be addressed of Copenhagen, Copenhagen, Denmark, 3H. Lundbeck A/S, Valby, Hovedstaden, Denmark, and 4Clinical Memory to A Juul Research Unit, Department of Clinical Sciences, Lund University, Lund, Sweden Email [email protected] Abstract This review aims to cover the subject of sex steroid action in adolescence. It will include situations with too little sex steroid action, as seen in for example, Turners syndrome and androgen insensitivity issues, too much sex steroid action as seen in adolescent PCOS, CAH and gynecomastia, too late sex steroid action as seen in constitutional delay of growth and puberty and too early sex steroid action as seen in precocious puberty. This review will cover the etiology, the signs and symptoms which the clinician should be attentive to, important differential diagnoses to know and be able to distinguish, long-term health and social consequences of these hormonal disorders and the course of action with regards to medical treatment in the pediatric endocrinological department and for the general practitioner. This review also covers situations with exogenous sex steroid application for therapeutic purposes in the adolescent and young adult. This includes gender-affirming therapy in the transgender child and hormone treatment of tall statured children. -
A Clinical Guide to Delayed Puberty
The Section of Endocrinology A Clinical Guide to Delayed Puberty Puberty is a normal component of a child’s growth and development into adulthood, yet delayed puberty is a frequent cause of anxiety and stress. Although many benign normal variants are common, pathology can be seen, and appropriate treatments are available to address pubertal abnormalities. Delayed Puberty Pubertal delay may result from a number of underlying disorders, including chronic endocrine, metabolic, and systemic disorders as well as under nutrition. In most cases, delayed puberty does not have a serious underlying cause and is simply due to a normal variant of growth known as constitutional delay of growth and development, otherwise known as a “late bloomer”. This is also a frequent cause of short stature referrals as well, and is much more commonly seen in boys than in girls. Physical Signs of Delayed Puberty Girls Boys • Lack of breast development (thelarche) by • Lack of testicular enlargement by age 14 age 13 • Lack of menses (menarche) by age 15 • Lack of menses within 3 years after start of breast development also warrants investigation Causes of Delayed Puberty Girls Boys • Genetic inheritance • Constitutional delay of puberty • Underweight/Decrease body fat (common • Genetic inheritance in athletes) • Chronic illness, such as: • Anorexia nervosa • Inflammatory Bowel Disease • Chronic illness, such as: • Celiac Disease • Inflammatory Bowel Disease • Sickle Cell Disease • Celiac Disease • Cystic Fibrosis • Sickle Cell Disease • Gonadal failure • Cystic Fibrosis • Deficiency of pituitary hormones LH and • Primary ovarian insufficiency FSH (Hypopituitarism) • Deficiency of pituitary hormones LH and FSH (Hypopituitarism) 1 Nationwide Children’s Hospital | Endocrinology Diagnostic Evaluation Classifying the cause as central (GnRH-dependent) or peripheral (GnRH-independent) can be helpful in a diagnostic evaluation. -
Diagnosis and Management of Primary Amenorrhea and Female Delayed Puberty
6 184 S Seppä and others Primary amenorrhea 184:6 R225–R242 Review MANAGEMENT OF ENDOCRINE DISEASE Diagnosis and management of primary amenorrhea and female delayed puberty Satu Seppä1,2 , Tanja Kuiri-Hänninen 1, Elina Holopainen3 and Raimo Voutilainen 1 Correspondence 1Departments of Pediatrics, Kuopio University Hospital and University of Eastern Finland, Kuopio, Finland, should be addressed 2Department of Pediatrics, Kymenlaakso Central Hospital, Kotka, Finland, and 3Department of Obstetrics and to R Voutilainen Gynecology, Helsinki University Hospital and University of Helsinki, Helsinki, Finland Email [email protected] Abstract Puberty is the period of transition from childhood to adulthood characterized by the attainment of adult height and body composition, accrual of bone strength and the acquisition of secondary sexual characteristics, psychosocial maturation and reproductive capacity. In girls, menarche is a late marker of puberty. Primary amenorrhea is defined as the absence of menarche in ≥ 15-year-old females with developed secondary sexual characteristics and normal growth or in ≥13-year-old females without signs of pubertal development. Furthermore, evaluation for primary amenorrhea should be considered in the absence of menarche 3 years after thelarche (start of breast development) or 5 years after thelarche, if that occurred before the age of 10 years. A variety of disorders in the hypothalamus– pituitary–ovarian axis can lead to primary amenorrhea with delayed, arrested or normal pubertal development. Etiologies can be categorized as hypothalamic or pituitary disorders causing hypogonadotropic hypogonadism, gonadal disorders causing hypergonadotropic hypogonadism, disorders of other endocrine glands, and congenital utero–vaginal anomalies. This article gives a comprehensive review of the etiologies, diagnostics and management of primary amenorrhea from the perspective of pediatric endocrinologists and gynecologists. -
Delayed Puberty and Its Management
Delayed puberty and its management Dr Malcolm Donaldson Honorary Senior Research Fellow Glasgow University Abnormalities of puberty IMAGE 2016: Insights into MAnaging Growth for Endocrine Nurses 17-18 November 2016, Lyon, France Hypothalamo-pituitary-gonadal axis Hypothalamus Gonadotrophin releasing hormone Pituitary gland Luteinising hormone and Follicle Stimulating Hormone Ovary and Testis Testosterone → 17β-estradiol Inhibin A and B Anti-Müllerian Hormone Target cell Pubertal (Tanner) staging Height velocity graph showing different growth patterns in boys (solid line) and girls (dotted line) Distance chart showing different growth patterns in boys (solid line) and girls (dotted line) Puberty – pattern of growth Girls • grow fast at start of puberty • peak height velocity at 12 yr (B2-3) • slow down in later stages of puberty when breast development is mature (B4-5) • when menarche occurs (13-13.5 yr) the girl is near final height Puberty – pattern of growth Boys • grow slowly at start of puberty (G2) - still in childhood growth phase • accelerate in mid-puberty (coincides with growth of penis, G3) • peak height velocity at 14 yr (G4) • further growth after pubertal development is complete (G5) Normal puberty – which statement is true? 1. Girls enter puberty 2 years earlier than boys 2. Girls grow at their fastest in late puberty (B4) 3. The first sign of puberty in boys is penile enlargement 4. Boys grow at their fastest in late puberty (G4) Normal puberty – which statement is true? 1. Girls enter puberty 2 years earlier than boys 2. Girls grow at their fastest in late puberty (B4) 3. The first sign of puberty in boys is penile enlargement 4. -
Management of Permanent Hypogonadism in Boys Yee-Ming Chan, M.D., Ph.D
Management of Permanent Hypogonadism in Boys Yee-Ming Chan, M.D., Ph.D. Stephanie B. Seminara, M.D. (in absentia) April 8, 2019 Disclosures • Y-MC was a medical advisory board member for Endo Pharmaceuticals. • SBS has nothing to disclose. • This presentation will discuss off-label use of medications. Outline • Review of male reproductive endocrine physiology • Causes of hypogonadism in boys • Diagnosis of permanent hypogonadism • Management of permanent hypogonadism Reproductive Endocrine Physiology Male Reproductive Endocrine Physiology The kisspeptin neurons Hypothalamic kisspeptin Pituitary GnRH neurons Gonadal axis… pulsatile GnRH pituitary gonadotropes FSH/LH gonads aromatase estradiol testosterone secondary sex characteristics Reproductive Endocrine Function Across the Life Cycle in utero infancy childhood puberty adulthood Reproductive Reproductive Activity Endocrine Age Androgen Effects: Fetal Development • First trimester • Virilization of the external genitalia • Stabilization of internal male genital structures (Wolffian duct-derived) • Second and third trimesters • Testicular descent from inguinal ring to scrotum • Growth of penis • Also has effects on the brain http://www.accessmedicine.ca/search/searchAMResultImg.asp x?rootterm=sex+differentiation&rootID=28735&searchType=1 Androgen Effects: Pediatric Years • Minipuberty: Role of testosterone unclear • Childhood: Very low-level testosterone production, unclear whether physiologically significant • Puberty • Hair growth • Voice deepening • Growth acceleration • Genital development -
Delayed Puberty Paul B
Article endocrinology Delayed Puberty Paul B. Kaplowitz, MD, Objectives After completing this article, readers should be able to: PhD* 1. Define the ages at which puberty is considered delayed in boys and girls. 2. Discuss the typical presentation and natural history of constitutional delayed puberty. Author Disclosure 3. Compare the differential diagnosis of delayed puberty for causes other than Dr Kaplowitz has constitutional delay in girls versus boys. disclosed no financial 4. Recognize the psychological consequences of pubertal delay. relationships relevant 5. Describe the evaluation and treatment of delayed puberty in boys and girls. to this article. This commentary does not Introduction contain a discussion Normal maturation of the hypothalamic-pituitary-gonadal (HPG) axis shows a period of of an unapproved/ activity in utero and in the first few postnatal months, particularly in boys. The HPG axis investigative use of a then becomes quiescent by 6 months of age and does not resume activity until the time of commercial product/ puberty. Pulsatile secretion of the hypothalamic-releasing factor gonadotropin-releasing device. hormone (GnRH) results in pulsatile secretion of the pituitary gonadotropins luteinizing hormone (LH) and follicle-stimulating hormone (FSH). Increasing LH triggers an increase in production of sex steroids; increasing FSH stimulates the growth and matura- tion of the seminiferous tubules involved in sperm production and the ovarian follicles involved in oocyte production. However, the changes within the brain that trigger the onset of pulsatile GnRH secretion at the time of puberty still are poorly understood. In most boys, physical changes of puberty start between the ages of 10 and 13 years, with the first change being enlargement of the testes, followed by pubic hair and penile growth, and subsequent growth at peak height velocity. -
Delayed Puberty” These Podcasts Are Designed to Give Medical Students an Overview of Key Topics in Pediatrics
PedsCases Podcast Scripts This is a text version of a podcast from Pedscases.com on “Puberty and Pubertal Disorders – Part 3: Delayed Puberty” These podcasts are designed to give medical students an overview of key topics in pediatrics. The audio versions are accessible on iTunes or at www.pedcases.com/podcasts. Puberty and Pubertal Disorders – Part 3: Delayed Puberty Developed by Ruojin Bu and Dr. Elizabeth Rosolowsky for PedsCases.com. April 13, 2018 Introduction: Hi! My name is Ruojin Bu, and I am a medical student at the University of Alberta. This video is the final instalment of a three-part series on puberty and pubertal disorders. This whole series was made possible with contributions from Dr. Elizabeth Rosolowsky, a pediatric endocrinologist at the University of Alberta. So far in our series, we’ve looked at the physiology and clinical presentations of normal puberty in part 1, as well as an approach to precocious puberty in part 2. In this final episode, we will be covering the topic of delayed puberty. Slide 2 At the end of this video, the learner should be able to: 1. Describe the clinical criteria for diagnosing delayed puberty 2. List the common causes of delayed puberty 3. Outline an approach for the common causes of delayed puberty Slide 3 As a continuation of our case example from part one and two… The next day at the family medicine clinic, you meet a 14-year 4-month old boy whose parents are concerned that he is not physically maturing like his peers. He has developed some pubic hair but no armpit hair. -
Sleep Timing in Patients with Precocious and Delayed Pubertal Development
Article Sleep Timing in Patients with Precocious and Delayed Pubertal Development Elena Jessen 1,†, Celine Vetter 2,3,†, Till Roenneberg 3, Klaus-Peter Liesenkötter 4, Helene Werner 5, Oskar G. Jenni 5 , Erwin Lankes 6,7, Oliver Blankenstein 1, Uta Neumann 1, Birgit Köhler 7, Susanna Wiegand 6, Heiko Krude 1 and Peter Kühnen 1,* 1 Institute for Experimental Pediatric Endocrinology, Charité—Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, 13353 Berlin, Germany; [email protected] (E.J.); [email protected] (O.B.); [email protected] (U.N.); [email protected] (H.K.) 2 Department of Integrative Physiology, University of Colorado at Boulder, Boulder, CO 80309, USA; [email protected] 3 Institute of Medical Psychology, Ludwig-Maximilians-University, 80336 Munich, Germany; [email protected] 4 Endokrinologikum, 10117 Berlin, Germany; [email protected] 5 Child Development Center, University Children’s Hospital Zurich, 8050 Zurich, Switzerland; [email protected] (H.W.); [email protected] (O.G.J.) 6 Center for Chronic Sick Children (SPZ), Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, 13353 Berlin, Germany; [email protected] (E.L.); [email protected] (S.W.) 7 Department for Pediatric Endocrinology and Diabetes, Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, 13353 Berlin, Germany; [email protected] * Correspondence: [email protected]; Tel.: +49-30-450-666-839 † These authors contributed equally to this work.