TERO VARIMO UNIVERSITY OF HELSINKI DELAYED PUBERTY PUBERTY DELAYED GROWTH WITH INTERACTIONS AND OUTCOME ETIOLOGY, DELAYED PUBERTY ETIOLOGY, OUTCOME AND INTERACTIONS WITH GROWTH TERO VARIMO ISBN 978-951-51-2838-6 (paperback) ISBN 978-951-51-2839-3 (PDF) http://ethesis.helsinki.fi Painosalama Oy Helsinki 2016 HELSINKI 2016 2016 Pediatric Graduate School Doctoral Programme in Clinical Research Children’s Hospital Helsinki University Hospital and University of Helsinki Helsinki, Finland DELAYED PUBERTY ETIOLOGY, OUTCOME AND INTERACTIONS WITH GROWTH Tero Varimo ACADEMIC DISSERTATION To be presented, with the permission of the Faculty of Medicine of the University of Helsinki, for public examination at the Niilo Hallman Auditorium, Children’s Hospital, on January 20th 2017, at 12 noon. Helsinki 2016 Supervised by Professor Taneli Raivio MD, PhD Matti Hero Children’s Hospital Children’s Hospital Helsinki University Hospital Helsinki University Hospital and Department of Physiology Helsinki, Finland Faculty of Medicine University of Helsinki Helsinki, Finland Reviewed by Professor Juha Tapanainen Docent Marja Ojaniemi Department of Obstetrics and Oulu University Hospital Gynecology and PEDEGO Research Unit, Medical Helsinki University Hospital Research Center Oulu, University of Helsinki University of Oulu Helsinki, Finland Oulu, Finland Official opponent Docent Antti Perheentupa Department of Obstetrics and Gynecology Turku University Hospital University of Turku Turku, Finland ISBN 978-951-51-2838-6 (Paperback) ISBN 978-951-51-2839-3 (PDF) Painosalama Oy Helsinki 2016 To Eveliina and Joonatan TABLE OF CONTENTS ABBREVIATIONS ................................................................................................ 7 ABSTRACT .......................................................................................................... 9 FINNISH SUMMARY (TIIVISTELMÄ) ................................................................ 11 INTRODUCTION ................................................................................................ 13 REVIEW OF THE LITERATURE ....................................................................... 15 1. HYPOTHALAMIC-PITUITARY-GONADAL (HPG) AXIS AND PUBERTY 15 1.1. Current concepts on the development and function of GnRH neurons .............................................................................................. 15 1.1.1. The ontogeny and migration of GnRH neurons ...................... 15 1.1.2. The composition and function of the GnRH pulse generator .. 16 1.1.3. The activation phases of the HPG axis ................................... 18 1.1.4. The regulation of the HPG axis ............................................... 19 1.2. Normal puberty .................................................................................. 19 1.2.1. General concepts .................................................................... 19 1.2.2. Normal variation in the timing of puberty and secular trends . 19 1.2.3. Clinical and biochemical markers of puberty .......................... 20 1.2.4. Molecular genetic basis of puberty ......................................... 21 1.3. Delayed puberty (DP) ........................................................................ 24 1.3.1. Diagnostic criteria in Finland ................................................... 24 1.3.2. Underlying causes .................................................................. 24 1.3.3. Evaluation of patient with DP .................................................. 25 1.3.4. Treatment ................................................................................ 27 1.4. Congenital hypogonadotropic hypogonadism (CHH) ........................ 27 1.4.1. Diagnostic criteria ................................................................... 28 1.4.2. Clinical and biochemical evaluation ........................................ 28 1.4.3. Clinical features ...................................................................... 29 1.4.4. The differential diagnosis between CHH and constitutional delay of growth and puberty ................................................... 29 1.4.5. Treatment ................................................................................ 30 1.4.6. Long-term impact of sex steroid deficiency on bone-health and health-related quality of life .............................................. 31 2. THE HORMONAL REGULATION OF GROWTH ...................................... 31 2.1. Fetal life and infancy .......................................................................... 31 2.2. Childhood ........................................................................................... 32 2.3. Puberty .............................................................................................. 33 2.4. Adult height ........................................................................................ 34 2.5. Evaluation of growth .......................................................................... 34 AIMS OF THE STUDY ....................................................................................... 36 PATIENTS AND METHODS .............................................................................. 37 3. STUDY SUBJECTS ................................................................................... 37 3.1. Boys with idiopathic short stature (ISS) (I) ........................................ 37 3.1.1. Collection and analyses of the serum samples ...................... 37 3.2. Patients with DP (II) ........................................................................... 37 TABLE OF CONTENTS 3.2.1. Classification of different DP types .......................................... 39 3.3. Patients with CHH (III-V) .................................................................... 40 3.3.1. Acquisition of growth data ....................................................... 40 3.3.2. Health-related quality of life ..................................................... 41 4. STATISTICS .............................................................................................. 41 5. ETHICS ...................................................................................................... 42 RESULTS ........................................................................................................... 43 1. Serum MKRN3 levels in boys before the clinical onset of puberty ............ 43 2. The underlying causes of DP ..................................................................... 45 3. The differential diagnosis of DP ................................................................. 46 4. The growth of patients with CHH from birth to adult height ....................... 48 5. Health-related quality of life in males with CHH ......................................... 50 DISCUSSION ...................................................................................................... 53 1. Circulating MKRN3 levels in boys before the clinical onset puberty .......... 53 2. The diagnoses and predictors of DP .......................................................... 55 3. The influence of sex steroid deficiency on growth during minipuberty, childhood and adolescence ........................................................................ 57 4. Health-related quality of life in males with CHH ......................................... 58 5. Future perspectives .................................................................................... 59 ACKNOWLEDGEMENTS................................................................................... 60 REFERENCES .................................................................................................... 62 ORIGINAL PUBLICATIONS............................................................................... 79 LIST OF ORIGINAL PUBLICATIONS This thesis is based on the following articles which are referred to in the text by Roman numerals I-V: I. Varimo T, Dunkel L, Vaaralahti K, Miettinen PJ, Hero M, Raivio T. Circulating makorin ring finger protein 3 (MKRN3) levels decline in boys before the clinical onset of puberty. Eur J Endocrinol. 2016;174:785-90. II. Varimo T, Miettinen PJ, Känsäkoski J, Raivio T, Hero M. Congenital hypogonadotropic hypogonadism, functional hypogonadotropism, or constitutional delay of growth and puberty? An analysis of a large patient series from a single tertiary center. Hum Reprod. In press. III. Varimo T, Hero M, Laitinen EM, Miettinen PJ, Tommiska J, Känsäkoski J, Juul A, Raivio T. Childhood growth in boys with congenital hypogonadotropic hypogonadism. Pediatr Res. 2016;79:705-9. IV. Hero M, Laitinen EM, Varimo T, Vaaralahti K, Tommiska J, Raivio T. Childhood growth of females with Kallmann syndrome and FGFR1 mutations. Clin Endocrinol (Oxf). 2015;82:122-6. V. Varimo T, Hero M, Laitinen EM, Sintonen H, Raivio T. Health-related quality of life in male patients with congenital hypogonadotropic hypogonadism. Clin Endocrinol (Oxf). 2015;83:141-3. 6 ABBREVIATIONS AI aromatase inhibitor AMH anti-müllerian hormone ANOS1 anosmin 1 ARC arcuate nucleus BDI beck’s depression index BMD bone mineral density BMI body mass index CAH congenital adrenal hyperplasia CDGP constitutional delay of growth and puberty CHD7 chromodomain helicase DNA-binding protein 7 CHH congenital hypogonadotropic hypogonadism CI confidence interval CNS central nervous system CPP central precocious puberty DP delayed puberty DYN dynorphin ELISA enzyme-linked immunosorbent assay FGFR1 fibroblast growth factor receptor 1 FHH functional