Genetic Regulation

.................................................................................................................................................................................................... 6 LIST OF ORIGINAL PUBLICATIONS.................................................................................................................................................. 9 ABBREVIATIONS........................................................................................................................................................................................ 10 INTRODUCTION.......................................................................................................................................................................................... 13 REVIEW OF THE LITERATURE............................................................................................................................................................ 14 1. TIMING OF PUBERTAL ONSET............................................................................................................................................. 14 1.1. PUBERTY AS A MATURATIONAL PROCESS.................................................................................................. 14 1.2. CLINICAL MARKERS AND NORMAL VARIATION OF PUBERTAL TIMING..................................... 15 1.2.1. SECONDARY SEX CHARACTERISTICS............................................................................................................... 15 1.2.2. MENARCHE OR SPERMARCHE............................................................................................................................ 16 1.2.3. PUBERTAL GROWTH SPURT................................................................................................................................ 17 1.3. SECULAR TRENDS IN TIMING OF PUBERTY................................................................................................. 21 2. GENETIC REGULATION OF PUBERTAL TIMING......................................................................................................... 22 2.1. EVIDENCE FOR GENETIC EFFECTS.................................................................................................................... 22 2.2. CURRENT CONCEPTS OF GENES RELATED TO PUBERTAL TIMING................................................ 23 2.2.1. GENES INVOLVED IN ONTOGENESIS OF GnRH NEURONS AND GONADOTROPES..................... 24 2.2.2. GENES INVOLVED IN GnRH NEURON AND GONADOTROPE FUNCTION.................................... 25 2.2.3. GENETIC LOCI RELATED TO PUBERTAL TIMING...................................................................... 27 3. ENVIRONMENTAL MODIFIERS OF PUBERTAL TIMING......................................................................................... 28 3.1. HYPOTHALAMIC EFFECTS OF GONADAL SEX STEROIDS..................................................................... 28 3.1.1. ENDOCRINE-DISRUPTING CHEMICALS........................................................................................................... 29 3.2. NUTRITION AS A REGULATOR OF PUBERTAL TIMING......................................................................... 30 3.2.1. SIGNALS INTEGRATING METABOLISM AND PUBERTAL ONSET......................................................... 31 3.2.2. EFFECTS OF WEIGHT GAIN ON TIMING OF PUBERTY............................................................................. 33 AIMS OF THE STUDY................................................................................................................................................................................ 36 SUBJECTS........................................................................................................................................................................................................ 37 1. POPULATION OF TWINS (II).............................................................................................................................................. 37 2. FAMILIES OF PATIENTS WITH DELAYED PUBERTY...... ...... ........................................................................... 37 2.1. PEDIGREE ANALYSIS (III).............................. ................................................................................................ 38 2.2. LINKAGE ANALYSIS (IV)....................................................................................................................................... 38 2.3. ANALYSIS OF GROWTH PATTERNS (I)................................................................................................................ 39