BasicBasic EndocrinologyEndocrinology

Estrogen Receptor IntroductionIntroduction

SystemSystem ofof ductlessductless glandsglands ProduceProduce chemicalchemical messengersmessengers calledcalled HORMONESHORMONES hormones help integrate body signals with neural and immune systems HormonesHormones traveltravel toto targettarget tissue/celltissue/cell viavia blood stream intercellular space

HormonesHormones

ComeCome inin twotwo majormajor formsforms peptides / proteins growth hormone, insulin, oxytocin Lipid-based hormones steroids and prostaglandins SteroidogenesisSteroidogenesis

Cholesterol

P450ssc

3!HSD P450c21 P450c11 Pregnenolone Progesterone Deoxycorticosterone Corticosterone Isomerases P450c17 P450c17

3!HSD P450c21 P450c11 17-OH Pregnenolone 17-OH Progesterone 11 Deoxycortisol Cortisol Isomerases P450c17 P450c17 P450 arom 3!HSD 17 Keto Dehydroepiandrosterone Androstenedione Testosterone 17! Estradiol Isomerases Reductase Target Tissues ReceptorsReceptors

•• atat thethe targettarget cell,cell, aa hormonehormone interactsinteracts withwith aa RECEPTORRECEPTOR •• peptidepeptide hormoneshormones usuallyusually interactinteract withwith membranemembrane receptorreceptor •• steroidsteroid hormoneshormones interactinteract withwith nuclearnuclear receptorreceptor • many steroid receptors are transcription factors

1. Membrane receptor activates G protein 2. G protein + GTP activates adenylyl cyclase 3. ATP converted to cAMP (2o messenger) 4. Results = cellular response amplified @ each step Amplification

Signal- transduction pathways allow for small amounts of a hormone to have a large effect

1. Steroid binds to cytoplasmic or nuclear receptor(transcription factor) 2. Receptor hormone complex binds to DNA in nucleus 3. Stimulates transcription of mRNA NuclearNuclear ReceptorReceptor EvolutionEvolution

•• SteroidSteroid receptorsreceptors •• TranscriptionTranscription factorsfactors •• LargeLarge familyfamily ofof relatedrelated moleculesmolecules ••GeneGene duplicationduplication ••AncestralAncestral formform unknownunknown The Nuclear Receptor Superfamily a,bgd A/B C D E F DNA LIGAND KNOWN RECEPTORS ORPHAN RECEPTORS Classical receptors (from biochemistry) Vertebrate Drosophila GR cortisol TR-2α,β DHR78 MR aldosterone NGFI-Bα,β,γ DHR38 PRα,β progesterone RORα,β,γ DHR3 ARα,β testosterone Rev-erb E75, E78 ERα,β,γ estrogen SF-1α,β FTZ-F1α,β? VDR 1,25 (OH)2 vit D3 COUPα,β,γ svp TRα,β Thyroid hormone HNF-4α,β HNF-4 EcR 20-OH ecdysone TLX tll

EX-orphans No known homologs α,β,γ RAR all-trans RA ERRα,β,γ knirps RXRα,β,γ 9-cis RA, ? DAX-1 knirps-related PPARα,β,γ fatty acids SHP egon LXRα,β oxy-sterols GCNF DHR96 FXRα,β bile acids BXRα,β benzoates C. elegans - 2-3% of genes are nuclear receptors ~250 Nearly EX-orphans Drosophila - only about 20 nuclear CAR androstans, xenobiotics receptors SXR steroids, xenobiotics PXR.1,2 pregnanes, xenobiotics Blumberg, UC Irvine Evolution of Steroid Receptors

•Two serial duplications •1st = ER and 3-ketosteroid R •2nd = duplication of 3-KR •Corticoid receptor (CR) •3-ketogonadal steroid R •Androgen •Progesterone •Or both •These 3 duplicated again to form 6 common forms found today in vertebrates Thornton (2001) PNAS 98:5671-5676 HypothalamusHypothalamus -- PituitaryPituitary •• consideredconsidered thethe mastermaster organsorgans ofof thethe endocrineendocrine systemsystem Hypothalamus HypothalamusHypothalamus

bottom of 3rd ventricle of brain secretes neurohormones that influence synthesis and release of pituitary hormones examples: gonadotropin releasing hormone (GnRH) thyrotropin releasing hormone (TRH) dopamine - Prolactin releasing inhibiting factor released into hypothalmo-hypophysial portal system blood vessel system between hypothalamus and pituitary Hypothalamo-hypophysialHypothalamo-hypophysial PortalPortal SystemSystem

• A portal system • Vein - vein • Low pressure system • Delivers hypothalamic factors to pituitary PituitaryPituitary -- HypophysisHypophysis

• center of the soul in classical times • derived from two tissues embryologically • adenohypophysis (anterior pituitary) - derived from outpocketing of mouth - Rathke’’s pouch • neurohypophysis (posterior pituitary) - derived from outpocketing of third ventricle and hypothalamus • these two extensions meet, interact and form pituitary with two distinct regions as noted NeurohypophysisNeurohypophysis AdenohypophysisAdenohypophysis