PGY452 552 Human Physiology Endocrinology Endocrine Principles I 1 Hormones A Endocrinology homeostasis B Steroid hormones C Protein hormones 1 Peptides 2 Glycoproteins What is a hormone Chemical produced in specific cells Transported blood or ECF Activates signaling in specific targets Influences homeostasis or development 2 We will cover 40 hormones 70 recognized hormones 100 s meet the technical definition Neurotransmitters Cytokines Free lipids Vitamins Other molecules Why are they not hormones We ll Cover Traditio Mostly classic Best known functions Principles apply to all hormones known unknown 3 What is Endocrinology Chemical regulation of physiological processes by hormones 4 Responsible for maintenance of homeostasis Homeostasis Change Relatively stable state of internal environment Must be actively maintained External challenges Internal challenges Not always homeostatic Change Homeostasis lost Endocrine compensatory mechanisms Failure Failure Death Death Success Success Survival Survival 5 Promotes long term nonhomeostatic processes Growth Sexual Development Pregnancy 6 Hormones are part of endocrine systems Input Endocrine tissue Hormone Adaptive Response Maladaptive pathophysiologic Response Feedback H H Receptor Signal Response H H H Target tissue Hormone H Input H H H H H H Target 7 Hormones come from endocrine tissues Hypothalamus Posterior pituitary Anterior pituitary Thyroid gland Parathyroid glands Skin Heart Endocrine glands classic Liver Adrenal cortex Adrenal medulla Specialized cells in other tissues Neurons Pineal gland Kidneys Testes Endocrine pancreas Ovaries Stomach small intestine Adipose tissue Placenta Blastocyst 8 Most of what you need to know about hormone systems can be reasoned from the hormone s chemical class Proteins Steroids Peptides small Glycoproteins large glycosylated 1 subunit Amides are a minor class 9 What does chemical class tell us Origin Synthesis mechanism Transport From the cell In the blood steam Half life I lied a little Presence of a binding protein Receptor type Signaling mechanism Time for action Regulation Exceptions Critical to understanding Therefore I will make a big deal out of them 10 Steroid hormones Properties Synthesis 11 Steroid hormones are derived from cholesterol CH3 18 CH3 12 19 11 CH3 3 HO A 4 10 5 B 6 17 13 14 9 1 2 C H C HC H H C 20 H H C H HC CH3 CH3 16 D 15 8 7 cyclopentanoperhydrophenanthrene Cholesterol is a fat STEROID Properties Stepwise synthesis Diffuses from cells Transported bound to a protein Lasts long All have nuclear receptors transcription factors 12 Steroid biosynthesis Almost all steroid synthesis by common pathways Cholesterol precursor Major source LDL Minor de novo synthesis Steroidogenesis requires specialized enzymes Cytochromes P450 CYP Mono oxygenases of hydrophobic organic molecules Iron containing protein NADH binding protein Many 4000 in 109 families 13 Steroid synthesis starts with cholesterol mobilization LDL 1 LDL receptor Cholestero l ester in lipid droplets 2 Usually the steps regulated by the endocrine system Pregnenolone 3 StAR Steroid acute regulatory protein 4 Cytochrome P450SCC Side Chain Cleavage 14 Most steroid synthesis starts with a common pathway Pathway for cholesterol mobilization 1 Cholesterol is carried within LDL low density lipoprotein in the blood which binds LDL receptors on the cell surface 2 The receptor LDL complex is internalized by endocytosis the lipoprotein degraded and the cholesterol stored in the form of cholesterol esters 3 Steroid synthesis starts with de esterification and transfer of the cholesterol into the mitochondria through StAR or the steroid acute regulatory protein 4 There it is cleaved by cholesterol side chain cleavage enzyme also called cytochrome P450SCC or 20 22 desmolase to give pregnenolone which passes out of the mitochondria for further processing These first two steps in steroid biosynthesis StAR and P450SCC as well as internalization of cholesterol by the LDL receptor limit the rate of steroid biosynthesis These are often the steps regulated by the endocrine system especially StAR SCC Therefore you should know them For the Biochemists in the room cholesterol can by synthesized de novo in the tissue in which it is going to be used but this is not very important in steroid hormone synthesis 15 Stepwise modification of pregnenolone Pregnenolone 11 hydroxylase 21 hydroxylase 3 hydroxysteroid dehydrogenase 17 hydroxylase Zona glomerulosa 17 20 desmolase aromatase Androgens Cortisol Zona fasciculata 17 hydroxysteroid dehydrogenase 5 reductase Aldosterone Estrogens Common pathways to multiple hormones Tissue specific Do not memorize 16 Important steroid hormones Aldosterone CortisolCH OH H O OH OH CH3 Calcitriol CH2OH 2 C Skin Liver Kidney OH CH3 O C C O OH CH3 O Adrenal Gland OH different C D synthesis pathway O Slow stress response K Na balance A HO Progesterone Estradiol E2 CH3 C CH3 CH3 O O Androgens Testosterone CH3 CH3 OH Ovaries OH Ca2 PO4 Dihydrotestosterone OH CH3 OH CH3 CH3 O CH2 O O H Testes Peripheral tissues 17 Steroid biosynthesis can span tissues Testes LDL Dihydrotestosterone DHT Cholesterol Pregnenolone Testosterone Skin Leydig cell Estradiol in general circulation Sertoli Estradiol for gonadogenesis Adipose 18 Steroid producing endocrine tissues High concentrations Skin Big glands or endocrine tissues NEVER Hypothalamus Pituitary Placenta Adrenal cortex Testes Ovaries Adipose tissue 19 Steroid binding proteins Hormones lipophilic Require binding protein in aqueous ECF Often made in liver Albumin Also Transcortin cortisol aldosterone progesterone Vitamin D binding protein Sex hormone binding globulin androgen binding protein androgen binding protein testosterone 20 Protein hormones Two types Biosynthesis 21 Second major class Proteins Sub classes Peptides Glycoproteins Property Glycosylation Size Subunits Synthesis Peptides No No Glycoproteins YesYes MostMost 100 100 aminoamino acids acids Many have 2 or more many have 2 or more Little proteolysis 3 to 100 acids acids 3 toamino 100 amino OneOne Extensive proteolytic Extensive proteloytic processing processing The two share most properties The distinction is not that important Unlike steroids vs proteins little proteolysis Size is not a good way to tell them apart 22 Peptide hormone synthesis ER ECF blood 4 Prohormone 2 3 Golgi 5 Acidified vesicle Preprohormone 6 AAAAAA 1 AAAAAA Pol II Hormone gene 23 Synthetic pathway of peptide hormones 1 2 3 4 5 6 The hormone gene