Endocrine Principles III 3 Regulation of hormone activity A B C D E Hormone synthesis release Persistence of hormone action Feedback regulation Inputs integration with the CNS Hypothalamic Pituitary axis Regulation of hormone activity Hormones Signals Hormone 3 4 H 2 Hormone synthesis release Persistence Feedback Input H H 1 H H Regulation key to homeostasis Mechanisms H Input Covered H H H H H Response 2 1 Regulation of hormone synthesis release Synthesis All hormones Release Only proteins 3 Levels of all hormones are regulated by gene expression Gene Pol II Transcriptional regulation AAAAAAAAAAA Steroid hormones Protein hormones AAAAAAAAAAA H mRNA Direct preprohormone AAAAAAAAAAA Indirect Steroidogenic cytochromes P450 4 Regulatory points unique to steroid hormone synthesis LDL Binding protein LDL R Steroid acute regulatory protein Cytochrome P450 side chain cleavage Unique biosynthetic enzymes Also Unique enzyme StAR LDL receptors Steroid binding proteins Unique enzyme P450SCC SCC PKA PKC StAR P450SCC PKA Fast kinase Slow transcription PKC P Pol II 5 Regulatory points unique to protein hormone synthesis 1 Transcription of the hormone gene 2 Exocytosis of stored vesicles 3 Protease activation in the blood stream rare blood ECF 3 Slow 1 Slow AAAAAA Pol II 2 Fast Universal 6 Vesicle release is THE critical step in protein hormone regulation Fast seconds Ca Main stimuli Ca2 H 2 G q IP3 Other stimuli Ca2 channels Ligand gated Voltage gated Ca PKA 2 Ca 2 Ca2 Ca2 H Direct activation of release Ca2 activated Ca2 release Distinction not important G s PKA Amount of hormone available for release regulated by transcription 7 H H GnRH pg mL H H Regulation of exocytosis results in pulsatile release Simultaneous release 35 FAST 30 25 Many vesicles in 20 each cell 15 10 Not all released at 5 0 once 0 120 240 360 480 H HH H H H H H H H H H H HH H H H H H H HHH H H H H H H H HH H H H HH H HH H H HH H H H H H H H HH H HH H HH H H H H H H H HH H H H H H HH H HH H HH HH H H H H H H H HH H H HH H H H H HH H H HHH H H H H H H H H H H H H H H H H H H Time min H HH H H H H HH HH H H HH H H H H H H H H H H H H H H HH H H HH H H H HHH H H HH H H H HH H H H H H HHH H H H HHH H HH HHH H H H HH H HH H H HH H H H H H H H HHH H H H HHH H H H HHH H H H H H H H H H HH H H H HHH H H H H HH HH H H H HH H HH H H H HHH H H H H HHH H H H H H H H HH H H H H HH H H HHH H H H H HH H H H HHH H H H H H H H H HHH H H H H HH H HH H H H H H HH H HH H H H HHH HH H H H H HHH H H H H H H H H HHH H H H H H H H HHH Input H H HH H HH HH H H H H H H Input strength determines release New vesicles require transcription SLOW H H 8 Proteases can modify peptide hormones in the bloodstream Proteases can be membrane bound or soluble Activate Peptides only Only a couple examples 9 2 Regulation by persistence The length of time a hormone lasts in the blood stream before disposal 10 Hormone amount per unit volume Interstitial Fluid hormone mole liter Lots of trivial units Liter of Extracellular fluid Blood Plasma Blood plasma Interstitial fluid Plasma blood stream ECF are often used interchangeably Measurement is local may be different elsewhere 11 Measuring persistence Half life The time it takes for the concentration of a hormone to decrease by half t Ranges Shortest epinephrine 1 min Longest Thyroxine 8 days Steroids glycoproteins peptides 500 min 100 90 80 70 60 60 min 50 40 30 20 5 min 10 0 0 50 100 150 200 250 300 Time min 0 1 10 100 1 000 10 000 Peptides Glycoproteins Steroids time log minutes 12 Protein hormone half life H Small amount taken up by target tissues Mostly renal filtration H H Small proteins Large proteins Endocytosis at luminal membrane Metabolized to amino acids Some have specific uptake receptors t Some have binding proteins t amino acids venous H H H H lumen apical basolateral 13 Proteases can also degrade peptide hormones in the bloodstream Both types are potential targets for regulation Peptide hormone General protease degrades completely Amino acids Peptide hormone Specific proteases inactivate Inactive peptide fragments 14 Steroid hormone metabolism Enzymatic modification Hydroxylation Glucuranation Sulfation Often 1 Make soluble Cytochromes P450 cortisol allotetrahydrocortisone progesterone pregnanediol 3 glucuronide Testosterone Etiocholanolone 3 sufate 15 Steroid metabolism allows clearance Other tissues Metabolized elsewhere Metabolized in the liver Excreted Circulating steroid hormone Eliminate d with bile 16 Hormone concentration ranges Response strength determined by Hormone concentration Hormone efficacy EC50 Hormones are never zero NO ON OFF switches Narrow range Concentrations Steroids glycoproteins peptides log concentration pM 0 1 10 100 1 000 10 000 100 000 1 000 000 Peptides Glycoproteins Steroids Insulin Glucagon ACTH Calcitonin GH Leptin FSH Cortisol Testosterone Estradiol Estradiol 17 Concentration is local Target2 Gland Target3 Target1 Target2 Target1 Target3 Small gland low concentration limited response Target3 Large gland high concentration broad response Target2 Target1 Response reflects Hormone 18 Gland size important predictor of hormone concentration Big glands lots of hormone Pineal gland Hypothalamus Posterior pituitary Anterior pituitary Skin Parathyroid glands Heart Liver Steroids always come from big glands Proteins often from small glands or few cells in secondary endocrine tissue Adrenal cortex Adipose tissue Kidneys Pancreas Stomach small intestine Testes Ovaries Blastocyst Placenta 19 3 Feedback regulation All hormones are regulated by feedback o Negative o Positive Homeostasis Feedback is one of the most important ideas in all of biology Claude Bernard 1813 1878 from page 576 of An Introduction to the History of Medicine by Fielding Hudson Garrison 1917 20 Most hormones are regulated by negative feedback Homeostasis Input Response H H Endocrine tissue Target Negative feedback Response inhibits further input 21 Positive feedback is non homeostatic Input Response H H Endocrine tissue Target Much less common than negative feedback 22 Feedback can be required for target tissue maintenance Hormone Endocrine Tissue Hypertrophy Proliferation Negative feedback maintains homeostasis Hormone Atrophy Apoptosis Tissue maintenance can be autocrine or paracrine Loss of feedback keeps hormone levels high 23 Review questions 1 Fill out the following table PROPERTY PROTEIN HORMONES STEROID HORMONES Synthesis Regulation of synthesis Location of synthesis Storage Release from parent cell