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Hormone Action Brian Feldman, MD, PhD Department of Pediatrics/ Endocrinology [email protected] NRs vs. Membrane Receptors Hormones that act at the membrane also have the potential to have nuclear (genomic) actions but usually not by translocating the receptor to the nucleus. Outline • • • • • Major steroid hormones and their source General properties of NHRs Specificity of hormone activity Therapeutic uses of hormones Diseases caused by hormonal abnormalities Major Types of Steroid Hormones Class Mineralocorticoid Glucocorticoid Androgen Estrogen Progestin Vitamin D Major Active Human Hormone Aldosterone Cortisol Dihydrotestosterone (Testosterone?) Estradiol Progesterone 1,25Dihydroxycholecalciferol Source Adrenal Glomerulosa Adrenal Fasiculata Testis Ovary Corpus Luteum Kidney Molecular Structure of Hormones General Properties of NRs This is not your mother’s Endo lecture • BUT hormones have tissue and context specific effects • Some genes are regulated by a hormone in one cell type but not another • Other genes are regulated by a hormone only during specific times (i.e. cell division, differentiation, etc) • We need to understand these details to understand physiology, pathophysiology and pharmacology Major Active Hormones and Receptors Specificity of hormone activity Hormones have complex systemic and tissue specific effects •Cushing’s syndrome: increased fat (central), decreased bone and muscle; metabolic syndrome •Metabolic syndrome: Insulin resistance/ diabetes , HTN, dyslipidemia Larsen: Williams Textbook of Endocrinology How is Diversity and Specificity Achieved? • (We don’t really know but part of) the explanation: • Intracellular regulation of hormone • Allosteric effects on receptor caused by hormone and other factors binding to receptor • DNA (availability and sequence) • Co-factor interactions (availability and complex) • RESULT: receptor/ligand complex form highly context specific structures Role of Intracellular Enzymes to Regulate Ligand Availability Testosterone DHT 5alpha reductase Cortisol 11BHSD Or Hormone Activation Cortisone 3 Ways to Decorate A Nuclear Receptor at the Response Element • Simple: Homodimer • Complex: Heterodimer • Tethering: Intermediate Protein Steroid Hormones Regulate transcription Via a Variety of Mechanisms Nuclear envelope GR NHR Co-regulator GR GR GR Response element Target gene Simple Steroid Hormones Regulate transcription Via a Variety of Mechanisms Nuclear envelope GR GR GR Response element Target gene Complex Steroid Hormones Regulate transcription Via a Variety of Mechanisms Nuclear envelope GR GR GR NHR Co-regulator Response element Target gene Tethering Allostery Receptor Conformation with Agonist or Antagonist Agonist Bound Antagonist Bound Note different positions of Helix 12 if an agonist or antagonist is bound in the LBD pocket. Antagonists alter receptor structure Availability of DNA is Regulated DNA sequence regulates Receptor complex formation AGGTCAxxxAGGTCA AGGTCAxxxxAGGTCA AGGTCAxxxxxAGGTCA The DNA Sequence Regulates Receptor Structure Meijsing et al , Science, 2009 Small Structural Differences Produce Specificity of Receptor Activity Meijsing et al , Science, 2009 Therapeutics With Complexity Comes Opportunity • • • • Physiologic replacement Design of potent agonists Design of potent antagonists Design of selective hormone receptor modifiers Pharmacological Use of Hormones • Use of hormones at physiological levels for replacement – Glucocorticoids, thyroid, estrogens, androgens, vitamin D • Use of hormones at pharmacological levels as drugs – Glucocorticoids, PPAR ligands, ATRA • Use of hormone antagonists as drugs – Spironolactone (anti-MR), anti-androgens • Use of selective receptor modifiers – (SERMs) to treat breast cancer – tamoxifen, raloxifene Agonist therapy: Differentiation Therapy for Acute Promyelocytic Leukemia (APL) with Retinoids (ATRA) APL is caused by a gene rearrangment of RAR (ch.15) and PML (ch.17) to give the PML-RAR fusion gene that acts as an oncoprotein and blocks normal RAR action. PML gene function is unclear. RAR action is essential to differentiate PMLs. Rx with ATRA overcomes the block and differentiates the malignant clone. Use of Hormone Receptor Antagonists as Drugs • Mineralocorticoid blockerspironolactone • Androgen blocker - flutamide, bicalutamide • Estrogen blocker - fluvestrant • Glucocorticoid blocker - RU486 • Progesterone blocker - RU486 What is the basis of antagonist or SERM activity? • How can a hormone/drug bind to the receptor but fail to act? • How can a hormone/drug have different actions in different organs although binding to the same receptor? Molecular basis for SERMs SERM Activity in Different Organs Breast Tamoxifen Antagonist Raloxifene Antagonist Uterus Agonist Neutral Bone Agonist Agonist Diseases caused by hormonal abnormalities What is your Dx? Patient also has decreased bone, muscle; diabetes Sperling: Pediatric Endocrinology 5 alpha reductase deficiency • 2% of live births in isolated village of Dominican Republic • Pseudohermaphrodites: first females, then males • Deficient in 5a-reductase • Lack dihydrotestosterone (DHT) • Adult males: scant beard, no acne, small prostate, small testes Hints: Patient did not shave Karyotype: 46 XY Androgen Insensitivity Syndrome • Absent pubic and axillary hair • Normal female external anatomy • Male internal anatomy (undescended testis) • Results from mutations in AR Hereditary 1,25 Dihydroxyvitamin D Resistant Rickets • AR disease • Early onset rickets, hypo Ca, elevated 1,25(OH)2D3, often alopecia • Results from mutation in VDR Clinical Importance of Steroid Receptor Mutations • Vitamin D receptor – hereditary vitamin D resistant rickets • Androgen receptor – testicular feminization – androgen independent prostate cancer • Estrogen receptor – ER negative breast cancer • Thyroid receptor – Thyroid hormone resistance