Steroid Hormones PDF

Steroid Hormones, Glucocorticoid, Mineralocorticoids and Sex Hormones Course: BC 100 MUHAS Dar es Salaam Tanzania By Dr Solomon Genet 1  Topics Covered in this Lecture Biosynthesis of steroid hormones Steroid...

Steroid Hormones, Glucocorticoid, Mineralocorticoids and Sex Hormones Course: BC 100 MUHAS Dar es Salaam Tanzania By Dr Solomon Genet 1  Topics Covered in this Lecture Biosynthesis of steroid hormones Steroid hormone receptors Plasma transport of steroids and metabolism Adrenal steroid hormones: Glucocorticoids, Mineralocorticoid, Androgens -Hormone Biosynthesis -Control of Hormone production -Actions of adrenal steroids Adrenal steroid hormones: Testosterone, Estrogen and progesterone -Hormone Biosynthesis -Control of Hormone production -Actions of gonadal steroids 2  Steroid Hormones Progesterone Cholesterol Aldosterone Testosterone Estradiol Cortisol 3  Endocrine glands * * * 4  Steroid hormone action Lipid soluble steroids diffuse into cell without any carrier Interact with intracellular receptors and steroid-receptors complex move to nucleus Interact with gene promotors at specific hormone response elements (HRE) Resultng in up or down regulation of transcription 5  Steroid receptor structure Transcriptional DNA Hormone Regulation Unit Binding Unit Binding Unit N ter C ter DNA strand contains specific hormone response elements, which binds to specific site on the DNA binding unit of the steroid hormone receptor. 6  Steroid Hormones Act on Intracellular Receptors Steroid Hormone plasma membrane SHR control of gene protein Steroid hormone transcription synthesis receptor HRE X gene X SHR are found in Both cytosol and the nucleus Timescale Nucleus. - hours! 7  Biosynthesis of Steroid Hormones The rate-limiting step in steroid biosynthesis involves the cleavage of a 6-carbon group from cholesterol by cytochorome P450 side chain cleaving enzyme (P450ssc or desmolase ) in the mitochondria to produce pregnenolone Desmolase enzyme activity is increases by cAMP- PKA by: -phosphorylation and activation of cholesterol ester hydrolase which generates free cholesterol -de novo synthesis of Steroid acute regulator protein (StAR)- translocates cholesterol from cytoplasm to mitochondria -increasing gene transcription of (P450ssc) Pregnenolone in the mitochondria is converted to 17-OH pregnenolone or progesterone by P450c17 or 3β-dehydrogenase Tissue dependent steroid 8 Control of Steroid Hormones Biosynthesis cAMP-PKA activity is stimulated by binding of tropic hormone to cell surface receptors on steroid producing cells Peptide hormones are responsible for stimulating the synthesis of steroid hormone: Adrenal steroid hormones Cortisol Adrenocorticotrophic hormone (ACTH) Aldosterone Angiotensin II/III Gonadal steroid hormones Progesterone and Testosterone Luteinizing Hormone(LH) Estradiol Follicle Stimulating Hormone (FSH) 9 Effect of ACTH on Adrenal Cortex Cells ACTH R Gs adenylate cyclase +ve cholesterol ester ATP cAMP cholesterol ester hydrolase activates + cholesterol protein kinase A / mitochondrial protein phosphorylation cholesterol activation + uptake CORTISOL 10  Action of Angiotensin II on Adrenal Cortex Cells Angiotensin L II R PLC diacylgycerol (DAG) PIP2 Gq activation of intracellular proteins protein kinase C inositol trisphosphate (IP3) calmodulin/Ca 2+ protein phosphorylation/ activation 2+ Ca Increased P450ssc hence Increased production of endoplasmic reticulum aldosterone 11  Plasma Transport of Steroids Plasma albumin binds all steroids with low affinity Cortisol Cortisol-binding globulin (CBG); binds 70-80% Aldosterone No high affinity binding protein (weakly to albumin) Adrenal androgens Sex hormone binding globulin (SHBG) Progesterone Binds CBG with the same affinity as cortisol Testosterone High affinity to SHBG, binds 97-99% Estrogen Binds SHBG five times less avidly than testosterone 12  Metabolism of Adrenal Steroids kidney filters free steroid hormones but reabsorbs ~90% Liver converts steroids to hydrophilic metabolites Liver damage e.g. cirrhosis leads to increased circulating steroids 13 Adrenal Steroid Hormones 14 Adrenal Structure Cortex Medulla 15  The Adrenal Cortex medulla cortex capsule zona reticularis zona fasciculata zona glomerulosa androgens cortisol aldosterone 16  Features of steroid producing cells Contain lipid droplets Have numerous mitochondria Smooth endoplasmic reticulum Lysosomes No secretory vesicles 17 Adrenal steroid hormone synthesis Made rapidly from cholesterol via enzymes in mitochondria and smooth ER- NOT STORED * Mitochondria Androstenedione Smooth ER Zona Reticularis Cortisol Zona Fasciculata aldosterone Zona Glomerulosa 18  Regulation of Adrenal Steroid Synthesis Mineralocorticoid secretion from the zona glomerulosa is stimulated by “Renin-angiotensin System” Glucocorticoid and adrenal androgen production in zona fasciculata and zona reticularis is controlled by hypothalamic CRF (corticosteroid releasing factor) and pituitary ACTH “ feedback loop of the HPA axis” 19  Control of Aldostrone Production Low blood pressure Kidney Or Low plasma Na+ Renin Angiotensinogen Angiotensin I Liver Lung Angiotensin Converting Enzyme (ACE) Angiotensin I Angiotensin II Increase K+ in plasma or ADH Adrenal Mineralocorticoid 20 aldosterone  Control of Cortisol Production stress Hypothalamus CRF Inhibitory Anterior feedback pituitary ACTH Adrenal glucocorticoids 21 cortisol  Glucocorticoids Act on glucocorticoid receptors (GR) and effect Metabolism -increase glucose production -promote lipolysis Maintenance of blood circulation Maintenance of plasma water and electrolyte balance Reduce inflammation and the immune response -increase vasodilation and fluid exudation -promote lymphocyte destruction -decrease leukocyte migration to sites of tissue damage -decrease the production of immunomediators 22  Glucocorticoids increase [Glucose] in blood Accelerate gluconeogenesis in liver Accelerate lipid and protein catabolism in liver and peripheral tissues - 23  Glucocorticoids Decrease the Production of Immuno-mediators Glucocorticoids decrease the production and action of many cytokines e.g. IL-1, IL-2, IL-3, IL-4, IL-5, IL6, IL-8, TNF γ Glucocorticoids decrease prostaglandin generation by: - inhibiting the expression of cycloxygenase (COX2) AP1-transcription factor activator protein - inhibiting the transcription of phospholipase A2 gene (PLA2 ) -inducing the formation of lipocortins 24  Lipid Messengers in Inflammation Membrane phospholipid cortisol inhibition Phospholipase A2 of expression Leukotrienes Arachidonic acid Cycloxygenase PGH2 Prostaglandin synthase Prostaglandin I2 Prostaglandin E2 25  Aldosterone Acts on mineralocorticoid receptors (MR) Regulates body sodium and fluid volume Stimulates re-absorption of Na+ in the kidney in exchange for K+ In salivary and sweat glands aldosterone regulates ion transport to retain Na+ 26 Aldosterone Induces Synthesis of Na/K ATPase Collecting duct cell blood kidney lumen 2 K+ K+ ATP 3 Na+ Na+ MR MR-mineralocorticoid aldosterone receptor 27 The Renin-Angiotensin System 28  Adrenal Androgens e.g. DHEA = dehydroepiandrostenedione minor component of adrenal secretion weak androgen stimulates pubertal hair growth 29 Gonadal Steroid Hormones 30  Gonadal Steroid hormone synthesis Aromatase Esterone 5α-reductase Aromatase Dihydrotestosterone Testosterone Estradiol 31  Regulation of Gonadal Steroid Synthesis Gonadal steroid synthesis are controlled by hypothalamic GnRH and pituitary FSH and LH In males, GnRH is pulsatile and constant – LH stimulates testosterone production from leydig cells in the testis – FSH stimulates spermatogenesis by acting on sertoli cells semineferous tubules In females, GnRH is also pulsatile, but FSH and LH levels are cyclical – FSH stimulates the production of estrogen in granulosa cells from androgen precursors produced by thecal cells stimulated by LH – LH also stimulates the production of progesterone from the corpus luteum after ovulation 32  Control of Estrogen and Progesterone Production Hypothalamus GnRH Anterior pituitary Inhibitory Positive feedback feedback FSH LH Ovary GF CL Estrogen Progesterone 33 Control of Testosterone Production Hypothalamus GnRH Anterior pituitary Inhibitory feedback FSH LH Testis Sertoli cells Leydig cells + Testosterone 34  Testosterone DHT = dihydrotestosterone is the most potent metabolite of testosterone, produced in target organs from testosterone by 5α-reductase Both Testosterone and DHT act on androgen receptors: Testosterone DHT Spermatogonia Prostate Muscle and Bone External genitalia Brain Genital skin Sexual differentiation Spermatogenesis and fertility Development of secondary sexual characteristics Male pattern behaviour 35  Estrogens Estrogens are formed by the aromatisation of androgens by Aromatase, Estradiol from testosterone and Esterone from androstenedione Act on estrogen receptors: Sexual differentiation Development of secondary sexual characteristics Can cause some degree of retention of salt and water Mild anabolic actions increase triglycerides and high density lipoproteins Increase coaguability of the blood Important for cycle regulation and pregnancy 36 Hormonal Regulation of the Menstural Cycle The menstural cycle results form a complex interaction between the Hypothalamus, Pituitary and Ovary and has two phases 1. Follecular phase FSH promotes follecular development and the formation of a “gaafian follicle” Fluid filled atrum Ovum Thecal cells Granulosa cells Granulosa cells produce Estrogen from androgen precursors derived from thecal cells in response to LH stimulation 37 Hormonal Regulation of the Menstural Cycle 2. Luteal phase The rising levels of estrogen trigger an ovulatory surge in LH and FSH possible by positive feedback to the pituitary and hypothalamus resulting in ovulation LH causes lutinisation of granulosa cells to form “corpus luteum” (CL) and stimulates progesterone production Granulosa cells Progesterone exert a negative feedback on FSH and LH If implantation of the ovum occur If it does not CL continues to release progesterone CL regresses As pregnancy proceeds the placenta takes over FSH LH feedback release....REPEAT CYCLE 38 Hormonal Regulation of the Menstural Cycle Follecular Phase Luteal Phase 17-hydroxy progesteron progesteron ng/ml ng/ml 17-β Estradiol ng/ml LH FSH ng/ml Days of cycle 39  Summary Steroid hormones are cholesterol derived lipids. They mediate their actions by binding to intracellular steroid hormone receptors and can activate the transcription of numerous genes The adrenal glands produce Aldosterone, a mineralocorticoid that is involved in the regulation of sodium balance and blood pressure in response to stimulation by angiotensin II or increased potassium concentrations, Cortisol, a glucocorticoid that is important in the stress response, and small amounts of androgens in response to ACTH The testis and ovary produce gonadal steroids Testosterone and Estrogen/progesterone which are important for sexual differentiation and development of secondary sexual characteristics and reproduction in response to LH and FSH 40 Hope you are well fed, any emptiness?? Love you all n bye for now!! 41