Lecture 28 Steroid Hormones PDF

Steroid Hormones All steroid hormones are derived from cholesterol(substrate) but their structure differ from the cholesterol (ring structure and side chains) Nomenclature: Steroids with : 21-carbon: pregnanes, 19-carbon: androstanes 18-carbon: estranes. Are not stored, but synthesized and immediate...

Steroid Hormones All steroid hormones are derived from cholesterol(substrate) but their structure differ from the cholesterol (ring structure and side chains) Nomenclature: Steroids with : 21-carbon: pregnanes, 19-carbon: androstanes 18-carbon: estranes. Are not stored, but synthesized and immediately released Steroid hormones are not water soluble so they have to be carried in the blood complexed to specific binding globulins (proteins). All steroid hormones are lipid soluble and thus diffuse across lipid membranes of the target cell Enzymes which produce steroid hormones from cholesterol are located in mitochondria and smooth ER memorize Types of steroid hormones Steroid hormones are classified according to their physiologic action and tissue of origin: Type of steroid hormone Endocrine gland Name of steroid Glucocorticoids Adrenal cortex Zona fasiculata cortisol, corticosterone Mineralocorticoids Adrenal cortex aldosterone Loading… Zona glomerulosa Androgens Adrenal cortex Zona reticularis Testis Androstenedione testosterone Estrogens Ovary estradiol, estrone, estriol Progestins Corpus luteum (ovary) progesterone Functions - promote gluconeogenesis; favor breakdown of fat and protein (fuel mobilization); -anti-inflammatory -Stress adaptation maintains blood volume and blood pressure by increasing sodium reabsorption by kidney (RAAS system) - Promote spermatogenesis development of male secondary sex characteristics; cremoval -prevents bone resorption -Brings about anabolic pathways -Regulates menstrual cycle -development of female secondary sex characteristics; -prevents bone resorption - Called as hormone of pregnancy prepares uterus lining for implantation of ovum Synthesis of Steroids first step Irreversible step cleavage of GC cholesterol to from pregnanc one The first enzymatic step in steroid synthesis is the irreversible cleavage of 6 C from cholesterol (C27) yielding pregnenolone (C21) The enzyme that catalyzes this reaction is Cholesterol side-chain cleavage enzyme (cytochrome P450scc enzyme), located in the inner mitochondrial membrane. The enzyme is also called as DESMOLASE +3NADPH+ 3O2 Cholesterol (C27) P450scc + pregnenolone (C21) +3NADP++3H2 O Cholesterol is mostly located in the external (Outer) mitochondrial membrane. The conversion of cholesterol to steroids occurs in the internal (Inner) mitochondrial membrane. We have aqueous phase between the 2 membranes (Intramembranous space) which can not be crossed by the lipophilic cholesterol water filled How does cholesterol get from the external membrane to the internal membrane? Answer: Steroidogenic acute regulatory protein (StAR), which transports cholesterol into the mitochondria, moving it from the outer membrane to the inner membrane. It’s the ratelimiting step in the synthesis of steroids. Loading… Pregnenolone The precusor molecule for all C18, C19 and C21 steroids. Produced directly from cholesterol, Synthesis of corticosteroids and androgens The corticotsteroids and androgens are made in different regions of the adrenal cortex (zona glomerulosa, fasciculata, reticularis) and secreted in blood in response to different signals P450sc c Adrenal cortex P450sc c P450sc c Androgens Secreted by the inner layer (zona reticularis) of adrenal cortex. The androgens produced in adrenal cortex are primary weak androgens which get converted to strong ones in respective reproductive organs. weak Estrone androgen Main product: androstenedione (an intermediate component) converted in the peripheral tissues into testosterone, estrone and estradiol. Testosterone: male sex hormone, responsible for secondary male sex characteristics and spermatogenesis. Estrone: female sex hormone, responsible for secondary female sex characteristics Estradiol: primary female sex hormone, essential for the development and maintenance of female reproductive tissues and regulate menstrual cycle Testosterone Estradiol Mechanism of steroid hormone action Each steroid diffuses across the plasma membrane of its target cell and bind to a specific cytosolic receptor. formation of active steroid-steroid receptor complex These complex translocate to nucleus where it binds to specific regulatory DNA sequences: hormone response element (HRE) in association with coactivator proteins, thereby causing promoter activation and increased transcription of targeted genes. Hormone-receptor complexes can also inhibit transcription in association with corepressor proteins. Degradation of Steroid Hormones Steroids are converted into inactive metabolic molecules in the liver Reactions include: Reduction of unsaturated double bonds to single bonds Introduction of additional OH groups The resulting structures are made more soluble (no need for protein carriers) by conjugation with glucouronic acid or sulfate These conjugate steroid metabolites: 20-30% of conjugated metabolites secreted in the bile and then excreted in feces Remainder (70-80%) are released into blood, filtered from the plasma in the kidney and passing into the urine.