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Transcript
Steroid Hormones Objectives Recall the overall role of steroids in human body. Understand the physiological roles of cholesterol especially in synthesis of steroid hormones. Recall the biochemical and clinical aspects of all types of adrenal steroids. Explain with appropriate details the biochemical and physiological aspects of steroids from the testis and ovaries Recognize the biochemical and clinical relations of congenital adrenal hyperplasia and testicular feminization syndrome Steroid Hormones Types of steroid hormones: Glucocorticoids: cortisol is the major representative in most mammals Mineralocorticoids: aldosterone being most prominent Sex hormones: Androgens: such as testosterone Estrogens: including estradiol & estrone Progestogens: also known a progestins such as progesterone Steroid Hormones All steroid hormones are: Derived from cholesterol & differ only in the ring structure & side chains attached to it. Lipid soluble & thus are freely permeable to membranes so are not stored in cells Steroid hormones are synthesized in: Adrenal cortex: cortisol, aldosterone & androgens (androstendione) Testis: testosterone Ovaries: estrogens & progesterone Placenta: progesterone Some peripheral tissues (as adipose tissue & the brain) Steroid Hormones Cholesterol is the precursor of steroid hormones Transport of Steroid Hormones in Blood Steroid hormones have to be carried in the blood complexed to specific binding plasma proteins (globulins). Cortisol: by corticosteroid binding globulin (transcortin) Sex steroids (testosterone & estradiol): by sex hormone-binding protein (SHBG) Aldosterone: by the plasma protein albumin General Functions of Steroid Hormones Steroid hormones play important roles in: Metabolic regulation (glucocorticoids i.e. cortisol) Electrolyte balance (mineralocorticoids i.e. aldosterone) Reproductive functions (gonadal steroids i.e. testosterone & estrogens) Steroids also play roles in: Inflammatory responses Stress responses Bone metabolism Cardiovascular fitness Behavior, cognition & mood Steroid Hormone Synthesis A series of enzymatic steps in the mitochondria & ER of steroidogenic tissues convert cholesterol into all of the other steroid hormones & intermediates. An important control point this process is the transport of free cholesterol from the cytoplasm into mitochondria. This step is carried out by the Steroidogenic Acute Regulatory Protein (STAR) Sources of Cholesterol for Steroid Synthesis Lipoproteins in Blood LH Cholesterol pool Acetyl CoA ATP cholesterol Protein Kinase mitochondria Desmolase cAMP STAR Pregnenolone Pregnenolone In: Adrenal Cortex Testis Ovary ALL STEROID HORMONES Steroid Hormone Synthesis The first enzymatic step is the conversion of cholesterol to pregnenolone which occurs in the mitochondria. This reaction is carried out by the enzyme desmolase This is a rate limiting, nonreversible step in the initiation of steroid biosynthesis. This step occurs in Adrenal Cortex, Ovary & Testis Steroid hormone synthesis in the Adrenal Cortex Organization of the Adrenal Gland The adrenal gland is composed of the adrenal cortex & adrenal medulla 1- The adrenal cortex: The zona glomerulosa: secretes aldosterone The zona fasciculata: secretes cortisol The zona reticularis: secretes the adrenal androgens 2- The adrenal medulla: Secretes adrenaline (epinephrine) Cholesterol Steroid Hormone Desmolase Synthesis Pregnenolone In Adrenal Cortex 3-β-Hydroxysteroid dehydrogenase Progesterone 17-α-Hydroxylase 21-α-Hydroxylase 17-α-Hydroxyprogesterone 11-Deoxycorticosterone 11- β -Hydroxylase 21-α-Hydroxylase 11-Deoxycortisol Corticosterone Aldosterone Cortisol androgen Androstenedione Testosterone NOT IN ADRENAL CORTEX Peripheral Tissues Estradiol Regulation of Cortisol Secretion from the Adrenal Cortex Negative feedback control: ACTH release from the anterior pituitary is stimulated by hypothalamic secretion of corticotrophin releasing hormone (CRH). CRH ACTH Cortisol Hypothalamus Pituitary Cortisol (or synthetic steroids) Adrenal Suppress CRH & ACTH secretion Testosterone Production in the Testis Pathway of Testosterone Production in the Testis The production of androgens from cholesterol is identical to that in the adrenal, except that it continues from androstenedione to testosterone. Cholesterol In the Testis Androstenedione Testosterone 17b-hydroxysteroid Oxidoreductase N.B. In the adrenal cortex, androstendione (adrenal androgen) is formed. They are released to blood & converted in the testis (& peripheral tissues) to testosterone Pathway of Testosterone Production in the Testis The main steroid produced in the male is testosterone produced from the testis. . - In the male, there is peripheral conversion of testosterone to: - Dihydrotestosterone: in androgen target tissues, like muscles by 5 a reductase Or to Estradiol : mostly in adipose tissue by enzyme cytochrome P450 aromatase Control of Testicular Function by the Pituitary Gonadotrophins (LH & FSH) Hypothalamus LH ++ testosterone synthesis in testis FSH ++ spermatogenesis in testis GnRH + Anterior Pituitary - LH FSH +Testis + Testosterone Spermatogenesis + Testosterone ++ Spermatogenesis ++ Development of secondary male sex characters ++ Anabolism Synthesis of Steroid Hormones in the Ovary Synthesis of Steroid Hormones in the Ovary In the ovary: Estradiol is formed from the conversion of androgens (testosterone) into estradiol by the enzyme cytochrome P450 aromatase (in granulosa cells). The androgens required for conversion come from the neighboring theca cells. Cholesterol Theca Cells Stimulated by FSH Stimulated by LH Granulosa Cells of the Ovary Androstendione Testosterone Estradiol Aromatase Synthesis of steroid Hormones in the Ovary LH ++ estrogen secretion ++ ovulation LH FSH FSH ++ secretion of estrogen Regulates growth of ovarian follicle FSH receptors LH receptor cholesterol Estradiol Theca cells Androstendione Granulosa cells Androstendione aromatase Testosterone LH & FSH stimulates estrogen secretion FSH regulates growth of ovarian follicles LH stimulates ovulation Mechanism of Action of Steroid Hormones Cytosolic Receptors Hormone Receptor Complex HRE of genes Transcription of genes is increased Mechanism of Action of Steroid Hormones Congenital Adrenal Hyperplasia (CAH) It is the result of an inherited enzyme defect in steroid hormones biosynthesis in the adrenal cortex. The Adrenal Cortex : Cannot secrete cortisol absent negative feedback to the pituitary) ACTH continues to drive steroid biosynthesis adrenal hyperplasia & accumulation of cortisol precursors (depending on which enzyme is lacking) Cannot secrete aldosterone electrolyte disturbances The condition might be fatal unless diagnosed early 21 a-Hydroxylase Deficiency Progesterone 17a-hydroxyprogesterone Androstenedione 21 a-hydroxylase In Peripheral Tissues 11-deoxycorticosterone 11-deoxycortisol Aldosterone Cortisol Testosterone Virilisation of ♀ Precocious sexual development in ♂ 21 a-Hydroxylase Deficiency Accounts for ~ 95% of all cases of CAH Autosomal recessive condition Low or absent synthesis of Cortisol & Aldosterone Cortisol ACTH secretion Adrenal Gland hyperplasia Some of the accumulated precursors are diverted to the biosynthesis of sex hormones Signs of Androgen Excess: stimulation of adrenal androgen production virilisation in baby girls & precocious puberty in boys In severe cases, Aldosterone Deficiency is evident salt & water loss hypovolaemia & shock neonatal adrenal crisis 21 a-Hydroxylase Deficiency Diagnosis: 1- Prenatal Diagnosis (Intrauterine, before birth) DNA testing and detection of mutations in the CYP21 gene can be helpful for prenatal diagnosis & confirmation of diagnosis 2- Neonatal Diagnosis (after birth) Serum sample taken at least 2 days after birth (earlier samples may contain maternally derived 17-hydroxyprogesterone) Classic 21-hydroxylase deficiency is characterized by markedly elevated serum levels of 17hydroxyprogesterone 3- Late-onset (in adult life) May require corticotropin stimulation test: Injecting a 0.125-mg or 0.25-mg bolus of corticotropin Measuring base-line and stimulated levels of 17-hydroxyprogesterone. High level after stimulation is diagnostic ( 2x upper reference range) Disorders of Male Sexual Differentiation They are rare group of disorders The defect may be in: Impaired Testosterone production Inactive androgen receptors target tissues cannot respond to stimulation by circulating testosterone e.g. Testicular Feminization Syndrome Testicular Feminization Syndrome 46, XY karyotype X-linked recessive disorder Androgen receptor resistance high testosterone blood level In peripheral tissue, testosterone will be converted by aromatase into estradiol feminization