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Steroid Hormones

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.

raymond-riley
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Steroid Hormones

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  1. Steroid Hormones

  2. 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

  3. 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 progestinssuch as progesterone

  4. 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)

  5. Steroid Hormones Cholesterol is the precursor of steroid hormones

  6. 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

  7. 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

  8. 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)

  9. Lipoproteins in Blood Sources of Cholesterol for Steroid Synthesis LH Acetyl CoA Cholesterolpool ATP cholesterol cAMP Protein Kinase mitochondria STAR Desmolase Pregnenolone Pregnenolone In: Adrenal Cortex Testis Ovary ALL STEROID HORMONES

  10. 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

  11. Steroid hormone synthesis in the Adrenal Cortex

  12. Organization of the Adrenal Gland 1- The adrenal cortex: The zonaglomerulosa: secretes aldosterone The zonafasciculata: secretes cortisol The zonareticularis: secretes the adrenal androgens 2- The adrenal medulla: Secretes adrenaline (epinephrine) The adrenal gland is composed of the adrenal cortex & adrenal medulla

  13. Cholesterol Steroid Hormone Synthesis In Adrenal Cortex Desmolase Pregnenolone 3-β-Hydroxysteroid dehydrogenase Progesterone 17-α-Hydroxylase 21-α-Hydroxylase 17-α-Hydroxyprogesterone 11-Deoxycorticosterone androgen 21-α-Hydroxylase Androstenedione 11-Deoxycortisol 11- β-Hydroxylase Testosterone Corticosterone Peripheral Tissues NOT IN ADRENAL CORTEX Aldosterone Cortisol Estradiol

  14. 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 •  Cortisol (or synthetic steroids) Suppress CRH & ACTH secretion Hypothalamus Pituitary Adrenal

  15. Testosterone Production in the Testis

  16. 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

  17. Pathway of Testosterone Production in the Testis • The main steroid produced in the male is testosteroneproduced 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 P450aromatase

  18. Control of Testicular Function by the Pituitary Gonadotrophins (LH & FSH) Hypothalamus GnRH LH ++ testosterone synthesis in testis FSH ++ spermatogenesis in testis + - Anterior Pituitary LH FSH + + Testis Testosterone ++ Spermatogenesis ++ Development of secondary male sex characters ++ Anabolism Testosterone + Spermatogenesis

  19. Synthesis of Steroid Hormones in the Ovary

  20. 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 Androstendione Testosterone Estradiol • Aromatase Stimulated by FSH Stimulated by LH Granulosa Cells of the Ovary

  21. FSH LH LH receptor cholesterol Androstendione Estradiol Granulosa cells Theca cells aromatase AndrostendioneTestosterone Synthesis of steroid Hormones in the Ovary FSH ++ secretion of estrogen Regulates growth of ovarian follicle LH ++ estrogen secretion ++ ovulation FSH receptors LH & FSH stimulates estrogen secretion FSH regulates growth of ovarian follicles LH stimulates ovulation

  22. Mechanism of Action of Steroid Hormones Cytosolic Receptors Hormone Receptor Complex HRE of genes Transcription of genes is increased

  23. Mechanism of Action of Steroid Hormones

  24. 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

  25. 21 -Hydroxylase Deficiency 17-hydroxy-progesterone Progesterone Androstenedione In Peripheral Tissues 21 -hydroxylase 11-deoxycortisol 11-deoxycorticosterone Testosterone Cortisol Aldosterone Precocious sexual development in ♂ Virilisation of ♀

  26. 21 -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

  27. 21 -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 17-hydroxyprogesterone 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)

  28. Disorders of Male Sexual Differentiation • They are raregroup 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

  29. 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

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