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 Steroid hormones are synthesized in: 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 Sources of Cholesterol for Steroid Synthesis LH Acetyl CoA Cholesterol pool ATP cholesterol cAMP Protein Kinase mitochondria STAR Desmolase 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

The adrenal gland is composed of the adrenal cortex & adrenal medulla 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) As you knowthe adrenal gland is:

Cholesterol Steroid Hormone Synthesis In Adrenal Cortex Pregnenolone Desmolase Pregnenolone 3-β-Hydroxysteroid dehydrogenase Progesterone 21-α-Hydroxylase 17-α-Hydroxylase 17-α-Hydroxyprogesterone 11-Deoxycorticosterone androgen 21-α-Hydroxylase Androstenedione 11- β -Hydroxylase 11-Deoxycortisol Testosterone Corticosterone NOT IN ADRENAL CORTEX Peripheral Tissues Aldosterone Cortisol 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  Cortisol (or synthetic steroids) Suppress CRH & ACTH secretion Hypothalamus Pituitary Adrenal

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 GnRH LH ++ testosterone synthesis in testis FSH ++ spermatogenesis in testis + - Anterior Pituitary FSH LH + + Testis Testosterone ++ Spermatogenesis ++ Development of secondary male sex characters ++ Anabolism Testosterone Spermatogenesis +

Synthesis of Steroid Hormones in the Ovary

Synthesis of Steroid Hormones 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

Synthesis of steroid Hormones in the Ovary LH ++ estrogen secretion ++ ovulation FSH ++ secretion of estrogen Regulates growth of ovarian follicle Theca cells Granulosa LH LH receptor cholesterol Androstendione Androstendione Testosterone FSH aromatase Estradiol FSH receptors 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

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

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