Steroid Hormones

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Types of Steroid Hormones

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Glucocorticoids: cortisol is the major representative in most mammals.

Mineralocorticoids: aldosterone being more prominent

Androgens such as testosterone

Estrogens including estradiol and estrone

Progestogens such as progesterone

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Mechanism of production - 1

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Cholesterol is composed of 4 isoprene ring, one alkyl chain at C17 and a hydroxyl group at C3. From cholesterol, pregnenolone is synthesized. From pregnenolone, progesterone is synthesized and pathways diverge differently to cortisol, corticosterone, and testosterone, then to aldosterone and estradiol from corticosterone and testosterone respectively.

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Mechanism of production - 2

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Cholesterol circulates in the body by binding to proteins like LDL or in a free form. Cells take cholesterol by simple diffusion or by LDL receptors through receptor mediated endocytosis

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Steroid hormone synthesis

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Produced in the adrenal cortex, testes, ovary, and some peripheral tissues like adipose tissue and brain. The first enzymatic step in steroid synthesis is the conversion of cholesterol into pregnenolone. For this reaction to occur, free cholesterol must be transported from cytosol to mitochondria. This is the rate limiting step and it is carried out by the Steroidogenic Acute Regulatory Protein (StAR)

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Enzymes involved in steroid synthesis

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P450 monooxygenases (Hydroxylases) catalyze the exchange of a hydrogen "H" with a hydroxyl "OH". This reaction is irreversible and its cofactors are NADPH and O2. Hydroxylation is accompanied by an electron transport chain.

NADPH › Flavoprotein › Non heme Fe protein › CytP450 › O2

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Cholesterol to Pregnenolone

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Cholesterol's alkyl chain is cut from the 21st C. This is the side chain cleavage by P450scc enzyme, which has hydroxylase and lyase activity. This is also the rate limiting step. Cholesterol is turned to 20,22-Dihydroxycholesterol with mixed function oxidase function and then to pregnenolone desmolase. For sex hormones, pregnenolone is converted to DHEA (dehydroepiandrosterone), from that to androstenedione, then testosterone, then to either dihydrotestosterone or estradiol.

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Enzymes

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Lyases (desmolases) cleave the side chain, dehydrogenases catalyze the reversible oxidation-reduction reactions (hydrogen transfer) and use oxidised or reduced NAD or NADP as cofactor, isomerases catalyze the displacement of double bonds.

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Testosterone and Estrogen Synthesis

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Aromatase converts male hormones to female hormones

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Control of Cortisol Synthesis and Secretion

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ACTH acts on zona fasciculata and increases

intracellular cAMP,

number of LDL receptors

cholesterol esterase activity, transport of cholesterol to mitochon

P450-scc activity,

pregnenolone pool. It is related with circadian rhythm and stress.

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Control of Aldosterone Synthesis and Secretion

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It is controlled by extracellular K concentration and renin-angiotensin-aldosterone system. Both mechanisms increase aldosterone synthesis and secretion. 18-hydroxydehydrogenase activity and on a lesser extent pregnenolone synthesis increase.

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Control of Estradiol Synthesis and Secretion

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FSH stimulates aromatase activity. FSH and estradiol stimulate de novo estradiol synthesis from pregnenolone

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Control of Testosterone Synthesis and Secretion

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LH stimulates androgen synthesis (androstenedion). Effects of LH at the rate limiting pregnenolone synthesis step. Circadian secretion, no relation to LH levels

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Transport of Steroid Hormones

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CBG (corticosteroid binding globulin) is specific to corticosteroids and high affinity for cortisol.

TeBG (SHBG - testosterone binding globulin) is specific to gonadal steroids and have a high affinity for androgens.

Albumin is non specific, has low affinity but high capacity.

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Metabolism of Steroid Hormones - 1

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Mechanisms are addition of a new hydroxyl group, dehydrogenation, reduction of the double bond, conjugation of one or more hydroxyl groups, and sulfation or glucuronidation. Major site of metabolism is liver.

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Metabolism of Steroid Hormones - 2

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Cortisol has a half life of 10 hours and its major metabolite is tetrahydrocortisol glucuronide.

Aldosterone has a half life of 30 hours and tetrahydroaldosterone glucuronide.

Testosterone metabolized to 17-ketosteroids, sulfated and glucuronide forms are excreted in urine. DHT metabolites are excreted in urine as glucuronide forms.

Estrogens are excreted as sulfated and glucuronide forms in urine

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Mechanism of Action of Steroid Hormones

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Nuclear receptors are eukaryotic transcription factors. Regulate functions concerning development, differentiation and metabolism

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Modular Structure of Nuclear Receptors

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The steroid hormone receptors have some common features (zinc fingers, leucine zippers. Enchancer sequence is a sequence away from gene but it can enhance the transcription. Dexamethasone is a cortisol agonist and Tamoxifen is a estrogen antagonist

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Disorders related to steroid hormones

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Congenital adrenal hyperplasia

Cushing syndrome

Adrenocortical deficiency (Addison's disease)

Primary or secondary hyperaldosteronism

Androgen insensitivity (AR mutations, 5ã-reductase deficiency)

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Congenital Adrenal Hyperplasia (Adrenogenital Syndrome)

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Cortisol decrease, ACTH increase, pregnenolone increase, adrenaline cortex hyperplasia and accumulation of intermediates.

21-hydroxylase, 11ß-hydroxylase, 17ã-hydroxylase, 3ß-hydroxysteroid dehydrogenase deficiencies

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21-Hydroxylase Deficiency

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It is rather common and takes place on the conversion of progesterone to hydroxyprogesterone, then deoxycortisol and cortisol. Hydroxyprogesterone also turns to adrenal androgens. Absolute deficiency causes no adrenal androgens to be produced

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Androgen Insensitivity

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Differentiation toward the male phenotype is moderated by testosterone, which is converted to DHT by the action of 5ã-reductase, present within the cytoplasm of cells of the external genitalia and the urogenital sinus. Without the hormonal action of the androgens testosterone and DHT, external genitalia appear phenotypically female.