Steroid Hormones Lecture PDF

# Structure of Steroid Hormones ## Signal transduction pathways - Signal transduction pathways are pathways of molecular interactions that provide communication between the cell membrane and intracellular endpoints, leading to change in the cell ## Hormones - Hormones are organic chemical messen...

# Structure of Steroid Hormones ## Signal transduction pathways - Signal transduction pathways are pathways of molecular interactions that provide communication between the cell membrane and intracellular endpoints, leading to change in the cell ## Hormones - Hormones are organic chemical messengers produced and secreted by endocrine cells into the bloodstream. - Hormones regulate, integrate and control a wide range of physiologic functions. - Hormones transport signals from one cell to another - There are four major chemical classes of hormones: - Steroid hormones - i.e. progesterone - Peptide hormones - i.e. insulin - Amino acid derivatives - epinephrine (adrenaline) - Prostaglandins and related compounds - There are three major functional types of hormones: - **Endocrine action (e.g. steroid hormones)**: - The hormone is distributed in blood and binds to distant target cells - **Paracrine action (e.g. prostaglandins)**: - The hormone acts locally by diffusing from its source to target cells in the neighbourhood - **Autocrine action (e.g. interleukin-2)**: - The hormone acts on the same cell that produced it - A hormone can do all three actions simultaneously, e.g. Corticotrophin Releasing Hormone (CRH) - Hormones are required in very small quantities - Hormones are degraded very rapidly, for this reason they have binding proteins to enable them to degrade and mask their bioactivity while in the blood stream - Modern analytical techniques and chemical synthesis are very important - A patient has come with symptoms due to an endocrinology disorder (either too high or too low). This is detected by blood tests to check the level of the particular hormone. Analytical techniques must be sensitive, accurate and specific to minuscule levels of hormones. ## Steroid hormones - Steroids are lipophilic, low-molecular weight compounds - Steroids are derived from cholesterol in the smooth endoplasmic reticulum and mitochondria of endocrine cells. - Cholesterol is the precursor molecule for all steroid hormones - Steroid hormones are produced mainly by endocrine glands such as: gonads (testes and ovaries) and adrenals and during pregnancy by the feto-placental unit. - Steroids coordinate physiological and behavioural responses for specific biological processes - Steroids are non-polar (no net charge), and can therefore diffuse across lipid membranes, such as the plasma membrane. They leave cells shortly after synthesis. ## Structure of steroids - Most steroid have a 'main' sterane structure. The sterane system is not broken down and remains stable. - The conversion of active to inactive forms involves alteration of ring substituents rather than the ring structure itself. - The regulation of steroidogenesis involves control of the enzymes which modify cholesterol into the steroid hormone of interest. ## Structure of Cholesterol - A diagram of cholesterol is displayed. ## Structure of major steroid hormones in humans - **Pregnenolone** - Produced directly from cholesterol - **Progesterone** - A progestin produced directly from pregnenolone and secreted from the corpus luteum - Responsible for changes associated with luteral phase of the menstrual cycle - Differentiation factor for mammary glands - **Aldosterone** - The principal mineralocorticoid produced from progesterone in the zona glomerulosa of the adrenal cortex - Raises blood pressure and fluid volume - Increase Na+ uptake - **Testosterone** - An androgen produced from progesterone - Male sex hormone synthesised in the testes - Responsible for secondary male sex characteristics - **Estradiol** - An oestrogen produced in the ovary - Female sex hormone - Reennncihle for corondary female cor characteristics ## Cortisol - Dominant glucocorticoid in humans - Synthesised from progesterone in the zona fasciculata of the adrenal cortex - Involved in stress adaptation - Elevates blood pressure and Na+ uptake - Numerous effects on the immune system - Important in all steroidal compounds is their stereochemistry or 3D configuration. Stereoisomerism is important for biological activity (i.e. for steroid-protein interactions) ## Synthesis of cholesterol - A diagram depicting the synthesis of cholesterol is displayed. ## Metabolism of cholesterol - Cholesterol can become bile acid through the liver or it can act as a hormone in various tissues. ## Biosynthesis of Steroid Hormones - **Adrenal gland diseases** - **Hyperfunction (too much) of adrenal cortex** - Cortisol excess (Cushing's syndrome) - Androgen excess - Hyperaldosteronism - **Hypofunction (not enough) of adrenal cortex** - Addison's disease - Acute adrenocortical insufficiency - Congenital adrenal hyperplasia - **Steroidogenic Acute Regulatory protein (STAR)** - STAR is a 37-kDa protein, It is identified in almost all steroidogenic tissues and is induced by trophic hormones - STAR Is the key protein that transports the cholesterol from outside of the cell to the Inside - 37 kDa STAR precursor attaches to a receptor in the mitochondria - P450 cleave off the cholesterol side chain - C-terminus of StAR functions in cholesterol transport and the N-terminus begins Import - Cholesterol is converted to pregnenolone or progesterone which leave the mitochondria - Matrix processing proteases yield the 30 kDa protein - The refolded 30 kDa StAR is degraded - It is responsible for cholesterol transport in mitochondria. It is the delivery of cholesterol to the site of first enzymatic conversion that constitutes the rate-limiting and hormonal regulated step in steroidogenesis. A mutation in this mechanism gives rise to congenital lipoid adrenal hyperplasia. This gives rise to hyperpigmentation, excess testosterone synthesis and so forth - The active form has a rapid turnover - Cytochrome P450 catalyse the hydroxylation and cleavage of steroid hormones - CYP11A, CYP11B1 and CYP11B2 are associated with mitochondrial membranes - CYP17, CYP19 and CYP21 are associated with the endoplasmic reticulum - See lecture handout to check the enzymatic activity of each cytochrome protein