Chapter 1 Steroid Chemistry and Steroid Hormone Action The first chapter includes an overview of steroid hormone structure nomenclature and action This introductory chapter contains biochemical language we will need to understand the more physiological concepts in the later chapters Steroid Nomenclature In humans all steroid hormones are derived from cholesterol Cholesterol is in turn synthesized de novo from acetate 90 or obtained from the diet 10 Cholesterol is mainly produced and stored in the liver and is transported to the cells in the form of high density lipoprotein HDL and low density lipoprotein LDL In normal individuals both the synthesis of cholesterol and its uptake into the target cells are tightly regulated The studies of Brown and Goldstein elucidated the mechanism for the entry of LDL particles into cells via the LDL receptor endocytotic pathway This pathway was thought to be the major if not the only pathway for the entry of cholesterol into steroidogenic tissues More recently however it was discovered that the steroidogenic cells of the adrenal ovary and testis have specific receptors for HDL These receptors do not result in the internalization of the HDL particle but instead mediate docking of the particle and transfer of some of the cholesterol in the form of cholesteryl esters into the cell The receptor then releases the partially depleted HDL particle back into the circulation This process is thought not to occur in the placenta which probably obtains its cholesterol from maternal LDL 21 18 12 11 1 2 3 HO A 4 C 19 10 5 9 B 13 8 14 20 22 23 24 17 D 16 15 26 25 27 7 6 Figure 1 The structure of cholesterol Figure 1 shows the structure of cholesterol The carbons are numbered according to the convention used for steroid nomenclature The rings are assigned letters from left to right for reference in discussion of the steroid backbone Cholesterol is a hydrophobic molecule in fact it is essentially insoluble in water In the body the majority of the cholesterol is associated with cell membranes where it has an important role in maintaining membrane fluidity During transport in HDL and LDL and storage in intracellular lipid droplets however the 3 position 1 Endocrine Dr Brandt Chapter 1 Steroid Chemistry and Steroid Hormone Action hydroxyl is modified to increase the hydrophobicity of the molecule still further by esterification with a fatty acid Figure 2 O O Figure 2 A cholesteryl ester As we will see in greater detail in the next chapter all steroid hormones are derived from cholesterol The production of the hormones involves a number of precise modifications to the cholesterol structure with different series of modifications occurring in different pathways These modifications include attack at the 11 16 17 18 19 20 and 21 positions conversion of the 3 hydroxyl to a ketone and isomerization of the 5 6 double bond to the 4 5 position Figure 3 A number of additional modifications not shown here occur during conversion of the steroid hormones to inactive metabolites Each set of alterations to the steroid backbone alters the affinity of the steroid for a given steroid receptor 21 20 18 11 19 17 16 3 O HO 5 4 6 5 Figure 3 Locations of attacks on the cholesterol backbone during conversion to steroid hormones In organic chemistry sites of unsaturation i e double bonds are often referred to using the Greek letter Thus steroids containing the 5 6 double bond such as cholesterol are designated 5 steroids those with a 4 5 double bond are called 4 steroids As we will see in Chapter 9 Vitamin D 3 and its metabolites are also derived from cholesterol The numbering used for the metabolites of Vitamin D is the same as that used for all of the other cholesterol metabolites however some aspects of the nomenclature can be somewhat confusing because during the synthesis of Vitamin D3 the 9 10 bond of the B ring is cleaved and the A ring is flipped around the 6 7 bond The active derivative of Vitamin D3 1 25 dihydroxy Vitamin D 3 is produced 2 Endocrine Dr Brandt Chapter 1 Steroid Chemistry and Steroid Hormone Action by successive hydroxylations at the 25 and 1 positions Figures 1 3 are representations of the steroid backbone that ignore most of the stereochemistry Figure 4 shows cholesterol with a little more attention to the stereochemical details For our purposes this representation contains more detail than we are usually going to need but it does illustrate a few important points The 3 hydroxyl the 18 and 19 methyl groups and the side chain attached to the 17carbon all project above the plane of the fused ring system Substituents located above the ring plane are denoted Substituents located below the ring plane such as the hydrogens shown in Figure 4 at the 3 and 17 positions are denoted The difference between and is often the difference between an active and an inactive compound CH3 CH3 HO H H Figure 4 Stereochemical projection of cholesterol Note that most of the hydrogens are omitted for clarity The names we will use for the biologically relevant steroids imply the correct stereochemistry unless specifically noted otherwise e g in order to be cholesterol the steroid must have a 3 hydroxyl and the branched 8 carbon side chain at the 17 position However there is a chemical nomenclature for each steroid that uniquely denotes the structure for that compound This nomenclature is based on describing the modifications to one of four possible backbones Figure 5 Cholestane C27 Pregnane C21 Androstane C19 Estrane C18 Figure 5 The basic backbone structures of the physiological steroids All physiological steroids are derivatives of one of these four backbone structures The differences among these basic structures are relatively minor The differences between cholestane which has 27 carbons pregnane which has 21 carbons and 3 Endocrine Dr Brandt Chapter 1 Steroid Chemistry and Steroid Hormone Action androstane which has 19 carbons are limited to the length of the side chain at the 17 position Estrane differs from androstane in that it lacks the 19 methyl group To generate the names of the actual compounds it is simply necessary to decide which backbone is correct and then make a note of the modifications For example the chemical name of cholesterol is 5 cholestene 3 ol In other words it is a C27 steroid cholestane with a 5 6 double bond 5 cholestene and a 3 hydroxyl 3 ol This same nomenclature is used for all physiological steroids Further examples of this nomenclature are given in Table I