Chapter 1Steroid Chemistry and Steroid Hormone ActionThe first chapter includes an overview of steroid hormone structure, nomenclature,and action. This introductory chapter contains biochemical language we will need tounderstand the more physiological concepts in the later chapters.Steroid NomenclatureIn humans, all steroid hormones are derived from cholesterol. Cholesterol is in turnsynthesized de novo from acetate (~90%) or obtained from the diet (~10%).Cholesterol is mainly produced and stored in the liver, and is transported to thecells in the form of high density lipoprotein (HDL) and low density lipoprotein(LDL). In normal individuals, both the synthesis of cholesterol and its uptake intothe target cells are tightly regulated.The studies of Brown and Goldstein elucidated the mechanism for the entry of LDL particles intocells via the LDL receptor endocytotic pathway. This pathway was thought to be the major, if not theonly, pathway for the entry of cholesterol into steroidogenic tissues. More recently, however, it wasdiscovered that the steroidogenic cells of the adrenal, ovary, and testis have specific receptors forHDL. These receptors do not result in the internalization of the HDL particle, but instead mediatedocking of the particle and transfer of some of the cholesterol (in the form of cholesteryl esters) intothe 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 frommaternal LDL.272526242322202118171615141312119876519123410HOA BC DFigure 1. The structure of cholesterolFigure 1 shows the structure of cholesterol. The carbons are numbered according tothe convention used for steroid nomenclature. The rings are assigned letters fromleft to right for reference in discussion of the steroid backbone.Cholesterol is a hydrophobic molecule; in fact, it is essentially insoluble in water. Inthe body, the majority of the cholesterol is associated with cell membranes, where ithas an important role in maintaining membrane fluidity. During transport (in HDLand LDL) and storage (in intracellular lipid droplets), however, the 3 position1Chapter 1. Steroid Chemistry and Steroid Hormone Action Endocrine -- Dr. Brandthydroxyl is modified to increase the hydrophobicity of the molecule still further, byesterification with a fatty acid (Figure 2).OOFigure 2. A cholesteryl ester.As we will see in greater detail in the next chapter, all steroid hormones are derivedfrom cholesterol. The production of the hormones involves a number of precisemodifications to the cholesterol structure, with different series of modificationsoccurring 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, andisomerization of the 5-6 double bond to the 4-5 position (Figure 3). A number ofadditional modifications, not shown here, occur during conversion of the steroidhormones to inactive metabolites. Each set of alterations to the steroid backbonealters the affinity of the steroid for a given steroid receptor.202118171611651934HOO∆5Figure 3. Locations of attacks on the cholesterol backbone during conversion tosteroid hormones.In organic chemistry, sites of unsaturation (i.e. double bonds) are often referred tousing the Greek letter ∆. Thus, steroids containing the 5-6 double bond, such ascholesterol, are designated ∆5 steroids; those with a 4-5 double bond are called ∆4steroids.As we will see in Chapter 9, Vitamin D3 and its metabolites are also derived fromcholesterol. The numbering used for the metabolites of Vitamin D is the same asthat used for all of the other cholesterol metabolites; however, some aspects of thenomenclature can be somewhat confusing because during the synthesis of VitaminD3 the 9-10 bond of the B-ring is cleaved and the A-ring is flipped around the 6-7bond. The active derivative of Vitamin D3, 1α,25-dihydroxy-Vitamin D3, is produced2Chapter 1. Steroid Chemistry and Steroid Hormone Action Endocrine -- Dr. Brandtby successive hydroxylations at the 25 and 1 positions.Figures 1-3 are representations of the steroid backbone that ignore most of thestereochemistry. Figure 4 shows cholesterol with a little more attention to thestereochemical details. For our purposes, this representation contains more detailthan we are usually going to need, but it does illustrate a few important points. The3-hydroxyl, the 18- and 19-methyl groups and the side-chain attached to the 17-carbon all project above the plane of the fused ring system. Substituents locatedabove the ring plane are denoted β. Substituents located below the ring plane (suchas the hydrogens shown in Figure 4 at the 3 and 17 positions) are denoted α. Thedifference between α and β is often the difference between an active and an inactivecompound. HOCH3HHCH3βαFigure 4. Stereochemical projection of cholesterol. Note that most of the hydrogensare omitted for clarity.The names we will use for the biologically relevant steroids imply the correctstereochemistry unless specifically noted otherwise (e.g. in order to be cholesterolthe steroid must have a 3β-hydroxyl, and the branched 8-carbon side-chain at the17β position). However, there is a chemical nomenclature for each steroid thatuniquely denotes the structure for that compound. This nomenclature is based ondescribing the modifications to one of four possible backbones (Figure 5).Cholestane(C27)Androstane(C19)Pregnane(C21)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 differencesbetween cholestane (which has 27 carbons), pregnane (which has 21 carbons), and3Chapter 1. Steroid Chemistry and Steroid Hormone Action Endocrine -- Dr. Brandtandrostane (which has 19 carbons) are limited to the length of the side-chain at the17β 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 decidewhich backbone is correct, and then make a note of the modifications. For examplethe chemical name of cholesterol is 5-cholestene-3β-ol. In other words it is a C27steroid (cholestane) with a 5-6 double bond (5-cholestene), and a 3β-hydroxyl (3β-ol).This same nomenclature is used for all