Essential Endocrinology and Diabetes. Richard I. G. Holt
the four‐carbon ring structure of cholesterol (Figure 2.6). The precise sequence of enzyme action determines which steroid hormones are generated (Box 2.5). In addition, cholesterol is a critical building block of all mammalian cell membranes and the starting point for synthesizing vitamin D, which functions, and can be classified, as a hormone (Chapter 9). Cholesterol is acquired in approximately equal measure from the diet and de novo synthesis mostly in the liver. Dietary cholesterol is delivered to cells as a complex with low‐density lipoprotein (LDL–cholesterol). Intracellular uptake is via the cell‐surface LDL receptor and endocytosis (Figure 2.3b). De novo biosynthesis commences with coenzyme A (CoA) synthesized from pantothenate, cysteine and adenosine, and proceeds via hydroxymethylglutaryl coenzyme A (HMG‐CoA) and mevalonic acid (Figure 2.5). The rate‐limiting step is the reduction of HMG‐CoA by the enzyme HMG‐CoA reductase. Pharmacological inhibition of this enzyme to treat hypercholesterolaemia and lessen cardiovascular disease has led to the most widely prescribed drug family in the world (the ‘statins’) and the award of the Nobel Prize to Michael Brown and Joseph Goldstein (Table 1.2).
Box 2.5 Hormones derived from cholesterol
Cholesterol from the diet and from de novo synthesis (mostly in the liver) used to synthesize:
Vitamin D (Chapter 10)
Steroid hormones:Adrenal cortex: aldosterone, cortisol and sex steroid precursors (Chapter 6)Testis: testosterone (Chapter 7)Ovary and placenta: oestrogens and progesterone (Chapter 7)
Figure 2.5 Synthesis of cholesterol. Step ① is catalyzed by the enzyme thiolase; otherwise, the enzymes are shown to the right of the cascade. The individual steps between squalene and cholesterol have been omitted.
Figure 2.6 Overview of the major steroidogenic pathways. Yellow shading indicates the enzymatic change since the last step. The enzymes are shown by proper name and common name according to their action. Note some enzymes perform multiple reactions (e.g. CYP17A1 acts as both a hydroxylase and lyase) and some reactions are performed by multiple enzyme isoforms (e.g. HSD3B exists as HSD3B1 and HSD3B2). For 17‐OH progesterone, the enzymatic change illustrated is that catalyzed by HSD3B activity rather than CYP17A1. The simplified pathways are grouped into three blocks: (a) common to both the adrenal cortex and the gonad; (b) adrenocortical steroidogenesis; and (c) pathways characteristic of the testis (testosterone) or ovary and placenta (oestradiol). OH, hydroxy; DHEA, dehydroepiandrosterone.
In steroidogenic cells, cholesterol is largely deposited as esters in large lipid‐filled vesicles (Figure 2.3b). Upon stimulation, cholesterol is released from these stores and transported into the mitochondria, a process that is facilitated by the steroid acute regulatory (StAR) protein in the adrenal and gonad and by the related protein, start domain containing 3 (STARD3), in the placenta. The first step in the synthesis of a steroid hormone is the rate‐limiting conversion of cholesterol to pregnenolone. Pregnenolone then undergoes a range of sequential modifications in the mitochondria or the ER to produce the wide range of steroid hormones.
Nomenclature of steroidogenic pathways
Figure 2.6 shows an overview of steroid hormone biosynthesis in human. Many of the enzymes that catalyze steps in these pathways are encoded by the cytochrome P450 (CYP ) family of related genes that is also critical for hepatic detoxification of xenobiotic compounds and drugs. Some of the enzymes are common to both the adrenal cortex and gonad (e.g. CYP11A1), whereas others are restricted and explain the distinct steroid profiles in each tissue (e.g. CYP21A2, needed for cortisol and aldosterone biosynthesis, is very largely limited to the adrenal cortex).
Historically, the enzymes have been named according to function at a specific carbon atom (e.g. hydroxylation), with a Greek letter indicating orientation above or below the four‐carbon ring structure (e.g. 17α‐hydroxylase attaches a hydroxyl group in the alpha position to carbon 17; Figure 2.6).
The common names used for steroids also adhere to a loose convention. The suffix ‐ol indicates an important hydroxyl group, as at the carbon‐3 position in cholesterol. The suffix ‐one indicates an important ketone group (testosterone). The extra presence of ‐di, as in ‐diol (oestradiol) or ‐dione (androstenedione), reflects two of the groups. ‘‐ene’ (androstenedione) indicates an important double bond in the steroid ring structure.
Storage of steroid hormones
In contrast to peptide hormones, which are stored and capable of rapid release, steroid hormones are synthesized on demand. This delays their release into the circulation following an initial stimulus explaining, at least in part, the slower onset of action for steroid hormones compared to peptide hormones.
Hormone transport
Most peptide hormones are hydrophilic and can circulate free in the bloodstream with little or no association with serum proteins. In contrast, steroid hormones and thyroid hormones are hydrophobic and circulate largely bound to proteins. There are relatively specific transport proteins for many of the steroid hormones, e.g. cortisol‐binding globulin (CBG) and sex hormone‐binding globulin (SHBG), as well as for thyroid hormones [thyroxine‐binding globulin (TBG)]. These hormones also associate more loosely with other circulating proteins, especially albumin. The amounts of protein‐bound and unbound (‘free’) hormone are in equilibrium in the circulation. Only the free hormone can diffuse readily into tissues and act on target cells. Many clinical assays still measure total hormone in blood and are consequently affected markedly by changes in the concentration of the binding protein. This can be misleading because shifts in the equilibrium mean that free hormone concentrations are relatively constant and biological activity remains the same. For instance, women on the combined oral contraceptive pill have raised serum CBG and increased total cortisol. However, free cortisol levels and cortisol action is unaltered.