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This chapter discusses the steroid hormones. The main sites of production of steroid hormones are the adrenal glands, the gonads, and the placenta. The precursor for steroid synthesis is cholesterol. All steroid producing tissues, except the placenta, can make cholesterol from acetate but the main source of cholesterol for steroidogenesis is plasma cholesterol which is carried in the blood, mainly by low density lipoprotein. Steroid hormones have a perhydrocyclopentanephenanthrene nucleus with three six carbon and one five carbon rings. Steroid hormones are produced not only in the adrenal glands, gonads and placenta, but also by peripheral conversion of precursors. For example, androstenedione is converted to estrone and estradiol, and to testosterone; estrone and testosterone are converted to estradiol, and estradiol is converted to estrone. In early pregnancy, the corpus luteum is stimulated to continue production of progesterone and estrogens by the action of hCG, which is produced by the conceptus soon after implantation. The concentration and affinity of steroid hormone receptors is markedly influenced by steroid hormones. Thus estradiol increases the number and affinity of estrogen, progestogen and androgen receptors, whereas progestogens cause a decrease in estrogen receptors.

Steroid nomenclature

Steroid hormones have a perhydrocyclopentanephenanthrene nucleus with three six carbon and one five carbon rings. Steroid nomenclature is based on the system of numbering shown in Figure 2.1. Progestogens and corticosteroids contain the 21-carbon atom (C21) pregnane nucleus, androgens the C19 androstrane nucleus and oestrogens the C18 oestrane nucleus. Steroidogenesis can only proceed from C21→C19→C18 and not in the reverse direction.

By convention the chemical names of steroids are based on the carbon nucleus which they contain. The abbreviated name of the basic nucleus may be preceded by numbers indicating the position and number of hydroxyl groups (e.g. 3β, 17α…diol). The site(s) and number of double bonds may be indicated after the abbreviated basic name (e.g. pregn-4-ene). Finally the site(s) and number of ketone groups are indicated (e.g. 3,20-dione). Thus, the chemical name of 17α-hydroxyprogesterone is 17α-hydroxy-pregn-4-ene-3,20-dione. The order of the prefixes and suffixes varies with different systems of nomenclature. Almost all naturally occurring active steroids are nearly flat molecules and substituents below and above the plane of the molecule are designated α(—) and β(—) respectively. The terms Δ4 (delta4) and Δ5 indicate the position of a double bond in the 4–5 and 5–6 positions respectively. Dehydro implies elimination of a hydrogen atom, and deoxy elimination of an oxygen atom.

Steroid pathways

Some steroidogenic pathways are shown diagrammatically in Figure 2.2. Types of reactions that may occur are summarized in Table 2.1.

The rate limiting step of conversion of cholesterol to pregnenolone takes place in the mitochondria and is accelerated by LH in the ovary and by ACTH in the adrenal. After the formation of pregnenolone, steroidogenesis can proceed either via the Δ5-3β-hydroxysteroid or the Δ4-3-ketone pathway. Although conversion of each Δ5 compound to the corresponding Δ4 compound can occur, the principal pathways are via dehydroepiandrosterone (DHEA) and progesterone. The different steroid producing tissues contain different enzymes. Thus the normal ovary does not contain 21-hydroxylase and 11α-hydroxylase enzymes and therefore cannot produce corticosteroids and mineralocorticoids.

The secretion, production and metabolism of steroid hormones are described using the terms defined in Table 2.2. The metabolic clearance rate can be determined by a technique involving infusion of the relevant radioactively labelled steroid (Baird et al., 1969).

Steroid hormones are produced not only in the adrenal glands, gonads and placenta but also by peripheral conversion of precursors. For example, androstenedione is converted to oestrone and oestradiol, and to testosterone; oestrone and testosterone are converted to oestradiol, and oestradiol is converted to oestrone (Horton and Tait, 1966; MacDonald et al., 1967; Baird and Fraser, 1974; Nimrod and Ryan, 1975). As well as being metabolized by peripheral conversion, steroid hormones are conjugated in the liver prior to excretion in the bile, and hence faeces, and urine.

The blood production rate of oestradiol in the early follicular, preovulatory and midluteal phases of the cycle was found to be approximately 60, 400 and 300 μg/24 hours respectively; that of oestrone was slightly lower (Baird and Fraser, 1974).

The blood production rate of progesterone in the follicular and midluteal phases of the cycle was calculated to be approximately 3 and 25 mg/24 hours respectively (Little et al., 1966). The blood production rates of testosterone and androstenedione in normal women were found to be approximately 230 μg and 3000 μg/24 hours respectively (Bardin and Lipsett, 1967).

Steroid production in pregnancy

In early pregnancy the corpus luteum is stimulated to continue production of progesterone and oestrogens by the action of hCG which is produced by the conceptus soon after implantation (about 7 days after fertilization).

Some maternal-placental-fetal steroid production pathways are shown diagrammatically in Figure 2.3.

Progesterone is produced by the placenta from cholesterol. The precursor for oestradiol production is dehydroepiandrosterone sulphate, produced both by the maternal and fetal adrenals with a roughly 50% contribution from each in late pregnancy (Siiteri and MacDonald, 1966). Dehydroepiandrosterone sulphate produced by the fetal adrenals is also 16α-hydroxylated in the fetal liver and converted to oestriol in the placenta. These pathways are discussed further in Chapter 3.

Measurement of steroid hormone levels

Steroid hormones are bound to a greater or lesser extent to plasma proteins (Dunn et al., 1981; Siiteri et al., 1982) and only a proportion of each steroid hormone in the plasma is free (unbound and unconjugated) and biologically active (Table 2.3).

The introduction of radioimmunoassays in the 1960s was a major advance which allowed an enormous expansion in endocrinological research and understanding.

Routine plasma radioimmunoassays measure bound and free hormone together. In a typical plasma steroid radioimmunoassay steroids are extracted from the plasma with ether and the relevant steroid is assayed using unlabelled standards, labelled tracer hormone and a specific antibody. Antibody bound and unbound steroids are separated after incubation using dextran coated charcoal; the radioactivity of the...