Steroid hormones are made from cholesterol

The steroids are classic hormones, synthesized in endocrine glands, and transported by the blood. The adrenal steroids regulate energy metabolism (glucocorticoids) and mineral balance (mineralocorticoids), and the gonadal steroids are concerned with sex. Table 16.1 lists representatives of the major classes of steroid hormones.

Table 16.1 Structures of Some Representative Steroids

All steroid hormones are synthesized from cholesterol. Structural changes that are introduced during hormone synthesis include the following:

Progestins are the biosynthetic precursors of all other steroid hormones

The precursor relationships of the steroid hormones can be summarized as follows:

The very first reaction (Fig. 16.1) is catalyzed by the mitochondrial side chain cleavage enzyme, also known as desmolase. It hydroxylates carbons 20 and 22, followed by cleavage of the carbon-carbon bond. This reaction produces pregnenolone, which is converted to progesterone by a nicotinamide adenine dinucleotide (NAD)-dependent enzyme. Progesterone is the major product of the corpus luteum and the placenta. The other endocrine glands convert pregnenolone and progesterone to other steroid hormones.

Figure 16.1 Synthesis of progesterone. NADP⁺, NADPH, Nicotinamide adenine dinucleotide phosphate.

The adrenal cortex processes the progestins into corticosteroids, including the major glucocorticoid cortisol (10–20 mg/day) and the major mineralocorticoid aldosterone (0.10–0.15 mg/day). The most important reactions of corticosteroid synthesis (Fig. 16.2) are hydroxylations with the overall balance

Figure 16.2 Synthesis of adrenal steroids. ER, Endoplasmic reticulum.

These reactions take place in the inner mitochondrial membrane or the endoplasmic reticulum (ER) membrane. They always require the heme-containing subunit cytochrome P-450. Molecular oxygen binds to the ferrous heme iron of P-450. An electron is then transferred from NADPH to the heme-bound oxygen, converting the oxygen into a highly reactive form that reacts with the substrate. In the microsomal enzyme complexes (those located in the ER), the electron is transferred through a flavoprotein that contains both flavin adenine dinucleotide (FAD) and flavin mononucleotide (FMN):

The mitochondrial forms of cytochrome P-450 receive their electrons through an FAD-containing flavoprotein and the iron-sulfur protein adrenodoxin:

CLINICAL EXAMPLE 16.1: Licorice-Induced Hypertension

The plasma concentration is more than 100 times higher for cortisol than for aldosterone. At this high concentration, cortisol can activate mineralocorticoid receptors in the kidneys and cause the typical mineralocorticoid effects of sodium retention and potassium excretion. This is normally prevented by the NAD⁺-dependent enzyme 11β-hydroxysteroid dehydrogenase in the kidneys, which converts cortisol to cortisone, which no longer has mineralocorticoid activity (Fig. 16.3).

Figure 16.3 Conversion of cortisol to cortisone. Cortisone is a product with little glucocorticoid and no mineralocorticoid activity.

Black licorice candy contains the sweet-tasting glycoside glycyrrhizic acid, which is extracted from the root of the licorice tree. Glycyrrhizic acid is hydrolyzed to the aglycone glycyrrhetinic acid in the intestine. This product is an inhibitor of 11β-hydroxysteroid dehydrogenase. People who eat excessive amounts of black licorice can develop edema, hypertension, and/or hypokalemia because their kidneys are exposed to the mineralocorticoid effect of cortisol. Cortisol levels are elevated during stress. Therefore people who abuse licorice while under stress are most likely to develop these signs.

Licorice extract has medical uses as treatment of peptic ulcer and as a mild laxative. These effects are caused by an unrelated effect of glycyrrhetinic acid in inhibiting the degradation of prostaglandin E.

Testosterone is the major testicular androgen. About 5 mg is produced by the Leydig cells in the testis every day. In the target tissues and, to a lesser extent, in the testis itself, testosterone is converted to dihydrotestosterone (DHT) by the enzyme 5α-reductase. The plasma level of DHT is only 10% of the testosterone level, but DHT is a considerably more potent androgen than is testosterone. Therefore testosterone acts in part as a precursor, or prohormone, of the active hormone DHT.

The adrenal cortex contributes approximately 20 mg of androgen per day. Adrenal androgens include dihydroepiandrosterone and androstenedione, but only trace amounts of testosterone. The adrenal androgens have a keto group instead of a hydroxy group at C-17 and therefore are far less potent than testosterone, but they are a major source of androgenic activity in females (Figs. 16.2 and 16.4).

Figure 16.4 Major pathways for synthesis of gonadal steroids. , All steroid-producing cells; , ovary, theca cells; , ovary, granulosa cells; , testis; , 17α-hydroxylase/C_17,20-lyase; , 17β-hydroxysteroid dehydrogenase; , 3β-dehydrogenase and Δ^5,4-isomerase; , aromatase; , 16α-hydroxylase; , 5α-reductase.

The granulosa cells of the ovarian follicles process testosterone into the potent estrogen estradiol. Postmenopausal women no longer make estradiol but still have the weak estrogen estrone, which is made from the adrenal androgen androstenedione. These reactions are catalyzed by the microsomal enzyme system aromatase.

Men produce only 65 μg/day of estrone from androstenedione and 45 μg of estradiol from testosterone. A small quantity of estradiol is synthesized in the testes, but most estrogen in the male is produced in adipose tissue, liver, skin, brain, and other nonendocrine tissues. Therefore testosterone is a precursor of two other hormones, DHT and estradiol:

Abnormalities in androgen synthesis lead to disorders of sexual development (Clinical Examples 16.2 and 16.3).

CLINICAL EXAMPLE 16.2: Congenital Adrenal Hyperplasia

In the adrenal cortex, 21-hydroxylase and 11β-hydroxylase are required for the synthesis of corticosteroids but not androgens (see Fig. 16.2). Recessively inherited deficiencies of either of these enzymes leads to congenital adrenal hyperplasia, also known as adrenogenital syndrome (incidence 1:10,000, 90% of this is 21-hydroxylase deficiency).

Ordinarily, the desmolase reaction in the adrenal cortex is stimulated by adrenocorticotropic hormone (ACTH) from the pituitary gland, and the glucocorticoids inhibit ACTH release. In adrenogenital syndrome, the deficiency of glucocorticoids enhances ACTH release. The excess ACTH causes adrenal hyperplasia and stimulates the desmolase reaction. With the pathway of corticosteroid synthesis blocked, the overproduced progestins are diverted into androgen synthesis (Fig. 16.5). This disorder produces ambiguous external genitalia in girls and precocious puberty in boys.

Figure 16.5 Adrenal steroid synthesis in adrenogenital syndrome. A, Normal. B, Untreated adrenogenital syndrome. C, Adrenogenital syndrome treated with cortisol (+ mineralocorticoid). ACTH, Adrenocorticotropic hormone.

Complete or near-complete deficiency of 21-hydroxylase leads to life-threatening hyponatremia and hyperkalemia due to aldosterone deficiency. The opposite is seen in deficiency of 11β-hydroxylase because 11-deoxycorticosterone accumulates. This 21-hydroxylated metabolite acts as a mineralocorticoid, and, because of its high levels, it causes signs of mineralocorticoid excess despite the absence of aldosterone.

Both the virilization and electrolyte imbalances can be cured by orally administered corticosteroids.

Thyroid hormones are synthesized from protein-bound tyrosine

The thyroid hormones are the only constituents of the human body that contain organically bound iodine:

The typical dietary intake of iodine, in the form of the iodide anion, is approximately 100 μg. Its plasma concentration is only 0.2 μg/dl, but the thyroid gland actively accumulates iodide from the blood by means of sodium cotransport. This carrier is inhibited by several inorganic ions including nitrate, perchlorate, pertechnetate, and isocyanate. Isocyanate is present in some foods, including cabbage and cassava, and can cause goiter when large quantities of these foods are consumed in the context of low dietary iodine.

Iodide enters the lumen of the thyroid follicle by facilitated diffusion from the follicular cells (Fig. 16.6). Here it meets the second ingredient for hormone synthesis, thyroglobulin. This large glycoprotein (two subunits, 2 × 330,000 D) is secreted into the lumen of the thyroid follicle by the follicular cells. Up to 40 tyrosine side chains in thyroglobulin become iodinated, but only 8 to 10 of them are processed to the active hormones.

Figure 16.6 Cellular compartmentation of thyroid hormone synthesis. DIT, Diiodotyrosine; MIT, monoiodotyrosine; TG, thyroglobulin; TP, thyroperoxidase.

Iodination of the tyrosine side chains requires the oxidation of iodide by the heme-containing enzyme thyroperoxidase on the apical (luminal) surface of the plasma membrane (see Fig. 16.6). The iodine reacts with tyrosine side chains, and the coupling of two iodinated tyrosines produces the protein-bound hormones (Fig. 16.7).

Figure 16.7 Synthesis of thyroid hormones from iodinated tyrosine residues in thyroglobulin. These reactions take place on the luminal surface of the follicular cells in the thyroid gland. T₃, Triiodothyronine; T₄, thyroxine.

The hormones are released when thyroglobulin is taken up into the cell by pinocytosis, followed by the complete breakdown of thyroglobulin in lysosomes. The hormones leave the cell, and iodine from iodinated but uncoupled tyrosine is recycled.

More than 99% of triiodothyronine (T₃) and more than 99.9% of thyroxine (T₄) in the blood are bound to plasma proteins. Protein binding protects the hormones from enzymatic attack and renal excretion. Therefore their biological half-lives are remarkably long: 6.5 days for T₄ and 1.5 days for T₃. The T₄ level in the plasma is 50 times higher than the T₃ level (80 ng/ml vs 1.5 ng/ml), but the concentrations of free, unbound hormone are more balanced because T₃ is less extensively bound to plasma proteins than is T₄. The concentration of the unbound hormone, not the total hormone, determines the biological effects on the tissues.

Ninety percent of the released hormone is T₄, and 10% is T₃. In the target tissues, some T₄ is converted to active T₃, and some is converted to the inactive reverse T₃ (Fig. 16.8). Eighty percent of the circulating T₃ does not come directly from the thyroid gland but is produced from T₄ in peripheral tissues. Of the two hormones, T₃ is about four times more potent than T₄. Therefore T₄ is a prohormone for the more potent T₃, much as testosterone is a prohormone for the more potent dihydrotestosterone.

Figure 16.8 In its target tissues, thyroxine (T₄) is converted to either the more active triiodothyronine (T₃) or to inactive reverse T₃.

Both hypothyroidism and hyperthyroidism are common disorders

The deficiency of thyroid hormone is called hypothyroidism. In adults, it is characterized by widespread subcutaneous edema due to excessive amounts of hyaluronic acid (“myxedema”), decreased basal metabolic rate, bradycardia, and sluggish thinking. Hypothyroidism in infants leads to severe and irreversible mental deficiency, stunted growth, and multiple physical deformities. This condition is called cretinism.

Iodine deficiency causes endemic hypothyroidism in areas of the world where the soil and the plants grown on it are deficient in this mineral. In the Alps, the condition was common until the early years of the twentieth century. Iodine deficiency now is rare in most countries because of the routine use of iodized salt, although there is still an extensive “goiter belt” in the Himalaya Mountains.

Autoimmune thyroiditis, also known as Hashimoto disease, is the most common form of adult hypothyroidism in areas with sufficient iodine, with a prevalence of at least 2% in women and 0.4% in men. It is characterized by episodes of inflammation with lymphocytic infiltration that can present with either hypothyroidism or hyperthyroidism. As the thyroid gland is progressively destroyed, lasting hypothyroidism finally develops.

The thyroid gland is stimulated by thyroid-stimulating hormone (TSH) from the pituitary gland. TSH release, in turn, is suppressed by thyroid hormones:

This feedback loop maintains a constant level of thyroid hormone under ordinary conditions. In autoimmune thyroiditis and iodine deficiency, the thyroid gland cannot make its hormones. The thyrotrophs of the pituitary gland are disinhibited, and the TSH level soars. TSH not only stimulates the biochemical steps in thyroid hormone synthesis but also causes hyperplasia of the follicular cells. This condition is called goiter.

Graves disease, which afflicts about 1% of women and 0.1% of men, is the most common cause of hyperthyroidism. It is an autoimmune disease in which an abnormal immunoglobulin G antibody binds to the TSH receptor. The antibody stimulates the receptor, causing excessive hormone secretion (thyrotoxicosis) and enlargement of the gland.

Insulin is released together with the C-peptide

Proteins, glycoproteins, and smaller peptides are the most diverse class of messenger molecules. They include many hormones and neurotransmitters, as well as growth factors and the cytokines that are released by white blood cells during inflammation.

All extracellular signaling proteins are made on the assembly line of the secretory pathway: from ER-bound ribosomes through the ER, Golgi apparatus, and secretory vesicles. Small peptide hormones are derived from larger polypeptides. These prohormones are processed by endopeptidases in the ER, Golgi apparatus, or secretory vesicles.

The synthesis of insulin in the pancreatic β-cells is an example (Fig. 16.9

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