Many Hormones Are Made From Cholesterol

Adrenal Steroidogenesis

The adrenal steroid hormones are synthesized from cholesterol. Cholesterol is mostly derived from the plasma, but a small portion is synthesized in situ from acetyl-CoA via mevalonate and squalene. Much of the cholesterol in the adrenal is esterified and stored in cy-toplasmic lipid droplets. Upon stimulation of the adrenal by ACTH, an esterase is activated, and the free cholesterol formed is transported into the mitochondrion, where a cytochrome P450 side chain cleavage enzyme (P450scc) converts cholesterol to preg-nenolone. Cleavage of the side chain involves sequential hydroxylations, first at C22 and then at C20, followed by side chain cleavage (removal of the six-carbon fragment isocaproaldehyde) to give the 21-carbon steroid (Figure 42-3, top). An ACTH-dependent steroidogenic acute regulatory (StAR) protein is essential for the transport of cholesterol to P450scc in the inner mitochondrial membrane.

All mammalian steroid hormones are formed from cholesterol via pregnenolone through a series of reactions that occur in either the mitochondria or endoplas-mic reticulum of the adrenal cell. Hydroxylases that require molecular oxygen and NADPH are essential, and dehydrogenases, an isomerase, and a lyase reaction are also necessary for certain steps. There is cellular specificity in adrenal steroidogenesis. For instance, 18-hydroxylase and 19-hydroxysteroid dehydrogenase, which are required for aldosterone synthesis, are found only in the zona glomerulosa cells (the outer region of the adrenal cortex), so that the biosynthesis of this min-eralocorticoid is confined to this region. A schematic representation of the pathways involved in the synthesis of the three major classes of adrenal steroids is presented in Figure 42-4. The enzymes are shown in the rectangular boxes, and the modifications at each step are shaded.

A. Mineralocorticoid Synthesis_

Synthesis of aldosterone follows the mineralocorticoid pathway and occurs in the zona glomerulosa. Preg-nenolone is converted to progesterone by the action of two smooth endoplasmic reticulum enzymes, 3P-hydroxysteroid dehydrogenase (3P-OHSD) and A5,4-isomerase. Progesterone is hydroxylated at the C21 position to form 11-deoxycorticosterone (DOC), which is an active (Na+-retaining) mineralocorticoid. The next hy-droxylation, at C11, produces corticosterone, which has glucocorticoid activity and is a weak mineralocorticoid (it has less than 5% of the potency of aldosterone). In some species (eg, rodents), it is the most potent glucocorticoid.

A. CHOLESTEROL DERIVATIVES

17ß-Estradiol

17ß-Estradiol

Testosterone

Cortisol

Testosterone ch2oh

CH3 CO

Progesterone

Cortisol

Progesterone

B. TYROSINE DERIVATIVES

OH O CH2CH COOH

OH O CH2CH COOH

Norepinephrine

Norepinephrine

HO H

1 113

HH Epinephrine

C. PEPTIDES OF VARIOUS SIZES

1 2345 6789 10 11

D. GLYCOPROTEINS (TSH, FSH, LH)

1 2345 6789 10 11

Structure of human ACTH.

Structure of human ACTH.

ACTH

common a subunits unique ß subunits

Figure 42-2. Chemical diversity of hormones. A. Cholesterol derivatives. B. Tyrosine derivatives. C. Peptides of various sizes D. Glycoproteins (TSH, FSH, LH) with common a subunits and unique ß subunits.

Estrane group (C18)

Basic steroid hormone structures

Testosterone

Androstane group (C19)

ch2oh I

Basic steroid hormone structures

ch2oh I

Testosterone

Cortisol

Progesterone

Cortisol

Progesterone

Pregnane group (C21)

Figure 42-3. Cholesterol side-chain cleavage and basic steroid hormone structures. The basic sterol rings are identified by the letters A-D. The carbon atoms are numbered 1-21 starting with the A ring. Note that the estrane group has 18 carbons (C18), etc.

C21 hydroxylation is necessary for both mineralocorticoid and glucocorticoid activity, but most steroids with a C17 hydroxyl group have more glucocorticoid and less miner-alocorticoid action. In the zona glomerulosa, which does not have the smooth endoplasmic reticulum enzyme 17a-hydroxylase, a mitochondrial 18-hydroxylase is present. The 18-hydroxylase (aldosterone synthase) acts on corticosterone to form 18-hydroxycorticosterone, which is changed to aldosterone by conversion of the 18-alcohol to an aldehyde. This unique distribution of enzymes and the special regulation of the zona glomerulosa by K+ and angiotensin II have led some investigators to suggest that, in addition to the adrenal being two glands, the adrenal cortex is actually two separate organs.

B. Glucocorticoid Synthesis_

Cortisol synthesis requires three hydroxylases located in the fasciculata and reticularis zones of the adrenal cortex that act sequentially on the C17, C21, and C11 positions. The first two reactions are rapid, while C11 hydroxylation is relatively slow. If the C11 position is hydroxylated first, the action of 17a-hydroxylase is impeded and the mineralocorticoid pathway is followed (forming corti-

costerone or aldosterone, depending on the cell type). 17a-Hydroxylase is a smooth endoplasmic reticulum enzyme that acts upon either progesterone or, more commonly, pregnenolone. 17a-Hydroxyprogesterone is hydroxylated at C21 to form 11-deoxycortisol, which is then hydroxylated at C11 to form cortisol, the most potent natural glucocorticoid hormone in humans. 21-Hy-droxylase is a smooth endoplasmic reticulum enzyme, whereas 1 ^-hydroxylase is a mitochondrial enzyme. Steroidogenesis thus involves the repeated shuttling of substrates into and out of the mitochondria.

C. Androgen Synthesis_

The major androgen or androgen precursor produced by the adrenal cortex is dehydroepiandrosterone (DHEA). Most 17-hydroxypregnenolone follows the glucocorticoid pathway, but a small fraction is subjected to oxidative fission and removal of the two-carbon side chain through the action of 17,20-lyase. The lyase activity is actually part of the same enzyme (P450c17) that catalyzes 17a-hydroxylation. This is therefore a dual function protein. The lyase activity is important in both the adrenals and

Cholesterol

Cholesterol

Pregnenolone

Pregnenolone ch3 3

ch3 3

17-Hydroxypregnenolone

Dehydroepiandrosterone

3ß-HYDROXYSTEROID DEHYDROGENASE: A54 ISOMERASE

17-Hydroxypregnenolone

Dehydroepiandrosterone

3ß-HYDROXYSTEROID DEHYDROGENASE: A54 ISOMERASE

Progesterone

A4 ANDROSTENE-3,17-DIOI

Progesterone

17-Hydroxyprogesterone

A4 ANDROSTENE-3,17-DIOI

17-Hydroxyprogesterone

21-HYDROXYLASE

CH2OH

CH2OH

' C = O '

' C = O

11-Deoxycorticosterone

11-Deoxycortisol

11-Deoxycorticosterone

11-Deoxycortisol

O

11 ß-HYDROXYLASE

CH2OH

CH2OH

' C = O '

CORTISOL

Corticosterone

CORTISOL

18-HYDROXYLASE 18-HYDROXYDEHYDROGENASE

II C = O H — C 1

Figure 42-4. Pathways involved in the synthesis of the three major classes of adrenal steroids (mineralocorticoids, glucocorticoids, and androgens). Enzymes are shown in the rectangular boxes, and the modifications at each step are shaded. Note that the 17a-hydroxylase and 17,20-lyase activities are both part of one enzyme, designated P450c17. (Slightly modified and reproduced, with permission, from Harding BW: In: Endocrinology, vol 2. DeGroot LJ [editor]. Grune & Stratton, 1979.)

the gonads and acts exclusively on 17a-hydroxy-contain-ing molecules. Adrenal androgen production increases markedly if glucocorticoid biosynthesis is impeded by the lack of one of the hydroxylases (adrenogenital syndrome). DHEA is really a prohormone, since the actions of 3P-OHSD and A5,4-isomerase convert the weak androgen DHEA into the more potent androstenedione. Small amounts of androstenedione are also formed in the adrenal by the action of the lyase on 17a-hydroxyproges-terone. Reduction of androstenedione at the C17 position results in the formation of testosterone, the most potent adrenal androgen. Small amounts of testosterone are produced in the adrenal by this mechanism, but most of this conversion occurs in the testes.

Testicular Steroidogenesis

Testicular androgens are synthesized in the interstitial tissue by the Leydig cells. The immediate precursor of the gonadal steroids, as for the adrenal steroids, is cholesterol. The rate-limiting step, as in the adrenal, is delivery of cholesterol to the inner membrane of the mitochondria by the transport protein StAR. Once in the proper location, cholesterol is acted upon by the side chain cleavage enzyme P450scc. The conversion of cholesterol to pregnenolone is identical in adrenal, ovary, and testis. In the latter two tissues, however, the reaction is promoted by LH rather than ACTH.

The conversion of pregnenolone to testosterone requires the action of five enzyme activities contained in three proteins: (1) 3P-hydroxysteroid dehydrogenase (3P-OHSD) and A5,4-isomerase; (2) 17a-hydroxylase and 17,20-lyase; and (3) 17P-hydroxysteroid dehydrogenase (17P-OHSD). This sequence, referred to as the progesterone (or A ) pathway, is shown on the right side of Figure 42-5. Pregnenolone can also be converted to testosterone by the dehydroepiandrosterone (or A5) pathway, which is illustrated on the left side of Figure 42-5. The A5 route appears to be most used in human testes.

The five enzyme activities are localized in the micro-somal fraction in rat testes, and there is a close functional association between the activities of 3P-OHSD and A5,4-isomerase and between those of a 17a-hydrox-ylase and 17,20-lyase. These enzyme pairs, both contained in a single protein, are shown in the general reaction sequence in Figure 42-5.

Dihydrotestosterone Is Formed From Testosterone in Peripheral Tissues

Testosterone is metabolized by two pathways. One involves oxidation at the 17 position, and the other involves reduction of the A ring double bond and the 3-ke-tone. Metabolism by the first pathway occurs in many tissues, including liver, and produces 17-ketosteroids that are generally inactive or less active than the parent compound. Metabolism by the second pathway, which is less efficient, occurs primarily in target tissues and produces the potent metabolite dihydrotestosterone (DHT).

The most significant metabolic product of testosterone is DHT, since in many tissues, including prostate, external genitalia, and some areas of the skin, this is the active form of the hormone. The plasma content of DHT in the adult male is about one-tenth that of testosterone, and approximately 400 |lg of DHT is produced daily as compared with about 5 mg of testosterone. About 50-100 |g of DHT are secreted by the testes. The rest is produced peripherally from testosterone in a reaction catalyzed by the NADPH-depen-dent 5«-reductase (Figure 42-6). Testosterone can thus be considered a prohormone, since it is converted into a much more potent compound (dihydrotestos-terone) and since most of this conversion occurs outside the testes. Some estradiol is formed from the peripheral aromatization of testosterone, particularly in males.

Ovarian Steroidogenesis

The estrogens are a family of hormones synthesized in a variety of tissues. 17P-Estradiol is the primary estrogen of ovarian origin. In some species, estrone, synthesized in numerous tissues, is more abundant. In pregnancy, relatively more estriol is produced, and this comes from the placenta. The general pathway and the subcellular localization of the enzymes involved in the early steps of estradiol synthesis are the same as those involved in androgen biosynthesis. Features unique to the ovary are illustrated in Figure 42-7.

Estrogens are formed by the aromatization of andro-gens in a complex process that involves three hydroxyla-tion steps, each of which requires O2 and NADPH. The aromatase enzyme complex is thought to include a P450 monooxygenase. Estradiol is formed if the substrate of this enzyme complex is testosterone, whereas estrone results from the aromatization of androstenedione.

The cellular source of the various ovarian steroids has been difficult to unravel, but a transfer of substrates between two cell types is involved. Theca cells are the source of androstenedione and testosterone. These are converted by the aromatase enzyme in granulosa cells to estrone and estradiol, respectively. Progesterone, a precursor for all steroid hormones, is produced and secreted by the corpus luteum as an end-product hormone because these cells do not contain the enzymes necessary to convert progesterone to other steroid hormones (Figure 42-8).

Significant amounts of estrogens are produced by the peripheral aromatization of androgens. In human males, the peripheral aromatization of testosterone to estradiol (E2) accounts for 80% of the production of the latter. In females, adrenal androgens are important

Figure 42-5. Pathways of testosterone biosynthesis. The pathway on the left side of the figure is called the A5 or dehydroepiandrosterone pathway; the pathway on the right side is called the A4 or progesterone pathway. The asterisk indicates that the 17a-hydroxy-lase and 17,20-lyase activities reside in a single protein, P450c17.

Pregnenolone

Progesterone

Pregnenolone

Progesterone

17a-HYDROXYLASE*

17a-HYDROXYLASE*

17a-HYDROXYLASE*

17a-HYDROXYLASE*

C = O --OH

Dehydroepiandrosterone

17ß-HYDROXYSTEROID DEHYDROGENASE

17ß-HYDROXYSTEROID DEHYDROGENASE

Figure 42-5. Pathways of testosterone biosynthesis. The pathway on the left side of the figure is called the A5 or dehydroepiandrosterone pathway; the pathway on the right side is called the A4 or progesterone pathway. The asterisk indicates that the 17a-hydroxy-lase and 17,20-lyase activities reside in a single protein, P450c17.

A5-Androstenediol

TESTOSTERONE

A5-Androstenediol

TESTOSTERONE

5a-REDUCTASE

Testosterone DIHYDROTESTOSTERONE (DHT)

Figure 42-6. Dihydrotestosterone is formed from testosterone through action of the enzyme 5a-reductase.

NADPH

Cholesterol

Other metabolites

Pregnenolone \

Progesterone

17a-Hydroxypregnenolone

Dehydroepiandrosterone \

Androstenedione it

Testosterone

Cholesterol

Pregnenolone \

Progesterone

17a-Hydroxypregnenolone it

Testosterone

Other metabolites

ESTRONE (E1)

ESTRONE (E1)

16a-Hydroxylase Other metabolites

Figure 42-7. Biosynthesis of estrogens. (Slightly modified and reproduced, with permission, from Ganong WF: Review of Medical Physiology, 20th ed. McGraw-Hill, 2001.)

Acetate

Cholesterol

Pregnenolone

Progesterone

Figure 42-8. Biosynthesis of progesterone in the corpus luteum.

substrates, since as much as 50% of the E2 produced during pregnancy comes from the aromatization of an-drogens. Finally, conversion of androstenedione to estrone is the major source of estrogens in post-menopausal women. Aromatase activity is present in adipose cells and also in liver, skin, and other tissues. Increased activity of this enzyme may contribute to the "estrogenization" that characterizes such diseases as cirrhosis of the liver, hyperthyroidism, aging, and obesity.

1,25(OH)2-D3 (Calcitriol) Is Synthesized From a Cholesterol Derivative

1,25(OH)2-D3 is produced by a complex series of enzymatic reactions that involve the plasma transport of precursor molecules to a number of different tissues (Figure 42-9). One of these precursors is vitamin D—really not a vitamin, but this common name persists. The active molecule, 1,25(OH)2-D3, is transported to other organs where it activates biologic processes in a manner similar to that employed by the steroid hormones.

Small amounts of the precursor for 1,25(OH)2-D3 synthesis are present in food (fish liver oil, egg yolk), but most of the precursor for 1,25(OH)2-D3 synthesis is produced in the malpighian layer of the epidermis from 7-dehydrocholesterol in an ultraviolet light-mediated, nonenzymatic photolysis reaction. The extent of this conversion is related directly to the intensity of the exposure and inversely to the extent of pigmentation in the skin. There is an age-related loss of 7-dehydrocho-lesterol in the epidermis that may be related to the negative calcium balance associated with old age.

A specific transport protein called the vitamin D-bind-ing protein binds vitamin D3 and its metabolites and moves vitamin D3 from the skin or intestine to the liver, where it undergoes 25-hydroxylation, the first obligatory reaction in the production of 1,25(OH)2-D3. 25-Hydroxylation occurs in the endoplasmic reticulum in a reaction that requires magnesium, NADPH, molecular oxygen, and an uncharacterized cytoplasmic factor. Two enzymes are involved: an NADPH-depen-dent cytochrome P450 reductase and a cytochrome P450. This reaction is not regulated, and it also occurs with low efficiency in kidney and intestine. The 25(OH)2-D3 enters the circulation, where it is the major form of vitamin D found in plasma, and is transported to the kidney by the vitamin D-binding protein.

C. Kidney_

25(OH)2-D3 is a weak agonist and must be modified by hydroxylation at position C1 for full biologic activity. This is accomplished in mitochondria of the renal proximal convoluted tubule by a three-component monooxygenase reaction that requires NADPH, Mg2+, molecular oxygen, and at least three enzymes: (1) a flavoprotein, renal ferredoxin reductase; (2) an iron sulfur protein, renal ferredoxin; and (3) cytochrome P450. This system produces 1,25(OH)2-D3, which is the most potent naturally occurring metabolite of vitamin D.

Diabetes 2

Diabetes 2

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