Synthesis and Secretion of Adrenocortical Hormones

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The Adrenal Cortex Has Three Distinct Layers. Figure 77-1 shows that the adrenal cortex is composed of three relatively distinct layers:

1. The zona glomerulosa, a thin layer of cells that lies just underneath the capsule, constitutes about 15 per cent of the adrenal cortex. These cells are the only ones in the adrenal gland capable of secreting significant amounts of aldosterone because they contain the enzyme aldosterone synthase, which is necessary for synthesis of aldosterone. The secretion of these cells is controlled mainly by the extracellular fluid concentrations of angiotensin II and potassium, both of which stimulate aldosterone secretion.

2. The zona fasciculata, the middle and widest layer, constitutes about 75 per cent of the adrenal cortex and secretes the glucocorticoids cortisol and

Adrenal Cortex Secretes

Secretion of adrenocortical hormones by the different zones of the adrenal cortex and secretion of catecholamines by the adrenal medulla.

corticosterone, as well as small amounts of adrenal androgens and estrogens. The secretion of these cells is controlled in large part by the hypothalamic-pituitary axis via adrenocorticotropic hormone (ACTH). 3. The zona reticularis, the deep layer of the cortex, secretes the adrenal androgens dehydroepiandrosterone (DHEA) and androstenedione, as well as small amounts of estrogens and some glucocorticoids. ACTH also regulates secretion of these cells, although other factors such as cortical androgen-stimulating hormone, released from the pituitary, may also be involved. The mechanisms for controlling adrenal androgen production, however, are not nearly as well understood as those for glucocorticoids and mineralocorticoids.

Aldosterone and cortisol secretion are regulated by independent mechanisms. Factors such as angiotensin II that specifically increase the output of aldosterone and cause hypertrophy of the zona glomerulosa have no effect on the other two zones. Similarly, factors such as ACTH that increase secretion of cortisol and adrenal androgens and cause hypertrophy of the zona fasciculata and zona reticularis have little or no effect on the zona glomerulosa.

Adrenocortical Hormones Are Steroids Derived from Cholesterol.

All human steroid hormones, including those produced by the adrenal cortex, are synthesized from cholesterol. Although the cells of the adrenal cortex can synthesize de novo small amounts of cholesterol from acetate, approximately 80 per cent of the cholesterol used for steroid synthesis is provided by low-density lipoproteins

(LDL) in the circulating plasma. The LDLs, which have high concentrations of cholesterol, diffuse from the plasma into the interstitial fluid and attach to specific receptors contained in structures called coated pits on the adrenocortical cell membranes. The coated pits are then internalized by endocytosis, forming vesicles that eventually fuse with cell lysosomes and release cholesterol that can be used to synthesize adrenal steroid hormones.

Transport of cholesterol into the adrenal cells is regulated by feedback mechanisms that can markedly alter the amount available for steroid synthesis. For example, ACTH, which stimulates adrenal steroid synthesis, increases the number of adrenocortical cell receptors for LDL, as well as the activity of enzymes that liberate cholesterol from LDL.

Once the cholesterol enters the cell, it is delivered to the mitochondria, where it is cleaved by the enzyme cholesterol desmolase to form pregnenolone; this is the rate-limiting step in the eventual formation of adrenal steroids (Figure 77-2). In all three zones of the adrenal cortex, this initial step in steroid synthesis is stimulated by the different factors that control secretion of the major hormone products aldosterone and cortisol. For example, both ACTH, which stimulates cortisol secretion, and angiotensin II, which stimulates aldosterone secretion, increase the conversion of cholesterol to pregnenolone.

Synthetic Pathways for Adrenal Steroids. Figure 77-2 gives the principal steps in the formation of the important steroid products of the adrenal cortex: aldosterone, cortisol, and the androgens. Essentially all these steps occur in two of the organelles of the cell, the mitochondria and the endoplasmic reticulum, some steps occurring in one of these organelles and some in the other. Each step is catalyzed by a specific enzyme system. A change in even a single enzyme in the schema can cause vastly different types and relative proportions of hormones to be formed. For example, very large quantities of masculinizing sex hormones or other steroid compounds not normally present in the blood can occur with altered activity of only one of the enzymes in this pathway.

The chemical formulas of aldosterone and cortisol, which are the most important mineralocorticoid and glucocorticoid hormones, respectively, are shown in Figure 77-2. Cortisol has a keto-oxygen on carbon number 3 and is hydroxylated at carbon numbers 11 and 21. The mineralocorticoid aldosterone has an oxygen atom bound at the number 18 carbon.

In addition to aldosterone and cortisol, other steroids having glucocorticoid or mineralocorticoid activities, or both, are normally secreted in small amounts by the adrenal cortex. And several additional potent steroid hormones not normally formed in the adrenal glands have been synthesized and are used in various forms of therapy. Some of the more important of the corticos-teroid hormones, including the synthetic ones, are the following as summarized in Table 77-1:

Mineralocorticoids

• Aldosterone (very potent, accounts for about 90 per cent of all mineralocorticoid activity)

• Desoxycorticosterone (1/30 as potent as aldosterone, but very small quantities secreted)

• Corticosterone (slight mineralocorticoid activity)

• 9a-Fluorocortisol (synthetic, slightly more potent than aldosterone)

Synthesis Cortical Hormones
Figure 77-2

Pathways for synthesis of steroid hormones by the adrenal cortex. The enzymes are shown in italics.

Table 77-1

Adrenal Steroid Hormones in Adults; Synthetic Steroids and Their Relative Glucocorticoid and Mineralocorticoid Activities

Steroids

Adrenal Steroids

Cortisol

Corticosterone

Aldosterone

Deoxycorticosterone

Dehydroepiandrosterone

Synthetic Steroids

Cortisone

Prednisolone

Methylprednisone

Dexamethasone

9a-fluorocortisol

Average Plasma Concentration (free and bound, mg/100 ml)

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