Adrenocortical Hormones: Subject Matter, Source and Biosynthesis

In this article we will discuss about Adrenocortical Hormones in Adrenal Gland. After reading this article you will learn about: 1. Subject matter of Adrenocortical Hormones 2. Source of Adrenocortical Hormones 3. Biosynthesis 4. Control 5. Transport 6. Catabolism.

Subject Matter of Adrenocortical Hormones:

Adrenal gland is one of the important endo­crine gland which secretes various hor­mones. Histologically, adrenal cortex se­cretes adrenocortical steroid hormones. Kendall et al. (1936) obtained crystalline extracts of the adrenal cortex. In 1945, ac­tive steroids were extracted from this zone. Three active steroid hormones of adrenal cortex are mineralocorticoids, glucocorti­coids and sex steroids.

Source of Adrenocortical Hormones:

Adrenal cortex is histologically divided into three zones, each zone secrete each hor­mone.

Mineralocorticoids and glucocorticoids are C₂₁ steroids whereas androstenedione is C₁₉ steroid.

Biosynthesis of Adrenocortical Hormone:

Synthesis of adrenocortical steroid hormones is complicated phenomenon.

The synthe­sis occurs in following steps:

(A) Conversion of cholesterol to pregnenolone:

The adrenal steroid hormones are synthe­sized from precursor cholesterol molecule. Cholesterol is mostly derived from plasma, but a small portion is synthesized in situ from acetyl CoA. Much of the cholesterol in the adrenal is esterified and steroid in cytoplas­mic lipid droplets.

Upon stimulation of the adrenal by ACTH (or cAMP), an esterase is activated, and the free cholesterol formed is transported into the mitochondrion, where cytochrome P₄₅₀ side chain cleavage en­zyme (P₄₅₀ sec) converts cholesterol to preg­nenolone. Pregnenolone acts as a pivot for synthesis of all adrenocorticosteroids. Preg­nenolone is then released from the mitochon­dria and enter into the smooth ER.

(B) Pregnenolone to different adrenocorticosteroids:

Pregnenolone leads to the synthesis of three hormones by successive reactions.

1. Mineralocorticoid synthesis or aldoster­one synthesis:

In the zona glomerulosa, pregnenolone is converted to progester­one by the action two smooth endoplas­mic reticulum enzymes 3β-OHSD and ∆^{5, 4} isomerase. Progesterone is then hydroxylated at C₂₁ position to form 11- deoxycorticosterone by the actions of microsomal enzyme 21-hydroxylase.

11-deoxycorticosterone is transferred into mitochondria where next hydroxylation at C₁₁ position, produces corticosterone by the action of 11 β-hydroxylase. The 18-hydroxylase acts on corticosterone to form 18-hydroxycorticosterone.

18-hydroxycorticosterone has its C¹⁸ hydroxyl group oxidized to an aldehyde groups by 18-hydroxysteroid dehydroge­nase, to be changed into the aldosterone.

2. Glucocorticoids synthesis:

In the zona fasiculata cells during glucocorticoid synthesis cholesterol is converted to pregnenolone like mineralocorticoid synthesis. Pregnenolone follows Cortisol synthesis in one hand and corticosterone synthesis on other hand.

Cortisol synthesis requires three hydroxy­lases that act sequentially on C₁₇ C₂₁ and C₁₁ positions. The first two reactions are rapid, while C₁₁ hydroxylation is rela­tively slow. Pregnenolone is changed successively through 1 7-hydroxypregnenolone and 1 7-hydroxyprogesterone to 11-deoxycortisol by the actions of mi­crosomal enzymes—1 7α-hydroxylase, 3β-OHSD, ∆^5,4 isomerase and 21 hy­droxylase respectively. 11 -deoxycortisol is then trans-located to mitochondria, where it is hydroxylated by mitochon­drial enzyme 11 β-hydroxylase to pro­duce Cortisol which is the most potent glucocorticoid hormone in humans.

A small amount of pregnenolone on other hand gives rise to another glucocorticoid hormone corticosterone. Corticosterone biosynthesis takes place through proges­terone like aldosterone pathway.

3. Sex steroid synthesis:

The zona reticularis cells mainly take part in this synthesis. In adrenal sex steroid synthe­sis, basic pregnenolone formation takes place from cholesterol like other adrenocorticosteroid synthesis. The C₁₇-side chain of small amounts of 1 7-hydroxypregnenolone, is oxidatively cleaved away and give rise to dehydroepiandrosterone (DHEA) under the ac­tion of microsomal 1 7, 20-Lyase.

Most of DHEA is rapidly modified by the addition of sulfate, about half of which oc­curs in the adrenal and the rest in the liver. DHEA sulfate is inactive, but removal of the sulfate results in reactivation. 3β-OHSD and ∆^5,4 isomerase convert DHEA into more po­tent sex steroid androstenedione (Fig. 6.1 7).

Control of Adrenocortical Hormones:

The synthesis and release of adrenocorticos­teroids is controlled by pituitary ACTH. In­crease in the concentration of glucocorti­coids in blood inhibits the secretion of ACTH by negative feedback mechanism. ACTH-RH of hypothalamus controls the secretion of pituitary ACTH. The different factors like stress, cold, excitement, diurnal rhythm etc. control the secretion of hypo­thalamus (Fig. 6.18)

Mineralocorticoids are mainly regulated by plasma concentrations of K⁺ and Na⁺, renin-angiotensin system.

Transport of Adrenocortical Hormones:

Glucocorticoids are transported through plasma α-globulin, called transcortin or Cor­ticosteroid Binding Globulin (CBG). Mineralocorticoid does not have a specific plasma transport protein, but it forms a very weak association with albumin. Sex steroid is transported through plasma protein.

Catabolism of Adrenocortical Hormones:

Mineralocorticoid is rapidly cleared from the plasma by the liver. The liver forms tetrahydroaldosterone glucuronide which is excreted via urine. Androstenedione and DHEA are excreted as 1 7-keto compounds. Glucocorticoids are metabolised in the liver and excreted in urine as conjugates with glu­curonide or sulfates.