There are two adrenal glands, each weighing about 4 g.
Each adrenal gland lies at the upper pole of a kidney (Fig. 78.1).
Each gland has two major parts: adrenal medulla and adrenal cortex.
The adrenal medulla forms the central 20% of the gland.
It is functionally connected to the sympathetic nervous system.
Sympathetic stimulation causes the medulla to release epinephrine and norepinephrine.
These hormones produce effects that are almost the same as direct sympathetic nerve stimulation throughout the body.
The adrenal cortex produces a different group of hormones called corticosteroids.
All corticosteroids are made from cholesterol.
They have similar chemical structures, but small structural differences give them different important functions.

KEY CONCEPT

Adrenal gland = Medulla + Cortex

Medulla → epinephrine + norepinephrine → sympathetic-type effects.
Cortex → corticosteroids → made from cholesterol.

CONCEPTUAL EXAMPLES

Sympathetic stimulation → adrenal medulla → epinephrine/norepinephrine.
Cholesterol → adrenal cortex → corticosteroid hormones.

CORTICOSTEROIDS: MINERALOCORTICOIDS, GLUCOCORTICOIDS, AND ANDROGENS

The adrenal cortex produces two major types of hormones: mineralocorticoids and glucocorticoids.
It also produces small amounts of sex hormones, especially androgens.
Adrenal androgens normally have only a small role, but excessive production can cause masculinizing effects.
Mineralocorticoids mainly affect extracellular-fluid electrolytes, especially sodium and potassium.
Glucocorticoids have important effects that increase blood glucose.
Glucocorticoids also strongly affect protein and fat metabolism.
More than 30 steroids have been identified from the adrenal cortex.
The two most important for normal human endocrine function are:
- Aldosterone → principal mineralocorticoid
- Cortisol → principal glucocorticoid

KEY CONCEPT

Adrenal cortex → Mineralocorticoids + Glucocorticoids + Androgens

Aldosterone → Na⁺/K⁺ and extracellular electrolytes
Cortisol → ↑ blood glucose + protein/fat metabolism
Androgens → minor normal role; excess → masculinizing effects

CONCEPTUAL EXAMPLES

Aldosterone → mineral balance
Cortisol → glucose metabolism
Excess adrenal androgens → masculinizing effects

SYNTHESIS AND SECRETION OF ADRENOCORTICAL HORMONES

The adrenal cortex has three distinct layers (Fig. 78.1):
- Zona glomerulosa → about 15% of cortex → mainly secretes aldosterone.
- Zona fasciculata → about 75% and widest layer → mainly secretes cortisol and corticosterone, plus small amounts of adrenal androgens and estrogens.
- Zona reticularis → inner layer → mainly secretes adrenal androgens, plus small amounts of estrogens and glucocorticoids.
Zona glomerulosa is the only adrenal region capable of significant aldosterone secretion because it contains aldosterone synthase.
Aldosterone secretion is mainly stimulated by angiotensin II and increased extracellular K⁺.
Zona fasciculata secretion is mainly controlled by ACTH through the hypothalamic-pituitary axis.
Zona reticularis secretion is also regulated by ACTH, although other pituitary factors may contribute.
Aldosterone and cortisol are controlled independently.
Angiotensin II mainly increases aldosterone and affects the zona glomerulosa.
ACTH mainly increases cortisol and adrenal androgens and affects the zona fasciculata and reticularis.
All adrenal steroid hormones are made from cholesterol.
About 80% of the cholesterol used for steroid synthesis comes from circulating LDLs.
LDL enters adrenal cells through receptor-mediated endocytosis and releases cholesterol for hormone synthesis.
ACTH increases LDL receptors and enzymes that release cholesterol from LDL.
Cholesterol enters the mitochondria and is converted by cholesterol desmolase into pregnenolone.
This is the rate-limiting step in adrenal steroid formation (Fig. 78.2).
Both ACTH and angiotensin II stimulate conversion of cholesterol to pregnenolone.
Formation of aldosterone, cortisol, and adrenal androgens occurs mainly in the mitochondria and endoplasmic reticulum.
Each step requires a specific enzyme.
A defect in even one enzyme can greatly change which adrenal steroids are produced and in what amounts.
For example, 21β-hydroxylase deficiency prevents normal cortisol formation.
Low cortisol → CRH ↑ → ACTH ↑ → adrenal cortex grows, especially the fasciculata and reticularis.
The enlarged cortex produces excess steroids such as androstenedione, which can be converted into active androgens.
Therefore, 21β-hydroxylase deficiency can cause excessive masculinizing hormones.
The major mineralocorticoid is aldosterone.
The major glucocorticoid is cortisol.
Important mineralocorticoids:
- Aldosterone → very potent; about 90% of mineralocorticoid activity.
- Deoxycorticosterone → about 1/30 as potent as aldosterone.
- Corticosterone → slight activity.
- 9α-Fluorocortisol → synthetic; slightly more potent than aldosterone.
- Cortisol and cortisone → slight mineralocorticoid activity.
Important glucocorticoids:
- Cortisol → very potent; about 95% of glucocorticoid activity.
- Corticosterone → about 4% of total activity and much less potent.
- Cortisone → almost as potent as cortisol.
- Prednisone → synthetic; about 4× cortisol potency.
- Methylprednisone → about 5× cortisol potency.
- Dexamethasone → about 30× cortisol potency.
Some corticosteroids have both glucocorticoid and mineralocorticoid activity.
Cortisol normally has some mineralocorticoid activity, so excessive cortisol can also produce mineralocorticoid effects.
Dexamethasone has very strong glucocorticoid activity with almost no mineralocorticoid activity.
About 90–95% of cortisol in plasma is bound to proteins, mainly cortisol-binding globulin (transcortin) and some albumin.
This protein binding slows cortisol removal, giving cortisol a half-life of about 60–90 minutes.
About 60% of aldosterone is protein-bound and 40% is free.
Therefore, aldosterone has a shorter half-life of about 20 minutes.
Protein binding acts as a reservoir, reducing rapid changes in free hormone levels and helping distribute hormones uniformly.
Adrenal steroids are mainly metabolized in the liver.
They are converted mainly into inactive compounds by conjugation with glucuronic acid and, to a lesser extent, sulfates.
About 25% of these conjugates leave through bile and feces.
The rest enter blood, are filtered by the kidneys, and are excreted in urine.
Liver disease slows hormone inactivation, while kidney disease reduces excretion of inactive conjugates.
Normal plasma aldosterone is about 6 ng/100 mL, with secretion about 150 μg/day.
Aldosterone levels vary greatly with sodium and potassium intake.
Plasma cortisol averages about 12 μg/100 mL, with secretion about 15–20 mg/day.
Cortisol secretion varies during the day: it is higher in the early morning and lower in the evening.

KEY CONCEPT

Adrenal cortex → 3 zones → different hormones

Glomerulosa → Aldosterone → Angiotensin II + K⁺
Fasciculata → Cortisol → ACTH
Reticularis → Androgens → mainly ACTH

Cholesterol → pregnenolone → adrenal steroid hormones

CONCEPTUAL EXAMPLES

Angiotensin II ↑ → zona glomerulosa → aldosterone ↑.
ACTH ↑ → zona fasciculata/reticularis → cortisol + androgens ↑.
Cholesterol → mitochondria → pregnenolone → steroid hormones.
21β-hydroxylase deficiency → cortisol ↓ → ACTH ↑ → adrenal cortex enlargement + androgen excess.
Cortisol → mostly protein-bound → slower removal.
Aldosterone → more free hormone → shorter half-life.