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  Endocrine Physiology

245

  Chapter 7 

3.  Actions of glucocorticoids (cortisol)

■ Overall, glucocorticoids are essential for the response to stress. a.  Stimulation of gluconeogenesis

■ Glucocorticoids increase gluconeogenesis by the following mechanisms:

(1)  They increase protein catabolism in muscle and decrease protein synthesis, thereby

providing more amino acids to the liver for gluconeogenesis.

(2)  They decrease glucose utilization and insulin sensitivity of adipose tissue.

(3)  They increase lipolysis, which provides more glycerol to the liver for gluconeogenesis­. b.  Anti-inflammatory effects

(1)  Glucocorticoids induce the synthesis of lipocortin, an inhibitor of phospholipase A2. (Phospholipase A2 is the enzyme that liberates arachidonate from membrane phospholipids, providing the precursor for prostaglandin and leukotriene synthesis.) Because prostaglandins and leukotrienes are involved in the inflammatory response, glucocorticoids have anti-inflammatory properties by inhibiting the for-

mation of the precursor (arachidonate).

(2)  Glucocorticoids inhibit the production of interleukin-2 (IL-2) and inhibit the prolifera-

tion of T lymphocytes.

(3)  Glucocorticoids inhibit the release of histamine and serotonin from mast cells and platelets.

c.  Suppression of the immune response

■Glucocorticoids inhibit the production of IL-2 and T lymphocytes, both of which are

critical for cellular immunity. In pharmacologic doses, glucocorticoids are used to prevent rejection of transplanted organs.

d.  Maintenance of vascular responsiveness to catecholamines

■Cortisol up-regulates a1 receptors on arterioles, increasing their sensitivity to the vasoconstrictor effect of norepinephrine. Thus, with cortisol excess, arterial pressure increases; with cortisol deficiency, arterial pressure decreases.

4.  Actions of mineralocorticoids (aldosterone) (see Chapters 3 and 5)

a.  ↑ renal Na+ reabsorption (action on the principal cells of the late distal tubule and collecting duct)

b.  ↑ renal K+ secretion (action on the principal cells of the late distal tubule and collecting duct)

c.  ↑ renal H+ secretion (action on the α-intercalated cells of the late distal tubule and collecting duct)

5.  Pathophysiology of the adrenal cortex (Table 7.6) a.  Adrenocortical insufficiency

(1)  Primary adrenocortical insufficiency—Addison disease

■is most commonly caused by autoimmune destruction of the adrenal cortex and causes acute adrenal crisis.

■is characterized by the following:

(a)  ↓ adrenal glucocorticoid, androgen, and mineralocorticoid

(b)  ↑ ACTH (Low cortisol levels stimulate ACTH secretion by negative feedback.)

(c)  Hypoglycemia (caused by cortisol deficiency)

(d)  Weight loss, weakness, nausea, and vomiting

(e)  Hyperpigmentation (Low cortisol levels stimulate ACTH secretion; ACTH contains the MSH fragment.)

(f)  ↓ pubic and axillary hair in women (caused by the deficiency of adrenal

androgens)

(g)  ECF volume contraction, hypotension, hyperkalemia, and metabolic acidosis

(caused by aldosterone deficiency)

246

BRS Physiology

 

 

 

 

 

 

 

 

 

 

 

 

t

a b l e

  7.6 

   Pathophysiology of the Adrenal Cortex

 

 

 

 

 

 

 

Disorder

Clinical Features

ACTH Levels

Treatment

 

 

 

 

Addison disease

Hypoglycemia

Increased (negative

Replacement of

 

(e.g., primary

Anorexia, weight loss, nausea,

feedback effect

glucocorticoids and

 

adrenocortical

vomiting

of decreased

mineralocorticoids

 

insufficiency)

Weakness

cortisol)

 

 

 

 

Hypotension

 

 

 

 

 

Hyperkalemia

 

 

 

 

 

Metabolic acidosis

 

 

 

 

 

Decreased pubic and axillary

 

 

 

 

 

hair in women

 

 

 

 

 

Hyperpigmentation

 

 

Cushing syndrome

Hyperglycemia

Decreased

Ketoconazole

 

(e.g., primary adrenal

Muscle wasting

(negative

Metyrapone

 

hyperplasia)

Central obesity

feedback effect

 

 

 

 

Round face, supraclavicular

of increased

 

 

 

 

fat, buffalo hump

cortisol)

 

 

 

 

Osteoporosis

 

 

 

 

 

Striae

 

 

 

 

 

Virilization and menstrual

 

 

 

 

 

disorders in women

 

 

 

 

 

Hypertension

 

 

Cushing disease

Same as Cushing syndrome

Increased

Surgical removal of

 

(excess ACTH)

 

 

ACTH-secreting tumor

Conn syndrome

Hypertension

 

Spironolactone

 

(aldosterone-

Hypokalemia

 

(aldosterone antagonist)

 

secreting tumor)

Metabolic alkalosis

 

Surgical removal of

 

 

 

Decreased renin

 

aldosterone-secreting

 

 

 

 

 

tumor

21β-Hydroxylase

Virilization of women

Increased (negative

Replacement of

 

deficiency

Early acceleration of linear

feedback effect

glucocorticoids and

(↓ glucocorticoids and

growth

of decreased

mineralocorticoids

 

mineralocorticoids; ↑

Early appearance of pubic and

cortisol)

 

 

adrenal androgens)

axillary hair

 

 

 

 

 

Symptoms of glucocorticoid

 

 

 

 

 

and mineralocorticoid

 

 

 

 

 

deficiency

 

 

17α-Hydroxylase

Lack of pubic and axillary hair

Increased (negative

Replacement of

 

deficiency

in women

feedback effect

glucocorticoids

 

(↓ adrenal androgens

Symptoms of glucocorticoid

of decreased

Aldosterone antagonist

 

and glucocorticoids;

deficiency

cortisol)

 

 

↑ mineralocorticoids)

Symptoms of

 

 

 

 

 

mineralocorticoid excess

 

 

See Table 7.1 for abbreviation.

(2)  Secondary adrenocortical insufficiency

■is caused by primary deficiency of ACTH.

■does not exhibit hyperpigmentation (because there is a deficiency of ACTH).

■does not exhibit volume contraction, hyperkalemia, or metabolic acidosis (because aldosterone levels are normal).

■Symptoms are otherwise similar to those of Addison disease.

b.  Adrenocortical excess—Cushing syndrome

■is most commonly caused by the administration of pharmacologic doses of glucocorticoids.

■is also caused by primary hyperplasia of the adrenal glands.

■is called Cushing disease when it is caused by overproduction of ACTH.

■is characterized by the following:

 

  Endocrine Physiology

247

  Chapter 7 

(1)  ↑ cortisol and androgen levels

(2)  ↓ ACTH (if caused by primary adrenal hyperplasia or pharmacologic doses of glucocorticosteroids); ↑ ACTH (if caused by overproduction of ACTH, as in Cushing

disease)

(3)  Hyperglycemia (caused by elevated cortisol levels)

(4)  ↑ protein catabolism and muscle wasting

(5)  Central obesity (round face, supraclavicular fat, buffalo hump)

(6)  Poor wound healing

(7)  Virilization of women (caused by elevated levels of adrenal androgens)

(8)  Hypertension (caused by elevated levels of cortisol and aldosterone)

(9)  Osteoporosis (elevated cortisol levels cause increased bone resorption) (10)  Striae

■Ketoconazole, an inhibitor of steroid hormone synthesis, can be used to treat Cushing disease.

c.  Hyperaldosteronism—Conn syndrome

■is caused by an aldosterone-secreting tumor.

■is characterized by the following:

(1)  Hypertension (because aldosterone increases Na+ reabsorption, which leads to

increases in ECF volume and blood volume)

(2)  Hypokalemia (because aldosterone increases K+ secretion)

(3)  Metabolic alkalosis (because aldosterone increases H+ secretion)

(4)  ↓ renin secretion (because increased ECF volume and blood pressure inhibit renin secretion by negative feedback)

d.  21b-Hydroxylase deficiency

■is the most common biochemical abnormality of the steroidogenic pathway (see Figure 7.11).

■belongs to a group of disorders characterized by adrenogenital syndrome.

■is characterized by the following:

(1)  ↓ cortisol and aldosterone levels (because the enzyme block prevents the production of 11-deoxycorticosterone and 11-deoxycortisol, the precursors for cortisol and aldosterone)

(2)  ↑ 17-hydroxyprogesterone and progesterone levels (because of accumulation of intermediates above the enzyme block)

(3)  ↑ ACTH (because of decreased feedback inhibition by cortisol)

(4)  Hyperplasia of zona fasciculata and zona reticularis (because of high levels of

ACTH)

(5)  ↑ adrenal androgens (because 17-hydroxyprogesterone is their major precursor) and ↑ urinary 17-ketosteroids

(6)  Virilization in women

(7)  Early acceleration of linear growth and early appearance of pubic and axillary hair

(8)  Suppression of gonadal function in both men and women e.  17a-Hydroxylase deficiency is characterized by the following:

(1)  ↓ androgen and glucocorticoid levels (because the enzyme block prevents the pro-

duction of 17-hydroxypregnenolone and 17-hydroxyprogesterone)

(2)  ↑ mineralocorticoid levels (because intermediates accumulate to the left of the enzyme block and are shunted toward the production of mineralocorticoids)

(3)  Lack of pubic and axillary hair (which depends on adrenal androgens) in women

(4)  Hypoglycemia (because of decreased glucocorticoids)

(5)  Metabolic alkalosis, hypokalemia, and hypertension (because of increased mineralocorticoids)

(6)  ↑ ACTH (because decreased cortisol levels stimulate ACTH secretion by negative feedback)

B. Adrenal medulla (see Chapter 2, I A 4)

248

Brs Physiology

vI. enDOCrIne PAnCreAs–GlUCAGOn AnD InsUlIn (TABle 7.7)

A.Organization of the endocrine pancreas

■The islets of Langerhans contain three major cell types (Table 7.8). Other cells secrete pancreatic polypeptide.

■Gap junctions link beta cells to each other, alpha cells to each other, and beta cells to alpha cells for rapid communication.

■The portal blood supply of the islets allows blood from the beta cells (containing insulin) to bathe the alpha and delta cells, again for rapid cell-to-cell communication.

B.Glucagon

1.regulation of glucagon secretion (Table 7.9)

■The major factor that regulates glucagon secretion is the blood glucose concentration.

Decreased blood glucose stimulates glucagon secretion.

■Increased blood amino acids stimulate glucagon secretion, which prevents hypoglycemia caused by unopposed insulin in response to a high protein meal.

2.Actions of glucagon

■Glucagon acts on the liver and adipose tissue.

■The second messenger for glucagon is CAmP.

a.Glucagon increases the blood glucose concentration.

(1)It increases glycogenolysis and prevents the recycling of glucose into glycogen.

(2)It increases gluconeogenesis. Glucagon decreases the production of fructose 2,6-bisphosphate, decreasing phosphofructokinase activity; in effect, substrate is directed toward glucose formation rather than toward glucose breakdown.

b.Glucagon increases blood fatty acid and ketoacid concentration.

■ Glucagon increases lipolysis. The inhibition of fatty acid synthesis in effect “shunts” substrates toward gluconeogenesis.

■Ketoacids (β-hydroxybutyrate and acetoacetate) are produced from acetyl coenzyme A (CoA), which results from fatty acid degradation.

c.Glucagon increases urea production.

■Amino acids are used for gluconeogenesis (stimulated by glucagon), and the resulting amino groups are incorporated into urea.

 

 

 

 

 

t a b l e

 

7.7

Comparison of Insulin and Glucagon

 

 

 

 

 

 

 

 

 

 

stimulus for

 

Overall effect on

 

 

secretion

major Actions

Blood levels

 

 

 

 

Insulin (tyrosine

↑ Blood glucose

Increases glucose uptake into cells and

↓ [glucose]

kinase

↑ Amino acids

glycogen formation

 

receptor)

↑ Fatty acids

Decreases glycogenolysis and

 

 

 

Glucagon

gluconeogenesis

↓ [amino acid]

 

 

GIP

 

Increases protein synthesis

 

 

Growth hormone

Increases fat deposition and decreases

↓ [fatty acid]

 

 

Cortisol

lipolysis

↓ [ketoacid]

 

 

 

 

 

Increases K+ uptake into cells

Hypokalemia

Glucagon (cAMP

↓ Blood glucose

Increases glycogenolysis and

↑ [glucose]

mechanism)

↑ Amino acids

gluconeogenesis

↑ [fatty acid]

 

 

CCK

 

Increases lipolysis and ketoacid production

 

 

Norepinephrine,

 

↑ [ketoacid]

 

 

epinephrine, ACh

 

 

ACh = acetylcholine; cAMP = cyclic adenosine monophosphate; CCK = cholecystokinin; GIP = glucose-dependent insulinotropic peptide.

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