Hypoadrenalism (Adrenal Insufficiency)—Addison
Disease, Hyperadrenalism—Cushing Syndrome ,Primary Aldosteronism (Conn Syndrome),Congenital Adrenal Hyperplasia, Adrenogenital Syndrome

• The adrenal cortex continuously secretes small amounts of male sex hormones called adrenal androgens.
• The most important adrenal androgen is dehydroepiandrosterone (DHEA).
• Their secretion is especially important during fetal life.
• The adrenal cortex also secretes very small amounts of the female sex hormones progesterone and estrogens.
• Normally, adrenal androgens have only weak effects in humans.
• In childhood, they contribute partly to the early development of male sex organs.
• In females, they have mild effects before puberty and throughout life.
• They are responsible for much of the growth of pubic and axillary hair in females.
• In tissues outside the adrenal gland, some adrenal androgens are converted into testosterone.
• This conversion to testosterone explains much of their androgenic activity.

Abnormalities of Adrenocortical Secretion

Hypoadrenalism (Adrenal Insufficiency)—Addison Disease

• Addison disease occurs when the adrenal cortices cannot produce enough adrenocortical hormones.
• It usually results from atrophy or damage of the adrenal cortex.
• In about 80% of cases, the adrenal cortex is damaged by autoimmunity.
• Adrenal hypofunction can also result from tuberculosis or cancer invading the adrenal cortex.
• Adrenal insufficiency can also occur when the pituitary gland produces too little ACTH.
• Low ACTH causes decreased production of cortisol and aldosterone.
• With prolonged lack of ACTH stimulation, the adrenal glands may eventually atrophy.
• This is called secondary adrenal insufficiency and is more common than Addison disease.
• Addison disease is therefore also called primary adrenal insufficiency.

Mineralocorticoid Deficiency

• Lack of aldosterone greatly decreases sodium reabsorption by the renal tubules.
• Therefore, large amounts of sodium, chloride, and water are lost in urine.
• This causes a major decrease in extracellular fluid (ECF) volume and produces hyponatremia.
• At the same time, reduced secretion of potassium and hydrogen ions causes:
  • Hyperkalemia
  • Mild acidosis
• As ECF volume continues to fall:
  • Plasma volume decreases
  • Red blood cell concentration increases
  • Cardiac output decreases
  • Blood pressure decreases
• Severe volume loss can finally cause shock.
• Without treatment, complete loss of mineralocorticoid secretion may cause death within about 4 days to 2 weeks.

KEY CONCEPT

• Adrenal androgens = weak sex hormones from the adrenal cortex, especially DHEA.
• They contribute to pubic and axillary hair, particularly in females, and some are converted to testosterone.
• Addison disease = primary failure of the adrenal cortex → inadequate adrenal hormones.
• Low aldosterone → Na⁺ + water loss → ↓ ECF and blood volume → ↓ blood pressure → possible shock.
• At the same time, K⁺ and H⁺ are retained → hyperkalemia + mild acidosis.

Conceptual Examples

• Adrenal androgen example:
  Adrenal androgens → act weakly themselves → some convert to testosterone → androgenic effects.
• Aldosterone deficiency example:
  ↓ Aldosterone → ↓ renal Na⁺ reabsorption → Na⁺ + water lost in urine → ↓ ECF volume → ↓ blood pressure.
• Potassium example:
  ↓ Aldosterone → ↓ K⁺ secretion → K⁺ stays in the body → hyperkalemia.
• Severe deficiency example:
  Severe fluid loss → ↓ plasma volume → ↓ cardiac output → ↓ blood pressure → shock.

Glucocorticoid Deficiency

• Loss of cortisol makes it difficult for a person with Addison disease to maintain normal blood glucose between meals.
• This happens because the body cannot produce enough glucose by gluconeogenesis.
• Lack of cortisol also decreases the mobilization of proteins and fats from tissues.
• Therefore, many metabolic functions become slower because the body cannot properly mobilize energy.
• Even when plenty of glucose and other nutrients are available, the muscles remain weak.
• This shows that glucocorticoids are needed not only for energy metabolism but also for maintaining other normal tissue metabolic functions.
• Inadequate glucocorticoids also make a person with Addison disease much less able to tolerate stress.
• Therefore, even a mild respiratory infection can become dangerous and may cause death.

Melanin Pigmentation

• Most people with Addison disease develop increased melanin pigmentation of the skin and mucous membranes.
• The pigmentation may be uneven and can appear as blotches.
• It is especially noticeable in thin areas such as:
  • Mucous membranes of the lips
  • Skin of the nipples
• ↓ Cortisol reduces the normal negative feedback on the hypothalamus and anterior pituitary.
• Therefore, secretion of ACTH becomes very high, along with increased MSH secretion.
• Large amounts of ACTH can stimulate melanocytes like MSH does.
• Thus, increased ACTH probably causes most of the increased pigmentation.

Treatment of People With Addison Disease

• Complete destruction of the adrenal glands without treatment can cause death within days to weeks.
• Death usually occurs because of severe weakness and circulatory shock.
• However, a person can survive for years if small amounts of mineralocorticoids and glucocorticoids are given every day.

Adrenal Crisis

• Normally, physical or mental stress causes secretion of large amounts of glucocorticoids.
• In Addison disease, glucocorticoid secretion cannot increase during stress.
• During severe stress such as:
  • Trauma
  • Disease
  • Surgery
  the body may suddenly need much more glucocorticoid.
• The person may need 10 or more times the normal glucocorticoid amount to prevent death.
• This severe need for extra glucocorticoids, together with marked weakness during acute stress, is called an adrenal crisis (Addisonian crisis).

KEY CONCEPT

• ↓ Cortisol → ↓ gluconeogenesis → difficulty maintaining blood glucose between meals.
• ↓ Cortisol → ↓ protein and fat mobilization → poor energy mobilization + muscle weakness.
• ↓ Cortisol → poor ability to tolerate stress.
• ↓ Cortisol → ↓ negative feedback → ↑ ACTH + ↑ MSH → increased skin and mucosal pigmentation.
• Addison disease requires daily glucocorticoid + mineralocorticoid replacement.
• During severe stress, glucocorticoid requirements rise greatly; failure to meet this need can cause an adrenal crisis.

Conceptual Examples

• Blood glucose:
  ↓ Cortisol → ↓ gluconeogenesis → blood glucose becomes difficult to maintain between meals.
• Pigmentation:
  ↓ Cortisol → ↓ negative feedback → ↑ ACTH → stimulation of melanocytes → increased pigmentation.
• Stress:
  Addison disease + surgery → glucocorticoids cannot rise normally → very high glucocorticoid requirement → risk of adrenal crisis.
• Treatment:
  Adrenal destruction → lack of adrenal hormones → daily mineralocorticoid + glucocorticoid replacement → long-term survival.

Hyperadrenalism—Cushing Syndrome

• Cushing syndrome results from excessive secretion of hormones by the adrenal cortex.
• Most abnormalities are caused by excess cortisol, although excess androgens may also contribute.
• Hypercortisolism can occur from several causes:
  • Pituitary adenoma → ↑ ACTH → adrenal hyperplasia → ↑ cortisol.
  • Abnormal hypothalamic function → ↑ CRH → ↑ ACTH → ↑ cortisol.
  • Ectopic ACTH secretion from a tumor elsewhere in the body.
  • Adrenal cortical adenoma → direct excess cortisol production.
• When excess cortisol results from excessive ACTH secretion by the anterior pituitary, it is called Cushing disease.
• Excess ACTH is the most common cause of Cushing syndrome.
• In ACTH-dependent disease:
  • ↑ ACTH
  • ↑ cortisol
• Primary adrenal overproduction of cortisol causes about 20%–25% of clinical cases.
• In primary adrenal disease:
  • ↑ cortisol
  • Cortisol produces negative feedback on the pituitary.
  • Therefore, ACTH becomes low.

Dexamethasone Test

• Dexamethasone is a synthetic glucocorticoid used to help distinguish ACTH-dependent from ACTH-independent Cushing syndrome.
• In a pituitary ACTH-secreting adenoma or hypothalamic-pituitary dysfunction:
  • Low-dose dexamethasone usually does not suppress ACTH normally.
  • Very high-dose dexamethasone can suppress ACTH in most patients with Cushing disease.
• In primary adrenal cortisol overproduction:
  • Cortisol is produced independently of ACTH.
  • Therefore, ACTH is usually low or undetectable.
• The dexamethasone test is not always completely accurate.
• Some pituitary ACTH-secreting tumors may suppress ACTH after dexamethasone.
• Some tumors outside the pituitary, such as certain lung carcinomas, produce ACTH and do not respond normally to glucocorticoid negative feedback.
• Therefore, the dexamethasone test is mainly used as a first step in differentiating causes of Cushing syndrome.

Glucocorticoid Treatment as a Cause

• Cushing syndrome can also develop when large doses of glucocorticoids are taken for a long time.
• For example, patients receiving glucocorticoids for chronic inflammatory diseases such as rheumatoid arthritis may develop features of Cushing syndrome.

Characteristic Features

• Fat is mobilized from the lower part of the body.
• At the same time, more fat is deposited in the thorax and upper abdomen.
• This produces a characteristic buffalo-like torso.
• Excess steroids also produce an edematous, rounded face.
• This characteristic appearance is called a “moon face” (Fig. 78.11).
• Androgenic effects may produce:
  • Acne
  • Hirsutism = excess facial hair growth
• About 80% of patients develop hypertension.
• This hypertension is thought to result mainly from the mineralocorticoid effects of excess cortisol.

KEY CONCEPT

• Cushing syndrome = excess cortisol effects in the body.
• Pituitary ↑ ACTH → ↑ cortisol = Cushing disease.
• Primary adrenal cortisol excess → ↑ cortisol + ↓ ACTH.
• Dexamethasone helps distinguish ACTH-dependent from ACTH-independent causes.
• Typical features include upper-body fat deposition, moon face, acne/hirsutism, and hypertension.

Conceptual Examples

• Pituitary cause:
  Pituitary adenoma → ↑ ACTH → adrenal stimulation → ↑ cortisol → Cushing disease.
• Adrenal cause:
  Adrenal adenoma → ↑ cortisol → negative feedback → ↓ ACTH.
• Dexamethasone:
  Pituitary Cushing disease + very high-dose dexamethasone → ACTH can usually be suppressed.
• Body appearance:
  Fat moves away from the lower body and accumulates in the thorax and upper abdomen → buffalo-like torso.
• Blood pressure:
  Excess cortisol → mineralocorticoid-like effects → hypertension.

Effects of Cushing Syndrome on Carbohydrate and Protein Metabolism

• Excess cortisol in Cushing syndrome can markedly increase blood glucose.
• After meals, blood glucose may reach about 200 mg/dL, which can be nearly twice normal.
• This mainly occurs because cortisol causes:
  • ↑ Gluconeogenesis → more glucose is formed.
  • ↓ Glucose utilization by tissues → less glucose is used.
• Excess glucocorticoids also cause marked protein breakdown.
• Tissue proteins decrease in almost all parts of the body, except the liver.
• Plasma proteins also remain relatively unaffected.
• Loss of muscle protein causes severe muscle weakness.
• Reduced protein synthesis in lymphoid tissues suppresses the immune system.
• Therefore, patients become highly susceptible to infections.
• Loss of collagen fibers in subcutaneous tissues makes the skin and underlying tissues weak and easy to tear.
• This produces large purplish striae.
• Reduced protein deposition in bones causes severe osteoporosis.
• As a result, the bones become weak.

Treatment of People With Cushing Syndrome

• Treatment depends on the cause of excess cortisol.
• If an adrenal tumor is responsible, the tumor can be removed.
• If excess ACTH is the cause, treatment aims to reduce ACTH secretion.
• An enlarged pituitary gland or a small ACTH-secreting pituitary tumor may be:
  • Surgically removed, or
  • Destroyed by radiation.
• When surgery is not possible, drugs may be used to reduce hormone production.
• Drugs that block steroid synthesis include:
  • Metyrapone
  • Ketoconazole
  • Aminoglutethimide
• Drugs that inhibit ACTH secretion may also be used.
• If ACTH cannot be adequately reduced, partial or total removal of both adrenal glands may be required.
• After adrenal removal, adrenal steroid replacement is given to correct the hormone deficiency that develops.

KEY CONCEPT

• Excess cortisol → ↑ gluconeogenesis + ↓ glucose use → hyperglycemia.
• Excess cortisol → ↑ protein breakdown → muscle weakness.
• ↓ Lymphoid proteins → suppressed immunity → increased infections.
• ↓ Collagen → thin, fragile tissues → purplish striae.
• ↓ Bone protein → osteoporosis → weak bones.
• Treatment aims to remove the hormone-producing tumor or reduce ACTH/cortisol production.

Conceptual Examples

• Blood glucose:
  Excess cortisol → ↑ glucose production + ↓ tissue glucose use → high blood glucose.
• Muscle:
  Excess cortisol → protein breakdown → loss of muscle protein → severe weakness.
• Skin:
  ↓ Collagen → weak subcutaneous tissue → easy tearing → purplish striae.
• Bone:
  ↓ Protein deposition in bone → osteoporosis → weak bones.
• Treatment:
  ACTH-secreting pituitary tumor → remove or destroy tumor → ↓ ACTH → ↓ cortisol.

Primary Aldosteronism (Conn Syndrome)

• Primary aldosteronism (Conn syndrome) occurs when the adrenal cortex secretes excessive aldosterone.
• It may result from:
  • A small tumor of zona glomerulosa cells.
  • Adrenal cortical hyperplasia that mainly secretes aldosterone.
• Excess aldosterone produces:
  • Hypokalemia
  • Mild metabolic alkalosis
  • Slight increase in extracellular fluid (ECF) volume
  • Slight increase in blood volume
  • Small rise in plasma Na⁺, usually <4–6 mEq/L
  • Almost always hypertension
• Severe hypokalemia may occasionally cause muscle paralysis.
• Low extracellular K⁺ depresses action potential transmission in nerve fibers, leading to paralysis.
• An important diagnostic finding is low plasma renin concentration.
• The sequence is: ↑ Aldosterone → ↑ ECF volume + ↑ arterial pressure → suppression of renin → ↓ plasma renin
• Treatment may include:
  • Surgical removal of an aldosterone-secreting tumor.
  • Removal of most adrenal tissue when hyperplasia is responsible.
  • Blocking mineralocorticoid receptors with spironolactone or eplerenone.

Congenital Adrenal Hyperplasia

• Congenital adrenal hyperplasia (CAH) is a group of autosomal-recessive genetic disorders.
• It causes enlargement of the adrenal cortex, especially:
  • Zona fasciculata
  • Zona reticularis
• CAH causes impaired production of cortisol and aldosterone.
• More than 95% of cases are caused by 21β-hydroxylase deficiency.
• Normally, 21β-hydroxylase helps convert: 17-hydroxyprogesterone → 11-deoxycortisol
• Therefore, deficiency of this enzyme causes:
  • ↓ Cortisol
  • ↓ Aldosterone
• ↓ Cortisol removes normal negative feedback on the hypothalamus and pituitary: ↓ Cortisol → ↑ CRH → ↑ ACTH
• ↑ ACTH then causes:
  • Adrenal hyperplasia
  • Accumulation of cortisol precursors such as 17-hydroxyprogesterone
  • Increased production of androgenic steroids
• These androgenic hormones do not suppress CRH and ACTH by negative feedback.
• Severity depends on how much 21β-hydroxylase activity remains.
• Nonclassic CAH:
  • Some enzyme activity remains.
  • Usually diagnosed in later childhood or adulthood.
  • Causes increased adrenal androgen production.
  • Produces minimal salt wasting.
• Classic CAH:
  • Little or no 21β-hydroxylase activity.
  • Usually diagnosed in infancy or early childhood.
  • It is the more severe form.
  • Untreated patients may develop severe salt wasting with:
    • ↓ Blood volume
    • Hypotension
    • Hyponatremia
    • Hyperkalemia
    • Metabolic acidosis
    • Adrenal crisis
• These patients require glucocorticoid and mineralocorticoid therapy to survive.

Adrenogenital Syndrome

• Adrenogenital syndrome may occur when an adrenocortical tumor secretes excessive androgens.
• Excess androgens cause strong masculinizing effects.
• In females, these effects may include:
  • Growth of a beard
  • Deepening of the voice
  • Possible baldness when genetically susceptible
  • Masculine distribution of body and pubic hair
  • Enlargement of the clitoris
  • Increased protein deposition in skin and especially muscles, producing more masculine features
• In a prepubertal male, a virilizing adrenal tumor causes similar masculinizing effects plus rapid development of the male sexual organs (Fig. 78.12).
• In an adult male, the disorder may be difficult to recognize because normal testicular testosterone already produces strong masculine characteristics.
• In adrenogenital syndrome, urinary 17-ketosteroids may rise to 10–15 times normal.
• This marked increase can help in diagnosis.

KEY CONCEPT

• Conn syndrome:
  ↑ Aldosterone → Na⁺/water retention + K⁺ loss → hypertension + hypokalemia + ↓ renin.
• CAH due to 21β-hydroxylase deficiency:
  ↓ Cortisol + ↓ aldosterone → ↓ negative feedback → ↑ ACTH → adrenal hyperplasia + ↑ androgen production.
• Classic CAH:
  Severe enzyme deficiency → salt wasting + hypotension + hyponatremia + hyperkalemia + metabolic acidosis + adrenal crisis.
• Adrenogenital syndrome:
  Excess adrenal androgens → masculinization, especially obvious in females and prepubertal males.

Conceptual Examples

• Conn syndrome:
  ↑ Aldosterone → ↑ Na⁺ and water retention → ↑ blood volume → hypertension → renin becomes low.
• Hypokalemia:
  ↑ Aldosterone → ↑ K⁺ loss → ↓ extracellular K⁺ → impaired nerve action potential transmission → muscle paralysis.
• CAH:
  21β-hydroxylase deficiency → ↓ cortisol → ↑ ACTH → adrenal enlargement + ↑ androgen production.
• Classic CAH:
  ↓ Aldosterone → salt and water loss → ↓ blood volume → hypotension and adrenal crisis.
• Adrenogenital syndrome:
  Adrenal tumor → ↑ androgens → masculinizing changes + markedly increased urinary 17-ketosteroids.

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