佚名

Hormonal regulation
	Rhythms
	Hormonal effects
Pathophysiologic manifestations
	Receptor-associated alterations
	Intracellular alterations
Disorders
	Adrenal hypofunction
	Congenital adrenal hyperplasia
	Cushing syndrome
	Diabetes insipidus
	Diabetes mellitus
	Gonadotropin deficiency
	Growth hormone deficiency
	Growth hormone excess
	Hyperparathyroidism
	Hypoparathyroidism
	Hyperthyroidism
	Hypopituitarism
	Hypothyroidism in adults
	Hypothyroidism in children
	Syndrome of inappropriate antidiuretic hormone

T he endocrine system consists of glands, specialized cell clusters, hormones, and target tissues. The glands and cell clusters secrete hormones in response to stimulation from the nervous system and other sites. Together with the nervous system, the endocrine system regulates and integrates the body's metabolic activities and maintains internal homeostasis. Each target tissue has receptors for specific hormones. Hormones connect with the receptors, and the resulting hormone-receptor complex triggers the response of the target cell.

HORMONAL REGULATION

The hypothalamus, the main integrative center for the endocrine and nervous systems, helps control some endocrine glands by neural and hormonal pathways. Neural pathways connect the hypothalamus to the posterior pituitary gland, or neurohypophysis. Neural stimulation of the posterior pituitary causes the secretion of two effector hormones: antidiuretic hormone (ADH, also known as vasopressin) and oxytocin.

The hypothalamus also exerts hormonal control at the anterior pituitary gland, or adenohypophysis, by releasing and inhibiting hormones and factors, which arrive by a portal system. Hypothalamic hormones stimulate the pituitary gland to synthesize and release trophic hormones, such as corticotropin (ACTH, also called adrenocorticostimulating hormone), thyroid-stimulating hormone (TSH), and gonadotropins, such as luteinizing hormone (LH) and follicle-stimulating hormone (FSH). Secretion of trophic hormones stimulates the adrenal cortex, thyroid gland, and gonads. Hypothalamic hormones also stimulate the pituitary gland to release or inhibit the release of effector hormones, such as growth hormone (GH) and prolactin.

In a patient with a possible endocrine disorder, this complex hormonal sequence requires careful assessment to identify the dysfunction, which may result from defects in the gland; defects of releasing, trophic, or effector hormones; or defects of the target tissue. Hyperthyroidism, for example, may result from excessive thyrotropin-releasing hormone (TSH), or thyroid hormones, or excessive response of the thyroid gland.

Besides hormonal and neural controls, a feedback system regulates the endocrine system. (See Feedback mechanism of the endocrine system .) The feedback mechanism may be simple or complex. Simple feedback occurs when the level of one substance regulates secretion of a hormone. For example, a low serum calcium level stimulates the parathyroid glands to secrete parathyroid hormone (PTH), and a high serum calcium level inhibits PTH secretion.

One example of complex feedback occurs through the hypothalamic-pituitary target organ axis. Secretion of the hypothalamic corticotropin-releasing hormone releases pituitary ACTH, which in turn stimulates adrenal cortisol secretion. Subsequently, an increase in serum cortisol levels inhibits ACTH by decreasing corticotropin-releasing hormone secretion or ACTH directly. Corticosteroid therapy disrupts the hypothalamic-pituitary-adrenal axis by suppressing the hypothalamic-pituitary secretion mechanism. Because abrupt withdrawal of steroids doesn't allow time for recovery of the hypothalamic-pituitary-adrenal axis to stimulate cortisol secretion, it can induce life-threatening adrenal crisis (hypocortisolism).

FEEDBACK MECHANISM OF THE ENDOCRINE SYSTEM The hypothalamus receives regulatory information (feedback) from its own circulating hormones (simple loop) and also from target glands (complex loop).

Rhythms

The endocrine system is also controlled by rhythms, many of which last 24 hours (circadian). Circadian rhythm control of ACTH and cortisol increases levels of these hormones in the early morning hours and decreases them in the late afternoon. The menstrual cycle is an example of an infradian rhythm ― in this case, 28 days.

Hormonal effects

The posterior pituitary gland secretes oxytocin and ADH. Oxytocin stimulates contraction of the uterus and is responsible for the milk-letdown reflex in lactating women. ADH controls the concentration of body fluids by altering the permeability of the distal and collecting tubules of the kidneys to conserve water. ADH secretion depends on plasma osmolality, the characteristic of a solution determined by the ionic concentration of the dissolved substance and the solution, which is monitored by hypothalamic neurons. Hypovolemia and hypotension are the most powerful stimulators of ADH release. Other stimulators include trauma, nausea, morphine, tranquilizers, certain anesthetics, and positive-pressure breathing.

In addition to the trophic hormones, the anterior pituitary secretes prolactin, which stimulates milk secretion, and GH. GH affects most body tissues. It triggers growth by stimulating protein synthesis and fat mobilization, and by decreasing carbohydrate use by muscle and fat tissue. The thyroid gland synthesizes and secretes the iodinated hormones, thyroxine and triiodothyronine. Thyroid hormones are necessary for normal growth and development, and act on many tissues to increase metabolic activity and protein synthesis.

The parathyroid glands secrete PTH, which regulates calcium and phosphate metabolism. PTH elevates serum calcium levels by stimulating resorption of calcium and excretion of phosphate and ― by stimulating the conversion of vitamin D to its most active form ― enhances absorption of calcium from the GI tract. Calcitonin, another hormone secreted by the thyroid gland, affects calcium metabolism, although its precise role in humans is unknown.

The pancreas produces glucagon from the alpha cells and insulin from the beta cells. Glucagon, the hormone of the fasting state, releases stored glucose from the liver to increase blood glucose levels. Insulin, the hormone of the postprandial state, facilitates glucose transport into the cells, promotes glucose storage, stimulates protein synthesis, and enhances free fatty acid uptake and storage.

The adrenal cortex secretes mineralocorticoids, glucocorticoids, and sex steroid hormones (androgens). Aldosterone, a mineralocorticoid, regulates the reabsorption of sodium and the excretion of potassium by the kidneys. Although affected by ACTH, aldosterone is mainly regulated by the renin-angiotension system. Together, aldosterone, angiotensin II, and renin may be implicated in the pathogenesis of hypertension.

Cortisol, a glucocorticoid, stimulates gluconeogenesis, increases protein breakdown and free fatty acid mobilization, suppresses the immune response, and facilitates an appropriate response to stress.

The adrenal medulla is an aggregate of nervous tissue that produces the catecholamines, epinephrine and norepinephrine, which cause vasoconstriction. In addition, epinephrine stimulates the fight-or-flight response ― dilation of bronchioles and increased blood pressure, blood glucose level, and heart rate. The adrenal cortex as well as the gonads secretes androgens, which are steroid sex hormones. In males and premenopausal females, the contribution of adrenal androgens is very small, but in postmenopausal females, the adrenals are the major source of sex hormones.

The testes synthesize and secrete testosterone in response to gonadotropic hormones, especially LH, from the anterior pituitary gland; spermatogenesis occurs in response to FSH. The ovaries produce sex steroid hormones (primarily estrogen and progesterone) in response to anterior pituitary trophic hormones.

PATHOPHYSIOLOGIC MANIFESTATIONS

Alterations in hormone levels, either significantly high or low, may result from various causes. Feedback systems may fail to function properly or may respond to the wrong signals. Dysfunction of an endocrine gland may manifest as either failure to produce adequate amounts of active hormone or excessive synthesis or release. Once the hormones are released, they may be degraded at an altered rate or inactivated by antibodies before reaching the target cell. Abnormal target cell responses include receptor-associated alterations and intracellular alterations.

Receptor-associated alterations

These alterations have been associated with water-soluble hormones (peptides) and involve:

• decreased number of receptors, resulting in diminished or defective hormone-receptor binding
• impaired receptor function, resulting in insensitivity to the hormone
• presence of antibodies against specific receptors, either reducing available binding sites or mimicking hormone action and suppressing or exaggerating target cell response
• unusual expression of receptor function.

Intracellular alterations

These involve the inadequate synthesis of the second messenger needed to convert the hormonal signal into intracellular events. The two different mechanisms that may be involved are:

• faulty response of target cells for water-soluble hormones to hormone-receptor binding and failure to generate the required second messenger
• abnormal response of the target cell to the second messenger and failure to express the usual hormonal effect.

Pathophysiologic aberrations affecting target cells for lipid-soluble (steroid hormones) hormones occur less frequently or may be recognized less frequently.

DISORDERS

Common dysfunctions of the endocrine system are classified as hypofunction and hyperfunction, inflammation, and tumor.

Adrenal hypofunction

Adrenal hypofunction is classified as primary or secondary. Primary adrenal hypofunction or insufficiency (Addison's disease) originates within the adrenal gland and is characterized by the decreased secretion of mineralocorticoids, glucocorticoids, and androgens. Secondary adrenal hypofunction is due to impaired pituitary secretion of corticotropin (ACTH) and is characterized by decreased glucocorticoid secretion. The secretion of aldosterone, the major mineralocorticoid, is often unaffected.

Addison's disease is relatively uncommon and can occur at any age and in both sexes. Secondary adrenal hypofunction occurs when a patient abruptly stops long-term exogenous steroid therapy or when the pituitary is injured by a tumor or by infiltrative or autoimmune processes ― these occur when circulating antibodies react specifically against adrenal tissue, causing inflammation and infiltration of the cells by lymphocytes. With early diagnosis and adequate replacement therapy, the prognosis for adrenal hypofunction is good.

Adrenal crisis (Addisonian crisis), a critical deficiency of mineralocorticoids and glucocorticoids, generally follows acute stress, sepsis, trauma, surgery, or the omission of steroid therapy in patients who have chronic adrenal insufficiency. Adrenal crisis is a medical emergency that needs immediate, vigorous treatment.

CULTURAL DIVERSITY Autoimmune Addison's disease is most common in white females, and a genetic predisposition is likely. It's more common in patients with a familial predisposition to autoimmune endocrine diseases. Most persons with Addison's disease are diagnosed in their third to fifth decades.

Causes

Primary and secondary adrenal hypofunction and adrenal crisis have different causes. The most common cause of primary hypofunction is:

• Addison's disease (destruction of more than 90% of both adrenal glands, usually due to an autoimmune process in which circulating antibodies react specifically against the adrenal tissue).

Other causes include:

• tuberculosis (once the chief cause, now responsible for less than 20% of adult cases)
• bilateral adrenalectomy
• hemorrhage into the adrenal gland
• neoplasms
• infections (histoplasmosis, cytomegalovirus [CMV])
• family history of autoimmune disease (may predispose the patient to Addison's disease and other endocrinopathies).

Causes of secondary hypofunction (glucocorticoid deficiency) include:

• hypopituitarism (causing decreased ACTH secretion)
• abrupt withdrawal of long-term corticosteroid therapy (long-term exogenous corticosteroid stimulation suppresses pituitary ACTH secretion, resulting in adrenal gland atrophy)
• removal of an ACTH-secreting tumor.

Adrenal crisis is usually caused by:

• exhausted body stores of glucocorticoids in a person with adrenal hypofunction after trauma, surgery, or other physiologic stress.

Pathophysiology

Addison's disease is a chronic condition that results from the partial or complete destruction of the adrenal cortex. It manifests as a clinical syndrome in which the symptoms are associated with deficient production of the adrenocortical hormones, cortisol, aldosterone, and androgens. High levels of ACTH and corticotropin-releasing hormone accompany the low glucocorticoid levels.

ACTH acts primarily to regulate the adrenal release of glucocorticoids (primarily cortisol); mineralocorticoids, including aldosterone; and sex steroids that supplement those produced by the gonads. ACTH secretion is controlled by corticotropin-releasing hormone from the hypothalamus and by negative feedback control by the glucocorticoids.

Addison's disease involves all zones of the cortex, causing deficiencies of the adrenocortical secretions, glucocorticoids, androgens, and mineralocorticoids.

Manifestations of adrenocortical hormone deficiency become apparent when 90% of the functional cells in both glands are lost. In most cases, cellular atrophy is limited to the cortex, although medullary involvement may occur, resulting in catecholamine deficiency. Cortisol deficiency causes decreased liver gluconeogenesis (the formation of glucose from molucules that are not carbohydrates). The resulting low blood glucose levels can become dangerously low in patients who take insulin on a routine basis.

Aldosterone deficiency causes increased renal sodium loss and enhances potassium reabsorption. Sodium excretion causes a reduction in water volume that leads to hypotension. Patients with Addison's disease may have normal blood pressure when supine, but show marked hypotension and tachycardia after standing for several minutes. Low plasma volume and arteriolar pressure stimulate renin release and a resulting increased production of angiotensin II.

Androgen deficiency may decrease hair growth in axillary and pubic areas as well as on the extremities of women. The metabolic effects of testicular androgens make such hair growth less noticeable in men.

Addison's disease is a decrease in the biosynthesis, storage, or release of adrenocortical hormones. In about 80% of the patients, an autoimmune process causes partial or complete destruction of both adrenal glands. Autoimmune antibodies can block the ACTH receptor or bind with ACTH, preventing it from stimulating adrenal cells. Infection is the second most common cause of Addison's disease, specifically tuberculosis, which causes about 20% of the cases. Other diseases that can cause Addison's disease include acquired immunodeficiency syndrome, systemic fungal infections, CMV, adrenal tumor, and metastatic cancers. Infection can impair cellular function and affect ACTH at any stage of regulation.

Signs and symptoms

Clinical features vary with the type of adrenal hypofunction. Signs and symptoms of primary hypofunction include:

• weakness
• fatigue
• weight loss
• nausea, vomiting, and anorexia
• conspicuous bronze color of the skin, especially in the creases of the hands and over the metacarpophalangeal joints (hand/finger), elbows, and knees
• darkening of scars, areas of vitiligo (absence of pigmentation), and increased pigmentation of the mucous membranes, especially the buccal mucosa, due to decreased secretion of cortisol, causing simultaneous secretion of excessive amounts of ACTH and melanocyte-stimulating hormone by the pituitary gland
• associated cardiovascular abnormalities, including orthostatic hypotension, decreased cardiac size and output, and weak, irregular pulse
• decreased tolerance for even minor stress
• fasting hypoglycemia due to decreased gluconeogenesis
• craving for salty food due to decreased mineralocorticoid secretion (which normally causes salt retention).

Signs and symptoms of secondary hypofunction are:

• similar to primary hypofunction, but without hyperpigmentation due to low ACTH and melanocyte-stimulating hormone levels
• possibly no hypotension and electrolyte abnormalities due to fairly normal aldosterone secretion
• usually normal androgen secretion.

Signs and symptoms of Addisonian crisis may include:

• profound weakness and fatigue
• nausea, vomiting, and dehydration
• hypotension
• high fever followed by hypothermia (occasionally).

Complications

Possible complications of adrenal hypofunction include:

• hyperpyrexia
• psychotic reactions
• deficient or excessive steroid treatment
• ultimate vascular collapse, renal shutdown, coma, and death (if untreated).

Diagnosis

Diagnosis of adrenal hypofunction is based on:

• plasma cortisol levels confirming adrenal insufficiency (ACTH stimulation test to differentiate between primary and secondary adrenal hypofunction)
• metyrapone test for suspicion of secondary adrenal hypofunction (oral or I.V. metyrapone blocks cortisol production and should stimulate the release of ACTH from the hypothalamic-pituitary system; in Addison's disease, the hypothalamic-pituitary system responds normally and plasma ACTH levels are high, but because the adrenal glands are destroyed, plasma concentrations of the cortisol precursor 11-deoxycortisol increase, as do urinary 17-hydroxycorticosteroids)
• rapid ACTH stimulation test by I.V. or I.M. administration of cosyntropin (Cortrosyn) after baseline sampling for cortisol and ACTH (samples drawn for cortisol 30 and 60 minutes after injection), to differentiate between primary and secondary adrenal hypofunction.

In a patient with typical Addisonian symptoms, the following laboratory findings strongly suggest acute adrenal insufficiency:

• decreased plasma cortisol level (less than10 mcg/dl in the morning; less in the evening)
• decreased serum sodium and fasting blood glucose levels
• increased serum potassium and blood urea nitrogen levels
• decreased hematocrit; increased lymphocyte and eosinophil counts
• X-rays showing adrenal calcification if the cause is infectious.

Treatment

Treatment for adrenal hypofunction may include:

• lifelong corticosteroid replacement, usually with cortisone or hydrocortisone, both of which have a mineralocorticoid effect (primary or secondary adrenal hypofunction)
• oral fludrocortisone (Florinef), a synthetic mineralocorticoid, to prevent dangerous dehydration, hypotension, hyponatremia, and hyperkalemia (Addison's disease)
• I.V. bolus of hydrocortisone, 100 mg every 6 hours for 24 hours; then, 50 to 100 mg I.M. or diluted with dextrose in saline solution and given I.V. until the patient's condition stabilizes; up to 300 mg/day of hydrocortisone and 3 to 5 L of I.V. saline and glucose solutions may be needed (adrenal crisis).

With proper treatment, adrenal crisis usually subsides quickly; blood pressure stabilizes, and water and sodium levels return to normal. After the crisis, maintenance doses of hydrocortisone preserve physiologic stability.

Congenital adrenal hyperplasia

Congenital adrenal hyperplasia (CAH) encompasses a group of genetic disorders resulting in the deficiency or absence of one of five enzymes needed for the biosynthesis of glucocorticoids and mineralocorticoids. Manifestations are usually present at birth or during early childhood, but symptoms may appear later in life in nonclassic CAH. CAH is uncommon and often has an autosomal recessive mode of inheritance. When successfully treated, sexual functioning and fertility aren't affected.

AGE ALERT Salt-losing CAH may cause fatal adrenal crisis in newborns.

The prevalent adrenal disorder in infants and children, simple virilizing CAH and salt-losing CAH, are the most common forms. Acquired adrenal virilism is rare and affects twice as many females as males. With successful treatment, a normal quality of life and life span are expected. In older patients, androgen excess may be part of the syndrome of polycystic ovaries or may be secondary to an adrenal carcinoma.

Causes

The cause of CAH is:

• genetic, as an autosomal recessive trait.

Pathophysiology

Cortisol levels are regulated by a negative-feedback mechanism. Corticotropin (ACTH) in the blood stimulates the release of cortisol precursors and, consequently, of cortisol, aldosterone, and androgens. In turn, cortisol suppresses ACTH secretion. With a deficiency of the enzyme 21-hydroxylase, cortical secretion of cortisol is impaired and pituitary secretion of ACTH is increased. ACTH stimulates the adrenal cortex, which in turn stimulates both aldosterone and androgen biosynthesis and release.

Signs and symptoms

Signs and symptoms of CAH may include:

• ambiguous genitalia (enlarged clitoris with urethral opening at the base and a combination of the labia and scrotum), normal genital tract and gonads (newborn females)
• pubic and axillary hair at an earlier age, a deep voice, acne, and facial hair, but no menarche (female approaching puberty)
• no apparent manifestations (newborn males)
• accentuated masculine characteristics, including a deepened voice, acne, enlarged phallus with small testes, and frequent erections (male approaching puberty)
• high androgen levels causing rapid bone and muscle growth (in children)
• short stature due to premature epiphyseal closure and high androgen levels (adults)
• more severe changes, including development of a penis in females (salt-losing CAH).

Because males have no external abnormalities, diagnosis is more difficult and commonly delayed until other symptoms occur. In the second week of life, symptoms of a salt-wasting crisis include apathy, failure to eat, diarrhea, and adrenal crisis (vomiting, dehydration from hyponatremia, and hyperkalemia). If adrenal crisis is not treated promptly, dehydration and electrolyte imbalance cause cardiovascular collapse and cardiac arrest.

Complications

Possible complications of CAH are:

• death (salt-wasting crisis)
• precocious puberty
• menstrual irregularities
• sexual dysfunction and infertility.

Diagnosis

Diagnosis of CAH may include:

• elevated urine 17-ketosteroid levels (can be suppressed by dexamethasone [Decadron])
• elevated serum 17-hydroxyprogesterone level after I.V. bolus of ACTH
• serum hyperkalemia, hyponatremia, and hypochloremia (present but not diagnostic)
• elevated 24-hour urine pregnanetriol level
• normal or decreased 24-hour urine 17-hydroxycorticosteroid levels.

Treatment

Treatment of CAH includes:

• daily cortisone (Cortone) or hydrocortisone (Cortef) to stop the excessive output of ACTH and subsequent excessive androgen production (initial and subsequent doses guided by urinary 17-ketosteroids levels) given I.M. until the infant is old enough to tolerate pills (usually about 18 months)
• I.V. sodium chloride and glucose to re-establish fluid and electrolyte balance, with desoxycorticosterone I.M. and hydrocortisone I.V. as needed (adrenal crisis); glucocorticoid (cortisone or hydrocortisone) and perhaps mineralocorticoids (desoxycorticosterone, fludrocortisone, or both after stabilization)
• sex chromatin and karyotype studies to determine genetic sex (with ambiguous external genitalia); possible reconstructive surgery for females between the ages of 1 and 3 years.

Cushing syndrome

Cushing syndrome is a cluster of clinical abnormalities caused by excessive adrenocortical hormones (particularly cortisol) or related corticosteroids and, to a lesser extent, androgens and aldosterone. Cushing's disease (pituitary corticotropin [ACTH] excess) accounts for about 70% of the cases of Cushing syndrome. Cushing's disease occurs most commonly between 20 and 40 years of age and is eight times more common in females.

AGE ALERT Cushing syndrome caused by ectopic corticotropin secretion is more common in adult men, with the peak incidence between 40 and 60 years of age. In 30% of patients, Cushing syndrome results from a cortisol-secreting tumor. Adrenal tumors, rather than pituitary tumors, are more common in children, especially girls.

The annual incidence of endogenous cortisol excess in the United States is 2 to 4 cases per 1 million people per year. The incidence of Cushing syndrome resulting from exogenous administration of cortisol is uncertain, but it is known to be much greater than that of endogenous types. The prognosis for endogenous Cushing syndrome is guardedly favorable with surgery, but morbidity and mortality are high without treatment. About 50% of the individuals with untreated Cushing syndrome die within 5 years of onset as a result of overwhelming infection, suicide, complications from generalized arteriosclerosis (coronary artery disease), and severe hypertensive disease.

Causes

Causes of Cushing syndrome include:

• anterior pituitary hormone (ACTH) excess
• autonomous, ectopic ACTH secretion by a tumor outside the pituitary (usually malignant, frequently oat cell carcinoma of the lung).

Pathophysiology

Cortisol excess results in anti-inflammatory effects and excessive catabolism of protein and peripheral fat to support hepatic glucose production. The mechanism may be ACTH dependent, in which elevated plasma ACTH levels stimulate the adrenal cortex to produce excess cortisol, or ACTH independent, in which excess cortisol is produced by the adrenal cortex or exogenously a