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The endocrine system

Explanation for working with teaching material.

Study the guide.

Give answers to the tests.

3.  Give the answers to one of the proposed variant of the final control.

The endocrine system affects all aspects of body function, including growth and development, energy metabolism, muscle and adipose tissue distribution, sexual development, fluid and electrolyte balance, inflammation and immune responses.

There are two types of organization of the endocrine system: cerebropituitary type and pituitary-independent type.

Cerebropituitary type includes the brain cortex, hypothalamus, anterior pituitary, peripheral endocrine gland, and the target cells. The brain cortex exerts neurogenic influence on the hypothalamus which produces liberins or statins. The hypothalamic hormones are secreted into the pituitary portal system and affect trophocytes producing tropins (e.g. ACTH, gonadotropins). The latter are secreted into general circulation and reach the peripheral endocrine glands where they exert stimulating or inhibitory effect.

In pituitary-independent system the pituitary stage is omitted. For example, parathyroid gland or beta-cells of the pancreas are not regulated by pituitary trophins.

Endocrinopathy can result from hormone deficiency (hypofunction), hormone excess (hyperfunction), resistance to hormone action, or constitutive mutations, that activate hormone response systems in the absence of ligand.

Primary, Secondary, and Tertiary Disorders

Endocrine disorders in general can be divided into primary,

secondary, and tertiary groups.

Primary defects in endocrine function originate in the target gland responsible for producing the hormone.

In secondary disorders of endocrine function, the target gland is essentially normal, but its function is altered by defective levels of stimulating hormones from the pituitary system. For example, adrenalectomy produces a primary deficiency of adrenal corticosteroid hormones.

Removal or destruction of the pituitary gland eliminates ACTH stimulation of the adrenal cortex and brings about

a secondary deficiency.

A tertiary disorder results from hypothalamic dysfunction (as may occur with craniopharyngiomas or cerebral irradiation); thus, both the pituitary and target organ are understimulated.

Causes of hypofunction of an endocrine gland

Congenital defects can result in the absence or impaired development of the gland or the absence of an enzyme needed for hormone synthesis.

The gland may be destroyed by a disruption in blood flow, infection, inflammation, autoimmune responses, or neoplastic growth.

There may be a decline in function with aging, or the gland may atrophy as the result of drug therapy or for unknown reasons.

Some endocrine-deficient states are associated with receptor defects (Peripheral (non-glandular) mechanism of hormone activity disturbance: blockade of hormonal receptors, hormone receptors may be absent, the receptor binding of hormones may be defective, or the cellular response to the hormone may be impaired.

In some cases a gland may produce a biologically inactive hormone or that an active hormone may be destroyed by circulating antibodies before it can exert its action.

Hyperfunction usually is associated with excessive hormone production. This can result from excessive stimulation and hyperplasia of the endocrine gland or from a hormoneproducing tumor of the gland. An ectopic tumor can produce hormones; for example, certain bronchogenic tumors produce hormones such as antidiuretic hormone (ADH) and adrenocorticotropic hormone (ACTH).

Causes of hypopituitarism

- Tumors and mass lesions—pituitary adenomas, cysts, metastatic cancer, and other lesions

- Pituitary surgery or radiation

- Infiltrative lesions and infections—hemochromatosis, lymphocytic hypophysitis

- Pituitary infarction—infarction of the pituitary gland after substantial blood loss during childbirth (Sheehan’s syndrome)

- Pituitary apoplexy—sudden hemorrhage into the pituitary gland

- Genetic diseases—rare congenital defects of one or more pituitary hormones

- Empty sella syndrome—an enlarged sella turcica that is not entirely filled with pituitary tissue

- Hypothalamic disorders—tumors and mass lesions

(e.g., craniopharyngiomas and metastatic malignancies),

hypothalamic radiation, infiltrative lesions (e.g., sarcoidosis),

trauma, infections.

Hypopituitarism is associated with increased morbidity and

mortality.

Hyperpituitarism

Hyperpituitarism is characterised by oversecretion of one or more of the pituitary hormones.

Three common syndromes of adenohypophyseal hyperfunction are: gigantism and acromegaly, hyperprolactinaemia and Cushing's disease.

1. Gigantism and acromegaly. Both these clinical syndromes result from excess of growth hormone (GH), most commonly by somatotroph adenoma.

Gigantism is produced when GH excess occurs in prepubertal period. The main clinical feature in gigantism is the excessive and proportionate growth of the child. There is enlargement and thickening of the bones resulting in considerable increase in height and enlarged thoracic cage.

Acromegaly results when there is overproduction of GH in adults following cessation of bone growth and is more common than gigantism. The term 'acromegaly' means increased growth of extremities. There is enlargement of hands and feet, coarseness of facial features with increase in soft tissues, prominent supraorbital ridges and prognathism (a more prominent lower jaw and protrusion of the lower teeth in front of upper teeth). Other features include enlargement of the tongue and lips, thickening of the skin and kyphosis. Sometimes, may be thyrotoxicosis, and gonadotropin insufficiency causing amenorrhoea in the females and impotence in the male, generalized muscle weakness, hypertension, arthritis, congestive heart failure.

2. Hyperprolactinaemia is the excessive production of prolactin (PRL), most commonly by prolactinoma. Several classes of drugs can cause hyperprolactinaemia, including dopamine receptor antagonists such as neuroleptic drugs (phenothiazines, haloperidol) and antihypertensive drugs such as reserpine, which inhibit dopamine storage. Other causes of hyperprolactinaemia include estrogens, renal failure, and hypothyroidism. In the female, hyperprolactinaemia causes amenorrhoea-galactorrhoea syndrome characterized clinically by infertility and expression of milk from breast, not related to pregnancy or puerperium. In the male, it may cause impotence or reduced libido.

       3. Cushing's Disease or pituitary-dependent hypercortisolism (about 60-70% cases of hypercortisolism) results from АСTН excess. Most frequently, it is caused by corticotroph adenoma. The adrenal glands in patients with Cushing's disease are characterized by of nodular cortical hyperplasia caused by elevated levels of ACTH.

Clinical features.

1. Deficiency of mineralocorticoids (i.e. aldosterone deficiency) results in salt deficiency, hyperkalaemia and dehydration.

2. Cortisol deficiency leads to hypoglycaemia, increased insulin sensitivity and vomiting.         

Hypoaldosteronism

Aldosterone is steroid hormone secreted by the adrenal cortex that regulates the salt and water balance in the body. Isolated deficiency of aldosterone with normal cortisol level may occur in association with reduced renin secretion.

Etiopathogenesis. The causes of hyporeninism are:

1. Congenital defect due to deficiency of an enzyme required for its synthesis.

2. Prolonged administration of heparin.

3. Certain diseases of the brain.

4. Excision of an aldosterone-secreting tumour.

Clinical features. The patients with isolated hypoaldosteronism are adults with mild renal failure and diabetes mellitus. The predominant features are hyperkalaemia and metabolic acidosis.

Pheochromocytoma

Pheochromocytoma is generally a benign tumour arising from the adrenal medulla. Pheochromocytoma may occur at any age but most patients are 20-60 years old. These tumours are commonly sporadic but about 10-20% are associated with familial syndromes of multiple endocrine neoplasia (MEN); and are associated with medullary carcinoma of the thyroid, hyperparathyroidism, pituitary adenoma, mucosal neuromas and von Recklinghausen's neurofibromatosis in varying combinations.

The clinical features of pheochromocytoma are predominantly due to secretion of catecholamines, both epinephrine and norepinephrine. The most common feature is hypertension. Other manifestations due to sudden release of catecholamines are congestive heart failure, myocardial infarction, pulmonary oedema, cerebral haemorrhage, and even death.

 

Diseases of thyroid gland are manifested by qualitative or quantitative alterations in hormone secretion, enlargement of the thyroid, or both. Insufficient hormone secretion results in hypothyroidism or myxedema, in which hypometabolism is a principal feature. Excessive secretion of hormone results in hypermetabolism and other features, together termed hyperthyroidism or thyrotoxicosis.

However isolated disturbances of thyroid hormone-plasma protein interaction, as well as decreased or increased concentration of hormone binding proteins are not accompanied by the development of hypo- and hyperthyroidism. For example, an increase in thyroxine-binding globulin concentration, initially lowers the concentration of free hormone and thus diminishes the quantity of hormone available to tissues. It causes the release of thyroid stimulating hormone and, therefore, increased production of thyroid hormones by the gland.

 As a result, the concentration of free hormone is restored to normal. Opposite changes occur when the concentration of thyroxine-binding globulin declines..

Thyroid hormone resistance: Generalized thyroid hormone resistance is a syndrome characterized by reduced responsiveness to elevated levels of thyroid hormone. The resistance to thyroid hormone action is associated with elevated circulating levels of free thyroxine and free triiodothyronine, elevated serum thyroid stimulating hormone, and intact thyroid stimulating hormone responsiveness to thyroid releasing hormone.

HYPOTHYROIDISM

The term myxedema designates severe hypothyroidism in which there is accumulation of hydrophylic mucopolysaccharides in the dermis and other tissues, leading to thikening of the facial features and doughy induration of the skin.

Etiology and pathogenesis

The most common causes are surgical or radioiodine ablation of the thyroid gland for the treatment of Graves’ disease, a primary idiopathic disorder, autoimmunity (autoimmune thyroiditis)which associated with circulating cytotoxic antithyroid antibodies or, in some cases, antibodies that block the thyroid stimulating hormone receptor, toxic blockade of iodine uptake and tyrosine compounds

Hashimoto's thyroiditis

Hashimoto's thyroiditis is caused primarily by a defect of T cells and this disorder has several pathophysiologic autoimmune mechanisms. T cells activated by thyroid antigens interact with B cells and stimulate the secretion of antithyroid antibodies.

The latter may activate antibody-dependent cytotoxicty mechanisms. Almost all patients with Hashimoto's thyroiditis have antibodies to both thyroglobulin or thyroid peroxidase. Some patients have antibodies against receptors of the thyroid-stimulating hormone that block the action of thyroid-stimulating hormone.

Goiter

The term goiter is defined as thyroid enlargement caused by compensatory hyperplasia and hypertrophy of the follicular epithelium in response to thyroid hormone deficiency. Epidemiologically, goiter occurs in 2 forms: endemic, and non-endemic or sporadic. Prevalence of goiter in a geographic area in more than 10% of the population is termed endemic goiter. Though most endemic goiter are caused by dietary lack of iodine, some cases occur due to goiterogens and genetic factors. Goiterogens are substances, which interfere with the synthesis of thyroid hormones. These substances are drugs used in the treatment of hyperthyroidism and certain items of food such as cabbage, cauliflower, turnips and cassava roots. The etiology of sporadic goitre is unknown. Deficient thyroid hormone production causes excessive TSH stimulation, which leads to hyperplasia of follicular epithelium as well as formation of new thyroid follicles.

Declined appetite

Cerebral ataxia

Constipation

Cold intolerance

Cool skin

Menorrhagia

Weight increases

Periorbital puffiness

H yperthyroidism (Thyrotoxicosis)

The most important of these disorders are those that lead to sustained overproduction of hormone by the thyroid gland itself. Sometimes, this hyperfunction results from excessive secretion of thyroid stimulating hormone by a pituitary tumor or as a result of resistance to thyroid hormone in the pituitary but not in peripheral tissues. Hyperthyroidism may result from excess present immunoglobulins TSIg (LATS), weak transport connection with blood proteins, intensive conversion of T4 to T3 in ‘target’ cells, the increase in the number of receptors T3, T4 in ‘target’ cells.

 Other causes are the action of nonphysiologic stimulator of extrapituitary origin, as in Graves’ disease and the development of one or more areas of autonomous hyperfunction within the gland itself.

Complications

Possible complications include:

- muscle wasting

- visual loss or diplopia

- cardiac failure

- hypoparathyroidism after surgical removal of thyroid

- hypothyroidism after radioiodine treatment.

 

Parathyroid Glands

Primary hyperparathyroidism is one of the most common endocrine disorders, and it is an impotent cause of hypercalcemia.

In more than 95% of cases, the disorder is caused by sporadic parathyroid adenomas or sporadic hyperplasia.

Primary hyperparathyroidism presents in one of two ways:

1) It may be asymptomatic and be identified after a routine chemistry profile, or

2) patients may have the classics clinical manifestations of primary hyperparathyroidism.

Bone disease includes bone pain secondary to fractures of bones weakened by osteoporosis or osteitis fibrosa cystica.

Nephrolithiasis (renal stones) occurs in 20% of newly diagnosed patients, with attendant pain and obstructive uropathy. Chronic renal insufficiency and a variety of abnormalities in renal function are found, including polyuria and secondary polydipsia.

Gastrointestinal disturbances include constipation, nausea, peptic ulcers, pancreatitis, and gallstones.

Central nervous system alterations include depression, lethargy, and eventually seizures.

Neuromuscular abnormalities include complaints of weakness and fatigue.

Cardiac manifestations include aortic and mitral valve calcifications (or both).

Secondary hyperparathyroidism occurs due to increased parathyroid hormone elaboration secondary to a disease elsewhere in the body. Hypocalcaemia stimulates compensatory hyperplasia of the parathyroid glands and causes secondary hyperparathyroidism.

Etiology.

1. Chronic renal insufficiency resulting in retention of phosphate and impaired intestinal absorption of calcium.

2. Vitamin D deficiency and consequent rickets and osteomalacia may cause parathyroid hyperfunction.

3. Intestinal malabsorption syndromes causing deficiency of calcium and vitamin D.

 Clinical features.

1. mild hypocalcaemia;

2. signs and symptoms of the disease which caused secondary hyperparathyroidism;

3. renal osteodystrophy (osteomalacia, osteoporosis and osteosclerosis);

4. soft tissue calcification.

Tertiary hyperparathyroidism is a complication of secondary hyperparathyroidism in which the hyperfunction persists in spite of removal of the cause of secondary hyperplasia. Possibly, a hyperplastic nodule in the parathyroid gland develops which becomes partially autonomous and continues to secrete large quantities of parathyroid hormone without regard to the needs of the body.

Hypoparathyroidism

Hypoparathyroidism is far less common then is hyperparathyroidism.

Hypoparathyroidism is of 2 types - primary hypoparathyroidism and pseudohypoparathyroidism. 

Primary Hypoparathyroidism.

Primary hypoparathyroidism is caused by disease of the parathyroid glands. Most common causes of primary hypoparathyroidism are:

1. surgical procedures involving thyroid, parathyroid, or radical neck dissection for cancer;

2. idiopathic hypoparathyroidism of autoimmune origin in children;

3. may occur as sporadic or familial cases;

4. congenital absence of all glands, such as thymic aplasia. 

Clinical Features. The main biochemical dysfunctions in primary hypoparathyroidism are hypocalcaemia, hyperphosphataemia and hypocalciuria. The clinical manifestations of these abnormalities are:

1. Increased neuromuscular irritability and tetany.

2. Calcification of the lens and cataract formation.

3. Abnormalities in cardiac conduction.

4. Disorders of the CNS due to intracranial calcification.

5. Abnormalities of the teeth.

6. Ocular disease results in calcification of the lens leading to cataract formation.

7. Mental status changes can include emotional instability, anxiety and depression, confusional states, hallucinations, and frank psychosis.

.

Pseudohypoparathyroidism.  Resistance of the organs to normal or elevated levels of PTH occurs of pseudohypoparathyroidism,

 It is a rare inherited condition with an autosomal dominant character. The patients are generally females and are characterised by signs and symptoms of hypoparathyroidism and other clinical features like short stature, flat nose, round face and multiple exostoses. Since renal tubules cannot adequately respond to parathyroid hormone, there is hypercalciuria, hypocalcaemia and hyperphosphataemia. Hypocalcaemia results, leading to secondary parathyroid hyperfunction, unanticipated elevated serum PTH levels.

Diabetes Mellitus

Diabetes mellitus is a chronic clinical syndrome characterised by hyperglycaemia due to deficiency or defective response of insulin. It is estimated that approximately 3% of population suffers from diabetes mellitus. The most common and important forms of diabetes mellitus arise from primary disorders jf the islet cell-insulin signaling system. These can be divided into two common variants type I and type II.

Type I diabetes, also called insulin-depended diabetes mellitus (IDDP) and referred to as juvenile-onset diabetes (10%). Type II diabetes (80 – 90%) also called non-insulin-depended diabetes mellitus (NIDDM).

Type I diabetes mellitus, is caused by absolute deficiency of insulin resulting from reduction in В cell mass. There are 3 mutually-interlinked mechanisms: genetic susceptibility, autoimmunity, and certain environmental factors.

I. Genetic susceptibility. Diabetes mellitus runs in families has been known for years.

II. Autoimmunity. Type I diabetes is believed to be an autoimmune disease that results in specific immunologic destruction of В cells of islet of Langerhans.

III.Environmental factors. Epidemiologic studies in type I diabetes have revealed involvement of certain environmental factors in its pathogenesis. These factors are certain viruses, chemicals and common environmental toxins.

 Type II diabetes mellitus diabetes is further of 2 subtypes-obese and non-obese.

The basic metabolic defect in this type of diabetes is unable the peripheral tissues to respond to insulin (insulin resistance).

Though much less is known about the mechanisms involved in the pathogenesis of type П diabetes, a number of factors have been implicated.

I. Obesity (Obese type II diabetes). Obesity is a common finding in type II diabetes. There is impaired insulin sensitivity of peripheral tissues such as muscle and fat cells to the action of insulin in obese individuals (insulin resistance).

II. Insulin receptor defect (Non-obese type II diabetes). In such individuals, the increased insulin resistance of peripheral tissues is due to either decrease in the number of insulin receptors or there is post-receptor defect.

 Type II diabetes is a complex multifactorial disease involving 'deranged insulin secretion' and 'insulin resistance', with possible genetic defects, obesity sand fault in the insulin receptors.

Pathologic changes in islets have been demonstrated in both types of diabetes, though the changes are more distinctive in type I diabetes.

Clinical Features.

Type I diabetes usually manifests at early age, generally below the age of 40. Characteristically, the plasma insulin levels are low and patients respond to exogenous insulin therapy. The onset of symptoms is generally abrupt with polyuria, polydipsia and polyphagia. The patients are not obese but have generally progressive loss of weight. These patients are prone to develop metabolic complications such as ketoacidosis and hypoglycaemic episodes.

Type II diabetes. This form of diabetes generally manifests in middle life or beyond, usually above the age of 40. The onset of symptoms in type II diabetes is slow and insidious. Generally, the patient is asymptomatic when the diagnosis is made on the basis of glucosuria or hyperglycaemia during physical examination. The patients are frequently obese and may present with polyuria, polydipsia, unexplained weakness and loss of weight. In contrast to type I diabetes, plasma insulin levels in type II diabetes are normal-to-high, though they are lower relative to the plasma glucose level i.e. there is relative insulin deficiency. Metabolic complications such as ketoacidosis are infrequent.

As a consequence of hyperglycaemia of diabetes, every tissue and organ of the body undergoes biochemical and structural alterations, which account for the major complications in diabetics.

Both types of diabetes mellitus may develop complications, which are broadly divided into 2 major groups:

I. Acute metabolic complications include:

- ketoacidosis - is almost exclu­sively a complication of type I diabetes. It can develop in patients with severe insulin deficiency combined with glucagon excess.

- hyperosmolar nonketotic coma, is usually a complication of type II diabetes. It is caused by severe dehydration resulting from sustained hyperglycaemic diuresis. The loss of glucose in urine is so intense that the patient is unable to drink sufficient water to maintain urinary fluid loss. The usual clinical features of ketoacidosis are absent but prominent central nervous signs are present. Blood sugar is extremely high and plasma osmolality is high. Thrombotic and bleeding complications are frequent due to high viscosity of blood. The mortality rate in hyperosmolar nonketotic coma is high.

- hypoglycaemia. Hypoglycaemic episode may develop in-patients with type I diabetes. It may result from excessive administration of insulin, missing a meal, or due to stress. Hypoglycaemic episodes are harmful as they produce permanent brain damage, or may result in worsening of diabetic control and rebound hyperglycaemia.

II. Late systemic complications:

These are atherosclerosis, diabetic microangiopathy, diabetic nephropathy, diabetic neuropathy, diabetic retinopathy and infections.

Renal Complications

There are a variety of complications involving the kidney. Both nodular and diffuse glomerulosclerosis can lead to chronic renal failure. Diabetics are prone to infections, particularly pyelonephritis. Both bacterial and fungal infections can occur.

Ocular Complications

The eyes can be affected in several ways by diabetes mellitus. Diabetic retinopathy is one of the leading causes for irreversible blindness. This retinopathy can occur with either type I or type II diabetes mellitus, usually a decade or so after the onset of diabetes. Most persons with type I diabetes and many of those with type II diabetes develop some background (non-proliferative) retinopathy. Proliferative retinopathy is more ominous and is more likely to occur when diabetes mellitus is poorly controlled.

Cataracts are more common in diabetics. This predilection for development of cataracts is felt to result from hyperglycemia leading to accumulation of sorbitol that results in osmotic damage to the crystalline lens.

Persons with diabetes mellitus, either type I or type II, have early and accelerated atherosclerosis. The most serious complications of this are atherosclerotic heart disease, cerebrovascular disease, and renal disease. The most common cause of death with diabetes mellitus is myocardial infarction.

Peripheral vascular disease is a particular problem with diabetes mellitus and is made worse through the development of diabetic neuropathy, leading to propensity for injury.

 

CONTROL QUESTIONS

1. Two types of organization of the endocrine system.

2. Primary, Secondary, and Tertiary Disorders of endocrine system.

3. Causes of hypofunction of an endocrine gland.

4. The pituitary gland disorders.

Gigantism and acromegaly.

Hyperprolactinaemia.

Cushing's Disease.

The endocrine system

Explanation for working with teaching material.

Study the guide.

Give answers to the tests.

3.  Give the answers to one of the proposed variant of the final control.

The endocrine system affects all aspects of body function, including growth and development, energy metabolism, muscle and adipose tissue distribution, sexual development, fluid and electrolyte balance, inflammation and immune responses.

There are two types of organization of the endocrine system: cerebropituitary type and pituitary-independent type.

Cerebropituitary type includes the brain cortex, hypothalamus, anterior pituitary, peripheral endocrine gland, and the target cells. The brain cortex exerts neurogenic influence on the hypothalamus which produces liberins or statins. The hypothalamic hormones are secreted into the pituitary portal system and affect trophocytes producing tropins (e.g. ACTH, gonadotropins). The latter are secreted into general circulation and reach the peripheral endocrine glands where they exert stimulating or inhibitory effect.

In pituitary-independent system the pituitary stage is omitted. For example, parathyroid gland or beta-cells of the pancreas are not regulated by pituitary trophins.

Endocrinopathy can result from hormone deficiency (hypofunction), hormone excess (hyperfunction), resistance to hormone action, or constitutive mutations, that activate hormone response systems in the absence of ligand.