|The Endocrine System.
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, hormone excess, resistance to hormone action, or constitutive mutations that activate hormone response systems in the absence of ligand.
With few exceptions (calcitonin), hormone deficiency results in pathologic manifestations. The destructive processes that cause failure of the endocrine organs include:
– tissue death due to infarction or inflammation,
– autoimmune processesic hormones,
– dietary inadequacy,
– hereditary defects in hormone synthesis.
With few exceptions (testosterone in men, progesterone in men and women) hormone excess causes pathologic effects. Hormone may be overproduced by the gland due to adenoma, autoantibodies that mimic the action of tropins (as in the case of thyroid-stimulating immunoglobulins in hyperthyroidism), mutations in receptor-effector mechanisms that impair feedback. A second type of hormone excess results when a hormone is produced by a tissue (usually malignant) that does not synthesize it ordinarily (for example, ACTH production by carcinoma of the lungi). A third type of hormone excess involves the overproduction of hormones in peripheral tissues from circulating precursors.
Production of abnormal hormones.
One form of diabetes mellitus is the result of a production of an abnormal insulin molecule that is ineffective because of defective binding to the insulin receptor. In other cases, hormone precursors, hormone subunits, or incompletely processed peptide hormones may be released into the circulation, as is common in so-called ectopic hormone production of neoplasia.
Hormone-resistance states frequently are due to mutations that impair hormone action, but they can be due to acquired defects in receptors and postreceptor effector mechanisms for hormones, to development of antibodies that block hormones or hormone receptors, or to the absence of target cells.
A common feature of hormone-resistance states is the presence of a normal or elevated level of the hormone in the circulation despite deficient hormone action. This feature is a consequence of the fact that hormones are normally under regulatory feedback control and that failure of hormone action leads to increased hormone production.
In general, disorders of the endocrine system can be classified as follows:
1. Disorders of the central regulation associated with dysfunction of pituitary (secondary) or hypothalamus (tertiary).
2. Disorders of the peripheral endocrine glands (primary).
3. Extraglandular disorders (abnormal transport of hormones, resistance to the effects of hormones, abnormal metablism of hormones).
Anatomy. The pituitary gland or hypophysis in an adult weighs about 500 mg and is slightly heavier in females. It is situated at the base of the brain in a hollow called sella turcica formed out of the sphenoid bone. The gland is composed of 2 major anatomic divisions: anterior lobe (adenohypophysis) and posterior lobe (neurohypophysis).
1. The anterior lobe or adenohypophysis is anectodermal derivative formed from Rathke's pouch which is an upward diverticulum fromthe primitive buccal cavity. The adenohypophysis has no direct neural connection but hasindirect connection through capillary portalcirculation by which the anterior pituitaryreceives the blood which has already passed through the hypothalamus.
2. The posterior lobe or neurohypophysis is adown growth from the primitive neural tissue.
The neurohypophysis, therefore, has direct neural connection superiorly with the hypothalamus.
Histology and functions. The histology and functions of the anterior and posterior lobes of the pituitary gland are quite distinct.
A. Anterior lobe (adenogypophysis). It is composed of round to polygonal epithelial cells arranged in cords and islands having fibrovascular stroma. These epithelial cells, depending upon their staining characteristics and functions, are divided into 3 types, each of which performs separate functions:
1. Chromophil cells with acidophilic granules: These cells comprise about 40% of the anterior lobe and are chiefly located in the lateral wings. The acidophils are further of 2 types:
i) Sormtotrophs (GH cells) which produce growth hormone (GH); and
ii) Lactotrophs (PRL cells) which produce prolactin (PRL).
Cell containing both GH and PRL, called mammosomatotrophs are also present.
2. Chromophil cells with basophilic granules: These cells constitute about 10% of the anterior lobe and are mainly found in the region of median wedge. The basophils include 3 types of cells:
i) Gonadotrophs (FSH-LH cells) which are the source of the FSH and LH or interstitial cell stimulating hormone (ICSH). ii) Thyrotrophs (TSH cells) are the cells producing TSH.
iii) Corticotrophs (ACTH-MSH cells) produce ACTH, melanocyte stimulating hormone. (MSH), β-lipoprotein and β-endorphin.
3. Chromophobe cells without visible granules: These cells comprise the remainder 50% of the adenohypophysis. These cells by light microscopy contain no visible granules, but on electron microcopy reveal sparsely granulatedcorticotrophs, thyrotrophs and gonadotrophs.
All these functions of the adenohypophysis are under the indirect control of the hypo-thalamus through stimulatory and inhibitory factors synthesized by the hypothalamus which reach the anterior lobe through capillary portal blood.
B. Posterior lobe (neurohypophysis). The neurohypophysis is composed mainly of interlacing nerve fibres in which are scattered specialised glial cells called pituicytes. These nerve fibres on electron microscpopy contain granules of neurosecretory material made up of 2 octapeptides - vasopressin or antidiuretic hormone (ADH), and oxytocin, both of which are produced by neurosecretory cells of the hypothalamus but are stored in the cells of posterior pituitary.
1. ADH causes reabsorption of water from the renal tubules and is essential for maintenance of osmolality of the plasma. Its deficiency results in diabetes insipidus characterised by uncontrolled diuresis and polydipsia.
2. Oxytocin causes contraction of mammary myoepithelial cells resulting in ejection of milk from the lactating breast and causes contraction of myometrium of the uterus at term.
It is obvious from the description above that pituitary, though a tiny organ, is concerned with a variety of diverse functions in the body. The pituitary gland and hypothalamus are so closely interlinked that diseases of the pituitary gland involve the hypothalamus, and dysfunctions of the hypothalamus cause secondary changes in the pituitary. The pituitary gland is involved in several diseases which include: non-neoplastic such as inflammations, haemorrhage, trauma, infarction and many other endocrine diseases; and neoplastic diseases. However, functionally and morphologically diseases of the pituitary can be classified as below, each of which includes diseases of anterior and posterior pituitary and hypothalamus, separately:
iii) Pituitary tumours
Hyperpituitarism is characterised by over-secretion of one or more of the pituitary hormones. Such hypersecretion may be due to diseases of the anterior pituitary, posterior pituitary or hypothalamus. For all practical purposes, however, hyperfunction of the anterior pituitary is due to the development of a hormone-secreting pituitary adenoma (discussed later), and rarely, a carcinoma. For each of the hormonal hyperfunction of the anterior pituitary, posterior pituitary and hypothalamus, a clinical syndrome is described. A few important syndromes are as follows:
A. Hyperfunction of Anterior Pituitary.
Three common syndromes of adenohypophyseal hyperfunction are: gigantism and acromegaly, hyperprolactinaemia and Cushing's syndrome.
1. Gigantilism and acromegaly. Both these clinical syndromes result from sustained excess of growth hormone (GH), most commonly by somatotroph (GH-secreting) adenoma.
Gigantism. When GH excess occurs prior to epiphyseal closure, gigantism is produced. Gigantism, therefore, occurs in prepubertal boys and girls and is much less frequent than acromegaly. The main clinical feature in gigantism is the excessive and proportionate growth of the child. There is enlargement as well as thickening of the bones resulting in considerable increase in height and enlarged thoracic cage.
Acromegaly. 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 supra-orbital ridges and a more prominent lower jaw which when clenched results in protrusion of the lower teeth in front of upper teeth (prognathism). Other features include enlargement of the tongue and lips, thickening of the skin and kyphosis. Sometimes, a few associated features such as TSH excess resulting in thyrotoxicosis, and gonadotropin insufficiency causing amenorrhea in the females and impotence in the male, are found.
2. Hyperprolactinaemia. Hyperprolactinaemia is the excessive production of prolactin(PRL), most commonly by lactotroph (PRL-secreting) adenoma, also called prolactinoma. Occasionally, hyperprolactinaemia results from hypothalamic inhibition of PRL secretion by certain drugs (e.g. chlorpromazine, reserpineand methyldopa). In the female, hyperprolactinaemia causes amenorrhoea-galactorrhoeasyndrome characterised clinically by infertility and expression of a drop or two of milk from breast, not related to pregnancy or puerperium. In the male, it may cause impotence or reduced libido. These features result either from associated inhibition of gonadotropin secretion or interference in gonadotropin effects.
3. Cushing’s syndrome. Pituitary-dependent Cushing's syndrome results from ACTH excess. Most frequently, it is caused by corticotrdph (ACTH-secreting) adenoma.
B. Hyperfunction of Posterior Pituitary and Hypothalamus.
Lesions of posterior pituitary and hypothalamus are uncommon. Two of the syndromes associated with hyperfunction of the posterior pituitary and hypothalamus are: inappropriate release of ADH and precocious puberty.
1. Inapropriate release of ADH. Inappropriate release of ADH results in its excessive secretion which manifests clinically by passage of concentrated urine due to increased reabsorption of water and loss of sodium in the urine, consequent hyponatraemia, haemodilution and expansion of intra- and extracellular fluid volume. Inappropriate release of ADH occurs most often in paraneoplastic syndrome e.g. in oat cell carcinoma of the lung, carcinoma of the pancreas, lymphoma and thymoma. Infrequently, lesions of the hypothalamus such as trauma, haemorrhage and meningitis may produce ADH hypersecretion. Rarely, pulmonary diseases such as tuberculosis, lung abscess, pneumoconiosis, empyema and pneumonia may cause overproduction of ADH.
2. Precocious puberty. A tumour in theregion of hypothalamus or the pineal gland may result in premature release of gonadotropinsca using the onset of pubertal changes prior to the age of 9 years. The features include premature development of genitalia both in the male and in the female, growth of pubic hair and axillary hair. In the female, there is breast growth and onset of menstruation.
In hypopituitarism, there is usually deficiency of one or more of the pituitary hormones affecting either anterior, pituitary, or posterior pituitary and hypothalamus.
A. Hypofunction of Anterior Pituitary.
Adenohypophyseal hypofunction is invariably due to destruction of the anterior lobe of more than 75% because the anterior pituitary possesses a large functional reserve. This may result from anterior pituitary lesions or pressure and destruction from adjacent lesions. Lesions of the anterior pituitary include nonsecretory (chromophobe) adenoma, metastatic carcinoma, craniopharyngioma, trauma, postpartum ischaemic necrosis (Sheehan's syndrome), empty-sella syndrome, and rarely, tuberculosis. Though a number of syndromes associated with deficiency of anterior pituitary hormones have been described, two important syndromes are: panhypopituitarism and dwarfism.
1. Panhypopituitarism. The classical clinical condition of major anterior pituitary insufficiency is called panhypopituitarism. Three most common causes of panhypopituitarism are: nonsecretory (chromophobe) adenoma (discussed later), Sheehan's syndrome and Simmond's disease, and empty-sella syndrome.
Sheehan's syndrome and Simmond's disease. Pituitary insufficiency occurring due to postpartum pituitary (Sheehan's) necrosis is called Sheehan's syndrome, whereas occurrence of similar process without preceding pregnancy as well as its occurrence in males is termed Simmond's disease. The main pathogenetic mechanism underlying Sheehan's necrosis is the enlargement of the pituitary occurring during pregnancy which may be followed by hypotensive shock precipitating isthaemic necrosis of the pituitary. Other mechanisms hypothesised are: DIC following delivery, traumatic injury to vessels, and excessive haemorrhage. Patients with long-standing diabetes mellitus appear to be at greater risk of developing this complication.
The first clinical manifestation of Sheehan's syndrome is failure of lactation following delivery which is due to deficiency of prolactin.
Subsequently, other symptoms develop which include loss of axillary and pubic hair, amenorrhea, sterility and loss of libido. Concomitant deficiency of TSH and ACTH may result in hypothyroidism and adrenocortical insufficiency.
The pathologic changes in the anterior pituitary in Sheehan's syndrome during early stage are ischaemic necrosis and haemorrhage, while later necrotic tissue is replaced by fibrous tissue.
Empty-sella syndrome. Empty-sella syndrome is characterised by the appearance of an empty sella and features of parthypopituitarism. Most commonly, it results from herniation of subarachnoid space into the sella turcica due to an incomplete diaphragma sella creating an empty sella. Other less common causes are Sheehan's syndrome, infarction and scarring in an adenoma, irradiation damage, or surgical removal of the gland.
2. Pituitary dwarfism. Severe deficiency of GH in children before growth is completed results in retarded growth and pituitary, dwarfism. Most commonly, isolated GH deficiency is the result of an inherited autosomal recessive disoder. Less often it may be due to a pituitary adenoma or craniopharyngioma, infarction and trauma to the pituitary. The clinical features of inherited cases of pituitary dwarfism appear after one year of age. These include proportionate retardation in growth of bones, normal mental state for age, poorly-developed genitalia, delayed puberty and episodes of hypoglycaemia. Pituitary dwarf must be distinguished from hypothyroid dwarf (cretinism) in which there is achondroplasia and mental retardation.
B. Hypofunction of Posterior Pituitary and Hypothalamus
Insufficiency of the posterior pituitary andhypothalamus is uncommon. The only significant clinical syndrome due to hypofunction of the neurohypophysis and hypothalamus is diabetes insipidus.
Diabetes insipipus. Deficient secretion of ADH causes diabetes insipidus. The causes of ADH deficiency are: inflammatory and neo-plastic lesions of the hypothalamo-hypophyseal axis, destruction of neurohypophysis due to surgery, radiation, head injury, and lastly, are those cases where no definite cause is known and are labelled as idiopathic. The main features of diabetes insipid us are excretion of a very large volume of dilute urine of low specific gravity, polyuria and polydipsia.
Anatomy. The adrenal glands lie at the upper pole of each kidney. Each gland weighs approximately 4 gm in the adult but in children the adrenals are proportionately larger. On sectioning, the adrenal is composed of 2 distinct parts: an outer yellow-brown cortex and an inner grey medulla. The anatomic and functional integrity of adrenal cortices are essential for life, while it does not hold true for adrenal medulla.
Histology and physiology. Microscopically and functionally, cortex and medulla are quite distinct.
Adrenal cortex. It is composed of 3 layers:
1. Zona glomerulosa is the outer layer andcomprises about 10% of the cortex. It consists of cords or columns of polyhedral cells just under the capsule. This layer is responsible for the synthesis of mineralocorticoids, the most important of which is aldosterone, the salt and water regulating hormone.
2. Zona fasciculata is the middle layer and constitutes approximately 70% of the cortex. It discomposed of columns of lipid-'rich cells which are precursors of various steroid hormones manufactured in the adrenal cortex such as glucocorticoids (e.g. cortisol) and sex steroids (e.g. testosterone).
3. Zona reticularis is the inner layer which makes up the remainder of the adrenal cortex. It consists of cords of more compact cells than those of zona fasciculata but has similar functional characteristics of synthesis and secretion of glucocorticoids and androgens.
The synthesis of glucocorticoids arid adrenal androgens is under the control of ACTH from hypothalamus-anterior pituitary. In turn, ACTH release is under the control of a hypothalamic releasing factor called corticotropin-releasing factor. Release of aldosterone, on the other hand, is independent of ACTH control and is largely regulated by the serum levels of potassium and renin-angiotensin mechanism.
Adrenal medulla. The adrenal medulla is a component of the dispersed neuroendocrine system derived from primitive neuroectoderm; the other components of this system being paraganglia distributed in the vagi, paravertebral and visceral autonomic ganglia. The cells comprising this system are neuroendocrine cells, the major function of which is synthesis and secretion of catecholamines (epinephrine and nor-epihephrine). Various other peptides such as calcitonin, somatostatin and vasoactive intestinal polypeptide (VIP) are also secreted by these cells. The major metabolites of catecholamine are metanephrine, normetanephrine, vanillyl mandelic acid (VMA) and homovanillic acid (HVA). In case of damage to the adrenal medulla, its function is taken over by other paraganglia.
Diseases affecting the two parts of adrenal glands are quite distinctive in view of distinct morphology, and function of the adrenal cortex and medulla. While the disorders of the adrenal cortex include adrenocortical hyperfunction (hyperadrenalism), adrenocortical insufficiency (hypoadrenalism) and adrenocortical tumours, the main lesions affecting the adrenal medulla are the medullary tumours.
Adrecortical hyperfunction (hyperadrenalism)
Hypersecretion of each of the three types of corticosteroids elaborated by the adrenal cortex causes distinct corresponding hyperadrenal clinical syndromes:
1. Cushing's syndrome caused by excess of glucocorticoids (i.e. cortisol); also called chronic hypercortisolism.
2. Conn's syndrome caused by oversecretion of mineralocorticoids (i.e. aldosterone); also called primary hyperaldosteronism.
3. Adrenogenital syndrome characterised by excessive production of adrenal sex steroids (i.e. androgens); and also called adrenal virilism. Mixed forms of these clinical syndromes may also occur.
Cushing's Syndrome (Chronic Hypercortisolism).
Cushing's syndrome is caused by excessive production of cortisol of whatever cause. The full clinical expression of the syndrome, however, includes contribution of the secondary derangements.
Etiopathogenesis. There are 4 major etiologic types of Cushing's syndrome which should be distinguished for effective treatment.
1. Pituitary Cushing's syndrome. About 60-70% cases of Cushing's syndrome are caused by excessive secretion of ACTH due to a lesion in the pituitary gland, most commonly a corticotroph adenoma or multiple corticotrophmicroadenomas. This group of cases was the first to be described by Harvey Cushing, an American neurosurgeon, who termed the condition as Cushing's disease. Also included in this group are cases with hypothalamic origin of excessive ACTH levels without apparent pituitary lesion. All cases with pituitary Cushing's syndrome are characterised by bilateral adrenalcortical hyperplasia and elevated ACTH levels. These cases show therapeutic response on administration of high doses of dexamethasone which suppresses ACTH secretion and causes fall in plasma cortical level.
2. Adrenal Cushing's syndrome. Approximately 20-25% cases of Cushing's syndrome are caused by disease in one or both the adrenal glands. These include adrenal cortical adenoma, carcinoma, and less often, cortical hyperplasia. This group of cases is characterised by low serum ACTH levels and absence of therapeutic response to administration of high doses of glucocorticoid.
3. Ectopic Cushing's syndrome. About 10-15% cases of Cushing's syndrome have an origin in ectopic ACTH elaboration by nonendocrine tumours. Most often, the tumour is an oat cell carcinoma of the lung but other lung cancers, malignant thymoma and pancreatic tumour shave also been implicated. The plasma ACTH level is high in these cases and cortisol secretionis not suppressed by dexamethasone administration.
4. Iatrogenic Cushing's syndrome. Prolonged therapeutic administration of high doses of glucocorticoids or ACTH may result in Cushing'ssyndrome e.g. in organ transplant recipients and in autoimmune diseases. These cases are generally associated with bilateral adrenocortical insufficiency.
Clinical features. Cushing's syndrome occurs more often in patients between the ages of 20-40 years with three time’s higher frequency in women than in men. The severity of the syndrome varies considerably, but in general the following features characterise a case of Cushing's syndrome:
1. Central or truncal obesity contrasted with relatively thin arms and legs, buffalo hump dueto prominence of fat over the shoulders, and rounded oedematous moon-face.
2. Increased protein breakdown resulting in wasting and thinning of the skeletal muscles, atrophy of the skin and subcutaneous tissue with formation of purple striae on the abdominal wall, osteoporosis and easy of the thin skin to minor trauma.
3. Systemic hypertension is present in 80% of cases because of associated retention of sodium and water.
4. Impaired glucose tolerance and diabetes mellitus are found in about 20% cases.
5. Amenorrhea, hirsutism and infertility in many women.
6. Insomnia, depression, confusion and psychosis.
Conn's Syndrome (Primary Hyperaldosteronism).
This is an uncommon syndrome occurring due to overproduction of aldosterone, the potent salt-retaining hormone.