Endocrine system

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The pituitary gland192

19.2 The adrenal gland195
19.3 The endocrine pancreas198
19.4 The thyroid gland200
19.5 Parathyroid glands203
19.6 The multiple endocrine neoplasia (MEN) syndromes204

Self-assessment: questions205
Self-assessment: answers207

Chapter overview
The endocrine system is a complex, highly integrated group of organs that have a central role in the maintenance of normal bodily functions. More specifically, the endocrine system plays an important part in the regulation of reproduction, growth and development, maintenance of the internal environment, and energy production, utilisation and storage. Disorders of the endocrine system are therefore important because they have far-reaching and devastating effects, which in some cases can be life-threatening (e.g. addisonian crisis, diabetic ketoacidosis). At the heart of the endocrine system are the endocrine glands, which include the pituitary, adrenals, thyroid, parathyroids and pancreas. Endocrine glands synthesise and secrete hormones into the bloodstream, via which they are carried to distant sites to exert their effects. In this way the endocrine glands are able to influence the function of distant target organs and tissues. Disorders of the endocrine system are usually due to either overproduction or underproduction of a particular hormone, or mass lesions, and to aid understanding, the pathology will be presented in a similar scheme.

Basic principles

The ability of the various organs and tissues in the body to function in an integrated fashion is made possible by extracellular signalling. Signalling is mediated by specialised molecules, which are synthesised within the cell and secreted into the extracellular environment, where they exert their effects on other cells. There are three main signalling modalities:

Paracrine, where molecules secreted by cells exert their effects on neighbouring tissues.
Autocrine, where the secreted molecules exert their effects on the cell of origin.
Endocrine, where the secreted molecules exert their effects at distant sites that can be accessed only by the bloodstream.
Molecules that exert their effects via the endocrine modality are called hormones, and hormones are secreted and synthesised by endocrine glands. The effects of hormones are often complex. A single hormone can have different effects on several tissues, and some target tissues require the interaction of several hormones to carry out their physiological functions.
A distinguishing characteristic of the endocrine system is the feedback control of hormone production. Increased activity of a target organ down-regulates the activity of the endocrine gland, a process known as negative feedback or feedback inhibition.
There are two broad categories of hormones:

Peptide or amino acid derivatives – these types of hormones bind to cell surface receptors and exert their effects by causing an increase in intracellular signalling molecules.
Steroid hormones – steroid hormones are able to diffuse across the lipid cell membrane and bind to intracellular receptors. The hormone/receptor complex then acts directly on the cell DNA.

19.1. The pituitary gland

Learning objectives
You should:

• know the structure and function of the pituitary gland
• know the causes of anterior pituitary hypo- and hyperfunction, and the clinical manifestations
• know the clinical syndromes associated with disorders of antidiuretic hormone (ADH) secretion from the posterior pituitary.

Structure

The pituitary gland is located at the base of the brain within the confines of the sella turcica. It lies beneath the hypothalamus, to which it is attached by means of a stalk, and in close proximity to the optic chiasm. Despite its small size (it measures only ∼1cm across), the pituitary gland has a pivotal role in the regulation of most other endocrine glands. The pituitary gland consists of two parts; the anterior pituitary (or adenohypophysis), and the posterior pituitary (or neurohypophysis) (Figure 51).

The anterior pituitary (adenohypophysis)

The anterior pituitary constitutes 75% of the gland and is derived from an outpouching of the embryonic oral cavity known as the Rathke pouch. This part of the gland secretes six different hormones into the bloodstream. There are five different cell types in the anterior pituitary, each responsible for synthesising and secreting one or more of the six hormones. The synthesis and secretion of anterior pituitary hormones is controlled by the hypothalamus (the hypothalamic-pituitary axis). Hypothalamic neurones in the median eminence release hypothalamic-releasing hormones, which are then carried to the anterior pituitary via a portal venous system in the pituitary stalk (Figure 51). There are several types of hypothalamic-releasing hormone, each acting on and controlling the functions of a specific cell type within the anterior pituitary (see Table 34). The secretion of hypothalamic-releasing hormones is under neural control from other parts of the central nervous system (CNS) and hormonal control from the levels of anterior pituitary hormones circulating in the blood. If there are high circulating levels of a particular hormone, the secretion of the relevant hypothalamic-releasing hormone is reduced (negative feedback or feedback inhibition).
Table 34 Anterior pituitary cell types, hormone products, and controlling hypothalamic hormones
Pituitary cell type Hormonal product Controlling hypothalamic hormone
Somatotroph Growth hormone (GH) Growth hormone-releasing hormone (GHRH)
Somatostatin (inhibits release of GH)
Corticotroph Pro-opiomelanocortin (POMC) from which adrenocorticotrophic hormone (ACTH) is a cleavage product Corticotrophin-releasing hormone (CRH)
Gonadotroph Follicle stimulating hormone (FSH) and luteinising hormone (LH) Gonadotrophin-releasing hormone (GRH)
Lactotroph Prolactin Prolactin-inhibiting factor (PIF)
Thyrotroph Thyroid stimulating hormone (TSH) Thyrotrophin-releasing hormone (TRH)

Hypopituitarism

The most common causes of hypopituitarism are:

• pituitary adenoma (commonest cause)
• craniopharyngioma
• Sheehan’s syndrome.

Non-secretory pituitary adenomas

Non-secretory pituitary adenomas are benign tumours that may arise from any of the hormone secreting cells in the anterior pituitary.

Craniopharyngiomas

Craniopharyngiomas are usually benign tumours that occur most commonly in children, and are thought to arise from squamous cell rests representing the remains of the Rathke pouch.
Clinical presentation of these two types of tumour is related to their local effects on the surrounding tissues, which include:

• compression damage to the adjacent pituitary tissue, leading to underproduction of the adenohypophysis hormones
• compression of the optic chiasm, which leads to abnormalities in the visual fields (bitemporal hemianopia)
• symptoms of raised intracranial pressure.

Sheehan’s syndrome (post-partum ischaemic necrosis)

During pregnancy, the pituitary enlarges to almost twice its normal size and becomes highly vascular. Sheehan’s syndrome occurs if haemorrhage during childbirth causes a severe fall in blood pressure sufficient to cause ischaemic necrosis of the anterior pituitary, resulting in hypofunction. The posterior pituitary is usually spared. The resultant syndrome associated with anterior pituitary hypofunction is known as Simmond’s disease, the first manifestation being failure of lactation due to prolactin deficiency. The effects of the loss of TSH, LH, FSH and ACTH follow.

Clinical manifestations of hypopituitarism

Lack of growth hormone In pre-pubertal children, lack of growth hormone causes symmetrical growth retardation termed pituitary dwarfism. In this condition, sexual development may also be retarded. Lack of growth hormone in adults may cause fasting hypoglycaemia.
Lack of LH and FSH In post-pubertal women, deficiency of LH and FSH induces amenorrhoea, sterility, atrophy of the ovaries and external genitalia, and loss of axillary and pubic hair. In men, deficiency is manifest by decreased libido, sterility, testicular atrophy, and loss of axillary and pubic hair.
Lack of TSH Deficiency of TSH induces hypothyroidism and atrophy of the thyroid gland.
Lack of ACTH Deficiency of ACTH induces hypo-adrenalism and atrophy of the adrenals.
Lack of prolactin In affected women who have just given birth there is failure of lactation.

Hyperpituitarism

Hyperfunction of the anterior pituitary is almost always due to a functioning adenoma. Functioning carcinomas are rare. Adenomas may produce any anterior pituitary hormone depending on their cell of origin. Clinical presentation is related to:

• overproduction of a particular hormone
• compression of the optic chiasm, causing visual abnormalities
• raised intracranial pressure.

Somatotrophic adenomas

These adenomas lead to growth hormone overproduction. When the growth hormone excess occurs in children (before the epiphyses have closed) the result is gigantism, which is extremely rare. When the growth hormone excess occurs in adults, the resulting condition is called acromegaly. The excess growth hormone affects the viscera, bones, skin and soft tissues. The main presenting features are enlargement of the hands, feet and head with development of prominent supraorbital ridges, prominent lower jaw (prognathism) and separating of the teeth. Around a third of all acromegalic patients develop cardiac disease, which can be life-threatening.

Corticotrophic adenomas

Excess production of ACTH leads to Cushing’s disease (see later section on The adrenal gland).

Gonadotrophic adenomas

These rare tumours tend to secrete the hormones LH and FSH inefficiently and variably. There is often no evidence of increased gonadotroph hormone production, but there may be evidence of underproduction.

Prolactinomas

These are the most common type of pituitary tumour. Hyperprolactinaemia induces galactorrhoea in females, and hypogonadism (infertility) in males and females. Prolactinomas are an important cause of amenorrhoea in women.

Thyrotroph adenomas

These tumours cause hyperthyroidism, but they are extremely uncommon.

The posterior pituitary (neurohypophysis)

The posterior pituitary is derived from a downgrowth of the hypothalamus. Only two hormones are secreted – ADH and oxytocin. These hormones are stored within secretory granules of modified nerve fibres that originate from the supraoptic and paraventricular nuclei. These modified nerve fibres ramify in the pituitary stalk and have their terminal endings in the posterior pituitary. The stored hormones are released in response to hypothalamic stimuli.
ADH is secreted in response to raised plasma osmolarity and induces conservation of body water. It does this by causing an increase in the permeability of the renal collecting ducts, resulting in increased resorption of water and reduced urine output. The urine becomes concentrated. The secretion of oxytocin stimulates uterine smooth muscle to contract during childbirth, and causes the ejection of milk during lactation.

Decreased ADH production

Damage to the hypothalamus, for example by a tumour or trauma, causes a deficiency of ADH, producing a syndrome known as diabetes insipidus, which is characterised by polyuria and hyperosmolarity of the blood leading to compensatory polydipsia (excessive drinking).

Increased or inappropriate ADH production

Inappropriate ADH production implies persistent release of ADH unrelated to the plasma osmolarity. The most common cause is ectopic production of ADH by tumours such as bronchogenic carcinoma (especially the small cell variant), and less commonly thymomas, pancreatic carcinomas and lymphomas. Other causes of inappropriate ADH production include CNS disorders (e.g. head injury, meningitis), non-neoplastic lung disorders (e.g. pneumonia, tuberculosis) and drugs.

19.2. The adrenal gland

Learning objectives
You should:

• understand the structure and function of the adrenal glands
• know the common disorders that can affect the adrenal medulla
• know the disorders that can cause hypo- or hyperfunction of the adrenal cortex.

Structure

The adrenal glands are located in the retroperitoneum, superomedial to the kidneys. Each is composed of two totally separate functional units: the central medulla and the peripheral cortex (Figure 52).
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Figure 52

The adrenal medulla

The adrenal medulla, which is derived from the embryonic neural crest, is part of the sympathetic nervous system. It consists of neuroendocrine cells (chromaffin cells) and sympathetic nerve endings. The main function of the chromaffin cells is to synthesise and secrete the catecholamines, adrenaline and noradrenaline. The adrenal medulla is the main source of endogenous adrenaline.
The most significant disorders arising from the adrenal medulla are neoplasms, which include phaeochromocytomas (most common), neuroblastomas and ganglioneuromas.

Phaeochromocytoma

This is a functioning tumour derived from the chromaffin cells of the adrenal medulla, and is classified as a paraganglioma. Overproduction of catecholamines produces hypertension (which may be intermittent) associated with headaches, sweating, palpitations, pallor, anxiety and nausea. The presence of a phaeochromocytoma should be suspected in any young hypertensive patient and, although rare, is one of the curable causes of hypertension. Around 10–20% of these tumours are associated with familial syndromes such as multiple endocrine neoplasia (MEN) syndrome, von Hippel–Lindau disease, von Recklinghausen’s disease, tuberous sclerosis, and Sturge–Weber syndrome. About half of these familial cases are bilateral. The diagnosis of phaeochromocytoma is based on estimating the urinary excretion of the catecholamine metabolite vanillylmandelic acid (VMA), which is at least doubled when the tumour is present.

The adrenal cortex

The adult cortex constitutes the peripheral 80% of the adrenal gland. The adrenal cortex is derived from mesoderm and synthesises and secretes the three main classes of steroid hormones: mineralocorticoids, glucocorticoids and sex steroids. There are three functional zones of the adrenal cortex:

• zona glomerulosa (10%), which lies beneath the capsule and secretes mineralocorticoids
• zona fasciculata (80%)
• zona reticularis (10%), which corresponds to the middle and inner zones of the adrenal cortex and secretes glucocorticoids and sex steroids.

Glucocorticoids

These hormones have important effects on a wide range of tissues and organs. The effects include:

• increased protein breakdown
• increased fat loss from the extremities, but fat accumulation in the trunk, neck and face
• effects on the immune system, bone, kidneys, CNS, circulatory system, other endocrine glands and connective tissue.
The most important glucocorticoid is cortisol. The synthesis and secretion of glucocorticoids is under negative feedback control by ACTH, which is synthesised by the anterior pituitary.

Mineralocorticoids

Aldosterone is the most important mineralocorticoid. Its function is to maintain intravascular volume. When intravascular volume is decreased, aldosterone acts on renal tubules to increase the reabsorption of sodium and elimination of potassium and hydrogen ions. The retention of sodium leads to retention of water and consequent restoration of the intravascular volume. The synthesis and secretion of the mineralocorticoids is controlled by the renin-angiotensin system and not the pituitary (see Figure 53).

Sex steroids

The sex steroids are involved in the development of the male and female sexual characteristics. Most of the body’s sex steroids are synthesised in the gonads, but the adrenal sex steroids usually have a role in the development of some of the secondary sexual characteristics.

Adrenocortical hyperfunction (hyperadrenalism)

The clinical syndromes of cortical hyperfunction are due to excess production of one of the adrenal steroids. Cushing’s syndrome is due to excess glucocorticoids, Conn’s syndrome is due to excess mineralocorticoids, and adrenogenital syndromes result from excess sex steroids.

Cushing’s syndrome

There are four main causes of excess circulating glucocorticoids. The commonest is administration of exogenous glucocorticoids. The three remaining causes are related to the overproduction of endogenous glucocorticoids as follows:

• excess production of ACTH from the anterior pituitary
• oversecretion of cortisol by an adrenal neoplasm
• secretion of ectopic ACTH.
Excess production of ACTH by the anterior pituitary Overproduction of ACTH by an adenoma results in bilateral adrenocortical hyperplasia and hypercortisolism. This form of Cushing’s syndrome is known as Cushing’s disease. Removal of the pituitary tumour is the treatment of choice. Removal of the adrenals is not advocated because this may result in the development of the Nelson syndrome, which is characterised by marked enlargement of the pituitary adenoma, high ACTH levels and skin pigmentation (due to the overproduction of melanocyte-stimulating hormone (MSH), which, as well as ACTH, is a cleavage product of POMC).
Oversecretion of cortisol by an adrenal neoplasm (ACTH-independent Cushing’s syndrome) Adrenal adenomas, carcinomas and cortical hyperplasia may cause autonomous production of cortisol independent of ACTH levels. If the neoplasm is unilateral, the uninvolved adrenal gland undergoes atrophy because of suppression of ACTH.
Production of ectopic ACTH Certain non-pituitary tumours, such as small cell carcinoma of the lung, may secrete ectopic ACTH, producing Cushing’s syndrome.

Clinical features of Cushing’s syndrome

A wide range of clinical features, which together are termed Cushing’s syndrome, result from oversecretion of cortisol, including:

• moon face
• buffalo hump
• hypertension
• hair thinning
• central obesity
• osteoporosis
• hirsutism
• abdominal striae
• hyperglycaemia
• acne
• proximal muscle intolerance
• plethora
• wasting and weakness
• tendency to infections
• menstrual abnormalities.

Diagnosis of Cushing’s syndrome

Diagnosis of Cushing’s syndrome depends on finding raised circulating or urinary cortisol levels. Establishing the cause of the Cushing’s syndrome depends on the performance of two tests (Figure 54):

• Measurement of urinary cortisol excretion after administration of high-dose dexamethasone (a potent steroid). This is called the high-dose dexamethasone suppression test.

low with pituitary adenomas
high with ectopic ACTH production.

Primary hyperaldosteronism (Conn’s syndrome)

In this condition, excess mineralocorticoid production is due to a lesion in the adrenal cortex. The commonest cause is an adenoma of the zona glomerulosa, although bilateral adrenal hyperplasia is sometimes responsible. High levels of aldosterone lead to excessive retention of sodium and water, excessive loss of potassium, and a metabolic alkalosis. The hypokalaemia may lead to muscular weakness, cardiac arrhythmias, paraesthesia and tetany. Diagnosis depends on finding raised levels of circulating aldosterone and low levels of renin (if the renin levels are raised, then the hyperaldosteronism is secondary to raised renin levels and is known as secondary hyperaldosteronism). Adrenal adenomas can be surgically excised, whereas adrenal hyperplasia can be managed medically.

Hypersecretion of the sex steroids

Disorders of sexual differentiation are known collectively as adrenogenital syndromes. There are two main causes of hypersecretion of sex steroids:

• adrenocortical neoplasms
• congenital enzyme deficiency in the pathways of steroid synthesis.

Adrenocortical neoplasm

Adenomas or carcinomas of the adrenal cortex may secrete sex steroids (usually androgens). The effect of these androgens is to cause masculinisation in females and precocious puberty in pre-pubertal males.

Congenital enzyme defects

There is a small group of rare congenital disorders characterised by a deficiency, or total lack, of a particular enzyme involved in the synthesis of steroids. The commonest of these disorders is 21-hydroxylase deficiency. This enzyme is necessary for the synthesis of cortisol and aldosterone. Its absence leads to low levels of cortisol and consequent elevated levels of ACTH resulting in bilateral adrenocortical hyperplasia. The underproduction of mineralocorticoids is life-threatening. Androgens are over-secreted because they are synthesised before the metabolic block, resulting in masculinisation in females and precocious puberty in males.

Adrenocortical hypofunction (adrenocortical insufficiency)

Adrenocortical insufficiency may be due to primary adrenal disease (primary adrenocortical insufficiency) or secondary to decreased stimulation of the adrenals due to a deficiency in ACTH (secondary adrenocortical insufficiency). Insufficiency may be acute or chronic, depending on the speed of onset of the symptoms. The symptoms and signs of adrenocortical hypofunction are related to deficiencies of both mineralocorticoids and glucocorticoids.

Acute adrenocortical insufficiency

Acute primary adrenocortical insufficiency can occur in several circumstances:

• patients with chronic adrenocortical insufficiency may have an acute insufficiency crisis if an event occurs that requires an increased output of steroid hormones by the adrenals
• patients on long-term steroid treatment have suppressed adrenal glands, which are unable to respond adequately if an event occurs that requires an increased output of steroid hormones, or if the steroid treatment is withdrawn too rapidly
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