COMMON CLINICAL PROBLEMS FROM ENDOCRINE DISEASE

Pathological basis of endocrine signs and symptoms

NORMAL STRUCTURE AND FUNCTION

An endocrine gland secretes hormones directly into the blood stream to reach distant ‘target organs’ where the secretory products exert their effects. Endocrine glands are thus distinguished from exocrine glands, whose secretions pass into the gut or respiratory tract, or on to the exterior of the body; examples of exocrine glands include the exocrine pancreas and the bronchial mucous glands. Closely related to the endocrine system is the paracrine (diffuse endocrine) system, consisting of regional distributions of specialised cells producing locally acting hormones, such as those regulating gut motility, and forming part of the neuroendocrine system (Ch. 15); autocrine effects are those acting on the cell producing the hormone (Fig. 17.1).

Fig. 17.1 Comparison of the autocrine, paracrine and endocrine systems. See text for details.

Hormones exert their effects on the target organs by binding to receptors, protein molecules with high and specific affinity for the hormone. These hormone receptors may be either on the cell surface (for example, thyroid-stimulating hormone receptors on the thyroid epithelium) or intracellular (for example, nuclear receptors for steroid hormones). The binding of a hormone to its cell surface receptor sets off a series of intracellular signals via secondary ‘messenger’ molecules (cyclic nucleotides), which results in changes in metabolic activity, differentiation or mitosis of the stimulated cell.

ENDOCRINE PATHOLOGY

The major disorders of an endocrine gland are:

There are several important general considerations in endocrine pathology. First, disease of one endocrine gland cannot usually be considered in isolation, because it almost always has implications for other endocrine glands:

Fig. 17.2 Multiple endocrine neoplasia (MEN) syndromes. MEN syndromes are characterised by the occurrence of tumours in more than one endocrine organ. MEN types 1 and 2 can be distinguished by the organs commonly involved.

Second, one hormone may have many diverse clinical effects, so that malfunction of one endocrine gland may produce numerous clinical features.

Third, the same hormone may be produced in more than one site; thus, ectopic hormone production by tumours of non-endocrine tissues may simulate primary endocrine disease.

PITUITARY

The pituitary is a small gland, weighing only 500–1000 mg. It is situated in the sella turcica of the skull beneath the hypothalamus. Despite its small size, it exerts many essential control functions over the rest of the endocrine system, earning it the title ‘conductor of the endocrine orchestra’. It consists of two parts (Fig. 17.3), each with separate functions. The anterior pituitary, the adenohypophysis, is developed from Rathke’s pouch, an outpouching of the roof of the embryonic oral cavity; it comprises about 75% of the bulk of the gland. The posterior pituitary, the neurohypophysis, is derived from a downgrowth of the hypothalamus.

Fig. 17.3 The pituitary and its physiological relationships.The pituitary is controlled both by hormones from its target glands, and via the hypothalamus.

ADENOHYPOPHYSIS

Classification of cell types

Modern histological classification of the types of hormone-secreting cell is based on immunohistochemistry, a technique in which antibodies raised to a hormone bind to the cells containing that hormone in tissue sections, leading to a coloured stain (Fig. 17.4). This has enabled the true hormone content of the cells to be determined, and has rendered obsolete the traditional classification of the cells into eosinophil, basophil and chromophobe types according to their staining by haematoxylin and eosin (H&E). By electron microscopy, the cells of the adenohypophysis are seen to contain electron-dense granules ranging from 50 to 500 nm in diameter (Fig. 17.5); these contain stored secretory products. The six types of hormone-secreting cell are shown in Table 17.1.

Fig. 17.4 Growth hormone-containing cells in an adenoma of the adenohypophysis. Immunoperoxidase localisation of growth hormone. Cells containing growth hormone are stained brown by this technique.

Fig. 17.5 Electron micrograph of a secretory cell of the adenohypophysis. The hormonal products are stored as electron-dense membrane-bound cytoplasmic granules (´ 300 000).

Table 17.1 Hormone-secreting cells of the adenohypophysis

Cell type	Staining reactionwith H&E	Hormonal product
Corticotroph	Basophilic	Adenocorticotrophic hormone (ACTH)
Thyrotroph	Basophilic	Thyroid-stimulating hormone (TSH)
Gonadotroph	Basophilic	Follicle-stimulating hormone (FSH) Luteinising hormone (LH)
Somatotroph	Eosinophilic	Growth hormone (GH)
Lactotroph	Eosinophilic	Prolactin (PL)
Chromophobe	Pale	Unknown

Hypofunction

Most cases due to destruction by tumour or extrinsic compression

Causes include adenomas, craniopharyngiomas and ischaemic necrosis

Leads to secondary hypofunction of adenohypophysial-dependent endocrine glands

Like other endocrine organs, the adenohypophysis has considerable reserve capacity, and deficiency of its hormones becomes manifest only after extensive destruction; hypofunction is therefore uncommon. Since the pituitary is tightly encased within the sella turcica, any expansile lesion, such as an adenoma, produces compression damage to the adjacent pituitary tissue, in addition to any effect from its own hormonal production. Damage to the hypothalamus or pituitary stalk may also produce adenohypophysial hypofunction through failure of control. Table 17.3 sets out the main causes of hypofunction. These conditions lead to a deficiency of all adenohypophysial hormones, a state known as panhypopituitarism. This is a life-threatening condition, as deficiency of ACTH leads to atrophy of the adrenal cortex and failure of production of vital adrenocorticoids. Diagnosis of hypopituitarism is by measurement of the individual hormones. The commonest causes of pituitary hypofunction are compression by metastatic carcinoma or by an adenoma, but two specific rarer syndromes will be mentioned because they illustrate how congenital and acquired disease may affect the pituitary.

Table 17.3 Causes of adenohypophysial hypofunction

Site	Lesions
Pituitary	Adenoma
	Metastatic carcinoma
	Trauma
	Post-partum ischaemic necrosis (Sheehan’s syndrome)
	Craniopharyngioma
	Infections
	Granulomatous diseases
	Autoimmunity
	Iatrogenic
Hypothalamus	Craniopharyngioma
	Gliomas

Pituitary dwarfism

Pituitary dwarfism is due to deficiency of GH, sometimes associated with deficiency of other adenohypophysial hormones. The child fails to grow, although remaining well proportioned. There is a variety of known causes including adenomas, craniopharyngiomas (rare tumours derived from remnants of Rathke’s pouch) and familial forms.

Post-partum ischaemic necrosis

During pregnancy, the pituitary enlarges and becomes highly vascular. Hypotensive shock due to haemorrhage at the time of birth, compounded by the lack of direct arterial supply to the adenohypophysis, may cause ischaemic necrosis. This specific cause of necrosis is known as Sheehan’s syndromeand the effects of the resulting adenohypophysial hypofunction are termed Simmond’s disease. The neurohypophysis is usually spared. The first symptom following delivery is failure of lactation due to PL deficiency; the effects of lack of FSH/LH, TSH and ACTH then follow—loss of sexual function, hypothyroidism, and the diverse effects of glucocorticoid deficiency. Improvements in obstetric management mean that Sheehan’s syndrome is now rare, although hypotensive shock due to trauma may produce similar effects.

Tumours: adenomas

Primary pituitary tumours are almost always benign

May be derived from any hormone-producing cell

If functional, the clinical effects of the tumour are secondary to the hormone being produced (e.g. acromegaly, Cushing’s disease)

Local effects are due to pressure on optic chiasma or adjacent pituitary cells

Pituitary tumours account for approximately 10% of primary intracranial neoplasms. They may be derived from any of the hormone-secreting cells and thus may be clinically manifest by virtue of single hormone overproduction, destruction of surrounding normal pituitary and consequent hypofunction, and mechanical effects due to intracranial pressure rise and specific location.

Adenomas are the commonest adenohypophysial tumours; carcinomas are rare. Small adenomas may be asymptomatic and found only at postmortem. Histologically, adenomas consist of nodules containing cells similar to those of the normal adenohypophysis, with many small blood vessels between them. They may produce clinical disease in two ways: excess hormone production and pressure effects.

Excess hormone production

Adenomas may produce any adenohypophysial hormone, depending on their cell of origin (Table 17.4); thus presentation may be via excess production of one of the hormones, for example acromegaly due to excess growth hormone production in an adult (Fig. 17.6), or gigantism if this occurs during childhood.

Table 17.4 Types of adenohypophysial adenoma

Type	Remarks
Prolactinoma (chromophobe)	Commonest type
	Produces galactorrhoea and menstrual disturbances
GH-secreting (eosinophil)	Produces gigantism in children and acromegaly in adults
ACTH-secreting (basophil)	Produces Cushing’s disease
Other	Exceptionally rare

Fig. 17.6 Systemic features of acromegaly. Acromegaly is the clinical syndrome resulting from growth hormone excess in adult life. The chief presenting features are enlargement of the hands, feet and head, but it may also present with secondary diabetes. The cardiovascular effects may be life-threatening.

Pressure effects

These may be either on the surrounding pituitary to produce hypofunction, or on the overlying optic chiasma (Fig. 17.7), producing a characteristic visual field defect called bitemporal hemianopia. Further growth may compress the hypothalamus.

Fig. 17.7 Pituitary adenoma. Coronal plane CT scan of the pituitary fossa showing the sella turcica widened by a pituitary adenoma, which is compressing the optic chiasma and hypothalamus. Pituitary adenoma revealed at autopsy, protruding above the sella turcica.

Types of adenoma

All the following adenomas comprise, histologically, nests and cords of a monotonous single cell type, the islands of cells being supported on a richly vascular sinusoidal framework. Amyloid deposition is not infrequent and calcification may occur.

Chromophobe adenoma

The commonest tumour is one derived from apparently inactive cells; thus hormonal manifestations may be absent but more sensitive biochemical assessments suggest that prolactin may be produced by many of these adenomas. The clinical effects may therefore be limited to infertility and be discovered only because of failed conception in the female.

Eosinophil adenoma

Approximately one-third of lesions are derived from the growth hormone-producing cells and are thus manifest by gigantism in the pre-pubertal patient and acromegaly in the adult.

Basophil adenoma

The rarer ACTH-producing adenoma has its effects by stimulating bilateral adrenocortical hyperplasia and hyperfunction, resulting in Cushing’s syndrome. Though rare, this remains the commonest cause of Cushing’s syndrome in the adult.

Microadenoma

The microadenoma is a small neoplasm, measuring less than 10 mm in diameter, with no mechanical effects and usually discovered only during intensive investigation of infertility; the lesion often produces prolactin in excess.

NEUROHYPOPHYSIS

Neurosecretory cells in the supra-optic and paraventricular nuclei of the hypothalamus give rise to modified nerve fibres which carry the two neurohypophysial hormones—antidiuretic hormone and oxytocin—into the posterior lobe of the pituitary (Fig. 17.3); both hormones are nonapeptides, and are stored until released in response to hypothalamic stimuli.

PINEAL GLAND

The pineal gland is a tiny organ lying above the third ventricle of the brain. Little is known of its function, although its secretory product, melatonin, is thought to be involved in circadian rhythm control and gonadal maturation. The most important tumours of the pineal gland are malignant germ cell tumours (teratomas and seminomas) and pinealoblastomas, resembling neuroblastomas.

ADRENALS

The adrenals consist essentially of two separate endocrine glands within a single anatomical organ. The medulla, of neural crest embryological origin, is part of the sympathetic nervous system; it secretes catecholamines, which are essential in the physiological responses to stress, e.g. infection, shock or injury. The cortex, derived from mesoderm, synthesises a range of steroid hormones with generalised effects on metabolism, the immune system, and water and electrolyte balance.

ADRENAL MEDULLA

Histologically, the adrenal medulla consists of chromaffin cells (so called because they produce brown pigments when fixed in solutions of chrome salts) and sympathetic nerve endings. The adrenal medulla is the main source of adrenaline (epinephrine), as it is produced there from noradrenaline (norepinephrine) by the enzyme phenylethanolamine-N-methyl transferase. Elsewhere in the body, sympathetic nerve endings lack this enzyme and their secretory product is thus noradrenaline. Electron microscopy reveals electron-dense granules in the chromaffin cells (Fig. 17.8), similar to those found in other tissues of the so-called amine precursor uptake and decarboxylation (APUD) system. Islands of similar tissue, known as the organs of Zuckerkandl, are sometimes found in other retroperitoneal sites; these have similar functions and a similar pattern of diseases to that seen in the adrenal medulla. Catecholamines are secreted in states of stress and of hypovolaemic shock, when they are vital in the maintenance of blood pressure by causing vasoconstriction in the skin, gut and skeletal muscles. At tissue level, these hormones bind to cell surface receptors, altering cellular levels of a second messenger, cyclic AMP, which brings about rapid functional changes in the cell.

Fig. 17.8 Electron micrograph of noradrenaline granules in a chromaffin cell. The granules characteristically have eccentric electron-dense cores (× 75 000).

Tumours

Phaeochromocytoma

Derived from adrenal medullary chromaffin cells

Symptoms due to excess catecholamine secretion (e.g. hypertension, sweating)

May be familial and associated with other endocrine tumours

Occasionally malignant

A curable cause of secondary hypertension

A phaeochromocytoma is derived from the adrenal medullary chromaffin cells (or from those lying in other sites); it is classified as a paraganglioma. The tumour presents through the effects of its catecholamine secretions: hypertension (which is sometimes intermittent), pallor, headaches, sweating and nervousness. Its presence should be suspected especially in younger hypertensive patients. Although it is a rare cause of hypertension, phaeochromocytoma must not be overlooked as it is one of the few curable causes of elevated blood pressure; other causes include adrenal cortical adenoma, renal artery stenosis and aortic coarctation.

The diagnosis of phaeochromocytoma is usually based on estimating the urinary excretion of vanillylmandelic acid (VMA), a catecholamine metabolite, which is generally at least doubled in the presence of the tumour. Localisation of the tumour is assisted by computed tomography of the abdomen and by radio-isotope scanning with ¹³¹I-mIBG, a catecholamine precursor that accumulates in the tumour.

Phaeochromocytoma may be familial, associated with medullary carcinoma of the thyroid or with hyperparathyroidism as part of a multiple endocrine neoplasia (MEN) syndrome. The familial cases are frequently bilateral. Other associations are with neurofibromatosis and the rare von Hippel–Lindau syndrome.

Phaeochromocytomas are brown, solid nodules, usually under 50 mm in diameter, often with areas of haemorrhagic necrosis (Fig. 17.9). Histologically, they consist of groups of polyhedral cells which give the chromaffin reaction, and are highly vascular (Fig. 17.10).

Fig. 17.9 Phaeochromocytoma. The adrenal medulla is expanded by a dark-coloured tumour with areas of degeneration and haemorrhage.

Fig. 17.10 Chromaffin cells in a phaeochromocytoma. There are groups of cells with granular cytoplasm, amidst which there are numerous branching capillaries.

Although most are benign, a few phaeochromocytomas pursue a malignant course. It is not generally possible to predict this behaviour from the histological appearance.

Neuroblastoma

Neuroblastoma is a rare and highly malignant tumour found in infants and children. Derived from sympathetic nerve cells it may, like phaeochromocytoma, secrete catecholamines, and there may be elevated levels of their metabolites in the urine. Neuroblastomas may also originate from parts of the sympathetic chain outside the adrenal medulla. Secondary spread to liver, skin and bones (especially those of the skull) is common. Surprisingly, neuroblastoma may occasionally mature spontaneously to ganglioneuroma, a benign tumour.

ADRENAL CORTEX

Histologically, the adrenal cortex has three zones (Fig. 17.11). Beneath the capsule lies the zona glomerulosa, so called because the cells are grouped into spherical clusters superficially resembling glomeruli. This zone produces mineralocorticoid steroids such as aldosterone. Most of the adrenal cortex comprises the middle and inner zones—zona fasciculata and zona reticularis, respectively. The middle zone is rich in lipid. The inner zone cells convert lipid into corticosteroids, principally glucocorticoids and sex steroids, for secretion.

Fig. 17.11 Adrenal cortex. The normal zones are: zona glomerulosa (top), zona fasciculata (middle) and zona reticularis (bottom).

Steroid hormones

Glucocorticoids

The glucocorticoids have important effects on a wide range of tissues and organs. At physiological levels they:

• inhibit protein synthesis

• increase protein breakdown

• increase gluconeogenesis.

In excess, as a result of therapeutic administration or high levels of endogenous secretion, they cause:

• adiposity of face and trunk

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