Chapter 17 Endocrine system
COMMON CLINICAL PROBLEMS FROM ENDOCRINE DISEASE
Pathological basis of endocrine signs and symptoms
| Sign or symptom | Pathological basis |
|---|---|
| Signs or symptoms of hormone excess (hyperfunction) |
Signs or symptoms of hormone deficiency (hypofunction)
Diffuse enlargement of gland
Nodular enlargement of glandTumour (benign or malignant)Some organ-specific features
Pituitary tumour
Increased thyroid hormone secretion due to hyperplasia or neoplasia of gland
Autoimmune involvement of retrobulbar connective tissue in Graves’ disease
Adrenocortical hyperplasia or neoplasia
Absolute or relative deficiency of insulin (diabetes mellitus)
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).
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.
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 |
SomatotrophEosinophilicGrowth hormone (GH)LactotrophEosinophilicProlactin (PL)ChromophobePaleUnknown
Control of hormone secretion
Hormonal control factors
The adenohypophysis lacks any direct arterial supply. Blood from the hypothalamus passes down venous portal channels in the pituitary stalk (Fig. 17.3) into sinusoids which ramify within the gland. In this way hormonal control factors produced by neurosecretory cells in the hypothalamus are carried directly to the hormone-producing cells of the adenohypophysis. The known hormonal control factors and their effects are listed in Table 17.2. In general, these factors stimulate the particular secretory cells under their control into activity; the exception is prolactin-inhibiting factor, whose effect on the lactotrophs is inhibitory.
Table 17.2 Hormonal control factors and their effects on the adenohypophysis
| Hormonal control factor | Effect |
|---|---|
| Corticotrophin-releasing factor (CRF) | Corticotrophs release ACTH |
| Thyrotrophin-releasing factor (TRF) | Thyrotrophs release TSH |
| Gonadotrophin-releasing factor (FSH/LH-RF) | Gonadotrophs release FSH/LH |
| Growth hormone-releasing factor (GHRF) | Somatotrophs release GH |
| Prolactin-inhibiting factor (PIF) | Lactotrophs inhibited from releasing PL |
Secretion of these hormonal control factors by the hypothalamus is under two types of control: neural and hormonal. Neural control is via nerves from other parts of the central nervous system, and is important in reactions to stress and in changes during sleep. Hormonal control is a negative feedback mechanism in which the hypothalamus monitors the level of adenohypophysial hormones in the blood and adjusts its output of hormonal control factors accordingly, so as to stabilise the level of each adenohypophysial hormone at the optimum level. This is called the hypothalamic–hypophysial feedback control.
Feedback control
In addition to control via the hypothalamus, a more direct method of control of the adenohypophysis also exists, whereby its cells respond directly to the levels of hormones and metabolites in the blood. Most adenohypophysial hormones stimulate another endocrine gland, termed the ‘target’ gland; for example, ACTH stimulates the adrenal cortex to produce steroid hormones, and TSH stimulates the thyroid to produce thyroxine.
In these examples, the level of hormone from the target gland is monitored for feedback control. However, in the case of growth hormone, which has no single target gland, it is the level of metabolites such as glucose that is monitored. A general scheme of the feedback control mechanisms operating in the regulation of a hypophysial hormone is shown in Figure 17.3.
Adenohypophysial hormones
Adrenocorticotrophic hormone
Adrenocorticotrophic hormone (ACTH), a peptide consisting of 39 amino acids, causes increased cell numbers (hyperplasia) and increased secretory activity in the adrenal cortex. Glucocorticoid output is elevated, but there is no effect on the output of mineralocorticoids, such as aldosterone, that are not under anterior pituitary control. ACTH levels show a marked circadian variation, being highest early in the morning.
Thyroid-stimulating hormone
Thyroid-stimulating hormone (TSH) is a glycoprotein that induces proliferation of the follicular cells of the thyroid, synthesis of thyroxine (T4) and tri-iodothyronine (T3), and secretion of these into the blood. Measurement of TSH levels provides information on the state of the control system of the thyroid and is valuable in the diagnosis of thyroid malfunction.
Gonadotrophic hormones
In the female, follicle-stimulating hormone (FSH) induces growth of Graafian follicles in the ovaries; these secrete oestrogens, which in turn cause endometrial proliferation. After rupture of the follicle at ovulation, luteinising hormone (LH) causes a change in the follicle cells known as luteinisation, whereby their secretory product changes from oestrogens to progesterone which induces secretory changes in the endometrium. Both gonadotrophic hormones are glycoproteins.
The hypothalamus monitors circulating levels of the sex steroids including oestrogens and progesterone, and releases probably a single hormonal control factor, FSH/LH-releasing factor (FSH/LH-RF), to control the adenohypophysial gonadotrophs. Their response to this factor depends on the prevailing levels of sex steroids. Cyclical changes in this feedback loop form the hormonal basis for the menstrual cycle.
In the male, FSH and LH both exist but, in the absence of ovaries as the target organ, their names are inappropriate to their actions. LH stimulates testosterone production by the interstitial cells of Leydig in the testes, while FSH stimulates spermatogenesis.
The circulating levels of FSH and LH vary markedly with age: they increase at puberty and are very high in females after the menopause.
Growth hormone
Growth hormone (GH) is a protein containing 191 amino acids; it binds to receptors on the surface of various cells and thus causes increased protein synthesis, accelerates breakdown of fatty tissue to produce energy, and tends to raise the blood glucose. It is vital for normal growth; deficiency causes dwarfism. Part of its action at tissue level is mediated by a group of peptide growth factors known as somatomedins. The hypothalamic control of GH release from the hypothalamus is complex, there being both a growth hormone-releasing factor (GH-RF) and an inhibitory factor, somatostatin.
Prolactin
Prolactin (PL) is a protein hormone with a structure very similar to that of GH. Although it is present in individuals of both sexes, its function in males remains uncertain. In females, it can produce lactation, provided that the breast has already been prepared during pregnancy by appropriate levels of sex steroids. Prolactin release is a good example of the neural form of hypothalamic control: the sensation of suckling causes reduction in hypothalamic prolactin-inhibiting factor (PIF) release and a consequent rise in PL levels.
Hypofunction
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
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.
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.
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.
Antidiuretic hormone
Antidiuretic hormone (ADH) controls plasma osmolarity and body water content by increasing the permeability of the renal collecting ducts; this means that more water is reabsorbed and the urine becomes more concentrated. ADH release is stimulated by increased plasma osmolarity and by hypovolaemia.
Damage to the hypothalamus, for example through trauma or tumours, causes deficiency of ADH, leading to production of large volumes of dilute urine accompanied by compensatory polydipsia (excess drinking). This is called diabetes insipidus, from the days when tasting of the patient’s urine was part of the diagnostic process: the urine is tasteless in this condition, whereas in diabetes mellitus it is sweet due to its high glucose content.
Excess ADH is occasionally produced by the neurohypophysis in response to head injury or meningitis, but most clinical cases of ADH excess are due to its ectopic production by tumours, including bronchial carcinomas. The tumours are almost certainly of neuroendocrine origin and thus equipped for the synthesis of peptide hormones.
The rarity of any neurohypophysial tumour secreting ADH (or oxytocin) is perhaps due to the incapacity of the neurones producing these hormones to undergo mitotic division.
Oxytocin
Oxytocin is an aptly named hormone (it is the Greek word for quick birth) as it stimulates the uterine smooth muscle to contract. Interestingly, it is oxytocin from the fetal pituitary that plays the greater role in initiating parturition, suggesting that the fetus orders its own birth. Oxytocin also causes ejection of milk during lactation. The hormone is present in males, although its function, if any, is unknown.
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
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:
