08-18 Endocrinology

18 Endocrinology

Endocrinology MWJ Strachan JDC Newell-Price Clinical examination in endocrine disease 630 An overview of endocrinology 632 Functional anatomy and physiology 632 Endocrine pathology 632 Investigation of endocrine disease 633 Presenting problems in endocrine disease 633 The thyroid gland 634 Functional anatomy, physiology and investigations 634 Presenting problems in thyroid disease 635 Thyrotoxicosis 635 Hypothyroidism 639 Asymptomatic abnormal thyroid function tests 642 Thyroid lump or swelling 642 Autoimmune thyroid disease 643 Transient thyroiditis 646 Iodine-associated thyroid disease 647 Simple and multinodular goitre 648 Thyroid neoplasia 649 Congenital thyroid disease 650 The reproductive system 651 Functional anatomy, physiology and investigations 651 Presenting problems in reproductive disease 653 Delayed puberty 653 Precocious puberty 654 Amenorrhoea 654 Male hypogonadism 655 Infertility 656 Gynaecomastia 657 Hirsutism 657 Polycystic ovarian syndrome 658 Turner’s syndrome 659 Klinefelter’s syndrome 660 The parathyroid glands 661 Functional anatomy, physiology and investigations 661 Presenting problems in parathyroid disease 661 Hypercalcaemia 661 Hypocalcaemia 662 Primary hyperparathyroidism 663 Familial hypocalciuric hypercalcaemia 664 Hypoparathyroidism 664 The adrenal glands 665 Functional anatomy and physiology 665 Presenting problems in adrenal disease 666 Cushing’s syndrome 666 Therapeutic use of glucocorticoids 670 Adrenal insufﬁciency 671 Incidental adrenal mass 673 Primary hyperaldosteronism 674 Phaeochromocytoma and paraganglioma 675 Congenital adrenal hyperplasia 676 The endocrine pancreas and gastrointestinal tract 676 Presenting problems in endocrine pancreas disease 676 Spontaneous hypoglycaemia 676 Gastroenteropancreatic neuro-endocrine tumours 678 The hypothalamus and the pituitary gland 679 Functional anatomy, physiology and investigations 679 Presenting problems in hypothalamic and pituitary disease 681 Hypopituitarism 681 Pituitary tumour 683 Hyperprolactinaemia/galactorrhoea 684 Prolactinoma 684 Acromegaly 685 Craniopharyngioma 687 Diabetes insipidus 687 Disorders affecting multiple endocrine glands 688 Multiple endocrine neoplasia 688 Autoimmune polyendocrine syndromes 689 Late effects of childhood cancer therapy 689

630 • ENDOCRINOLOGY Hands Palmar erythema Tremor Acromegaly Carpal tunnel syndrome Skin Hair distribution Dry/greasy Pigmentation/pallor Bruising Vitiligo Striae Thickness Pulse Atrial fibrillation Sinus tachycardia Bradycardia Breasts Galactorrhoea Gynaecomastia Neck Voice Hoarse, e.g. hypothyroid Virilised Thyroid gland (see opposite) Goitre Nodules

Observation • Most examination in endocrinology is by observation • Astute observation can often yield ‘spot’ diagnosis of endocrine disorders • The emphasis of examination varies depending on which gland or hormone is thought to be involved Body fat Central obesity in Cushing’s syndrome and growth hormone deficiency

Height and weight Bones Fragility fractures (e.g. of vertebrae, neck of femur or distal radius)

Genitalia Virilisation Pubertal development Testicular volume

Legs Proximal myopathy Myxoedema

Blood pressure Hypertension in Cushing’s and Conn’s syndromes, phaeochromocytoma Hypotension in adrenal insufficiency Eyes Graves’ disease (see opposite) Diplopia Visual field defect (see opposite) Hair Alopecia Frontal balding Facial features Hypothyroid Hirsutism Acromegaly Cushing’s

Prognathism in acromegaly Acromegalic hands. Note soft tissue enlargement causing ‘spade-like’ changes Pigmentation of creases due to high ACTH levels in Addison’s disease Vitiligo in organ-specific autoimmune disease Multinodular goitre Pretibial myxoedema in Graves' disease Head Mental state Lethargy Depression Delirium Libido

Clinical examination in endocrine disease Endocrine disease causes clinical syndromes with symptoms and signs involving many organ systems. The emphasis of the clinical examination depends on the gland or hormone that is thought to be abnormal. Diabetes mellitus (described in detail in Ch. 20) and thyroid disease are the most common endocrine disorders.

Clinical examination in endocrine disease • 631

6 Examination of the visual ﬁelds by confrontation • Sit opposite patient • You and patient cover opposite eyes • Bring red pin (or wiggling finger) slowly into view from extreme of your vision, as shown • Ask patient to say ‘now’ when it comes into view • Continue to move pin into centre of vision and ask patient to tell you if it disappears • Repeat in each of four quadrants • Repeat in other eye A bitemporal hemianopia is the classical finding in pituitary macroadenomas (p. 683) 6 Examination in Graves’ ophthalmopathy • Inspect from front and side Periorbital oedema (Fig. 18.8) Conjunctival inflammation (chemosis) Corneal ulceration Proptosis (exophthalmos)* Lid retraction* • Range of eye movements Lid lag on descending gaze* Diplopia on lateral gaze • Pupillary reflexes Afferent defect (pupils constrict further on swinging light to unaffected eye, Box 25.22) • Vision Visual acuity impaired Loss of colour vision Visual field defects • Ophthalmoscopy Optic disc pallor Papilloedema *Note position of eyelids relative to iris. Normal

Proptosis

Right proptosis and afferent pupillary defect

Lid retraction

Normal

Normal descent

Lid lag descent

7 Examination of the thyroid gland Diffuse firm goitre

Hashimoto’s thyroiditis (p. 646) Diffuse tender goitre

Subacute thyroiditis (p. 646) Abnormal findings Diffuse soft goitre with bruit

Graves’ disease (p. 643) Multinodular goitre (p. 648)

± Retrosternal extension, tracheal compression Solitary nodule (p. 642)

Adenoma, cyst or carcinoma Cervical lymphadenopathy

Suggests carcinoma • Inspect from front to side • Palpate from behind Thyroid moves on swallowing Check if lower margin is palpable Cervical lymph nodes Tracheal deviation • Auscultate for bruit Ask patient to hold breath If present, check for radiating murmur • Percuss for retrosternal thyroid • Consider systemic signs of thyroid dysfunction (Box 18.7) incl. tremor, palmar erythema, warm peripheries, tachycardia, lid lag • Consider signs of Graves’ disease incl. ophthalmopathy, pretibial myxoedema • Check for Pemberton’s sign, i.e. facial engorgement when arms raised above head

632 • ENDOCRINOLOGY to affect adjacent cells, or act in an autocrine way to affect behaviour of the cell that produces the hormone. Endocrine pathology For each endocrine axis or major gland, diseases can be classiﬁed as shown in Box 18.1. Pathology arising within the gland is often called ‘primary’ disease (e.g. primary hypothyroidism in Hashimoto’s thyroiditis), while abnormal stimulation of the gland is often called ‘secondary’ disease (e.g. secondary hypothyroidism in patients with a pituitary tumour and thyroid-stimulating hormone Endocrinology concerns the synthesis, secretion and action of hormones. These are chemical messengers released from endocrine glands that coordinate the activities of many different cells. Endocrine diseases can therefore affect multiple organs and systems. This chapter describes the principles of endocrinology before dealing with the function and diseases of each gland in turn. Some endocrine disorders are common, particularly those of the thyroid, parathyroid glands, reproductive system and β cells of the pancreas (Ch. 20). For example, thyroid dysfunction occurs in more than 10% of the population in areas with iodine deﬁciency, such as the Himalayas, and 4% of women aged 20–50 years in the UK. Less common endocrine syndromes are described later in the chapter. Few endocrine therapies have been evaluated by randomised controlled trials, in part because hormone replacement therapy (e.g. with levothyroxine) has obvious clinical beneﬁts and placebocontrolled trials would be unethical. Where trials have been performed, they relate mainly to use of therapy that is ‘optional’ and/or more recently available, such as oestrogen replacement in post-menopausal women, androgen therapy in older men and growth hormone replacement. An overview of endocrinology Functional anatomy and physiology Some endocrine glands, such as the parathyroids and pancreas, respond directly to metabolic signals, but most are controlled by hormones released from the pituitary gland. Anterior pituitary hormone secretion is controlled in turn by substances produced in the hypothalamus and released into portal blood, which drains directly down the pituitary stalk (Fig. 18.1). Posterior pituitary hormones are synthesised in the hypothalamus and transported down nerve axons, to be released from the posterior pituitary. Hormone release in the hypothalamus and pituitary is regulated by numerous stimuli and through feedback control by hormones produced by the target glands (thyroid, adrenal cortex and gonads). These integrated endocrine systems are called ‘axes’ and are listed in Figure 18.2. A wide variety of molecules can act as hormones, including peptides such as insulin and growth hormone, glycoproteins such as thyroid-stimulating hormone, and amines such as noradrenaline (norepinephrine). The biological effects of hormones are mediated by binding to receptors. Many receptors are located on the cell surface. These interact with various intracellular signalling molecules on the cytosolic side of the plasma membrane to affect cell function, usually through changes in gene expression. Some hormones, most notably steroids, triiodothyronine (T3) and vitamin D, bind to speciﬁc intracellular receptors. The hormone/ receptor complex forms a ligand-activated transcription factor, which regulates gene expression directly (p. 39). The classical model of endocrine function involves hormones synthesised in endocrine glands, which are released into the circulation and act at sites distant from those of secretion (as in Fig. 18.1). However, additional levels of regulation are now recognised. Many other organs secrete hormones or contribute to the peripheral metabolism and activation of prohormones. A notable example is the production of oestrogens from adrenal androgens in adipose tissue by the enzyme aromatase. Some hormones, such as neurotransmitters, act in a paracrine fashion Fig. 18.1 An archetypal endocrine axis. Regulation by negative feedback and direct control is shown, along with the equilibrium between active circulating free hormone and bound or metabolised hormone. Feedback regulation Trophic hormone Hormone Binding protein Target organ Metabolism Endocrine gland Pituitary Neural control Action Receptor Direct regulation 18.1 Classiﬁcation of endocrine disease Hormone excess • Primary gland over-production • Secondary to excess trophic substance Hormone deﬁciency • Primary gland failure • Secondary to deﬁcient trophic hormone Hormone hypersensitivity • Failure of inactivation of hormone • Target organ over-activity/hypersensitivity Hormone resistance • Failure of activation by hormone • Target organ resistance Non-functioning tumours • Benign • Malignant

An overview of endocrinology • 633

deﬁciency). Some pathological processes can affect multiple endocrine glands (p. 688); these may have a genetic basis (such as organ-speciﬁc autoimmune endocrine disorders and the multiple endocrine neoplasia (MEN) syndromes) or be a consequence of therapy for another disease (e.g. following treatment of childhood cancer with chemotherapy and/or radiotherapy). Investigation of endocrine disease Biochemical investigations play a central role in endocrinology. Most hormones can be measured in blood but the circumstances in which the sample is taken are often crucial, especially for hormones with pulsatile secretion, such as growth hormone; those that show diurnal variation, such as cortisol; or those that demonstrate monthly variation, such as oestrogen or progesterone. Some hormones are labile and need special collection, handling and processing requirements, e.g. collection in a special tube and/or rapid transportation to the laboratory on ice. Local protocols for hormone measurement should be carefully followed. Other investigations, such as imaging and biopsy, are more frequently reserved for patients who present with a tumour. The principles of investigation are shown in Box 18.2. The choice of test is often pragmatic, taking local access to reliable sampling facilities and laboratory measurements into account. Presenting problems in endocrine disease Endocrine diseases present in many different ways and to clinicians in many different disciplines. Classical syndromes are described in relation to individual glands in the following sections. Often, however, the presentation is with non-speciﬁc symptoms (Box 18.3) or with asymptomatic biochemical abnormalities. In Fig. 18.2 The principal endocrine ‘axes’. Some major endocrine glands are not controlled by the pituitary. These include the parathyroid glands (regulated by calcium concentrations, p. 661), the adrenal zona glomerulosa (regulated by the renin–angiotensin system, p. 665) and the endocrine pancreas (Ch. 20). Italics show negative regulation. (ACTH = adrenocorticotrophic hormone; CRH = corticotrophin-releasing hormone; FSH = folliclestimulating hormone; GH = growth hormone; GHRH = growth hormone-releasing hormone; GnRH = gonadotrophin-releasing hormone; IGF-1 = insulin-like growth factor-1; IGF-BP3 = IGF-binding protein-3; LH = luteinising hormone: T3 = triiodothyronine; T4 = thyroxine; TRH = thyrotrophin-releasing hormone; TSH = thyroid-stimulating hormone; vasopressin = antidiuretic hormone (ADH)) Regulation Circadian rhythm Stress Cortisol Osmolality Intravascular volume Oestrogen Progesterone Androgen Prolactin Inhibin T3 IGF-1 GnRH TRH Dopamine GHRH Somatostatin CRH Oxytocin Hypothalamus TSH Prolactin GH ACTH Posterior Pituitary LH FSH Gonads: testes or ovaries Thyroid Breast Liver Adrenal cortex Distal nephron Uterus Breast Oestrogen Progesterone Androgen T4 T3 IGF-1 IGF-BP3 Cortisol Androgen Glands/targets Target hormones Function Reproduction Metabolism Lactation Growth Stress Metabolism Water balance Parturition Lactation Oestrogen Stress Anterior Vasopressin 18.2 Principles of endocrine investigation Timing of measurement • Release of many hormones is rhythmical (pulsatile, circadian or monthly), so random measurement may be invalid and sequential or dynamic tests may be required Choice of dynamic biochemical test • Abnormalities are often characterised by loss of normal regulation of hormone secretion • If hormone deﬁciency is suspected, choose a stimulation test • If hormone excess is suspected, choose a suppression test • The more tests there are to choose from, the less likely it is that any single test is infallible, so avoid interpreting one result in isolation Imaging • ‘Functional’ as well as conventional ‘structural’ imaging can be performed as secretory endocrine cells can also take up labelled substrates, e.g. radio-labelled iodine or octreotide • Most endocrine glands have a high prevalence of ‘incidentalomas’, so do not scan unless the biochemistry conﬁrms endocrine dysfunction or the primary problem is a tumour Biopsy • Many endocrine tumours are difﬁcult to classify histologically (e.g. adrenal carcinoma and adenoma) addition, endocrine diseases are encountered in the differential diagnosis of common complaints discussed in other chapters of this book, including electrolyte abnormalities (Ch. 14), hypertension (Ch. 16), obesity (Ch. 19) and osteoporosis (Ch. 24). Although diseases of the adrenal glands, hypothalamus and pituitary are relatively rare, their diagnosis often relies on astute clinical observation in a patient with non-speciﬁc complaints, so it is important that clinicians are familiar with their key features.

634 • ENDOCRINOLOGY free hormone measurements is that they are not inﬂuenced by changes in the concentration of binding proteins. For example, TBG levels are increased by oestrogen (such as in the combined oral contraceptive pill) and this will result in raised total T3 and T4, although free thyroid hormone levels are normal. Production of T3 and T4 in the thyroid is stimulated by thyrotrophin (thyroid-stimulating hormone, TSH), a glycoprotein released from the thyrotroph cells of the anterior pituitary in response to the hypothalamic tripeptide, thyrotrophin-releasing hormone (TRH). A circadian rhythm of TSH secretion can be demonstrated with a peak at 0100 hrs and trough at 1100 hrs, but the variation is small so that thyroid function can be assessed reliably from a single blood sample taken at any time of day and does not usually require any dynamic stimulation or suppression tests. There is a negative feedback of thyroid hormones on the hypothalamus and pituitary such that in thyrotoxicosis, when plasma concentrations of T3 and T4 are raised, TSH secretion is suppressed. Conversely, in hypothyroidism due to disease of the thyroid gland, low T3 and T4 are associated with high circulating TSH levels. The relationship between TSH and T4 is classically described as inverse log-linear (Fig. 18.4). The anterior pituitary is, though, very sensitive to minor changes in thyroid hormone levels within the reference range. For example, in an individual whose free T4 level is usually 15 pmol/L (1.17 ng/dL), a rise or fall of 5 pmol/L (0.39 ng/dL) would be associated on the one hand with undetectable TSH, and on the other hand with a raised TSH. For this reason, TSH is usually regarded as the most useful investigation of thyroid function. However, interpretation of TSH values without considering thyroid hormone levels may be misleading in patients with pituitary disease; for example, TSH is inappropriately low or ‘normal’ in secondary hypothyroidism (see Box 18.5 and Box 18.53, p. 680). Moreover, TSH may take several weeks to ‘catch up’ with T4 and T3 levels; for example, levothyroxine therapy will raise T4 and T3 levels within approximately 2 weeks but it may take 4–6 weeks for the TSH to reach a steady state. Heterophilic antibodies (host antibodies with afﬁnity to the animal antibodies used in biological assays, p. 242) can also interfere with the TSH assay and cause a spurious high or low measurement. Common patterns of abnormal thyroid function test results and their interpretation are shown in Box 18.5. Other modalities commonly employed in the investigation of thyroid disease include measurement of antibodies against The thyroid gland Diseases of the thyroid, summarised in Box 18.4, predominantly affect females and are common, occurring in about 5% of the population. The thyroid axis is involved in the regulation of cellular differentiation and metabolism in virtually all nucleated cells, so that disorders of thyroid function have diverse manifestations. Structural diseases of the thyroid gland, such as goitre, commonly occur in patients with normal thyroid function. Functional anatomy, physiology and investigations Thyroid physiology is illustrated in Figure 18.3. The parafollicular C cells secrete calcitonin, which is of no apparent physiological signiﬁcance in humans. The follicular epithelial cells synthesise thyroid hormones by incorporating iodine into the amino acid tyrosine on the surface of thyroglobulin (Tg), a protein secreted into the colloid of the follicle. Iodide is a key substrate for thyroid hormone synthesis; a dietary intake in excess of 100 μg/day is required to maintain thyroid function in adults. The thyroid secretes predominantly thyroxine (T4) and only a small amount of triiodothyronine (T3); approximately 85% of T3 in blood is produced from T4 by a family of monodeiodinase enzymes that are active in many tissues, including liver, muscle, heart and kidney. Selenium is an integral component of these monodeiodinases. T4 can be regarded as a prohormone, since it has a longer half-life in blood than T3 (approximately 1 week compared with approximately 18 hours), and binds and activates thyroid hormone receptors less effectively than T3. T4 can also be converted to the inactive metabolite, reverse T3. T3 and T4 circulate in plasma almost entirely (> 99%) bound to transport proteins, mainly thyroxine-binding globulin (TBG). It is the unbound or free hormones that diffuse into tissues and exert diverse metabolic actions. Some laboratories use assays that measure total T4 and T3 in plasma but it is increasingly common to measure free T4 and free T3. The theoretical advantage of the 18.4 Classiﬁcation of thyroid disease Primary Secondary Hormone excess Graves’ disease Multinodular goitre Adenoma Subacute thyroiditis TSHoma Hormone deﬁciency Hashimoto’s thyroiditis Atrophic hypothyroidism Hypopituitarism Hormone hypersensitivity – Hormone resistance Thyroid hormone resistance syndrome 5′-monodeiodinase deﬁciency Non-functioning tumours Differentiated carcinoma Medullary carcinoma Lymphoma 18.3 Examples of non-speciﬁc presentations of endocrine disease Symptom Most likely endocrine disorder(s) Lethargy and depression Hypothyroidism, diabetes mellitus, hyperparathyroidism, hypogonadism, adrenal insufﬁciency, Cushing’s syndrome Weight gain Hypothyroidism, Cushing’s syndrome Weight loss Thyrotoxicosis, adrenal insufﬁciency, diabetes mellitus Polyuria and polydipsia Diabetes mellitus, diabetes insipidus, hyperparathyroidism, hypokalaemia (Conn’s syndrome) Heat intolerance Thyrotoxicosis, menopause Palpitation Thyrotoxicosis, phaeochromocytoma Headache Acromegaly, pituitary tumour, phaeochromocytoma Muscle weakness (usually proximal) Thyrotoxicosis, Cushing’s syndrome, hypokalaemia (e.g. Conn’s syndrome), hyperparathyroidism, hypogonadism Coarsening of features Acromegaly, hypothyroidism

The thyroid gland • 635

the TSH receptor or other thyroid antigens (see Box 18.8), radioisotope imaging, ﬁne needle aspiration biopsy and ultrasound. Their use is described below. Presenting problems in thyroid disease The most common presentations are hyperthyroidism (thyrotoxicosis), hypothyroidism and enlargement of the thyroid (goitre or thyroid nodule). Widespread availability of thyroid function tests has led to the increasingly frequent identiﬁcation of patients with abnormal results who either are asymptomatic or have non-specific complaints such as tiredness and weight gain. Thyrotoxicosis Thyrotoxicosis describes a constellation of clinical features arising from elevated circulating levels of thyroid hormone. The most common causes are Graves’ disease, multinodular goitre and autonomously functioning thyroid nodules (toxic adenoma) (Box 18.6). Thyroiditis is more common in parts of the world where relevant viral infections occur, such as North America. Clinical assessment The clinical manifestations of thyrotoxicosis are shown in Box 18.7 and an approach to differential diagnosis is given in Fig. 18.3 Structure and function of the thyroid gland. (1) Thyroglobulin (Tg) is synthesised and secreted into the colloid of the follicle. (2) Inorganic iodide (I–) is actively transported into the follicular cell (‘trapping’). (3) Iodide is transported on to the colloidal surface by a transporter (pendrin, defective in Pendred’s syndrome, p. 650) and ‘organiﬁed’ by the thyroid peroxidase enzyme, which incorporates it into the amino acid tyrosine on the surface of Tg to form monoiodotyrosine (MIT) and diiodotyrosine (DIT). (4) Iodinated tyrosines couple to form T3 and T4. (5) Tg is endocytosed. (6) Tg is cleaved by proteolysis to free the iodinated tyrosine and thyroid hormones. (7) Iodinated tyrosine is dehalogenated to recycle the iodide. (8) T4 is converted to T3 by 5′-monodeiodinase. Colloid Follicular cell Extracellular fluid T4 MIT DIT T4 T3 Stimulates all steps

hyperplasia Iodide TSH T3 T4 MIT Tg DIT T3 Iodide MIT Tg DIT Tg

Protein-bound T4, T3 ( > 99%) Increased metabolic rate Mimic β-adrenergic action, e.g. on heart rate, gut motility CNS activation Bone demineralisation Cellular differentiation etc. rT3 T4 T3

Blood Target tissues HO CH2 COOH NH2 CH Tyrosine Monoiodotyrosine (MIT) Diiodotyrosine (DIT) HO O CH2 COOH NH2 CH Triiodothyronine (T3) HO O CH2 COOH NH2 CH Thyroxine (T4) HO O CH2 COOH NH2 CH Reverse T3 (rT3) Negative feedback

HO CH2 COOH NH2 CH HO CH2 COOH NH2 CH Parafollicular (C) cells Colloid Follicular epithelium Red blood cells Free T4,T3 ( < 1%) Fig. 18.4 The relationship between serum thyroid-stimulating hormone (TSH) and free T4. Due to the classic negative feedback loop between T4 and TSH, there is an inverse relationship between serum free T4 and the log of serum TSH. To convert pmol/L to ng/dL, divide by 12.87. LogTSH (mlU/L) Free T4 (pmol/L) 2.5 2.0 1.5 1.0 0.5

-0.5 -1.0 -1.5 -2.0 -2.5

636 • ENDOCRINOLOGY Figure 18.5. The most common symptoms are weight loss with a normal or increased appetite, heat intolerance, palpitations, tremor and irritability. Tachycardia, palmar erythema and lid lag are common signs. Not all patients have a palpable goitre, but experienced clinicians can discriminate the diffuse soft goitre of Graves’ disease from the irregular enlargement of a multinodular goitre. All causes of thyrotoxicosis can cause lid retraction and lid lag, due to potentiation of sympathetic innervation of the levator palpebrae muscles, but only Graves’ disease causes other features of ophthalmopathy, including periorbital oedema, conjunctival irritation, exophthalmos and diplopia. Pretibial myxoedema (p. 646) and the rare thyroid acropachy (a periosteal hypertrophy, indistinguishable from ﬁnger clubbing) are also speciﬁc to Graves’ disease. Investigations The ﬁrst-line investigations are serum T3, T4 and TSH. If abnormal values are found, the tests should be repeated and the abnormality confirmed in view of the likely need for prolonged medical treatment or destructive therapy. In most patients, serum T3 and T4 are both elevated, but T4 is in the upper part of the reference range and T3 is raised (T3 toxicosis) in about 5%. Serum TSH is undetectable in primary thyrotoxicosis, but values can be raised in the very rare syndrome of secondary thyrotoxicosis caused by a TSH-producing pituitary adenoma. When biochemical thyrotoxicosis has been conﬁrmed, further investigations should be undertaken to determine the underlying cause, including measurement of TSH receptor antibodies (TRAb, elevated in Graves’ disease; Box 18.8) and radioisotope scanning, as shown in Figure 18.5. Other non-speciﬁc abnormalities are common 18.5 How to interpret thyroid function test results TSH T4 T3 Most likely interpretation(s) U.D. Raised Raised Primary thyrotoxicosis U.D. or low Raised Normal Over-treatment of hypothyroidism with levothyroxine Factitious thyrotoxicosis U.D. Normal1 Raised Primary T3 toxicosis U.D. Normal1 Normal1 Subclinical thyrotoxicosis U.D. or low Raised Low or normal Non-thyroidal illness Amiodarone therapy U.D. or low Low Raised Over-treatment of hypothyroidism with liothyronine (T3) U.D. Low Low Secondary hypothyroidism4 Transient thyroiditis in evolution Normal Low Low2 Secondary hypothyroidism4 Mildly elevated 5–20 mIU/L Low Low2 Primary hypothyroidism Secondary hypothyroidism4 Elevated > 20 mIU/L Low Low2 Primary hypothyroidism Mildly elevated 5–20 mIU/L Normal3 Normal2 Subclinical hypothyroidism Elevated 20–500 mIU/L Normal Normal Artefact Heterophilic antibodies (host antibodies with afﬁnity to the animal antibodies used in TSH assays) Elevated Raised Raised Non-adherence to levothyroxine replacement – recent ‘loading’ dose Secondary thyrotoxicosis4 Thyroid hormone resistance 1Usually upper part of reference range. 2T3 is not a sensitive indicator of hypothyroidism and should not be requested. 3Usually lower part of reference range. 4i.e. Secondary to pituitary or hypothalamic disease. Note that TSH assays may report detectable TSH. (TSH = thyroid-stimulating hormone; U.D. = undetectable) 18.6 Causes of thyrotoxicosis and their relative frequencies Cause Frequency1 (%) Graves’ disease

Multinodular goitre

Solitary thyroid adenoma

Thyroiditis Subacute (de Quervain’s)2

Post-partum2 0.5 Iodide-induced Drugs (amiodarone)2

Radiographic contrast media2 – Iodine supplementation programme2 – Extrathyroidal source of thyroid hormone Factitious thyrotoxicosis2 0.2 Struma ovarii2,3 – TSH-induced TSH-secreting pituitary adenoma 0.2 Choriocarcinoma and hydatidiform mole4 – Follicular carcinoma ± metastases 0.1 1ln a series of 2087 patients presenting to the Royal Inﬁrmary of Edinburgh over a 10-year period. 2Characterised by negligible radioisotope uptake. 3i.e. Ovarian teratoma containing thyroid tissue. 4Human chorionic gonadotrophin has thyroid-stimulating activity. (TSH = thyroid-stimulating hormone)

The thyroid gland • 637

conventional thyrotoxicosis) is increased to above 70 : 1 because circulating T3 in factitious thyrotoxicosis is derived exclusively from the peripheral monodeiodination of T4 and not from thyroid secretion. The combination of negligible iodine uptake, high T4:T3 ratio and a low or undetectable thyroglobulin is diagnostic. Management Deﬁnitive treatment of thyrotoxicosis depends on the underlying cause and may include antithyroid drugs, radioactive iodine or surgery. A non-selective β-adrenoceptor antagonist (β-blocker), such as propranolol (160 mg daily) or nadolol (40–80 mg daily), will alleviate but not abolish symptoms in most patients within 24–48 hours. Beta-blockers should not be used for long-term (Box 18.9). An electrocardiogram (ECG) may demonstrate sinus tachycardia or atrial ﬁbrillation. Radio-iodine uptake tests measure the proportion of isotope that is trapped in the whole gland but have been largely superseded by 99mtechnetium scintigraphy scans, which also indicate trapping, are quicker to perform with a lower dose of radioactivity, and provide a higher-resolution image. In low-uptake thyrotoxicosis, the cause is usually a transient thyroiditis (p. 646). Occasionally, patients induce ‘factitious thyrotoxicosis’ by consuming excessive amounts of a thyroid hormone preparation, most often levothyroxine. The exogenous levothyroxine suppresses pituitary TSH secretion and hence iodine uptake, serum thyroglobulin and release of endogenous thyroid hormones. The T4:T3 ratio (typically 30 : 1 in 18.7 Clinical features of thyroid dysfunction Thyrotoxicosis Hypothyroidism Symptoms Signs Symptoms Signs Common Weight loss despite normal or increased appetite Heat intolerance, sweating Palpitations, tremor Dyspnoea, fatigue Irritability, emotional lability Weight loss Tremor Palmar erythema Sinus tachycardia Lid retraction, lid lag Weight gain Cold intolerance Fatigue, somnolence Dry skin Dry hair Menorrhagia Weight gain Less common Osteoporosis (fracture, loss of height) Diarrhoea, steatorrhoea Angina Ankle swelling Anxiety, psychosis Muscle weakness Periodic paralysis (predominantly in Chinese and other Asian groups) Pruritus, alopecia Amenorrhoea/oligomenorrhoea Infertility, spontaneous abortion Loss of libido, impotence Excessive lacrimation Goitre with bruit1 Atrial ﬁbrillation2 Systolic hypertension/increased pulse pressure Cardiac failure2 Hyper-reﬂexia Ill-sustained clonus Proximal myopathy Bulbar myopathy2 Constipation Hoarseness Carpal tunnel syndrome Alopecia Aches and pains Muscle stiffness Deafness Depression Infertility Hoarse voice Facial features: Purplish lips Malar ﬂush Periorbital oedema Loss of lateral eyebrows Anaemia Carotenaemia Erythema ab igne Bradycardia hypertension Delayed relaxation of reﬂexes Dermal myxoedema Rare Vomiting Apathy Anorexia Exacerbation of asthma Gynaecomastia Spider naevi Onycholysis Pigmentation Psychosis (myxoedema madness) Galactorrhoea Impotence Ileus, ascites Pericardial and pleural effusions Cerebellar ataxia Myotonia 1ln Graves’ disease only. 2Features found particularly in elderly patients. 18.8 Prevalence of thyroid autoantibodies (%) Antibodies to: Thyroid peroxidase1 Thyroglobulin TSH receptor2 Normal population 8–27 5–20

Graves’ disease 50–80 50–70 80–95 Autoimmune hypothyroidism 90–100 80–90 10–20 Multinodular goitre ~30–40 ~30–40

Transient thyroiditis ~30–40 ~30–40

1Thyroid peroxidase (TPO) antibodies are the principal component of what was previously measured as thyroid ‘microsomal’ antibodies. 2Thyroid-stimulating hormone receptor antibodies (TRAb) can be agonists (stimulatory, causing Graves’ thyrotoxicosis) or antagonists (‘blocking’, causing hypothyroidism).

638 • ENDOCRINOLOGY Fig. 18.5 Establishing the differential diagnosis in thyrotoxicosis. 1Graves’ ophthalmopathy refers to clinical features of exophthalmos and periorbital and conjunctival oedema, not simply the lid lag and lid retraction that can occur in all forms of thyrotoxicosis. 2Thyroid-stimulating hormone (TSH) receptor antibodies are very rare in patients without autoimmune thyroid disease but occur in only 80–95% of patients with Graves’ disease; a positive test is therefore conﬁrmatory but a negative test does not exclude Graves’ disease. Other thyroid antibodies (e.g. anti-peroxidase and anti-thyroglobulin antibodies) are unhelpful in the differential diagnosis since they occur frequently in the population and are found with several of the disorders that cause thyrotoxicosis. 3Scintigraphy is not necessary in most cases of drug-induced thyrotoxicosis. 4 99mTechnetium pertechnetate scans of patients with thyrotoxicosis. In low-uptake thyrotoxicosis, most commonly due to a viral, post-partum or iodine-induced thyroiditis, there is negligible isotope detected in the region of the thyroid, although uptake is apparent in nearby salivary glands (not shown here). In a toxic adenoma there is lack of uptake of isotope by the rest of the thyroid gland due to suppression of serum TSH. In multinodular goitre there is relatively low, patchy uptake within the nodules; such an appearance is not always associated with a palpable thyroid. In Graves’ disease there is diffuse uptake of isotope. ↓TSH and ↑T3 ± T4 Scenario? Clinically thyrotoxic Repeat when acute illness has resolved Possible non-thyroidal illness Any features of non-Graves’ thyrotoxicosis? • Recent (< 6 months) pregnancy • Neck pain/flu-like illness • Drugs (amiodarone, T4)3 • Palpable multinodular goitre or solitary nodule Any features of Graves’ disease? • Diffuse goitre with bruit • Ophthalmopathy1 • Pretibial myxoedema • Positive TSH receptor antibodies2 Yes No Yes Thyroid scintigraphy4 Low-uptake thyrotoxicosis • Transient thyroiditis • Extrathyroidal T4 source Toxic multinodular goitre Graves’ disease Toxic adenoma No These abnormalities are not useful in differential diagnosis, so the tests should be avoided and any further investigation undertaken only if abnormalities persist when the patient is euthyroid. 18.9 Non-speciﬁc laboratory abnormalities in thyroid dysfunction Thyrotoxicosis • Serum enzymes: raised alanine aminotransferase, γ-glutamyl transferase (GGT), and alkaline phosphatase from liver and bone • Raised bilirubin • Mild hypercalcaemia • Glycosuria: associated diabetes mellitus, ‘lag storage’ glycosuria Hypothyroidism • Serum enzymes: raised creatine kinase, aspartate aminotransferase, lactate dehydrogenase (LDH) • Hypercholesterolaemia • Anaemia: normochromic normocytic or macrocytic • Hyponatraemia treatment of thyrotoxicosis but are extremely useful in the short term, while patients are awaiting hospital consultation or following 131I therapy. Verapamil may be used as an alternative to β-blockers, e.g. in patients with asthma, but usually is only effective in improving tachycardia and has little effect on the other systemic manifestations of thyrotoxicosis. Atrial ﬁbrillation in thyrotoxicosis Atrial ﬁbrillation occurs in about 10% of patients with thyrotoxicosis. The incidence increases with age, so that almost half of all males with thyrotoxicosis over the age of 60 are affected. Moreover, subclinical thyrotoxicosis (p. 642) is a risk factor for atrial ﬁbrillation. Characteristically, the ventricular rate is little inﬂuenced by digoxin but responds to the addition of a β-blocker. Thromboembolic vascular complications are particularly common in thyrotoxic atrial fibrillation so that anticoagulation is required, unless contraindicated. Once thyroid hormone and TSH concentrations have been returned to normal, atrial ﬁbrillation will spontaneously revert to sinus rhythm in about 50% of patients but cardioversion may be required in the remainder.

The thyroid gland • 639

hormones but also reduces the conversion of T4 to T3, and is therefore more effective than potassium iodide or Lugol’s solution. Dexamethasone (2 mg 4 times daily) and amiodarone have similar effects. Oral carbimazole 40–60 mg daily (p. 644) should be given to inhibit the synthesis of new thyroid hormone. If the patient is unconscious or uncooperative, carbimazole can be administered rectally with good effect but no preparation is available for parenteral use. After 10–14 days the patient can usually be maintained on carbimazole alone. Hypothyroidism Hypothyroidism is a common condition with various causes (Box 18.11), but autoimmune disease (Hashimoto’s thyroiditis) and thyroid failure following 131I or surgical treatment of thyrotoxicosis account for over 90% of cases, except in areas where iodine deﬁciency is endemic. Women are affected approximately six times more frequently than men. Clinical assessment The clinical presentation depends on the duration and severity of the hypothyroidism. Those in whom complete thyroid failure has developed insidiously over months or years may present with many of the clinical features listed in Box 18.7. A consequence of prolonged hypothyroidism is the inﬁltration of many body tissues by the mucopolysaccharides hyaluronic acid and chondroitin Thyrotoxic crisis (‘thyroid storm’) This is a rare but life-threatening complication of thyrotoxicosis. The most prominent signs are fever, agitation, delirium, tachycardia or atrial ﬁbrillation and, in the older patient, cardiac failure. The Burch–Wartofsky system may be used to help establish the diagnosis (Box 18.10). Thyrotoxic crisis is a medical emergency and has a mortality of 10% despite early recognition and treatment. It is most commonly precipitated by infection in a patient with previously unrecognised or inadequately treated thyrotoxicosis. It may also develop in known thyrotoxicosis shortly after thyroidectomy in an ill-prepared patient or within a few days of 131I therapy, when acute radiation damage may lead to a transient rise in serum thyroid hormone levels. Patients should be rehydrated and given propranolol, either orally (80 mg 4 times daily) or intravenously (1–5 mg 4 times daily). Sodium ipodate (500 mg per day orally) will restore serum T3 levels to normal in 48–72 hours. This is a radiographic contrast medium that not only inhibits the release of thyroid 18.10 The Burch–Wartofsky scoring system for thyrotoxic crisis Diagnostic parameters Score Temperature (°C) ≤ 37.1

37.2–37.7

37.8–38.2

38.3–38.8

38.9–39.2

39.3–39.9

≥ 40.0

Central nervous system Absent

Mild (agitation)

Moderate (delirium, psychosis, extreme lethargy)

Severe (seizures, coma)

Gastrointestinal system Absent

Moderate (diarrhoea, nausea, vomiting, abdominal pain)

Severe (unexplained jaundice)

Cardiovascular system: pulse rate (beats/min) ≤ 89

90–109

110–119

120–129

130–139

≥ 140

Atrial ﬁbrillation Absent

Present

Congestive heart failure Absent

Mild (peripheral oedema)

Moderate (bi-basal crepitations)

Severe (pulmonary oedema)

Precipitant history Absent

Present

Scores should be totalled. Score ≥ 45 = likely thyrotoxic crisis; 25–44 = impending thyrotoxic crisis; < 25 = unlikely to represent thyroid crisis. Adapted from Burch HB, Wartofsky L. Life-threatening thyrotoxicosis. Thyroid storm. Endocrinol Metab Clin N Am 1993; 22:263–277. 18.11 Causes of hypothyroidism Causes Anti-TPO antibodies1 Goitre2 Autoimmune Hashimoto’s thyroiditis ++ ± Spontaneous atrophic hypothyroidism – – Graves’ disease with TSH receptorblocking antibodies + ± Iatrogenic Radioactive iodine ablation + ± Thyroidectomy + – Drugs: Carbimazole, methimazole, propylthiouracil + ± Amiodarone + ± Lithium – ± Transient thyroiditis Subacute (de Quervain’s) thyroiditis + ± Post-partum thyroiditis + ± Iodine deﬁciency e.g. In mountainous regions – ++ Congenital Dyshormonogenesis – ++ Thyroid aplasia – – Inﬁltrative Amyloidosis, Riedel’s thyroiditis, sarcoidosis etc. + ++ Secondary hypothyroidism TSH deﬁciency – – 1As shown in Box 18.8, thyroid autoantibodies are common in the healthy population, so might be present in anyone. ++ high titre; + more likely to be detected than in the healthy population; – not especially likely. 2Goitre: – absent; ± may be present; ++ characteristic. (TPO = thyroid peroxidase; TSH = thyroid-stimulating hormone)

640 • ENDOCRINOLOGY by failure of TSH secretion in an individual with hypothalamic or anterior pituitary disease. Other non-speciﬁc abnormalities are shown in Box 18.9. In severe, prolonged hypothyroidism, the ECG classically demonstrates sinus bradycardia with lowvoltage complexes and ST-segment and T-wave abnormalities. Measurement of thyroid peroxidase antibodies is helpful but further investigations are rarely required (Fig. 18.6). Management Treatment is with levothyroxine replacement. It is customary to start with a low dose of 50 μg per day for 3 weeks, increasing thereafter to 100 μg per day for a further 3 weeks and ﬁnally to a maintenance dose of 100–150 μg per day. In younger patients, it is safe to initiate levothyroxine at a higher dose (e.g. 100 μg per day), to allow a more rapid normalisation of thyroid hormone levels. Levothyroxine has a half-life of 7 days so it should always be taken as a single daily dose and at least 6 weeks should pass before repeating thyroid function tests (as TSH takes several weeks to reach a steady state) and adjusting the dose. Patients feel better within 2–3 weeks. Reduction in weight and periorbital pufﬁness occurs quickly but the restoration of skin and hair texture and resolution of any effusions may take 3–6 months. As illustrated in Figure 18.6, most patients do not require specialist review but will need life-long levothyroxine therapy. The dose of levothyroxine should be adjusted to maintain serum TSH within the reference range. To achieve this, serum T4 often needs to be in the upper part of the reference range because the T3 required for receptor activation is derived exclusively from conversion of T4 within the target tissues, without the usual contribution from thyroid secretion. Some physicians advocate Fig. 18.6 An approach to adults with suspected primary hypothyroidism. This scheme ignores congenital causes of hypothyroidism (see Box 18.11), such as thyroid aplasia and dyshormonogenesis (associated with nerve deafness in Pendred’s syndrome, p. 650), which are usually diagnosed in childhood. 1Immunoreactive thyroid-stimulating hormone (TSH) may be detected at normal or even modestly elevated levels in patients with pituitary failure; unless T4 is only marginally low, TSH should be > 20 mIU/L to conﬁrm the diagnosis of primary hypothyroidism. 2The usual abnormality in sick euthyroidism is a low TSH but any pattern can occur. 3Thyroid peroxidase (TPO) antibodies are highly sensitive but not very speciﬁc for autoimmune thyroid disease (see Boxes 18.8 and 18.11). 4Specialist advice is most appropriate where indicated. Secondary hypothyroidism is rare, but is suggested by deﬁciency of pituitary hormones or by clinical features of pituitary tumour such as headache or visual ﬁeld defect (p. 683). Rare causes of hypothyroidism with goitre include dyshormonogenesis and inﬁltration of the thyroid (see Box 18.11). ↑TSH and ↓T4 Scenario? TSH < 20 mlU/L1 Repeat when acute illness has resolved Possible non-thyroidal illness2 Relevant drugs? • Amiodarone • Lithium Any features of transient thyroiditis? • Neck pain • < 12 months post-partum • Recent symptoms of thyrotoxicosis • < 6 months since 131I or thyroidectomy No Yes Permanent T4 replacement Any features of secondary hypothyroidism? 4 Thyroid ablation? • > 6 months since 131I or thyroidectomy No Positive antithyroid peroxidase antibodies?3 No No TSH > 20 mlU/L Consider rare causes and refer to specialist4 Spontaneous atrophic hypothyroidism Hashimoto’s thyroiditis Temporary T4 replacement4 • After 4 months with normal TSH, reduce to 50 μg/day for 6 weeks and repeat TSH • If normal, stop T4 for 6 weeks and repeat Yes T4 replacement for as long as other drug is required Yes Yes No Yes No Goitre? sulphate, resulting in a low-pitched voice, poor hearing, slurred speech due to a large tongue, and compression of the median nerve at the wrist (carpal tunnel syndrome). Inﬁltration of the dermis gives rise to non-pitting oedema (myxoedema), which is most marked in the skin of the hands, feet and eyelids. The resultant periorbital pufﬁness is often striking and may be combined with facial pallor due to vasoconstriction and anaemia, or a lemon-yellow tint to the skin caused by carotenaemia, along with purplish lips and malar ﬂush. Most cases of hypothyroidism are not clinically obvious, however, and a high index of suspicion needs to be maintained so that the diagnosis is not overlooked in individuals complaining of non-speciﬁc symptoms such as tiredness, weight gain, depression or carpal tunnel syndrome. The key discriminatory features in the history and examination are highlighted in Figure 18.6. Care must be taken to identify patients with transient hypothyroidism, in whom life-long levothyroxine therapy is inappropriate. This is often observed during the ﬁrst 6 months after thyroidectomy or 131I treatment of Graves’ disease, in the post-thyrotoxic phase of subacute thyroiditis and in post-partum thyroiditis. In these conditions, levothyroxine treatment is not always necessary, as the patient may be asymptomatic during the short period of thyroid failure. Investigations In the vast majority of cases, hypothyroidism results from an intrinsic disorder of the thyroid gland (primary hypothyroidism). In this situation, serum T4 is low and TSH is elevated, usually in excess of 20 mIU/L. Measurements of serum T3 are unhelpful since they do not discriminate reliably between euthyroidism and hypothyroidism. Secondary hypothyroidism is rare and is caused

The thyroid gland • 641

replacement should be introduced at low dose and increased very slowly under specialist supervision. It has been suggested that T3 has an advantage over T4, since T3 has a shorter half-life and any adverse effect will reverse more quickly, but the more distinct peak in hormone levels after each dose of T3 is a disadvantage. Coronary intervention may be required if angina is exacerbated by levothyroxine replacement therapy. Hypothyroidism in pregnancy Women with hypothyroidism usually require an increased dose of levothyroxine in pregnancy; inadequately treated hypothyroidism in pregnancy has been associated with impaired cognitive development in the fetus. This is discussed in more detail on page 1279 (see also Box 18.18). Myxoedema coma This is a very rare presentation of hypothyroidism in which there is a depressed level of consciousness, usually in an elderly patient who appears myxoedematous. Body temperature may be as low as 25°C, convulsions are not uncommon, and cerebrospinal ﬂuid (CSF) pressure and protein content are raised. The mortality rate is 50% and survival depends on early recognition and treatment of hypothyroidism and other factors contributing to the altered consciousness level, such as medication, cardiac failure, pneumonia, dilutional hyponatraemia and respiratory failure. Myxoedema coma is a medical emergency and treatment must begin before biochemical conﬁrmation of the diagnosis. Suspected cases should be treated with an intravenous injection of 20 μg liothyronine, followed by further injections of 20 μg 3 times daily until there is sustained clinical improvement. In survivors, there is a rise in body temperature within 24 hours and, after 48–72 hours, it is usually possible to switch patients to oral levothyroxine in a dose of 50 μg daily. Unless it is apparent that the patient has primary hypothyroidism, the thyroid failure should also be assumed to be secondary to hypothalamic or pituitary disease and treatment given with hydrocortisone 100 mg IM 3 times daily, pending the results of T4, TSH and cortisol measurement (p. 680). Other measures include slow rewarming (p. 166), cautious use of intravenous ﬂuids, broad-spectrum antibiotics and high-ﬂow oxygen. Symptoms of hypothyroidism with normal thyroid function tests The classic symptoms of hypothyroidism are, by their very nature, non-speciﬁc (see Box 18.3). There is a wide differential diagnosis for symptoms such as ‘fatigue’, ‘weight gain’ and ‘low mood’. As has been noted, outside the context of pituitary and hypothalamic disease, serum TSH is an excellent measure of an individual’s thyroid hormone status. However, some individuals believe that they have hypothyroidism despite normal serum TSH concentrations. There are a large number of websites that claim that serum TSH is not a good measure of thyroid hormone status and suggest that other factors, such as abnormalities of T4 to T3 conversion, may lead to low tissue levels of active thyroid hormones. Such websites often advocate a variety of tests of thyroid function of dubious scientiﬁc validity, including measurement of serum reverse T3, 24-hour urine T3, basal body temperature, skin iodine absorption, and levels of selenium in blood and urine. Individuals who believe they have hypothyroidism, despite normal conventional tests of thyroid function, can be difﬁcult to manage. They require reassurance that their symptoms are being taken seriously and that organic disease has been carefully considered; if their symptoms persist, referral to a combined replacement with T4 (levothyroxine) and T3 (liothyronine) or preparations of animal thyroid extract but this approach remains controversial and is not supported by robust evidence. Some patients remain symptomatic despite normalisation of TSH and may wish to take extra levothyroxine, which suppresses TSH. However, suppressed TSH is a risk factor for osteoporosis and atrial ﬁbrillation (see below; subclinical thyrotoxicosis), so this approach cannot be recommended. It is important to measure thyroid function every 1–2 years once the dose of levothyroxine is stabilised. This encourages adherence to therapy and allows adjustment for variable underlying thyroid activity and other changes in levothyroxine requirements (Box 18.12). Some patients have a persistent elevation of serum TSH despite an ostensibly adequate replacement dose of levothyroxine; most commonly, this is a consequence of suboptimal adherence to therapy. There may be differences in bioavailability between the numerous generic preparations of levothyroxine and so, if an individual is experiencing marked changes in serum TSH despite optimal adherence, the prescription of a branded preparation of levothyroxine could be considered. There is some limited evidence that suggests levothyroxine absorption may be better when the drug is taken before bed and can be further optimised by adding a vitamin C supplement; such strategies may be considered in patients with malabsorption. In some poorly compliant patients, levothyroxine is taken diligently or even in excess for a few days prior to a clinic visit, resulting in the seemingly anomalous combination of a high serum T4 and high TSH (see Box 18.5). Levothyroxine replacement in ischaemic heart disease Hypothyroidism and ischaemic heart disease are common conditions that often occur together. Although angina may remain unchanged in severity or paradoxically disappear with restoration of metabolic rate, exacerbation of myocardial ischaemia, infarction and sudden death are recognised complications of levothyroxine replacement, even using doses as low as 25 μg per day. In patients with known ischaemic heart disease, thyroid hormone Mechanism not fully established. 18.12 Situations in which an adjustment of the dose of levothyroxine may be necessary Increased dose required Use of other medication • Increase T4 clearance: phenobarbital, phenytoin, carbamazepine, rifampicin, sertraline, chloroquine* • Interfere with intestinal T4 absorption: colestyramine, sucralfate, aluminium hydroxide, ferrous sulphate, dietary ﬁbre supplements, calcium carbonate Pregnancy or oestrogen therapy • Increases concentration of serum thyroxine-binding globulin After surgical or 131I ablation of Graves’ disease • Reduces thyroidal secretion with time Malabsorption Decreased dose required Ageing • Decreases T4 clearance Graves’ disease developing in patient with long-standing primary hypothyroidism • Switch from production of blocking to stimulating TSH receptor antibodies

642 • ENDOCRINOLOGY team specialising in medically unexplained symptoms should be considered. Asymptomatic abnormal thyroid function tests One of the most common problems in medical practice is how to manage patients with abnormal thyroid function tests who have no obvious signs or symptoms of thyroid disease. These can be divided into three categories. Subclinical thyrotoxicosis Serum TSH is undetectable and serum T3 and T4 are at the upper end of the reference range. This combination is most often found in older patients with multinodular goitre. These patients are at increased risk of atrial ﬁbrillation and osteoporosis, and hence the consensus view is that they have mild thyrotoxicosis and require therapy, usually with 131I. Otherwise, annual review is essential, as the conversion rate to overt thyrotoxicosis with elevated T4 and/or T3 concentrations is 5% each year. Subclinical hypothyroidism Serum TSH is raised and serum T3 and T4 concentrations are at the lower end of the reference range. This may persist for many years, although there is a risk of progression to overt thyroid failure, particularly if antibodies to thyroid peroxidase are present or if the TSH rises above 10 mIU/L. In patients with non-speciﬁc symptoms, a trial of levothyroxine therapy may be appropriate. In those with positive autoantibodies or a TSH greater than 10 mIU/L, it is better to treat the thyroid failure early rather than risk loss to follow-up and subsequent presentation with profound hypothyroidism. Levothyroxine should be given in a dose sufﬁcient to restore the serum TSH concentration to normal. Non-thyroidal illness (‘sick euthyroidism’) This typically presents with a low serum TSH, raised T4 and normal or low T3 in a patient with systemic illness who does not have clinical evidence of thyroid disease. These abnormalities are caused by decreased peripheral conversion of T4 to T3 (with conversion instead to reverse T3), altered levels of binding proteins and their afﬁnity for thyroid hormones, and often reduced secretion of TSH. During convalescence, serum TSH concentrations may increase to levels found in primary hypothyroidism. As thyroid function tests are difﬁcult to interpret in patients with non-thyroidal illness, it is wise to avoid performing thyroid function tests unless there is clinical evidence of concomitant thyroid disease. If an abnormal result is found, treatment should only be given with specialist advice and the diagnosis should be re-evaluated after recovery. Thyroid lump or swelling A lump or swelling in the thyroid gland can be a source of considerable anxiety for patients. There are numerous causes but, broadly speaking, a thyroid swelling is either a solitary nodule, a multinodular goitre or a diffuse goitre (Box 18.13). Nodular thyroid disease is more common in women and occurs in approximately 30% of the adult female population. The majority of thyroid nodules are impalpable but may be identiﬁed when imaging of the neck is performed for another reason, such as during Doppler ultrasonography of the carotid arteries or computed tomographic pulmonary angiography. Increasingly, thyroid nodules are identiﬁed during staging of patients with cancer with computed tomography (CT), magnetic resonance 18.13 Causes of thyroid enlargement Diffuse goitre • Simple goitre • Hashimoto’s thyroiditis1 • Graves’ disease • Drugs: iodine, amiodarone, lithium • Iodine deﬁciency (endemic goitre)1 • Suppurative thyroiditis2 • Transient thyroiditis2 • Dyshormonogenesis1 • Inﬁltrative: amyloidosis, sarcoidosis etc. • Riedel’s thyroiditis2 Multinodular goitre Solitary nodule • Colloid cyst • Hyperplastic nodule • Follicular adenoma • Papillary carcinoma • Follicular carcinoma • Medullary cell carcinoma • Anaplastic carcinoma • Lymphoma • Metastasis 1Goitre likely to shrink with levothyroxine therapy. 2Usually tender. imaging (MRI) or positron emission tomography (PET) scans. Palpable thyroid nodules occur in 4–8% of adult women and 1–2% of adult men, and classically present when the individual (or a friend or relative) notices a lump in the neck. Multinodular goitre and solitary nodules sometimes present with acute painful enlargement due to haemorrhage into a nodule. Patients with thyroid nodules often worry that they have cancer but the reality is that only 5–10% of thyroid nodules are malignant. A nodule presenting in childhood or adolescence, particularly if there is a past history of head and neck irradiation, or one presenting in an elderly patient should heighten suspicion of a primary thyroid malignancy (p. 649). The presence of cervical lymphadenopathy also increases the likelihood of malignancy. Rarely, a secondary deposit from a renal, breast or lung carcinoma presents as a painful, rapidly growing, solitary thyroid nodule. Thyroid nodules identiﬁed on PET scanning have an approximately 33% chance of being malignant. Clinical assessment and investigations Swellings in the anterior part of the neck most commonly originate in the thyroid and this can be conﬁrmed by demonstrating that the swelling moves on swallowing (p. 631). It is often possible to distinguish clinically between the three main causes of thyroid swelling. There is a broad differential diagnosis of anterior neck swellings, which includes lymphadenopathy, branchial cysts, dermoid cysts and thyroglossal duct cysts (the latter are classically located in the midline and move on protrusion of the tongue). An ultrasound scan should be performed urgently, if there is any doubt as to the aetiology of an anterior neck swelling. Serum T3, T4 and TSH should be measured in all patients with a goitre or solitary thyroid nodule. The ﬁnding of biochemical thyrotoxicosis or hypothyroidism (both of which may be subclinical) should lead to investigations, as already described on pages 636 and 640. Thyroid scintigraphy Thyroid scintigraphy with 99mtechnetium should be performed in an individual with a low serum TSH and a nodular thyroid to conﬁrm the presence of an autonomously functioning (‘hot’) nodule (see Fig. 18.5). In such circumstances, further evaluation is not necessary. ‘Cold’ nodules on scintigraphy have a much higher likelihood of malignancy, but the majority are benign and so scintigraphy is not routinely used in the evaluation of thyroid nodules when TSH is normal.

The thyroid gland • 643

Autoimmune thyroid disease Thyroid diseases are amongst the most prevalent antibodymediated autoimmune diseases and are associated with other organ-speciﬁc autoimmunity (Ch. 4 and p. 689). Autoantibodies may produce inﬂammation and destruction of thyroid tissue, resulting in hypothyroidism, goitre (in Hashimoto’s thyroiditis) or sometimes even transient thyrotoxicosis (‘Hashitoxicosis’), or they may stimulate the TSH receptor to cause thyrotoxicosis (in Graves’ disease). There is overlap between these conditions, since some patients have multiple autoantibodies. Graves’ disease Graves’ disease can occur at any age but is unusual before puberty and most commonly affects women aged 30–50 years. The most common manifestation is thyrotoxicosis with or without a diffuse goitre. The clinical features and differential diagnosis are described on page 635. Graves’ disease also causes ophthalmopathy and, rarely, pretibial myxoedema (p. 646). These extrathyroidal features usually occur in thyrotoxic patients but can arise in the absence of thyroid dysfunction. Graves’ thyrotoxicosis Pathophysiology The thyrotoxicosis results from the production of immunoglobulin G (IgG) antibodies directed against the TSH receptor on the thyroid follicular cell, which stimulate thyroid hormone production and proliferation of follicular cells, leading to goitre in the majority of patients. These antibodies are termed thyroid-stimulating immunoglobulins or TSH receptor antibodies (TRAb) and can be detected in the serum of 80–95% of patients with Graves’ disease. The concentration of TRAb in the serum is presumed to ﬂuctuate to account for the natural history of Graves’ thyrotoxicosis (Fig. 18.7). Thyroid failure seen in some patients may result from the presence of blocking antibodies against the TSH receptor, and from tissue destruction by cytotoxic antibodies and cell-mediated immunity. Thyroid ultrasound If thyroid function tests are normal, an ultrasound scan will often determine the nature of the thyroid swelling. Ultrasound can establish whether there is generalised or localised swelling of the thyroid. Inﬂammatory disorders causing a diffuse goitre, such as Graves’ disease and Hashimoto’s thyroiditis, demonstrate a diffuse pattern of hypoechogenicity and, in the case of Graves’ disease, increased thyroid blood ﬂow may be seen on colour-ﬂow Doppler. The presence of thyroid autoantibodies will support the diagnosis of Graves’ disease or Hashimoto’s thyroiditis, while their absence in a younger patient with a diffuse goitre and normal thyroid function suggests a diagnosis of ‘simple goitre’ (p. 648). Ultrasound can readily determine the size and number of nodules within the thyroid and can distinguish solid nodules from those with a cystic element. Ultrasound is used increasingly as the key investigation in deﬁning the risk of malignancy in a nodule. Size of the nodule is not a predictor of the risk of malignancy but there are other ultrasound characteristics that are associated with a higher likelihood of malignancy. These include hypoechoicity, intranodular vascularity, the presence of microcalciﬁcation and irregular or lobulated margins. A purely cystic nodule is highly unlikely to be malignant and a ‘spongiform’ appearance is also highly predictive of a benign aetiology. Individual nodules within a multinodular goitre have the same risk of malignancy as a solitary nodule. Thyroid ultrasonography is a highly specialised investigation and the accurate stratiﬁcation of risk of malignancy of a thyroid nodule requires skill and expertise. Fine needle aspiration cytology Fine needle aspiration cytology is recommended for thyroid nodules that are suspicious for malignancy or are radiologically indeterminate. Fine needle aspiration of a thyroid nodule can be performed in the outpatient clinic, usually under ultrasound guidance. Aspiration may be therapeutic for a cyst, although recurrence on more than one occasion is an indication for surgery. Fine needle aspiration cytology cannot differentiate between a follicular adenoma and a follicular carcinoma, and in 10–20% of cases an inadequate specimen is obtained. Management Nodules with a benign appearance on ultrasound may be observed in an ultrasound surveillance programme; when the suspicion of malignancy is very low, the patient may be reassured and discharged. In parts of the world with borderline low iodine intake, there is evidence that levothyroxine therapy, in doses that suppress serum TSH, may reduce the size of some nodules. This should not be routine practice in iodine-sufﬁcient populations. Nodules that are suspicious for malignancy are treated by surgical excision, by either lobectomy or thyroidectomy. Nodules that are radiologically and/or cytologically indeterminate are more of a management challenge and often end up being surgically excised. Molecular techniques may, in the future, improve the diagnostic accuracy of thyroid cytology and allow a more conservative strategy for individuals with an indeterminate biopsy. Nodules in which malignancy is conﬁrmed by formal histology are treated as described on page 649. A diffuse or multinodular goitre may also require surgical treatment for cosmetic reasons or if there is compression of local structures (resulting in stridor or dysphagia). 131I therapy may also cause some reduction in size of a multinodular goitre. Levothyroxine therapy may shrink the goitre of Hashimoto’s disease, particularly if serum TSH is elevated. Fig. 18.7 Natural history of the thyrotoxicosis of Graves’ disease. A and B The majority (60%) of patients have either prolonged periods of thyrotoxicosis of ﬂuctuating severity, or periods of alternating relapse and remission. C It is the minority who experience a single short-lived episode followed by prolonged remission and, in some cases, by the eventual onset of hypothyroidism. Time in years

Thyrotoxic Euthyroid Hypothyroid A B C

644 • ENDOCRINOLOGY UK). Propylthiouracil is equally effective. These drugs reduce the synthesis of new thyroid hormones by inhibiting the iodination of tyrosine (see Fig. 18.3). Carbimazole also has an immunosuppressive action, leading to a reduction in serum TRAb concentrations, but this is not enough to inﬂuence the natural history of the thyrotoxicosis signiﬁcantly. Antithyroid drugs should be introduced at high doses (carbimazole 40–60 mg daily or propylthiouracil 400–600 mg daily). Usually, this results in subjective improvement within 10–14 days and renders the patient clinically and biochemically euthyroid at 6–8 weeks. At this point, the dose can be reduced and titrated to maintain T4 and TSH within their reference range. In most patients, carbimazole is continued at 5–20 mg per day for 12–18 months in the hope that remission will occur. Between 50% and 70% of patients with Graves’s disease will subsequently relapse, usually within 2 years of stopping treatment. Risk factors for relapse include younger age, male sex, presence of a goitre, and higher TRAb titres at both diagnosis and cessation of antithyroid therapy. Rarely, T4 and TSH levels ﬂuctuate between those of thyrotoxicosis and hypothyroidism at successive review appointments, despite good drug adherence, presumably due to rapidly changing concentrations of TRAb. In these patients, satisfactory control can be achieved by blocking thyroid hormone synthesis with carbimazole 30–40 mg daily and adding levothyroxine 100–150 μg daily as replacement therapy (a ‘block and replace’ regime). Antithyroid drugs can have adverse effects. The most common is a rash. Agranulocytosis is a rare but potentially serious complication that cannot be predicted by routine measurement of white blood cell count but which is reversible on stopping treatment. Patients should be warned to stop the drug and seek medical advice immediately, should a severe sore throat or fever develop while on treatment. Propylthiouracil is associated with a small but deﬁnite risk of hepatotoxicity, which, in some instances, has resulted in liver failure requiring liver transplantation, and even in death. It should therefore be considered second-line therapy to carbimazole and be used only during pregnancy or breastfeeding (p. 1279), or if an adverse reaction to carbimazole has occurred. Graves’ disease has a strong genetic component. There is 50% concordance for thyrotoxicosis between monozygotic twins but only 5% concordance between dizygotic twins. Genomewide association studies have identiﬁed polymorphisms at the MHC, CTLA4, PTPN22, TSHR1 and FCRL3 loci as predisposing genetic variants. Many of these loci have been implicated in the pathogenesis of other autoimmune diseases. A suggested trigger for the development of thyrotoxicosis in genetically susceptible individuals may be infection with viruses or bacteria. Certain strains of the gut organisms Escherichia coli and Yersinia enterocolitica possess cell membrane TSH receptors and it has been suggested that antibodies to these microbial antigens may cross-react with the TSH receptors on the host thyroid follicular cell. In regions of iodine deﬁciency (p. 647), iodine supplementation can precipitate thyrotoxicosis, but only in those with pre-existing subclinical Graves’ disease. Smoking is weakly associated with Graves’ thyrotoxicosis but strongly linked with the development of ophthalmopathy. Management Symptoms of thyrotoxicosis respond to β-blockade (p. 637) but deﬁnitive treatment requires control of thyroid hormone secretion. The different options are compared in Box 18.14. Some clinicians adopt an empirical approach of prescribing a course of antithyroid drug therapy and then recommending 131I or surgery if relapse occurs. In many centres, however, 131I is used extensively as a ﬁrst-line therapy, given the high risk of relapse following a course of antithyroid drugs. A number of observational studies have linked therapeutic 131I with increased incidence of some malignancies, particularly of the thyroid and gastrointestinal tract, but the results have been inconsistent; the association may be with Graves’ disease rather than its therapy, and the magnitude of the effect, if any, is small. Experience from the disaster at the Chernobyl nuclear power plant in 1986 suggests that younger people are more sensitive to radiation-induced thyroid cancer. Antithyroid drugs The most commonly used are carbimazole and its active metabolite, methimazole (not available in the 18.14 Comparison of treatments for the thyrotoxicosis of Graves’ disease Management Common indications Contraindications Disadvantages/complications Antithyroid drugs (carbimazole, propylthiouracil) First episode in patients < 40 years Breastfeeding (propylthiouracil suitable) Hypersensitivity rash 2% Agranulocytosis 0.2% Hepatotoxicity (with propylthiouracil) – very rare but potentially fatal

50% relapse rate usually within 2 years of stopping drug Subtotal thyroidectomy1 Large goitre Poor drug adherence, especially in young patients Recurrent thyrotoxicosis after course of antithyroid drugs in young patients Previous thyroid surgery Dependence on voice, e.g. opera singer, lecturer2 Hypothyroidism (~25%) Transient hypocalcaemia (10%) Permanent hypoparathyroidism (1%) Recurrent laryngeal nerve palsy2 (1%) Radio-iodine Patients > 40 years3 Recurrence following surgery irrespective of age Other serious comorbidity Pregnancy or planned pregnancy within 6 months of treatment Active Graves’ ophthalmopathy4 Hypothyroidism: ~40% in ﬁrst year, 80% after 15 years Most likely treatment to result in exacerbation of ophthalmopathy4 1A near-total thyroidectomy is now the favoured operation for Graves’ thyrotoxicosis in many institutions and is associated with a higher risk of some complications, including hypothyroidism (nearly 100%), but a reduced risk of persistent or recurrent thyrotoxicosis. 2lt is not only vocal cord palsy due to recurrent laryngeal nerve damage that alters the voice following thyroid surgery; the superior laryngeal nerves are frequently transected and this results in minor changes in voice quality. 3ln many institutions, 131I is used more liberally and is prescribed for much younger patients. 4The extent to which radio-iodine exacerbates ophthalmopathy is controversial and practice varies; some use prednisolone to reduce this risk.

The thyroid gland • 645

18.15 Thyrotoxicosis in adolescence • Presentation: may present with a deterioration in school performance or symptoms suggestive of attention deﬁcit hyperactivity disorder. • Antithyroid drug therapy: prolonged courses may be required because remission rates following an 18-month course of therapy are much lower than in adults. • Adherence: adherence to antithyroid drug therapy is often suboptimal, resulting in poor disease control that may adversely affect performance at school. • Radio-iodine therapy: usually avoided in adolescents because of concerns about risk of future malignancy. Ophthalmopathy, like thyrotoxicosis (see Fig. 18.7), typically follows an episodic course and it is helpful to distinguish patients with active inﬂammation (periorbital oedema and conjunctival inﬂammation with changing orbital signs) from those in whom the inﬂammation has ‘burnt out’. Eye disease is detectable in up to 50% of thyrotoxic patients at presentation, but active ocular inflammation may occur before or after thyrotoxic episodes (exophthalmic Graves’ disease). It is more common in cigarette smokers and is exacerbated by poor control of thyroid function, especially hypothyroidism. The most frequent presenting symptoms are related to increased exposure of the cornea, resulting from proptosis and lid retraction. There may be excessive lacrimation made worse by wind and bright light, a ‘gritty’ sensation in the eye, and pain due to conjunctivitis or corneal ulceration. In addition, there may be reduction of Thyroid surgery Patients should be rendered euthyroid with antithyroid drugs before operation. Oral potassium iodide, 60 mg three times daily, is often added for 10 days before surgery to inhibit thyroid hormone release and reduce the size and vascularity of the gland, making surgery technically easier. Traditionally, a ‘subtotal’ thyroidectomy is performed, in which a portion of one lobe of the thyroid is left in situ, with the aim of rendering the patient euthyroid. While complications of surgery are rare and 80% of patients are euthyroid, 15% are permanently hypothyroid and 5% remain thyrotoxic. As a consequence, many endocrine surgeons now opt to perform a ‘near-total’ thyroidectomy, leaving behind only a small portion of gland adjacent to the recurrent laryngeal nerves. This strategy invariably results in permanent hypothyroidism and is probably associated with a higher risk of hypoparathyroidism, but maximises the potential for cure of thyrotoxicosis. Radioactive iodine 131I is administered orally as a single dose and is trapped and organiﬁed in the thyroid (see Fig. 18.3). 131I emits both β and γ radiation and, although it decays within a few weeks, it has long-lasting inhibitory effects on survival and replication of follicular cells. The variable radio-iodine uptake and radiosensitivity of the gland means that the choice of dose is empirical; in most centres, approximately 400–600 MBq (approximately 10–15 mCi) is administered. This regimen is effective in 75% of patients within 4–12 weeks. During the lag period, symptoms can be controlled by a β-blocker or, in more severe cases, by carbimazole. However, carbimazole reduces the efﬁcacy of 131I therapy because it prevents organiﬁcation of 131I in the gland, and so should be avoided until 48 hours after radio-iodine administration. If thyrotoxicosis persists after 6 months, a further dose of 131I can be given. The disadvantage of 131I treatment is that the majority of patients eventually develop hypothyroidism. 131I is usually avoided in patients with Graves’ ophthalmopathy and evidence of signiﬁcant active orbital inﬂammation. It can be administered with caution in those with mild or ‘burnt-out’ eye disease, when it is customary to cover the treatment with a 6-week tapering course of oral prednisolone. In women of reproductive age, pregnancy must be excluded before administration of 131I and avoided for 6 months thereafter; men are also advised against fathering children for 6 months after receiving 131I. Thyrotoxicosis in pregnancy Thyrotoxicosis in pregnancy may be associated with signiﬁcant maternal and fetal morbidity. Management is very specialised and is discussed on page 1279 (see also Box 18.18). Thyrotoxicosis in adolescence Thyrotoxicosis can occasionally occur in adolescence and is almost always due to Graves’ disease. The presentation may be atypical and management challenging, as summarised in Box 18.15. Graves’ ophthalmopathy This condition is immunologically mediated but the autoantigen has not been identiﬁed. Within the orbit (and the dermis) there is cytokine-mediated proliferation of ﬁbroblasts that secrete hydrophilic glycosaminoglycans. The resulting increase in interstitial ﬂuid content, combined with a chronic inﬂammatory cell inﬁltrate, causes marked swelling and ultimately ﬁbrosis of the extraocular muscles (Fig. 18.8) and a rise in retrobulbar pressure. The eye is displaced forwards (proptosis, exophthalmos, p. 631) and in severe cases there is optic nerve compression. Fig. 18.8 Graves’ disease. A Bilateral ophthalmopathy in a 42-year-old man. The main symptoms were diplopia in all directions of gaze and reduced visual acuity in the left eye. The periorbital swelling is due to retrobulbar fat prolapsing into the eyelids, and increased interstitial ﬂuid as a result of raised intraorbital pressure. B Transverse CT of the orbits, showing the enlarged extraocular muscles. This is most obvious at the apex of the left orbit (arrow), where compression of the optic nerve caused reduced visual acuity. A B

646 • ENDOCRINOLOGY In this context, the dose of levothyroxine should be sufﬁcient to suppress serum TSH to low but detectable levels. Transient thyroiditis Subacute (de Quervain’s) thyroiditis In its classical painful form, subacute thyroiditis is a transient inﬂammation of the thyroid gland occurring after infection with Coxsackie, mumps or adenoviruses. There is pain in the region of the thyroid that may radiate to the angle of the jaw and the ears, and is made worse by swallowing, coughing and movement of the neck. The thyroid is usually palpably enlarged and tender. Systemic upset is common. Affected patients are usually females aged 20–40 years. Painless transient thyroiditis can also occur after viral infection and in patients with underlying autoimmune disease. The condition can also be precipitated by drugs, including interferon-α and lithium. Irrespective of the clinical presentation, inﬂammation in the thyroid gland occurs and is associated with release of colloid and stored thyroid hormones, but also with damage to follicular cells and impaired synthesis of new thyroid hormones. As a result, T4 and T3 levels are raised for 4–6 weeks until the pre-formed colloid is depleted. Thereafter, there is usually a period of hypothyroidism of variable severity before the follicular cells recover and normal thyroid function is restored within 4–6 months (Fig. 18.9). In the thyrotoxic phase, the iodine uptake is low because the damaged follicular cells are unable to trap iodine and because TSH secretion is suppressed. Low-titre thyroid autoantibodies appear transiently in the serum, and the erythrocyte sedimentation rate (ESR) is usually raised. High-titre autoantibodies suggest an underlying autoimmune pathology and greater risk of recurrence and ultimate progression to hypothyroidism. The pain and systemic upset usually respond to simple measures such as non-steroidal anti-inflammatory drugs (NSAIDs). Occasionally, however, it may be necessary to prescribe prednisolone 40 mg daily for 3–4 weeks. The thyrotoxicosis is mild and treatment with a β-blocker is usually adequate. Antithyroid drugs are of no beneﬁt because thyroid hormone synthesis is impaired rather than enhanced. Careful monitoring of thyroid function and symptoms is required so that levothyroxine can be prescribed temporarily in the hypothyroid phase. Care must be taken to identify patients presenting with hypothyroidism who visual acuity and/or visual ﬁelds as a consequence of corneal oedema or optic nerve compression. Other signs of optic nerve compression include reduced colour vision and a relative afferent pupillary defect (pp. 631 and 1088). If the extraocular muscles are involved and do not act in concert, diplopia results. The majority of patients require no treatment other than reassurance. Smoking cessation should be actively encouraged. Methylcellulose eye drops and gel counter the gritty discomfort of dry eyes, and tinted glasses or side shields attached to spectacle frames reduce the excessive lacrimation triggered by sun or wind. In patients with mild Graves’ ophthalmopathy, oral selenium (100 μg twice daily for 6 months) improves quality of life, reduces ocular involvement and slows progression of disease; the mechanism of action is not known but may relate to an antioxidant effect. More severe inﬂammatory episodes are treated with glucocorticoids (e.g. pulsed intravenous methylprednisolone) and sometimes orbital radiotherapy. There is also an increasing trend to use alternative immunosuppressive therapies, such as rituximab and ciclosporin. Loss of visual acuity is an indication for urgent surgical decompression of the orbit. In ‘burnt-out’ disease, surgery to the extraocular muscles, and later the eyelids, may improve diplopia, conjunctival exposure and cosmetic appearance. Pretibial myxoedema This inﬁltrative dermopathy occurs in fewer than 5% of patients with Graves’ disease and has similar pathological features as occur in the orbit. It takes the form of raised pink-coloured or purplish plaques on the anterior aspect of the leg, extending on to the dorsum of the foot (p. 630). The lesions may be itchy and the skin may have a ‘peau d’orange’ appearance with growth of coarse hair; less commonly, the face and arms are affected. Treatment is rarely required but in severe cases topical glucocorticoids may be helpful. Hashimoto’s thyroiditis Hashimoto’s thyroiditis is characterised by destructive lymphoid inﬁltration of the thyroid, ultimately leading to a varying degree of ﬁbrosis and thyroid enlargement. There is an increased risk of thyroid lymphoma (p. 650), although this is exceedingly rare. The nomenclature of autoimmune hypothyroidism is confusing. Some authorities reserve the term ‘Hashimoto’s thyroiditis’ for the condition of patients with positive antithyroid peroxidase autoantibodies and a ﬁrm goitre who may or may not be hypothyroid, and use the term ‘spontaneous atrophic hypothyroidism’ for the condition of hypothyroid patients without a goitre in whom TSH receptor-blocking antibodies may be more important than antithyroid peroxidase antibodies. However, these syndromes can both be considered as variants of the same underlying disease process. Hashimoto’s thyroiditis increases in incidence with age and affects approximately 3.5 per 1000 women and 0.8 per 1000 men each year. Many present with a small or moderately sized diffuse goitre, which is characteristically ﬁrm or rubbery in consistency. Around 25% of patients are hypothyroid at presentation. In the remainder, serum T4 is normal and TSH normal or raised, but these patients are at risk of developing overt hypothyroidism in future years. Antithyroid peroxidase antibodies are present in the serum in more than 90% of patients with Hashimoto’s thyroiditis. In those under the age of 20 years, antinuclear factor (ANF) may also be positive. Levothyroxine therapy is indicated as treatment for hypothyroidism (p. 640) and also to shrink an associated goitre. Fig. 18.9 Thyroid function tests in an episode of transient thyroiditis. This pattern might be observed in classical subacute (de Quervain’s) thyroiditis, painless thyroiditis or post-partum thyroiditis. The duration of each phase varies between patients. Thyrotoxic Hypothyroid Euthyroid Reference range

Months T4, T3 TSH

The thyroid gland • 647

schemes to administer oral or intramuscular iodised oil to at-risk populations and the addition of iodine to wells supplying water to local communities. These schemes have been extremely effective in reducing the prevalence of iodine deﬁciency, but lower consumption of table salt has actually led to an increase in iodine deﬁciency in some developed countries like Australia and New Zealand. Iodine-induced thyroid dysfunction Iodine has complex effects on thyroid function. Very high concentrations of iodine inhibit thyroid hormone synthesis and release (known as the Wolff–Chaikoff effect) and this forms the rationale for iodine treatment in thyroid crisis (p. 637) and prior to thyroid surgery for thyrotoxicosis (p. 645). This is an autoregulatory response to protect the body from the sudden release of large amounts of thyroid hormone in response to the ingestion of a substantial load of iodine. This effect only lasts for about 10 days, after which it is followed by an ‘escape phenomenon’: essentially, the return to normal organiﬁcation of iodine and thyroid peroxidase action (see Fig. 18.3). Therefore, if iodine is given to prepare an individual with Graves’ disease for surgery, the operation must happen within 10–14 days; otherwise, a signiﬁcant relapse of the thyrotoxicosis could occur. Iodine deﬁciency and underlying thyroid disease can both moderate the effects of iodine on thyroid function. In iodinedeﬁcient parts of the world, transient thyrotoxicosis may be precipitated by prophylactic iodinisation programmes. In iodine-sufﬁcient areas, thyrotoxicosis can be precipitated by iodine-containing radiographic contrast medium or expectorants in individuals who have underlying thyroid disease predisposing to thyrotoxicosis, such as multinodular goitre or Graves’ disease in remission. Induction of thyrotoxicosis by iodine is called the Jod–Basedow effect. Chronic excess iodine administration can also result in hypothyroidism; this is, in effect, a failure to escape from the Wolff–Chaikoff effect and usually occurs in the context of prior insult to the thyroid by, for example, autoimmune disease, thyroiditis, lithium, antithyroid drugs or surgery. Amiodarone The anti-arrhythmic agent amiodarone has a structure that is analogous to that of T4 (Fig. 18.10) and contains huge amounts of iodine; a 200 mg dose contains 75 mg iodine. Amiodarone also has a cytotoxic effect on thyroid follicular cells and inhibits conversion of T4 to T3 (increasing the ratio of T4:T3). Most patients receiving amiodarone have normal thyroid function but up to 20% develop hypothyroidism or thyrotoxicosis, and so thyroid function should be monitored regularly. TSH provides the best indicator of thyroid function. The thyrotoxicosis can be classiﬁed as either: • type I: iodine-induced excess thyroid hormone synthesis in patients with an underlying thyroid disorder, such as are in the later stages of a transient thyroiditis, since they are unlikely to require life-long levothyroxine therapy (see Fig. 18.6). Post-partum thyroiditis The maternal immune response, which is modified during pregnancy to allow survival of the fetus, is enhanced after delivery and may unmask previously unrecognised subclinical autoimmune thyroid disease. Surveys have shown that transient biochemical disturbances of thyroid function occur in 5–10% of women within 6 months of delivery (see Box 18.18). Those affected are likely to have antithyroid peroxidase antibodies in the serum in early pregnancy. Symptoms of thyroid dysfunction are rare and there is no association between postnatal depression and abnormal thyroid function tests. However, symptomatic thyrotoxicosis presenting for the ﬁrst time within 12 months of childbirth is likely to be due to post-partum thyroiditis and the diagnosis is conﬁrmed by a negligible radio-isotope uptake. The clinical course and treatment are similar to those of painless subacute thyroiditis (see above). Post-partum thyroiditis tends to recur after subsequent pregnancies, and eventually patients progress over a period of years to permanent hypothyroidism. Iodine-associated thyroid disease Iodine deﬁciency Iodine is an essential micronutrient and is a key component of T4 and T3. The World Health Organisation (WHO) recommends a daily intake of iodine of 150 μg/day for adult men and women; higher levels are recommended for pregnant women (p. 1279). Dietary sources of iodine include seafood, dairy products, eggs and grains. Dietary iodine deﬁciency is a major worldwide public health issue, with an estimated one-third of the world population living in areas of iodine insufﬁciency. Iodine deﬁciency is particularly common in Central Africa, South-east Asia and the Western Paciﬁc. It is associated with the development of thyroid nodules and goitre (endemic goitre); the reduced substrate available for thyroid hormone production increases thyroid activity to maximise iodine uptake and recycling, and this acts as a potent stimulus for enlargement of the thyroid and nodule formation. Most affected patients are euthyroid with normal or raised TSH levels, although hypothyroidism can occur with severe iodine deﬁciency. Suspected iodine deﬁciency can be assessed by measuring iodine in urine (either a 24-hour collection or a spot sample). Endemic goitre can be treated by iodine supplementation, and a reduction in nodule and goitre size can be seen, particularly if it is commenced in childhood. Iodine deﬁciency is not associated with an increased risk of Graves’ disease or thyroid cancer, but the high prevalence of nodular autonomy does result in an increased risk of thyrotoxicosis and this risk may be further increased by iodine supplementation. Conversely, iodine supplementation may also increase the prevalence of subclinical hypothyroidism and autoimmune hypothyroidism. These complex effects of iodine supplementation are further discussed below. In pregnancy, iodine deﬁciency is associated with impaired brain development, and severe deﬁciency can cause cretinism. Worldwide, iodine deficiency is the most common cause of preventable impaired cognitive development in children (p. 1279). The WHO and other international organisations have made reversal of iodine deﬁciency a priority and have helped organise national supplementation programmes. These have mainly involved the iodisation of table salt, but have also included Fig. 18.10 The structure of amiodarone. Note the similarities to T4 (see Fig. 18.3). C4H9 O I C CH2 CH2 N O C2H5 C2H5 I O

648 • ENDOCRINOLOGY Fig. 18.12 Computed tomogram showing retrosternal multinodular goitre (black arrow). This is causing acute severe breathlessness and stridor due to tracheal compression (white arrow). R Fig. 18.11 Natural history of simple goitre. Age (in years) Goitre Tracheal compression/ deviation T3, T4 TSH 15–25 Diffuse No Normal Normal 26–55 Nodular Minimal Normal Normal or undetectable

55 Nodular Yes Raised Undetectable nodular goitre or latent Graves’ disease (an example of the Jod–Basedow effect). • type II: thyroiditis due to a direct cytotoxic effect of amiodarone administration. These patterns can overlap and may be difﬁcult to distinguish clinically, as iodine uptake is low in both. There is no widely accepted management algorithm, although the iodine excess renders the gland resistant to 131I. Antithyroid drugs may be effective in patients with the type I form but are ineffective in type II thyrotoxicosis. Prednisolone is beneﬁcial in the type II form. A pragmatic approach is to commence combination therapy with an antithyroid drug and glucocorticoid in patients with signiﬁcant thyrotoxicosis. A rapid response (within 1–2 weeks) usually indicates a type II picture and permits withdrawal of the antithyroid therapy; a slower response suggests a type I picture, in which case antithyroid drugs may be continued and prednisolone withdrawn. Potassium perchlorate can also be used to inhibit iodine trapping in the thyroid. If the cardiac state allows, amiodarone should be discontinued, but it has a long half-life (50–60 days) and so its effects are long-lasting. To minimise the risk of type I thyrotoxicosis, thyroid function should be measured in all patients prior to commencement of amiodarone therapy, and amiodarone should be avoided if TSH is suppressed. Hypothyroidism should be treated with levothyroxine, which can be given while amiodarone is continued. Simple and multinodular goitre These terms describe diffuse or multinodular enlargement of the thyroid, which occurs sporadically and is of unknown aetiology. Simple diffuse goitre This form of goitre usually presents between the ages of 15 and 25 years, often during pregnancy, and tends to be noticed by friends and relatives rather than the patient. Occasionally, there is a tight sensation in the neck, particularly when swallowing. The goitre is soft and symmetrical, and the thyroid enlarged to two or three times normal. There is no tenderness, lymphadenopathy or overlying bruit. Concentrations of T3, T4 and TSH are normal and no thyroid autoantibodies are detected in the serum. No treatment is necessary and the goitre usually regresses. In some, however, the unknown stimulus to thyroid enlargement persists and, as a result of recurrent episodes of hyperplasia and involution during the following 10–20 years, the gland becomes multinodular with areas of autonomous function. Multinodular goitre The natural history is shown in Figure 18.11. Patients with thyroid enlargement in the absence of thyroid dysfunction or positive autoantibodies (i.e. with ‘simple goitre’; see above) as young adults may progress to develop nodules. These nodules grow at varying rates and secrete thyroid hormone ‘autonomously’, thereby suppressing TSH-dependent growth and function in the rest of the gland. Ultimately, complete suppression of TSH occurs in about 25% of cases, with T4 and T3 levels often within the reference range (subclinical thyrotoxicosis, p. 642), but sometimes elevated (toxic multinodular goitre; see Fig. 18.5). Clinical features and investigations Multinodular goitre is usually diagnosed in patients presenting with thyrotoxicosis, a large goitre with or without tracheal compression, or sudden painful swelling caused by haemorrhage into a nodule or cyst. The goitre is nodular or lobulated on palpation and may extend retrosternally; however, not all multinodular goitres causing thyrotoxicosis are easily palpable. Very large goitres can cause mediastinal compression with stridor (Fig. 18.12), dysphagia and obstruction of the superior vena cava. Hoarseness due to recurrent laryngeal nerve palsy can occur but is far more suggestive of thyroid carcinoma. The diagnosis can be conﬁrmed by ultrasonography and/or thyroid scintigraphy (see Fig. 18.5). In patients with large goitres, a flow-volume loop is a good screening test for significant tracheal compression (see Fig. 17.7, p. 554). If intervention is contemplated, a CT or MRI of the thoracic inlet should be performed to quantify the degree of tracheal displacement or compression and the extent of retrosternal extension. Nodules should be evaluated for the possibility of thyroid neoplasia, as described on page 649. Management If the goitre is small, no treatment is necessary but annual thyroid function testing should be arranged, as the natural history is progression to a toxic multinodular goitre. Thyroid surgery is indicated for large goitres that cause mediastinal compression

The thyroid gland • 649

thyrotoxicosis is usually mild and in almost 50% of patients the plasma T3 alone is elevated (T3 thyrotoxicosis). 131I (400–800 MBq (10–20 mCi)) is highly effective and is an ideal treatment since the atrophic cells surrounding the nodule do not take up iodine and so receive little or no radiation. For this reason, permanent hypothyroidism is unusual. Hemithyroidectomy is an alternative management option. Differentiated carcinoma Papillary carcinoma This is the most common of the malignant thyroid tumours and accounts for 90% of radiation-induced thyroid cancer. It may be multifocal and spread is initially to regional lymph nodes. Some patients present with cervical lymphadenopathy and no apparent thyroid enlargement; in such instances, the primary lesion may be less than 10 mm in diameter. Follicular carcinoma This is usually a single encapsulated lesion. Spread to cervical lymph nodes is rare. Metastases are blood-borne and are most often found in bone, lungs and brain. Management The management of thyroid cancers should be individualised and planned in multidisciplinary team meetings that include all specialists involved in the service; this should include thyroid surgeons, endocrinologists, oncologists, pathologists, radiologists and nurse specialists. Large tumours, those with adverse histological features and/or tumours with metastatic disease at presentation are usually managed by total thyroidectomy followed by a large dose of 131I (1100 or 3700 MBq (approximately 30 or 100 mCi)) to ablate any remaining normal or malignant thyroid tissue. Thereafter, long-term treatment with levothyroxine in a dose sufﬁcient to suppress TSH (usually 150–200 μg daily) is given, as there is evidence that growth of differentiated thyroid carcinomas is TSH-dependent. Smaller tumours with no adverse histological features may require only thyroid lobectomy. Follow-up involves measurement of serum thyroglobulin, which should be undetectable in patients whose normal thyroid has been ablated and who are taking a suppressive dose of levothyroxine. Thyroglobulin antibodies may interfere with the assay and, depending on the method employed, may result in a falsely low or high result. Detectable thyroglobulin, in the absence of assay interference, is suggestive of tumour recurrence or metastases, particularly if the thyroglobulin titre is rising across serial measurements. Local recurrence or metastatic disease may be localised by ultrasound, CT, MRI and/or whole-body scanning with 131I, and may be treated with further surgery and/or 131I therapy. 131I treatment in thyroid cancer and isotope scanning both require serum TSH concentrations to be elevated (> 20 mIU/L). This may be achieved by stopping levothyroxine for 4–6 weeks, inducing symptomatic hypothyroidism, or by administering intramuscular injections of recombinant human TSH. Patients usually ﬁnd the latter approach preferable but it is more expensive. Those with locally advanced or metastatic papillary and follicular carcinoma that is refractive to 131I may be considered for therapy with sorafenib or lenvatinib. These drugs are multi-targeted tyrosine kinase inhibitors and have been shown in trials to prolong progression-free survival by between 5 and 14 months. They have multiple toxicities, however, including poor appetite, weight loss, fatigue, diarrhoea, mucositis, rashes, hypertension and blood dyscrasias. The potential beneﬁts of or that are cosmetically unattractive. 131I can result in a signiﬁcant reduction in thyroid size and may be of value in elderly patients. Levothyroxine therapy is of no beneﬁt in shrinking multinodular goitres in iodine-sufﬁcient countries and may simply aggravate any associated thyrotoxicosis. In toxic multinodular goitre, treatment is usually with 131I. The iodine uptake is lower than in Graves’ disease, so a higher dose may be administered (up to 800 Mbq (approximately 20 mCi)) and hypothyroidism is less common. In thyrotoxic patients with a large goitre, thyroid surgery may be indicated. Long-term treatment with antithyroid drugs is not usually employed, as relapse is invariable after drug withdrawal; drug therapy is normally reserved for frail older patients in whom surgery or 131I is not an appropriate option. Asymptomatic patients with subclinical thyrotoxicosis (p. 642) are increasingly being treated with 131I on the grounds that a suppressed TSH is a risk factor for atrial ﬁbrillation and, particularly in post-menopausal women, osteoporosis. Thyroid neoplasia Patients with thyroid tumours usually present with a solitary nodule (p. 642). Most are benign and a few of these, called ‘toxic adenomas’, secrete excess thyroid hormones. Primary thyroid malignancy is rare, accounting for less than 1% of all carcinomas, and has an incidence of 25 per million per annum. As shown in Box 18.16, it can be classified according to the cell type of origin. With the exception of medullary carcinoma, thyroid cancer is more common in females. Toxic adenoma A solitary toxic nodule is the cause of less than 5% of all cases of thyrotoxicosis. The nodule is a follicular adenoma, which autonomously secretes excess thyroid hormones and inhibits endogenous TSH secretion, with subsequent atrophy of the rest of the thyroid gland. The adenoma is usually greater than 3 cm in diameter. Most patients are female and over 40 years of age. Although many nodules are palpable, the diagnosis can be made with certainty only by thyroid scintigraphy (see Fig. 18.5). The 18.16 Malignant thyroid tumours Type of tumour Frequency (%) Age at presentation (years) 10-year survival (%) Follicular cells Differentiated carcinoma: Papillary 75–85 20–40

Follicular 10–20 40–60

Anaplastic < 5

60

Parafollicular C cells Medullary carcinoma 5–8

40*

Lymphocytes Lymphoma < 5

60

*Patients with medullary carcinoma as part of multiple endocrine neoplasia (MEN) types 2 and 3 (p. 688) may present in childhood.

650 • ENDOCRINOLOGY Riedel’s thyroiditis This is not a form of thyroid cancer but the presentation is similar and the differentiation can usually be made only by thyroid biopsy. It is an exceptionally rare condition of unknown aetiology, in which there is extensive inﬁltration of the thyroid and surrounding structures with ﬁbrous tissue. There may be associated mediastinal and retroperitoneal ﬁbrosis. Presentation is with a slow-growing goitre that is irregular and stony-hard. There is usually tracheal and oesophageal compression necessitating partial thyroidectomy. Other recognised complications include recurrent laryngeal nerve palsy, hypoparathyroidism and eventually hypothyroidism. Congenital thyroid disease Early treatment with levothyroxine is essential to prevent irreversible brain damage in children (cretinism) with congenital hypothyroidism. Routine screening of TSH levels in heel-prick blood samples obtained 5–7 days after birth (as part of the Guthrie test) has revealed an incidence of approximately 1 in 3000, resulting from thyroid agenesis, ectopic or hypoplastic glands, or dyshormonogenesis. Congenital hypothyroidism is thus six times more common than phenylketonuria. It is now possible to start levothyroxine replacement therapy within 2 weeks of birth. Developmental assessment of infants treated at this early stage has revealed no differences between cases and controls in most children. Dyshormonogenesis Several autosomal recessive defects in thyroid hormone synthesis have been described; the most common results from deﬁciency of the intrathyroidal peroxidase enzyme. Homozygous individuals present with congenital hypothyroidism; heterozygotes present in the ﬁrst two decades of life with goitre, normal thyroid hormone levels and a raised TSH. The combination of dyshormonogenetic goitre and nerve deafness is known as Pendred’s syndrome and is due to mutations in pendrin, the protein that transports iodide to the luminal surface of the follicular cell (see Fig. 18.3). therapy therefore have to be carefully weighed against side-effects that can signiﬁcantly impair quality of life. Prognosis Most patients with papillary and follicular thyroid cancer will be cured with appropriate treatment. Adverse prognostic factors include older age at presentation, the presence of distant metastases, male sex and certain histological subtypes. However, 131I therapy can be effective in treating those with distant metastases, particularly small-volume disease in the lungs, and so prolonged survival is quite common. Anaplastic carcinoma and lymphoma These two conditions are difﬁcult to distinguish clinically but are distinct cytologically and histologically. Patients are usually over 60 years of age and present with rapid thyroid enlargement over 2–3 months. The goitre is hard and there may be stridor due to tracheal compression and hoarseness due to recurrent laryngeal nerve palsy. There is no effective treatment for anaplastic carcinoma, although surgery and radiotherapy may be considered in some circumstances. In older patients, median survival is only 7 months. The prognosis for lymphoma, which may arise from preexisting Hashimoto’s thyroiditis, is better (p. 961), with a median survival of 9 years. Some 98% of tumours are non-Hodgkin’s lymphomas, usually the diffuse large B-cell subtype. Treatment is with combination chemotherapy and external beam radiotherapy (p. 965). Medullary carcinoma This tumour arises from the parafollicular C cells of the thyroid. In addition to calcitonin, the tumour may secrete 5-hydroxytryptamine (5-HT, serotonin), various peptides of the tachykinin family, adrenocorticotrophic hormone (ACTH) and prostaglandins. As a consequence, carcinoid syndrome (p. 678) and Cushing’s syndrome (p. 666) may occur. Patients usually present in middle age with a ﬁrm thyroid mass. Cervical lymph node involvement is common but distant metastases are rare initially. Serum calcitonin levels are raised and are useful in monitoring response to treatment. Despite the very high levels of calcitonin found in some patients, hypocalcaemia is extremely rare; however, hypercalcitoninaemia can be associated with severe, watery diarrhoea. Treatment is by total thyroidectomy with removal of regional cervical lymph nodes. Since the C cells do not concentrate iodine and are not responsive to TSH, there is no role for 131I therapy or TSH suppression with levothyroxine. External beam radiotherapy may be considered in some patients at high risk of local recurrence. Vandetanib and cabozantinib are tyrosine kinase inhibitors licensed for patients with progressive advanced medullary cancer. The prognosis is less good than for papillary and follicular carcinoma, but individuals can live for many decades with persistent disease that behaves in an indolent fashion. Medullary carcinoma of the thyroid occurs sporadically in 70–90% cases; in 10–30% of cases, there is a genetic predisposition that is inherited in an autosomal dominant fashion and is due to an activating mutation in the RET gene. This inherited tendency normally forms part of one of the MEN syndromes (MEN 2 (also known as MEN 2a) or MEN 3 (also known as MEN 2b), p. 688) but, occasionally, susceptibility to medullary carcinoma is the only inherited trait (familial medullary thyroid cancer). 18.17 The thyroid gland in old age Thyrotoxicosis • Causes: commonly due to multinodular goitre. • Clinical features: apathy, anorexia, proximal myopathy, atrial ﬁbrillation and cardiac failure predominate. • Non-thyroidal illness: thyroid function tests are performed more frequently in the elderly but interpretation may be altered by intercurrent illness. Hypothyroidism • Clinical features: non-speciﬁc features, such as physical and mental slowing, are often attributed to increasing age and the diagnosis is delayed. • Myxoedema coma (p. 641): more likely in the elderly. • Levothyroxine dose: to avoid exacerbating latent or established heart disease, the starting dose should be 25 μg daily. Levothyroxine requirements fall with increasing age and few patients need more than 100 μg daily. • Other medication (see Box 18.12): may interfere with absorption or metabolism of levothyroxine, necessitating an increase in dose.

The reproductive system • 651

Functional anatomy, physiology and investigations The physiology of male and female reproductive function is illustrated in Figures 18.13 and 18.14, respectively. Pathways for synthesis of sex steroids are shown in Figure 18.19 (p. 667). The male In the male, the testis serves two principal functions: synthesis of testosterone by the interstitial Leydig cells under the control of luteinising hormone (LH), and spermatogenesis by Sertoli cells under the control of follicle-stimulating hormone (FSH) (but also requiring adequate testosterone). Negative feedback suppression of LH is mediated principally by testosterone, while secretion of another hormone by the testis, inhibin, suppresses FSH. The axis can be assessed easily by a random blood sample for testosterone, LH and FSH. Testosterone levels are higher in the morning and therefore, if testosterone is marginally low, sampling should be repeated with the patient fasted at 0900 hrs. Testosterone is largely bound in plasma to sex hormone-binding globulin and this can also be measured to calculate the ‘free androgen index’ or the ‘bioavailable’ testosterone. Testicular function can also be tested by semen analysis. There is no equivalent of the menopause in men, although testosterone concentrations decline slowly from the fourth decade onwards. 18.18 Thyroid disease in pregnancy Normal pregnancy • Trimester-speciﬁc reference ranges: should be used to interpret thyroid function test results in pregnancy. Iodine deﬁciency • Iodine requirements: increased in pregnancy. The World Health Organisation (WHO) recommends a minimum intake of 250 μg/day. • Iodine deﬁciency: the major cause of preventable impaired cognitive development in children worldwide. Hypothyroidism • Impaired cognitive development in the offspring: may be associated with hypothyroidism that is not adequately treated. • Levothyroxine replacement therapy dose requirements: increase by 30–50% from early in pregnancy. Monitoring to maintain TSH results within the trimester-speciﬁc reference range is recommended in early pregnancy and at least once in each trimester. Thyrotoxicosis • Gestational thyrotoxicosis: associated with multiple pregnancies and hyperemesis gravidarum. Transient and usually does not require antithyroid drug treatment. • Graves’ disease: the most common cause of sustained thyrotoxicosis in pregnancy • Antithyroid drugs: propylthiouracil should be used in the ﬁrst trimester, with carbimazole substituted in the second and third trimesters. Post-partum thyroiditis • Screening: not recommended for every woman, but thyroid function should be tested 4–6 weeks post-partum in those with a personal history of thyroid disease, goitre or other autoimmune disease including type 1 diabetes, in those known to have positive antithyroid peroxidase antibodies, or when there is clinical suspicion of thyroid dysfunction. Thyroid hormone resistance This is a rare disorder in which the pituitary and hypothalamus are resistant to feedback suppression of TSH by T3, sometimes due to mutations in the thyroid hormone receptor β or because of defects in monodeiodinase activity. The result is high levels of TSH, T4 and T3, often with a moderate goitre that may not be noted until adulthood. Thyroid hormone signalling is highly complex and involves different isozymes of both monodeiodinases and thyroid hormone receptors in different tissues. For that reason, other tissues may or may not share the resistance to thyroid hormone and there may be features of thyrotoxicosis (e.g. tachycardia). This condition can be difﬁcult to distinguish from an equally rare TSH-producing pituitary tumour (TSHoma; see Box 18.5, p. 636); administration of TRH results in elevation of TSH in thyroid hormone resistance and not in TSHoma, but an MRI scan of the pituitary may be necessary to exclude a macroadenoma. The reproductive system Clinical practice in reproductive medicine is shared between several specialties, including gynaecology, urology, paediatrics, psychiatry and endocrinology. The following section is focused on disorders managed by endocrinologists. Fig. 18.13 Male reproductive physiology. (FSH = follicle-stimulating hormone; LH = luteinising hormone) Negative feedback LH FSH Interstitial (Leydig) cells Sertoli cells in seminiferous tubules Inhibin Spermatogenesis Testosterone • Facial, axillary and body hair growth • Scalp balding • Skin sebum production • Penis and scrotal development • Prostate development and function • Laryngeal enlargement • Muscle power • Bone metabolism/epiphyseal closure • Libido • Aggression Testis

652 • ENDOCRINOLOGY The female In the female, physiology varies during the normal menstrual cycle. FSH stimulates growth and development of ovarian follicles during the ﬁrst 14 days after the menses. This leads to a gradual increase in oestradiol production from granulosa cells, which initially suppresses FSH secretion (negative feedback) but then, above a certain level, stimulates an increase in both the frequency and amplitude of gonadotrophin-releasing hormone (GnRH) pulses, resulting in a marked increase in LH secretion (positive feedback). The mid-cycle ‘surge’ of LH induces ovulation. After release of the ovum, the follicle differentiates into a corpus luteum, which secretes progesterone. Unless pregnancy occurs during the cycle, the corpus luteum regresses and the fall in progesterone levels results in menstrual bleeding. Circulating levels of oestrogen and progesterone in pre-menopausal women are, therefore, critically dependent on the time of the cycle. The most useful ‘test’ of ovarian function is a careful menstrual history: if menses are regular, measurement of gonadotrophins and oestrogen is not necessary. In addition, ovulation can be conﬁrmed by measuring plasma progesterone levels during the luteal phase (‘day 21 progesterone’). Cessation of menstruation (the menopause) occurs at an average age of approximately 50 years in developed countries. In the 5 years before, there is a gradual increase in the number of anovulatory cycles and this is referred to as the climacteric. Oestrogen and inhibin secretion falls and negative feedback results in increased pituitary secretion of LH and FSH (both typically to levels above 30 IU/L (3.3 μg/L)). The pathophysiology of male and female reproductive dysfunction is summarised in Box 18.19. Fig. 18.14 Female reproductive physiology and the normal menstrual cycle. (FSH = follicle-stimulating hormone; LH = luteinising hormone) Feedback LH FSH Inhibin Oestradiol • Endometrial proliferation • Genital development and lubrication • Breast proliferation • Bone epiphyseal closure and mineral content • Brain • Body fat distribution • Skin sebum Progesterone • Endometrial secretory change • Increased myometrial contractility • Thermogenesis • Breast swelling Days after start of last menstrual period FSH LH Oestradiol Progesterone Ovulation Luteal phase Follicular phase Primary Dominant vesicular Mature Haemorrhagic Mature Regressing Oestradiol Oestradiol Oestradiol Progesterone Oestradiol Progesterone Corpus luteum Ovary Menses Follicle

18.19 Classiﬁcation of diseases of the reproductive system Primary Secondary Hormone excess Polycystic ovarian syndrome Granulosa cell tumour Leydig cell tumour Teratoma Pituitary gonadotrophinoma Hormone deﬁciency Menopause Hypogonadism (see Box 18.20) Turner’s syndrome Klinefelter’s syndrome Hypopituitarism Kallmann’s syndrome (isolated GnRH deﬁciency) Severe systemic illness, including anorexia nervosa Hormone hypersensitivity Idiopathic hirsutism Hormone resistance Androgen resistance syndromes Complete (‘testicular feminisation’) Partial (Reifenstein’s syndrome) 5α-reductase type 2 deﬁciency Non-functioning tumours Ovarian cysts Carcinoma Teratoma Seminoma (GnRH = gonadotrophin-releasing hormone)

The reproductive system • 653

usually be obtained from health records, are extremely useful. Healthy growth usually follows a centile. Usually, children with constitutional delay have always been small but have maintained a normal growth velocity that is appropriate for bone age. Poor linear growth, with ‘crossing of the centiles’, is more likely to be associated with acquired disease. Issues that are commonly encountered in the management of adolescents with delayed puberty are summarised in Box 18.21. Constitutional delay of puberty This is the most common cause of delayed puberty, but is a much more frequent explanation for lack of pubertal development in boys than in girls. Affected children are healthy and have usually been more than 2 SD below the mean height for their age throughout childhood. There is often a history of delayed puberty in siblings or parents. Since sex steroids are essential for fusion of the epiphyses, ‘bone age’ can be estimated by X-rays of epiphyses, usually in the wrist and hand; in constitutional delay, bone age is lower than chronological age. Constitutional delay of puberty should be considered as a normal variant, as puberty will commence spontaneously. However, affected children can experience signiﬁcant psychological distress because of their lack of physical development, particularly when compared with their peers. Hypogonadotrophic hypogonadism This may be due to structural, inﬂammatory or inﬁltrative disorders of the pituitary and/or hypothalamus (see Box 18.54, p. 681). In such circumstances, other pituitary hormones, such as growth hormone, are also likely to be deﬁcient. ‘Functional’ gonadotrophin deﬁciency is caused by a variety of factors, including low body weight, chronic systemic illness (as a consequence of the disease itself or secondary malnutrition), endocrine disorders and profound psychosocial stress. Isolated gonadotrophin deﬁciency is usually due to a genetic abnormality that affects the synthesis of either GnRH or gonadotrophins. The most common form is Kallmann’s syndrome, in which there is primary GnRH deﬁciency and, in most affected individuals, agenesis or hypoplasia of the olfactory bulbs, resulting in anosmia or hyposmia. If isolated gonadotrophin deﬁciency is left untreated, the epiphyses fail to fuse, resulting in tall stature with disproportionately long arms and legs relative to trunk height (eunuchoid habitus). Cryptorchidism (undescended testes) and gynaecomastia are commonly observed in all forms of hypogonadotrophic hypogonadism. Presenting problems in reproductive disease Delayed puberty Normal pubertal development is discussed on page 1290. Puberty is considered to be delayed if the onset of the physical features of sexual maturation has not occurred by a chronological age that is 2.5 standard deviations (SD) above the national average. In the UK, this is by the age of 14 in boys and 13 in girls. Genetic factors have a major inﬂuence in determining the timing of the onset of puberty, such that the age of menarche (the onset of menstruation) is often comparable within sibling and mother–daughter pairs and within ethnic groups. However, because there is also a threshold for body weight that acts as a trigger for normal puberty, the onset of puberty can be inﬂuenced by other factors including nutritional status and chronic illness (p. 694). Clinical assessment The differential diagnosis is shown in Box 18.20. The key issue is to determine whether the delay in puberty is simply because the ‘clock is running slow’ (constitutional delay of puberty) or because there is pathology in the hypothalamus/ pituitary (hypogonadotrophic hypogonadism) or the gonads (hypergonadotrophic hypogonadism). A general history and physical examination should be performed with particular reference to previous or current medical disorders, social circumstances and family history. Body proportions, sense of smell and pubertal stage should be carefully documented and, in boys, the presence or absence of testes in the scrotum noted. Current weight and height may be plotted on centile charts, along with parental heights. Previous growth measurements in childhood, which can 18.20 Causes of delayed puberty and hypogonadism Constitutional delay Hypogonadotrophic hypogonadism • Structural hypothalamic/pituitary disease (see Box 18.54, p. 681) • Functional gonadotrophin deﬁciency: Chronic systemic illness (e.g. asthma, malabsorption, coeliac disease, cystic ﬁbrosis, renal failure) Psychological stress Anorexia nervosa Excessive physical exercise Hyperprolactinaemia Other endocrine disease (e.g. Cushing’s syndrome, primary hypothyroidism) • Isolated gonadotrophin deﬁciency (Kallmann’s syndrome) Hypergonadotrophic hypogonadism • Acquired gonadal damage: Chemotherapy/radiotherapy to gonads Trauma/surgery to gonads Autoimmune gonadal failure Mumps orchitis Tuberculosis Haemochromatosis • Developmental/congenital gonadal disorders: Steroid biosynthetic defects Anorchidism/cryptorchidism in males Klinefelter’s syndrome (47XXY, male phenotype) Turner’s syndrome (45XO, female phenotype) 18.21 Delayed puberty • Aetiology: in boys the most common cause is constitutional delay, whereas in girls there is inevitably a structural hypothalamic/pituitary abnormality or a factor that affects their function. • Psychological effects: whatever the underlying cause, delayed puberty is often associated with substantial psychological distress. • Investigations: a karyotype should be performed in all adolescents with hypergonadotrophic hypogonadism, to exclude Turner’s and Klinefelter’s syndromes, unless there is an obvious precipitating cause. • Medical induction of puberty: if this is being considered, it needs to be managed carefully and carried out in a controlled fashion, to avoid premature fusion of the epiphyses.

654 • ENDOCRINOLOGY Management Social and psychological difﬁculties may accompany the onset of PP and the premature closure of the epiphyses can result in reduced ﬁnal height. In central PP, development can be arrested with long-acting GnRH analogues. In both central and peripheral PP, treatment of any underlying cause is indicated. Amenorrhoea Primary amenorrhoea may be diagnosed in a female who has never menstruated; this usually occurs as a manifestation of delayed puberty but may also be a consequence of anatomical defects of the female reproductive system, such as endometrial hypoplasia or vaginal agenesis. Secondary amenorrhoea describes the cessation of menstruation in a female who has previously had periods. The causes of this common presentation are shown in Box 18.22. In non-pregnant women, secondary amenorrhoea is almost invariably a consequence of either ovarian or hypothalamic/pituitary dysfunction. Premature ovarian failure (premature menopause) is deﬁned, arbitrarily, as occurring before 40 years of age. Rarely, endometrial adhesions (Asherman’s syndrome) can form after uterine curettage, surgery or infection with tuberculosis or schistosomiasis, preventing endometrial proliferation and shedding. Clinical assessment The underlying cause can often be suspected from associated clinical features and the patient’s age. Hypothalamic/pituitary disease and premature ovarian failure result in oestrogen deﬁciency, which causes a variety of symptoms usually associated with the menopause (Box 18.23). A history of galactorrhoea should be sought. Signiﬁcant weight loss of any cause can cause amenorrhoea by suppression of gonadotrophins. Weight gain may suggest hypothyroidism, Cushing’s syndrome or, very rarely, a hypothalamic lesion. Hirsutism, obesity and long-standing irregular periods suggest polycystic ovarian Hypergonadotrophic hypogonadism Hypergonadotrophic hypogonadism associated with delayed puberty is usually due to Klinefelter’s syndrome in boys and Turner’s syndrome in girls (pp. 659 and 660). Other causes of primary gonadal failure are shown in Box 18.20. Investigations Key measurements are LH and FSH, testosterone (in boys) and oestradiol (in girls). Chromosome analysis should be performed if gonadotrophin concentrations are elevated. If gonadotrophin concentrations are low, then the differential diagnosis lies between constitutional delay and hypogonadotrophic hypogonadism. A plain X-ray of the wrist and hand may be compared with a set of standard ﬁlms to obtain a bone age. Full blood count, renal function, liver function, thyroid function and coeliac disease autoantibodies (p. 806) should be measured, but further tests may be unnecessary if the blood tests are normal and the child has all the clinical features of constitutional delay. If hypogonadotrophic hypogonadism is suspected, neuroimaging and further investigations are required (p. 680). Management Puberty can be induced using low doses of oral oestrogen in girls (e.g. ethinylestradiol 2 μg daily) or testosterone in boys (testosterone gel or depot testosterone esters). Higher doses carry a risk of early fusion of epiphyses. This therapy should be given in a specialist clinic where the progress of puberty and growth can be carefully monitored. In children with constitutional delay, this ‘priming’ therapy can be discontinued when endogenous puberty is established, usually in less than a year. In children with hypogonadism, the underlying cause should be treated and reversed if possible. If hypogonadism is permanent, sex hormone doses are gradually increased during puberty and full adult replacement doses given when development is complete. Precocious puberty Precocious puberty (PP) is the early development of any secondary sexual characteristics before the age of 9 years in a boy and 6–8 years of age in a girl. Central PP is due to the early maturation of the hypothalamic–pituitary–gonadal axis and thus is gonadotrophin-dependent. It is more common in girls than boys and often no structural cause is identiﬁed, i.e. ‘the physiological clock is running fast’. Structural causes are found more commonly in younger children and in boys and include: • central nervous system (CNS) tumours such as astrocytomas, germ-cell tumours secreting human chorionic gonadotrophin (hCG) and hypothalamic harmartomas • CNS injury caused by infection, inﬂammation or trauma/ surgery • congenital CNS structural abnormalities. Pseudo (or peripheral) PP is much less common, and is due to excess sex steroids in the absence of pituitary gonadotrophins, with causes including congenital adrenal hyperplasia and McCune–Albright syndrome (p. 1055). Investigations Measurement of basal and GnRH-stimulated gonadotrophin levels will allow categorisation into central or peripheral PP, with gonadotrophin levels rising in central PP. Imaging of the CNS is required in cases of central PP, while adrenal and ovarian imaging is indicated in peripheral PP. 18.23 Symptoms of oestrogen deﬁciency Vasomotor effects • Hot ﬂushes • Sweating Psychological • Anxiety • Irritability • Emotional lability Genitourinary • Dyspareunia • Urgency of micturition • Vaginal infections 18.22 Causes of secondary amenorrhoea Physiological • Pregnancy • Menopause Hypogonadotrophic hypogonadism (see Box 18.20) Ovarian dysfunction • Hypergonadotrophic hypogonadism (see Box 18.20) • Polycystic ovarian syndrome • Androgen-secreting tumours Uterine dysfunction • Asherman’s syndrome

The reproductive system • 655

patient’s age. In patients with premature menopause, HRT should be continued up to the age of around 50 years, but continued beyond this age only if there are continued symptoms of oestrogen deﬁciency on discontinuation. Management of infertility in oestrogen-deﬁcient women is described on page 656. Male hypogonadism The clinical features of both hypo- and hypergonadotrophic hypogonadism include loss of libido, lethargy with muscle weakness, and decreased frequency of shaving. Patients may also present with gynaecomastia, infertility, delayed puberty, osteoporosis or anaemia of chronic disease. The causes of hypogonadism are listed in Box 18.20. Mild hypogonadism may also occur in older men, particularly in the context of central adiposity and the metabolic syndrome (p. 730). Postulated mechanisms are complex and include reduction in sex hormonebinding globulin by insulin resistance and reduction in GnRH and gonadotrophin secretion by cytokines or oestrogen released by adipose tissue. Testosterone levels also fall gradually with age in men (see Box 18.30) and this is associated with gonadotrophin levels that are low or inappropriately within the ‘normal’ range. There is an increasing trend to measure testosterone in older men, typically as part of an assessment of erectile dysfunction and lack of libido. Investigations Male hypogonadism is conﬁrmed by demonstrating a low fasting 0900-hr serum testosterone level. The distinction between hypo- and hypergonadotrophic hypogonadism is by measurement of random LH and FSH. Patients with hypogonadotrophic hypogonadism should be investigated as described for pituitary disease on page 680. Patients with hypergonadotrophic hypogonadism should have the testes examined for cryptorchidism or atrophy, and a karyotype should be performed (to identify Klinefelter’s syndrome). Management Testosterone replacement is clearly indicated in younger men with signiﬁcant hypogonadism to prevent osteoporosis and to restore muscle power and libido. Debate exists as to whether replacement therapy is of beneﬁt in mild hypogonadism associated with ageing and central adiposity, particularly in the absence of structural pituitary/hypothalamic disease or other pituitary hormone deﬁciency. In such instances, a therapeutic trial of testosterone therapy may be considered if symptoms are present (e.g. low libido and erectile dysfunction), but the beneﬁts of therapy must be carefully weighed against the potential for harm. Routes of testosterone administration are shown in Box 18.24. First-pass hepatic metabolism of testosterone is highly efﬁcient, so bioavailability of ingested preparations is poor. Doses of systemic testosterone can be titrated against symptoms; circulating testosterone levels may provide only a rough guide to dosage because they may be highly variable (Box 18.24). Testosterone therapy can aggravate prostatic carcinoma; prostate-speciﬁc antigen (PSA) should be measured before commencing testosterone therapy in men older than 50 years and monitored annually thereafter. Haemoglobin concentration should also be monitored in older men, as androgen replacement can cause polycythaemia. Testosterone replacement inhibits spermatogenesis; treatment for fertility is described below. syndrome (PCOS, p. 658). The presence of other autoimmune disease raises the possibility of autoimmune premature ovarian failure. Investigations Pregnancy should be excluded in women of reproductive age by measuring urine or serum hCG. Serum LH, FSH, oestradiol, prolactin, testosterone, T4 and TSH should be measured and, in the absence of a menstrual cycle, can be taken at any time. Investigation of hyperprolactinaemia is described on page 684. High concentrations of LH and FSH with low or low-normal oestradiol suggest primary ovarian failure. Ovarian autoantibodies may be positive when there is an underlying autoimmune aetiology, and a karyotype should be performed in younger women to exclude mosaic Turner’s syndrome. Elevated LH, prolactin and testosterone levels with normal oestradiol are common in PCOS. Low levels of LH, FSH and oestradiol suggest hypothalamic or pituitary disease and a pituitary MRI is indicated. There is some overlap in gonadotrophin and oestrogen concentrations between women with hypogonadotrophic hypogonadism and PCOS. If there is doubt as to the underlying cause of secondary amenorrhoea, then the response to 5 days of treatment with an oral progestogen (e.g. medroxyprogesterone acetate 10 mg twice daily) can be assessed. In women with PCOS, the progestogen will cause maturation of the endometrium and menstruation will occur a few days after the progestogen is stopped. In women with hypogonadotrophic hypogonadism, menstruation does not occur following progestogen withdrawal because the endometrium is atrophic as a result of oestrogen deﬁciency. If doubt persists in distinguishing oestrogen deﬁciency from a uterine abnormality, the capacity for menstruation can be tested with 1 month of treatment with cyclical oestrogen and progestogen (usually administered as a combined oral contraceptive pill). Assessment of bone mineral density by dual X-ray absorptiometry (DXA, p. 989) may be appropriate in patients with low androgen and oestrogen levels. Management Where possible, the underlying cause should be treated. For example, women with functional amenorrhoea due to excessive exercise and low weight should be encouraged to reduce their exercise and regain some weight. The management of structural pituitary and hypothalamic disease is described on page 684 and that of PCOS on page 658. In oestrogen-deﬁcient women, replacement therapy may be necessary to treat symptoms and/or to prevent osteoporosis. Women who have had a hysterectomy can be treated with oestrogen alone but those with a uterus should be treated with combined oestrogen/progestogen therapy, since unopposed oestrogen increases the risk of endometrial cancer. Cyclical hormone replacement therapy (HRT) regimens typically involve giving oestrogen on days 1–21 and progestogen on days 14–21 of the cycle, and this can be conveniently administered as the oral contraceptive pill. If oestrogenic side-effects (ﬂuid retention, weight gain, hypertension and thrombosis) are a concern, then lower-dose oral or transdermal HRT may be more appropriate. The timing of the discontinuation of oestrogen replacement therapy is still a matter of debate. In post-menopausal women, HRT has been shown to relieve menopausal symptoms and to prevent osteoporotic fractures but is associated with adverse effects, which are related to the duration of therapy and to the

656 • ENDOCRINOLOGY Clinical assessment A history of previous pregnancies, relevant infections and surgery is important in both men and women. A sexual history must be explored sensitively, as some couples have intercourse infrequently or only when they consider the woman to be ovulating, and psychosexual difficulties are common. Irregular and/or infrequent menstrual periods are an indicator of anovulatory cycles in the woman, in which case causes such as PCOS should be considered. In men, the testes should be examined to conﬁrm that both are in the scrotum and to identify any structural abnormality, such as small size, absent vas deferens or the presence of a varicocele. Investigations Investigations should generally be performed after a couple has failed to conceive despite unprotected intercourse for 12 months, unless there is an obvious abnormality like amenorrhoea. Both partners need to be investigated. The male partner needs a semen analysis to assess sperm count and quality. Home testing for ovulation (by commercial urine dipstick kits, temperature measurement, or assessment of cervical mucus) is not recommended, as the information is often counterbalanced by increased anxiety if interpretation is inconclusive. In women with regular periods, ovulation can be conﬁrmed by an elevated serum progesterone concentration on day 21 of the menstrual cycle. Transvaginal ultrasound can be used to assess uterine and ovarian anatomy. Tubal patency may be examined at laparoscopy or by hysterosalpingography (HSG; a radio-opaque medium is injected into the uterus and should normally outline the Fallopian tubes). In vitro assessments of sperm survival in cervical mucus may be done in cases of unexplained infertility but are rarely helpful. Management Couples should be advised to have regular sexual intercourse, ideally every 2–3 days throughout the menstrual cycle. It is not uncommon for ‘spontaneous’ pregnancies to occur in couples undergoing investigations for infertility or with identiﬁed causes of male or female subfertility. In women with anovulatory cycles secondary to PCOS (p. 658), clomifene, which has partial anti-oestrogen action, blocks negative feedback of oestrogen on the hypothalamus/pituitary, causing gonadotrophin secretion and thus ovulation. In women with gonadotrophin deﬁciency or in whom anti-oestrogen therapy is unsuccessful, ovulation may be induced by direct stimulation of the ovary by daily injection of FSH and an injection of hCG to Infertility Infertility affects around 1 in 7 couples of reproductive age, often causing psychological distress. The main causes are listed in Box 18.25. In women, it may result from anovulation or abnormalities of the reproductive tract that prevent fertilisation or embryonic implantation, often damaged Fallopian tubes from previous infection. In men, infertility may result from impaired sperm quality (e.g. reduced motility) or reduced sperm number. Azoospermia or oligospermia is usually idiopathic but may be a consequence of hypogonadism (see Box 18.20). Microdeletions of the Y chromosome are increasingly recognised as a cause of severely abnormal spermatogenesis. In many couples, more than one factor causing subfertility is present, and in a large proportion no cause can be identiﬁed. 18.24 Options for androgen replacement therapy Route of administration Preparation Dose Frequency Comments Intramuscular Testosterone enantate 50–250 mg Every 3–4 weeks Produces peaks and troughs of testosterone levels that are outside the physiological range and may be symptomatic Testosterone undecanoate 1000 mg Every 3 months Smoother proﬁle than testosterone enantate, with less frequent injections Subcutaneous Testosterone pellets 600–800 mg Every 4–6 months Smoother proﬁle than testosterone enantate but implantation causes scarring and infection Transdermal Testosterone patch 5–10 mg Daily Stable testosterone levels but high incidence of skin hypersensitivity Testosterone gel 50–100 mg Daily Stable testosterone levels; transfer of gel can occur following skin-to-skin contact with another person Oral Testosterone undecanoate 40–120 mg Twice daily Very variable testosterone levels; risk of hepatotoxicity 18.25 Causes of infertility Female factor (35–40%) • Ovulatory dysfunction: Polycystic ovarian syndrome Hypogonadotrophic hypogonadism (see Box 18.20) Hypergonadotrophic hypogonadism (see Box 18.20) • Tubular dysfunction: Pelvic inﬂammatory disease (chlamydia, gonorrhoea) Endometriosis Previous sterilisation Previous pelvic or abdominal surgery • Cervical and/or uterine dysfunction: Congenital abnormalities Fibroids Treatment for cervical carcinoma Asherman’s syndrome Male factor (35–40%) • Reduced sperm quality or production: Y chromosome microdeletions Varicocele Hypergonadotrophic hypogonadism (see Box 18.20) Hypogonadotrophic hypogonadism (see Box 18.20) • Tubular dysfunction: Varicocele Congenital abnormality of vas deferens/epididymis Previous sexually transmitted infection (chlamydia, gonorrhoea) Previous vasectomy Unexplained or mixed factor (20–35%)

The reproductive system • 657

reach adult levels before testosterone) and in elderly men (due to decreasing testosterone concentrations). Prolactin excess alone does not cause gynaecomastia (p. 684). Clinical assessment A drug history is important. Gynaecomastia is often asymmetrical and palpation may allow breast tissue to be distinguished from the prominent adipose tissue (lipomastia) around the nipple that is often observed in obesity. Features of hypogonadism should be sought (see above) and the testes examined for evidence of cryptorchidism, atrophy or a tumour. Investigations If a clinical distinction between gynaecomastia and adipose tissue cannot be made, then ultrasonography or mammography is required. A random blood sample should be taken for testosterone, LH, FSH, oestradiol, prolactin and hCG. Elevated oestrogen concentrations are found in testicular tumours and hCG-producing neoplasms. Management An adolescent with gynaecomastia who is progressing normally through puberty may be reassured that the gynaecomastia will usually resolve once development is complete. If puberty does not proceed normally, then there may be an underlying abnormality that requires investigation (p. 653). Gynaecomastia may cause signiﬁcant psychological distress, especially in adolescent boys, and surgical excision may be justiﬁed for cosmetic reasons. Androgen replacement will usually improve gynaecomastia in hypogonadal males and any other identiﬁable underlying cause should be addressed if possible. The anti-oestrogen tamoxifen may also be effective in reducing the size of the breast tissue. Hirsutism Hirsutism refers to the excessive growth of terminal hair (the thick, pigmented hair usually associated with the adult male chest) in an androgen-dependent distribution in women (upper lip, chin, chest, back, lower abdomen, thigh, forearm) and is one of the most common presentations of endocrine disease. It should be distinguished from hypertrichosis, which is generalised excessive growth of vellus hair (the thin, non-pigmented hair that is typically found all over the body from childhood onwards). The aetiology of androgen excess is shown in Box 18.27. Clinical assessment The severity of hirsutism is subjective. Some women suffer profound embarrassment from a degree of hair growth that others would not consider remarkable. Important observations are a drug and menstrual history, calculation of body mass index, measurement of blood pressure, and examination for virilisation (clitoromegaly, deep voice, male-pattern balding, breast atrophy) and associated features, including acne vulgaris or Cushing’s syndrome (p. 666). Hirsutism of recent onset associated with virilisation is suggestive of an androgen-secreting tumour but this is rare. Investigations A random blood sample should be taken for testosterone, prolactin, LH and FSH. If there are clinical features of Cushing’s syndrome, further investigations should be performed (p. 667). If testosterone levels are more than twice the upper limit of normal for females, idiopathic hirsutism and PCOS are less likely, especially if LH and FSH levels are low. Under these induce follicular rupture at the appropriate time. In hypothalamic disease, pulsatile GnRH therapy with a portable infusion pump can be used to stimulate pituitary gonadotrophin secretion (note that non-pulsatile administration of GnRH or its analogues paradoxically suppresses LH and FSH secretion). Whatever method of ovulation induction is employed, monitoring of response is essential to avoid multiple ovulation. For clomifene, ultrasound monitoring is recommended for at least the ﬁrst cycle. During gonadotrophin therapy, closer monitoring of follicular growth by transvaginal ultrasonography and blood oestradiol levels is mandatory. ‘Ovarian hyperstimulation syndrome’ is characterised by grossly enlarged ovaries and capillary leak with circulatory shock, pleural effusions and ascites. Anovulatory women who fail to respond to ovulation induction or who have primary ovarian failure may wish to consider using donated eggs or embryos, surrogacy and adoption. Surgery to restore Fallopian tube patency can be effective but in vitro fertilisation (IVF) is normally recommended. IVF is widely used for many causes of infertility and in unexplained cases of prolonged (> 3 years) infertility. The success of IVF depends on age, with low success rates in women over 40 years. Men with hypogonadotrophic hypogonadism who wish fertility are usually given injections of hCG several times a week (recombinant FSH may also be required in men with hypogonadism of pre-pubertal origin); it may take up to 2 years to achieve satisfactory sperm counts. Surgery is rarely an option in primary testicular disease but removal of a varicocele can improve semen quality. Extraction of sperm from the epididymis for IVF, and intracytoplasmic sperm injection (ICSI, when single spermatozoa are injected into each oöcyte) are being used increasingly in men with oligospermia or poor sperm quality who have primary testicular disease. Azoospermic men may opt to use donated sperm but this may be in short supply. Gynaecomastia Gynaecomastia is the presence of glandular breast tissue in males. Normal breast development in women is oestrogen-dependent, while androgens oppose this effect. Gynaecomastia results from an imbalance between androgen and oestrogen activity, which may reﬂect androgen deﬁciency or oestrogen excess. Causes are listed in Box 18.26. The most common are physiological: for example, in the newborn baby (due to maternal and placental oestrogens), in pubertal boys (in whom oestradiol concentrations 18.26 Causes of gynaecomastia Idiopathic Physiological Drug-induced • Cimetidine • Digoxin • Anti-androgens (cyproterone acetate, spironolactone) • Some exogenous anabolic steroids (diethylstilbestrol) • Cannabis Hypogonadism (see Box 18.20) Androgen resistance syndromes Oestrogen excess • Liver failure (impaired steroid metabolism) • Oestrogen-secreting tumour (e.g. of testis) • Human chorionic gonadotrophin-secreting tumour (e.g. of testis or lung)

658 • ENDOCRINOLOGY Women with PCOS are at increased risk of glucose intolerance and some authorities recommend screening for type 2 diabetes and other cardiovascular risk factors associated with the metabolic syndrome (p. 730). Management This should be directed at the presenting complaint but all PCOS patients who are overweight should be encouraged to lose weight, as this can improve several symptoms, including menstrual irregularity, and reduces the risk of type 2 diabetes. circumstances, other causes of androgen excess should be sought. Congenital adrenal hyperplasia due to 21-hydroxylase deﬁciency is diagnosed by a short ACTH stimulation test with measurement of 17-OH-progesterone (p. 676). In patients with androgen-secreting tumours, serum testosterone does not suppress following a 48-hour low-dose dexamethasone suppression test. The tumour should then be sought by CT or MRI of the adrenals and ovaries. Management This depends on the cause (Box 18.27). Options for the treatment of PCOS and idiopathic hirsutism are similar and are described below. Polycystic ovarian syndrome Polycystic ovarian syndrome (PCOS) affects up to 10% of women of reproductive age. It is a heterogeneous disorder (Box 18.28), often associated with obesity, for which the primary cause remains uncertain. Genetic factors probably play a role, since PCOS often affects several family members. The severity and clinical features of PCOS vary markedly between individual patients but diagnosis is usually made during the investigation of hirsutism (p. 657) or amenorrhoea/oligomenorrhoea (p. 655). Infertility may also be present (p. 656). There is no universally accepted deﬁnition but it has been recommended that a diagnosis of PCOS requires the presence of two of the following three features: • menstrual irregularity • clinical or biochemical androgen excess • multiple cysts in the ovaries (most readily detected by transvaginal ultrasound; Fig. 18.15). 18.27 Causes of hirsutism Cause Clinical features Investigation ﬁndings Treatment Idiopathic Often familial Mediterranean or Asian background Normal Cosmetic measures Anti-androgens Polycystic ovarian syndrome Obesity Oligomenorrhoea or secondary amenorrhoea Infertility LH:FSH ratio > 2.5:1 Minor elevation of androgens* Mild hyperprolactinaemia Weight loss Cosmetic measures Anti-androgens (Metformin, glitazones may be useful) Congenital adrenal hyperplasia (95% 21-hydroxylase deﬁciency) Pigmentation History of salt-wasting in childhood, ambiguous genitalia, or adrenal crisis when stressed Jewish background Elevated androgens* that suppress with dexamethasone Abnormal rise in 17-OH-progesterone with ACTH Glucocorticoid replacement administered in reverse rhythm to suppress early morning ACTH Exogenous androgen administration Athletes Virilisation Low LH and FSH Analysis of urinary androgens may detect drug of misuse Stop steroid misuse Androgen-secreting tumour of ovary or adrenal cortex Rapid onset Virilisation: clitoromegaly, deep voice, balding, breast atrophy High androgens* that do not suppress with dexamethasone Low LH and FSH CT or MRI usually demonstrates a tumour Surgical excision Cushing’s syndrome Clinical features of Cushing’s syndrome (p. 667) Normal or mild elevation of adrenal androgens* See investigations (p. 667) Treat the cause (p. 667) e.g. Serum testosterone levels in women: < 2 nmol/L (< 58 ng/dL) is normal; 2–5 nmol/L (58–144 ng/dL) is minor elevation; > 5 nmol/L (> 144 ng/dL) is high and requires further investigation. (ACTH = adrenocorticotrophic hormone; CT = computed tomography; FH = follicle-stimulating hormone; LH = luteinising hormone; MRI = magnetic resonance imaging) 18.28 Features of polycystic ovarian syndrome Mechanisms Manifestations Pituitary dysfunction High serum LH High serum prolactin Anovulatory menstrual cycles Oligomenorrhoea Secondary amenorrhoea Cystic ovaries Infertility Androgen excess Hirsutism Acne Obesity Hyperglycaemia Elevated oestrogens Insulin resistance Dyslipidaemia Hypertension *These mechanisms are interrelated; it is not known which, if any, is primary. PCOS probably represents the common endpoint of several different pathologies. (LH = luteinising hormone)

The reproductive system • 659

doctor. Electrolysis and laser treatment are effective for small areas like the upper lip and for chest hair but are expensive. Eﬂornithine cream inhibits ornithine decarboxylase in hair follicles and may reduce hair growth when applied daily to affected areas of the face. If conservative measures are unsuccessful, anti-androgen therapy is given (Box 18.29). The life cycle of a hair follicle is at least 3 months and no improvement is likely before this time, when follicles have shed their hair and replacement hair growth has been suppressed. Metformin and thiazolidinediones are less effective at treating hirsutism than at restoring menstrual regularity. Unless weight is lost, hirsutism will return if therapy is discontinued. The patient should know that prolonged exposure to some agents may not be desirable and they should be stopped before pregnancy. Turner’s syndrome Turner’s syndrome affects around 1 in 2500 females. It is classically associated with a 45XO karyotype but other cytogenetic abnormalities may be responsible, including mosaic forms (e.g. 45XO/46XX or 45XO/46XY) and partial deletions of an X chromosome. Clinical features These are shown in Figure 18.16. Individuals with Turner’s syndrome invariably have short stature from an early age and this is often the initial presenting symptom. It is probably due to haploinsufﬁciency of the SHOX gene, one copy of which is found on both the X and Y chromosomes, which encodes a protein that is predominantly found in bone ﬁbroblasts. The genital tract and external genitalia in Turner’s syndrome are female in character, since this is the default developmental outcome in the absence of testes. Ovarian tissue develops normally until the third month of gestation, but thereafter there is gonadal dysgenesis with accelerated degeneration of oöcytes and increased ovarian stromal ﬁbrosis, resulting in ‘streak ovaries’. The inability of ovarian tissue to produce oestrogen results in loss of negative feedback and elevation of FSH and LH concentrations. There is a wide variation in the spectrum of associated somatic abnormalities. The severity of the phenotype is, in part, related to Menstrual irregularity and infertility Most women with PCOS have oligomenorrhoea, with irregular, heavy menstrual periods. This may not require treatment unless fertility is desired. Metformin (p. 746), by reducing insulin resistance, may restore regular ovulatory cycles in overweight women, although it is less effective than clomifene (p. 656) at restoring fertility as measured by successful pregnancy. Thiazolidinediones (p. 747) also enhance insulin sensitivity and restore menstrual regularity in PCOS but are contraindicated in women planning pregnancy. In women who have very few periods each year or are amenorrhoeic, the high oestrogen concentrations associated with PCOS can cause endometrial hyperplasia. Progestogens can be administered on a cyclical basis to induce regular shedding of the endometrium and a withdrawal bleed, or a progestogenimpregnated intrauterine coil can be ﬁtted. Hirsutism For hirsutism, most patients will have used cosmetic measures, such as shaving, bleaching and waxing, before consulting a Fig. 18.15 Polycystic ovary. A transvaginal ultrasound scan showing multiple cysts (some indicated by small arrows) in the ovary (highlighted by bigger arrows) of a woman with polycystic ovarian syndrome. 18.29 Anti-androgen therapy Mechanism of action Drug Dose Hazards Androgen receptor antagonism Cyproterone acetate 2, 50 or 100 mg on days 1–11 of 28-day cycle with ethinylestradiol 30 μg on days 1–21 Hepatic dysfunction Feminisation of male fetus Progesterone receptor agonist Dysfunctional uterine bleeding Spironolactone 100–200 mg daily Electrolyte disturbance Flutamide Not recommended Hepatic dysfunction 5α-reductase inhibition (prevent conversion of testosterone to active dihydrotestosterone) Finasteride 5 mg daily Limited clinical experience; possibly less efﬁcacious than other treatments Suppression of ovarian steroid production and elevation of sex hormone-binding globulin Oestrogen See combination with cyproterone acetate above or Conventional oestrogen-containing contraceptive Venous thromboembolism Hypertension Weight gain Dyslipidaemia Increased breast and endometrial carcinoma

660 • ENDOCRINOLOGY Clinical features The diagnosis is typically made in adolescents who have presented with gynaecomastia and failure to progress normally through puberty. Affected individuals usually have small, ﬁrm testes. Tall stature is apparent from early childhood, reﬂecting characteristically long leg length associated with 47XXY, and may be exacerbated by androgen deﬁciency with lack of epiphyseal closure in puberty. Other clinical features may include learning difﬁculties and behavioural disorders, as well as an increased risk of breast cancer and type 2 diabetes in later life. The spectrum of clinical features is wide and some individuals, especially the underlying cytogenetic abnormality. Mosaic individuals may have only mild short stature and may enter puberty spontaneously before developing gonadal failure. Diagnosis and management The diagnosis of Turner’s syndrome can be confirmed by karyotype analysis. Short stature, although not directly due to growth hormone deficiency, responds to high doses of growth hormone. Prophylactic gonadectomy is recommended for individuals with 45XO/46XY mosaicism because there is an increased risk of gonadoblastoma. Pubertal development can be induced with oestrogen therapy but causes fusion of the epiphyses and cessation of growth. The timing of pubertal induction therefore needs to be carefully planned. Adults with Turner’s syndrome require long-term oestrogen replacement therapy and should be monitored periodically for the development of aortic root dilatation, hearing loss and other somatic complications. Klinefelter’s syndrome Klinefelter’s syndrome affects approximately 1 in 1000 males and is usually associated with a 47XXY karyotype. However, other cytogenetic variants may be responsible, especially 46XY/47XXY mosaicism. The principal pathological abnormality is dysgenesis of the seminiferous tubules. This is evident from infancy (and possibly even in utero) and progresses with age. By adolescence, hyalinisation and ﬁbrosis are present within the seminiferous tubules and Leydig cell function is impaired, resulting in hypogonadism. Fig. 18.16 Clinical features of Turner’s syndrome (45XO). (IGT = impaired glucose tolerance; LFTs = liver function tests) Psychological problems Impaired visuospatial processing Reduced IQ (ring chromosome X) Low-set ears Sensorineural/conduction hearing loss Webbing of neck (25–40%) Widely spaced nipples Shield chest Type 2 diabetes/IGT (10–30%) Wide carrying angle of elbows Lymphoedema of hands and feet ( 30%) Reduced bone mineral density Inflammatory bowel disease (0.2–0.3%) Horseshoe kidneys and other renal and collecting system abnormalities Bicuspid aortic valve Aortic root dilatation Coronary artery disease Autoimmune thyroid disease (20%) Streak gonads Gonadoblastoma (XY mosaic) Abnormal LFTs (30 – 80%) Short stature Fish-like mouth High-arched palate Coarctation of aorta Hypertension 18.30 Gonadal function in old age • Post-menopausal osteoporosis: a major public health issue due to the high incidence of associated fragility fractures, especially of hip. • Hormone replacement therapy: should be prescribed only above the age of 50 for the short-term relief of symptoms of oestrogen deﬁciency. • Sexual activity: many older people remain sexually active. • ‘Male menopause’: does not occur, although testosterone concentrations do fall with age. Testosterone therapy in mildly hypogonadal men may be of beneﬁt for body composition, muscle and bone. Large randomised trials are required to determine whether beneﬁts outweigh potentially harmful effects on the prostate and cardiovascular system. • Androgens in older women: hirsutism and balding occur. In those rare patients with elevated androgen levels, this may be pathological, e.g. from an ovarian tumour.

The parathyroid glands • 661

metabolite, 1,25-dihydroxyvitamin D; the 1,25-dihydroxyvitamin D, in turn, enhances calcium absorption from the gut. More than 99% of total body calcium is in bone. Prolonged exposure of bone to high levels of PTH is associated with increased osteoclastic activity and new bone formation, but the net effect is to cause bone loss with mobilisation of calcium into the extracellular ﬂuid. In contrast, pulsatile release of PTH causes net bone gain, an effect that is exploited therapeutically in the treatment of osteoporosis (p. 1048). The differential diagnosis of disorders of calcium metabolism requires measurement of calcium phosphate, alkaline phosphatase, renal function, PTH and 25-hydroxyvitamin D. Although the parathyroid glands detect and respond to ionised calcium levels, most clinical laboratories measure only total serum calcium levels. About 50% of total calcium is bound to organic ions, such as citrate or phosphate, and to proteins, especially albumin. Accordingly, if the serum albumin level is reduced, total calcium concentrations should be ‘corrected’ by adjusting the value for calcium upwards by 0.02 mmol/L (0.08 mg/dL) for each 1 g/L reduction in albumin below 40 g/L. If albumin concentrations are signiﬁcantly low, as in severe acute illness and other chronic illness such as liver cirrhosis, this correction is less accurate and measurement of ionised calcium is needed. Calcitonin is secreted from the parafollicular C cells of the thyroid gland. Although it is a useful tumour marker in medullary carcinoma of thyroid (p. 650) and can be given therapeutically in Paget’s disease of bone (p. 1053), its release from the thyroid is of no clinical relevance to calcium homeostasis in humans. Disorders of the parathyroid glands are summarised in Box 18.31. Presenting problems in parathyroid disease Hypercalcaemia Hypercalcaemia is one of the most common biochemical abnormalities and is often detected during routine biochemical analysis in asymptomatic patients. However, it can present with chronic symptoms, as described below, and occasionally as an acute emergency with severe hypercalcaemia and dehydration. those with 46XY/47XXY mosaicism, may pass through puberty normally and be identiﬁed only during investigation for infertility. Diagnosis and management Klinefelter’s syndrome is suggested by the typical phenotype in a patient with hypergonadotrophic hypogonadism and can be conﬁrmed by karyotype analysis. Individuals with clinical and biochemical evidence of androgen deﬁciency require androgen replacement (see Box 18.24). There are reports of successful pregnancy occurring following ICSI therapy where spermatocytes have been retrieved from the gonads of men with Klinefelter’s syndrome. The parathyroid glands Parathyroid hormone (PTH) plays a key role in the regulation of calcium and phosphate homeostasis and vitamin D metabolism, as shown in Figure 24.61 (p. 1051). The consequences of altered function of this axis in gut and renal disease are covered on pages 783 and 418, respectively. Other metabolic bone diseases are explored on page 1044. Here, the investigation of hypercalcaemia and hypocalcaemia and disorders of the parathyroid glands are discussed. Functional anatomy, physiology and investigations The four parathyroid glands lie behind the lobes of the thyroid and weigh between 25 and 40 mg. The parathyroid chief cells respond directly to changes in calcium concentrations via a G protein-coupled cell surface receptor (the calcium-sensing receptor) located on the cell surface (see Fig. 25.55). When serum ionised calcium levels fall, PTH secretion rises. PTH is a single-chain polypeptide of 84 amino acids. It acts on the renal tubules to promote reabsorption of calcium and reduce reabsorption of phosphate, and on the skeleton to increase osteoclastic bone resorption and bone formation. PTH also promotes the conversion of 25-hydroxyvitamin D to the active 18.31 Classiﬁcation of diseases of the parathyroid glands Primary Secondary Hormone excess Primary hyperparathyroidism Parathyroid adenoma Parathyroid carcinoma1 Parathyroid hyperplasia2 Tertiary hyperparathyroidism Following prolonged secondary hyperparathyroidism Secondary hyperparathyroidism Chronic kidney disease Malabsorption Vitamin D deﬁciency Hormone deﬁciency Hypoparathyroidism Post-surgical Autoimmune Inherited Hormone hypersensitivity Autosomal dominant hypercalciuric hypocalcaemic (CASR-activating mutation) Hormone resistance Pseudohypoparathyroidism Familial hypocalciuric hypercalcaemia Non-functioning tumours Parathyroid carcinoma1 1Parathyroid carcinomas may or may not produce parathyroid hormone. 2ln multiple endocrine neoplasia (MEN) syndromes (p. 688). (CASR = calcium-sensing receptor)

662 • ENDOCRINOLOGY 5% of ﬁrst stone formers and 15% of recurrent stone formers have primary hyperparathyroidism (p. 663). Hypertension is a common feature of hyperparathyroidism. Parathyroid tumours are almost never palpable. A family history of hypercalcaemia raises the possibility of FHH or MEN (p. 688). Investigations The most discriminatory investigation is measurement of PTH. If PTH levels are detectable or elevated in the presence of hypercalcaemia, then primary hyperparathyroidism is the most likely diagnosis. High plasma phosphate and alkaline phosphatase accompanied by renal impairment suggest tertiary hyperparathyroidism. Hypercalcaemia may cause nephrocalcinosis and renal tubular impairment, resulting in hyperuricaemia and hyperchloraemia. Patients with FHH can present with a similar biochemical picture to primary hyperparathyroidism but typically have low urinary calcium excretion (a ratio of urinary calcium clearance to creatinine clearance of < 0.01). The diagnosis of FHH can be conﬁrmed by screening family members for hypercalcaemia and/ or identifying an inactivating mutation in the gene encoding the calcium-sensing receptor. If PTH is low and no other cause is apparent, then malignancy with or without bony metastases is likely. PTH-related peptide, which is often responsible for the hypercalcaemia associated with malignancy, is not detected by PTH assays, but can be measured by a speciﬁc assay (although this is not usually necessary). Unless the source is obvious, the patient should be screened for malignancy with a chest X-ray, myeloma screen (p. 967) and CT as appropriate. Management Treatment of severe hypercalcaemia and primary hyperparathyroidism is described on pages 663 and 1327, respectively. FHH does not require any speciﬁc intervention. Hypocalcaemia Aetiology Hypocalcaemia is much less common than hypercalcaemia. The differential diagnosis is shown in Box 18.33. The most common Causes of hypercalcaemia are listed in Box 18.32. Of these, primary hyperparathyroidism and malignant hypercalcaemia are by far the most common. Familial hypocalciuric hypercalcaemia (FHH) is a rare but important cause that needs differentiation from primary hyperparathyroidism (HPT). Lithium may cause hyperparathyroidism by reducing the sensitivity of the calciumsensing receptor. Clinical assessment Symptoms and signs of hypercalcaemia include polyuria and polydipsia, renal colic, lethargy, anorexia, nausea, dyspepsia and peptic ulceration, constipation, depression, drowsiness and impaired cognition. Patients with malignant hypercalcaemia can have a rapid onset of symptoms and may have clinical features that help to localise the tumour. The classic symptoms of primary hyperparathyroidism are described by the adage ‘bones, stones and abdominal groans’, but few patients present in this way nowadays and the disorder is most often picked up as an incidental ﬁnding on biochemical testing. About 50% of patients with primary hyperparathyroidism are asymptomatic while others have non-speciﬁc symptoms such as fatigue, depression and generalised aches and pains. Some present with renal calculi and it has been estimated that 18.32 Causes of hypercalcaemia With normal or elevated parathyroid hormone (PTH) levels • Primary or tertiary hyperparathyroidism • Lithium-induced hyperparathyroidism • Familial hypocalciuric hypercalcaemia With low PTH levels • Malignancy (lung, breast, myeloma, renal, lymphoma, thyroid) • Elevated 1,25-dihydroxyvitamin D (vitamin D intoxication, sarcoidosis, human immunodeﬁciency virus, other granulomatous disease) • Thyrotoxicosis • Paget’s disease with immobilisation • Milk-alkali syndrome • Thiazide diuretics • Glucocorticoid deﬁciency 18.33 Differential diagnosis of hypocalcaemia Total serum calcium Ionised serum calcium Serum phosphate Serum PTH Comments Hypoalbuminaemia ↓ ↔ ↔ ↔ Adjust calcium upwards by 0.02 mmol/L (0.1 mg/dL) for every 1 g/L reduction in albumin below 40 g/L Alkalosis ↔ ↓ ↔ ↔ or ↑ p. 366 Vitamin D deﬁciency ↓ ↓ ↓ ↑ p. 1049 Chronic renal failure ↓ ↓ ↑ ↑ Due to impaired vitamin D hydroxylation Serum creatinine ↑ Hypoparathyroidism ↓ ↓ ↑ ↓ See text Pseudohypoparathyroidism ↓ ↓ ↑ ↑ Characteristic phenotype (see text) Acute pancreatitis ↓ ↓ ↔ or ↓ ↑ Usually clinically obvious Serum amylase ↑ Hypomagnesaemia ↓ ↓ Variable ↓ or ↔ Treatment of hypomagnesaemia may correct hypocalcaemia (↑ = levels increased; ↓ = levels reduced; ↔ = levels normal)

The parathyroid glands • 663

Primary hyperparathyroidism Primary hyperparathyroidism is caused by autonomous secretion of PTH, usually by a single parathyroid adenoma, which can vary in diameter from a few millimetres to several centimetres. It should be distinguished from secondary hyperparathyroidism, in which there is a physiological increase in PTH secretion to compensate for prolonged hypocalcaemia (such as in vitamin D deﬁciency, p. 1049), and from tertiary hyperparathyroidism, in which continuous stimulation of the parathyroids over a prolonged period of time results in adenoma formation and autonomous PTH secretion (Box 18.35). This is most commonly seen in individuals with advanced chronic kidney disease (p. 418). The prevalence of primary hyperparathyroidism is about 1 in 800 and it is 2–3 times more common in women than men; 90% of patients are over 50 years of age. It also occurs in the familial MEN syndromes (p. 688), in which case hyperplasia or multiple adenomas of all four parathyroid glands are more likely than a solitary adenoma. Clinical and radiological features The clinical presentation of primary hyperparathyroidism is described on page 667. Parathyroid bone disease is now rare due to earlier diagnosis and treatment. Osteitis ﬁbrosa results from increased bone resorption by osteoclasts with fibrous replacement in the lacunae. This may present as bone pain and tenderness, fracture and deformity. Chondrocalcinosis can occur due to deposition of calcium pyrophosphate crystals within articular cartilage. It typically affects the menisci at the knees and can result in secondary degenerative arthritis or predispose to attacks of acute pseudogout (p. 1016). Skeletal X-rays are usually normal in mild primary hyperparathyroidism, but in patients with advanced disease characteristic changes are observed. In the early stages there is demineralisation, with subperiosteal erosions and terminal resorption in the phalanges. A ‘pepper-pot’ appearance may be seen on lateral X-rays of the skull. Reduced bone mineral density, resulting in either osteopenia or osteoporosis, is now the most common skeletal manifestation of hyperparathyroidism. This is usually not evident radiographically and requires assessment by DXA (p. 989). In nephrocalcinosis, scattered opacities may be visible within the renal outline. There may be soft tissue calciﬁcation in arterial walls and hands and in the cornea. Investigations The diagnosis can be conﬁrmed by ﬁnding a raised PTH level in the presence of hypercalcaemia, provided that FHH is excluded cause of hypocalcaemia is a low serum albumin with normal ionised calcium concentration. Conversely, ionised calcium may be low in the face of normal total serum calcium in patients with alkalosis: for example, as a result of hyperventilation. Hypocalcaemia may also develop as a result of magnesium depletion and should be considered in patients with malabsorption, those on diuretic or proton pump inhibitor therapy, and/or those with a history of alcohol excess. Magnesium deﬁciency causes hypocalcaemia by impairing the ability of the parathyroid glands to secrete PTH (resulting in PTH concentrations that are low or inappropriately in the reference range) and may also impair the actions of PTH on bone and kidney. Clinical assessment Mild hypocalcaemia is often asymptomatic but, with more profound reductions in serum calcium, tetany can occur. This is characterised by muscle spasms due to increased excitability of peripheral nerves. Children are more liable to develop tetany than adults and present with a characteristic triad of carpopedal spasm, stridor and convulsions, although one or more of these may be found independently of the others. In carpopedal spasm, the hands adopt a characteristic position with ﬂexion of the metacarpophalangeal joints of the ﬁngers and adduction of the thumb (‘main d’accoucheur’). Pedal spasm can also occur but is less frequent. Stridor is caused by spasm of the glottis. Adults can also develop carpopedal spasm in association with tingling of the hands and feet and around the mouth, but stridor and ﬁts are rare. Latent tetany may be detected by eliciting Trousseau’s sign: inﬂation of a sphygmomanometer cuff on the upper arm to more than the systolic blood pressure is followed by carpal spasm within 3 minutes. Less speciﬁc is Chvostek’s sign, in which tapping over the branches of the facial nerve as they emerge from the parotid gland produces twitching of the facial muscles. Hypocalcaemia can cause papilloedema and prolongation of the ECG QT interval, which may predispose to ventricular arrhythmias. Prolonged hypocalcaemia and hyperphosphataemia (as in hypoparathyroidism) may cause calciﬁcation of the basal ganglia, grand mal epilepsy, psychosis and cataracts. Hypocalcaemia associated with hypophosphataemia, as in vitamin D deﬁciency, causes rickets in children and osteomalacia in adults (p. 1049). Management Emergency management of hypocalcaemia associated with tetany is given in Box 18.34. Treatment of chronic hypocalcaemia is described on page 1051. 18.34 Management of severe hypocalcaemia Immediate management • 10–20 mL 10% calcium gluconate IV over 10–20 mins • Continuous IV infusion may be required for several hours (equivalent of 10 mL 10% calcium gluconate/hr) • Cardiac monitoring is recommended If associated with hypomagnesaemia • 50 mmol (1.23 g) magnesium chloride IV over 24 hrs • Most parenteral magnesium will be excreted in the urine, so further doses may be required to replenish body stores 18.35 Hyperparathyroidism Type Serum calcium PTH Primary Single adenoma (90%) Multiple adenomas (4%) Nodular hyperplasia (5%) Carcinoma (1%) Raised Not suppressed Secondary Chronic renal failure Malabsorption Osteomalacia and rickets Low Raised Tertiary Raised Not suppressed

664 • ENDOCRINOLOGY always asymptomatic and complications do not occur. The main risk of FHH is that of the patient being subjected to an unnecessary (and ineffective) parathyroidectomy if misdiagnosed as having primary hyperparathyroidism. Testing of family members for hypercalcaemia is helpful in conﬁrming the diagnosis and it is also possible to perform genetic testing. No treatment is necessary. Hypoparathyroidism The most common cause of hypoparathyroidism is damage to the parathyroid glands (or their blood supply) during thyroid surgery. Rarely, hypoparathyroidism can occur as a result of inﬁltration of the glands with iron in haemochromatosis (p. 895) or copper in Wilson’s disease (p. 896). There are a number of rare congenital or inherited forms of hypoparathyroidism. One form is associated with autoimmune polyendocrine syndrome type 1 (p. 689) and another with DiGeorge syndrome (p. 79). Autosomal dominant hypoparathyroidism is the mirror image of FHH (see above), in that an activating mutation in the calcium-sensing receptor reduces PTH levels, resulting in hypocalcaemia and hypercalciuria. Pseudohypoparathyroidism In this disorder, the individual is functionally hypoparathyroid but, instead of PTH deﬁciency, there is tissue resistance to the effects of PTH, such that PTH concentrations are markedly elevated. The PTH receptor itself is normal but the downstream signalling pathways are defective due to mutations that affect GNAS1, which encodes the Gsα protein, a molecule involved in signal transduction downstream of the PTH receptor and other G protein-coupled receptors. There are several subtypes but the most common (pseudohypoparathyroidism type 1a) is characterised by hypocalcaemia and hyperphosphataemia, in association with short stature, short fourth metacarpals and metatarsals, rounded face, obesity and subcutaneous calciﬁcation; these features are collectively referred to as Albright’s hereditary osteodystrophy (AHO). Type 1a pseudohypoparathyroidism occurs only when the GNAS1 mutation is inherited on the maternal chromosome (maternal imprinting, p. 49). The term pseudopseudohypoparathyroidism is used to describe patients who have clinical features of AHO but normal serum calcium and PTH concentrations; it occurs when the GNAS1 mutation is inherited on the paternal chromosome. The inheritance of these disorders is an example of genetic imprinting (p. 49). The difference in clinical features occurs as a result of the fact that renal cells exclusively express the maternal GNAS1 allele, whereas both maternal and paternal alleles are expressed in other cell types; this explains why maternal inheritance is associated with hypocalcaemia and resistance to PTH (which regulates (p. 664). Parathyroid scanning by 99mTc-sestamibi scintigraphy (MIBI; Fig. 18.17) and an ultrasound examination can be performed prior to surgery, in an attempt to localise an adenoma; a concordant ﬁnding of tissue consistent with a parathyroid gland and uptake on the MIBI scan allows a targeted resection. Negative imaging does not exclude the diagnosis, however, and four-gland exploration may be needed. Management The treatment of choice for primary hyperparathyroidism is surgery, with excision of a solitary parathyroid adenoma or hyperplastic glands. Experienced surgeons will identify solitary tumours in more than 90% of cases. Patients with parathyroid bone disease run a signiﬁcant risk of developing hypocalcaemia post-operatively but the risk of this can be reduced by correcting vitamin D deﬁciency pre-operatively. Surgery is usually indicated for individuals aged less than 50 years, with clear-cut symptoms or documented complications (such as renal stones, renal impairment or osteoporosis), and (in asymptomatic patients) signiﬁcant hypercalcaemia (corrected serum calcium > 2.85 mmol/L (> 11.4 mg/dL)). Patients who are treated conservatively without surgery should have calcium biochemistry and renal function checked annually and bone density monitored periodically. They should be encouraged to maintain a high oral ﬂuid intake to avoid renal stones. Occasionally, primary hyperparathyroidism presents with severe life-threatening hypercalcaemia. This is often due to dehydration and should be managed medically with intravenous ﬂuids and bisphosphonates, as described on page 1327. If this is not effective, then urgent parathyroidectomy should be considered. Cinacalcet (p. 419) is a calcimimetic that enhances the sensitivity of the calcium-sensing receptor, so reducing PTH levels, and is licensed for tertiary hyperparathyroidism and as a treatment for patients with primary hyperparathyroidism who are unwilling to have surgery or are medically unﬁt. Familial hypocalciuric hypercalcaemia This autosomal dominant disorder is caused by an inactivating mutation in one of the alleles of the calcium-sensing receptor gene, which reduces the ability of the parathyroid gland to ‘sense’ ionised calcium concentrations. As a result, higher than normal calcium levels are required to suppress PTH secretion. The typical presentation is with mild hypercalcaemia with PTH concentrations that are ‘inappropriately’ at the upper end of the reference range or are slightly elevated. Calcium-sensing receptors in the renal tubules are also affected and this leads to increased renal tubular reabsorption of calcium and hypocalciuria (as measured in the vitamin D-replete individual by a fractional calcium excretion or 24-hour calcium excretion). The hypercalcaemia of FHH is Fig. 18.17 99mTc-sestamibi scan of a patient with primary hyperparathyroidism secondary to a parathyroid adenoma. A After 1 hour, there is uptake in the thyroid gland (thick arrow) and the enlarged left inferior parathyroid gland (thin arrow). B After 3 hours, uptake is evident only in the parathyroid (thin arrow). A B

The adrenal glands • 665

the control of the renin–angiotensin system. These functions are important in the integrated control of cardiovascular, metabolic and immune responses to stress. There is increasing evidence that subtle alterations in adrenal function contribute to the pathogenesis of common diseases such as hypertension, obesity and type 2 diabetes mellitus. However, classical syndromes of adrenal hormone deﬁciency and excess are relatively rare. Functional anatomy and physiology Adrenal anatomy and function are shown in Figure 18.18. Histologically, the cortex is divided into three zones, but these function as two units (zona glomerulosa and zonae fasciculata/ reticularis) that produce corticosteroids in response to humoral stimuli. Pathways for the biosynthesis of corticosteroids are shown in Figure 18.19. Investigation of adrenal function is described under speciﬁc diseases below. The different types of adrenal disease are shown in Box 18.37. Glucocorticoids Cortisol is the major glucocorticoid in humans. Levels are highest in the morning on waking and lowest in the middle of the night. Cortisol rises dramatically during stress, including any illness. This elevation protects key metabolic functions (such as the maintenance of cerebral glucose supply during starvation) and inhibits potentially damaging inﬂammatory responses to infection and injury. The clinical importance of cortisol deficiency is, therefore, most obvious at times of stress. More than 95% of circulating cortisol is bound to protein, principally cortisol-binding globulin, which is increased by oestrogens. It is the free fraction that is biologically active. Cortisol regulates cell function by binding to glucocorticoid receptors that regulate the transcription of many genes. Cortisol can also activate mineralocorticoid receptors, but it does not normally do so because most cells containing mineralocorticoid receptors also express an enzyme called 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2), which inactivates cortisol by converting it to cortisone. Inhibitors of 11β-HSD2 (such as liquorice) or mutations in the gene that encodes 11β-HSD2 cause cortisol to act as a mineralocorticoid, resulting in sodium retention and hypertension (see Box 18.46). serum calcium and phosphate levels largely by an effect on the renal tubule), and why paternal inheritance is associated with skeletal and other abnormalities in the absence of hypocalcaemia and raised PTH values. Management of hypoparathyroidism Persistent hypoparathyroidism and pseudohypoparathyroidism are treated with oral calcium salts and vitamin D analogues, either 1α-hydroxycholecalciferol (alfacalcidol) or 1,25dihydroxycholecalciferol (calcitriol). This therapy needs careful monitoring because of the risks of iatrogenic hypercalcaemia, hypercalciuria and nephrocalcinosis. Recombinant PTH is available as subcutaneous injection therapy for osteoporosis (p. 1048) and, although not currently licensed, has been used in hypoparathyroidism (but not in pseudohypoparathyroidism). It is much more expensive than calcium and vitamin D analogue therapy but has the advantage that it is less likely to cause hypercalciuria. There is no speciﬁc treatment for AHO other than to try to maintain calcium levels within the reference range using active vitamin D metabolites. 18.36 The parathyroid glands in old age • Osteoporosis: always exclude osteomalacia and hyperparathyroidism by checking vitamin D and calcium concentrations. • Primary hyperparathyroidism: more common with ageing. Older people can often be observed without surgical intervention. • Hypercalcaemia: may cause delirium. • Vitamin D deﬁciency: common because of limited exposure to the sun and reduced ability of older skin to synthesise cholecalciferol. 18.37 Classiﬁcation of diseases of the adrenal glands Primary Secondary Hormone excess Non-ACTH-dependent Cushing’s syndrome Primary hyperaldosteronism Phaeochromocytoma ACTH-dependent Cushing’s syndrome Secondary hyperaldosteronism Hormone deﬁciency Addison’s disease Congenital adrenal hyperplasia Hypopituitarism Hormone hypersensitivity 11β-hydroxysteroid dehydrogenase type 2 deﬁciency Liddle’s syndrome Hormone resistance Pseudohypoaldosteronism Glucocorticoid resistance syndrome Non-functioning tumours Adenoma Carcinoma (usually functioning) Metastatic tumours (ACTH = adrenocorticotrophic hormone) The adrenal glands The adrenals comprise several separate endocrine glands within a single anatomical structure. The adrenal medulla is an extension of the sympathetic nervous system that secretes catecholamines into capillaries rather than synapses. Most of the adrenal cortex is made up of cells that secrete cortisol and adrenal androgens, and form part of the hypothalamic–pituitary–adrenal (HPA) axis. The small outer glomerulosa of the cortex secretes aldosterone under

666 • ENDOCRINOLOGY Fig. 18.18 Structure and function of the adrenal glands. (ACE = angiotensin-converting enzyme; ACTH = adrenocorticotrophic hormone; JGA = juxtaglomerular apparatus; MR = mineralocorticoid receptor) Sympathetic nervous system Medulla Adrenaline (epinephrine) Noradrenaline (norepinephrine) β-adrenoceptor α-adrenoceptor Vasodilatation Tachycardia Insulin resistance Vasoconstriction Sympathetic nervous system Adrenal medulla ACTH Cortex Zonae fasciculata and reticularis Hypothalamic – pituitary– adrenal axis Adrenal cortex Zonae fasciculata and reticularis Androgens Cortisol Androgen receptor Glucocorticoid receptor Pubic and axillary hair Libido, especially females Protein catabolism Insulin resistance Immune response Hypertension Increased appetite Memory Na retention K wasting Metabolic alkalosis Low renal perfusion Low filtered Na Sympathetic activation Angiotensin II Cortex Zona glomerulosa Aldosterone Renin – angiotensin – aldosterone axis Adrenal cortex Zona glomerulosa Angiotensin I Angiotensinogen Renin ACE MR JGA Adrenal gland Negative feedback Mineralocorticoids Aldosterone is the most important mineralocorticoid. It binds to mineralocorticoid receptors in the kidney and causes sodium retention and increased excretion of potassium and protons (p. 351). The principal stimulus to aldosterone secretion is angiotensin II, a peptide produced by activation of the renin–angiotensin system (see Fig. 18.18). Renin activity in the juxtaglomerular apparatus of the kidney is stimulated by low perfusion pressure in the afferent arteriole, low sodium ﬁltration leading to low sodium concentrations at the macula densa, or increased sympathetic nerve activity. As a result, renin activity is increased in hypovolaemia and renal artery stenosis, and is approximately doubled when standing up from a recumbent position. Catecholamines In humans, only a small proportion of circulating noradrenaline (norepinephrine) is derived from the adrenal medulla; much more is released from sympathetic nerve endings. Conversion of noradrenaline to adrenaline (epinephrine) is catalysed by catechol O-methyltransferase (COMT), which is induced by glucocorticoids. Blood ﬂow in the adrenal is centripetal, so that the medulla is bathed in high concentrations of cortisol and is the major source of circulating adrenaline. However, after surgical removal of the adrenal medullae, there appear to be no clinical consequences attributable to deﬁciency of circulating catecholamines. Adrenal androgens Adrenal androgens are secreted in response to ACTH and are the most abundant steroids in the blood stream. They are probably important in the initiation of puberty (adrenarche). The adrenals are also the major source of androgens in adult females and may be important in female libido. Presenting problems in adrenal disease Cushing’s syndrome Cushing’s syndrome is caused by excessive activation of glucocorticoid receptors. It is most commonly iatrogenic, due to prolonged administration of synthetic glucocorticoids such as

The adrenal glands • 667

pigmentation because of binding to melanocortin 1 receptors on melanocytes in the skin. The high cortisol levels also overcome the capacity of 11β-HSD2 to inactivate cortisol in the kidney (p. 665), causing hypokalaemic alkalosis that aggravates myopathy and hyperglycaemia (by inhibiting insulin secretion). When the tumour that is secreting ACTH is malignant, then the onset is usually rapid and may be associated with cachexia. For these reasons, the classical features of Cushing’s syndrome are less common in ectopic ACTH syndrome; if present, they suggest that a less aggressive tumour, such as a bronchial carcinoid, is responsible. In Cushing’s disease, the pituitary tumour is usually a microadenoma (< 10 mm in diameter); hence other features of a pituitary macroadenoma (hypopituitarism, visual failure or disconnection hyperprolactinaemia, p. 684) are rare. Investigations The large number of tests available for Cushing’s syndrome reﬂects the fact that each one has limited speciﬁcity and sensitivity prednisolone. Endogenous Cushing’s syndrome is uncommon but is caused by chronic over-production of cortisol by the adrenal glands, either as the result of an adrenal tumour or because of excessive production of ACTH by a pituitary tumour or ectopic ACTH production by other tumours. Aetiology The causes are shown in Box 18.38. Amongst endogenous causes, pituitary-dependent cortisol excess (by convention, called Cushing’s disease) accounts for approximately 80% of cases. Both Cushing’s disease and cortisol-secreting adrenal tumours are four times more common in women than men. In contrast, ectopic ACTH syndrome (often due to a small-cell carcinoma of the bronchus) is more common in men. Clinical assessment The diverse manifestations of glucocorticoid excess are shown in Figure 18.20. Many of these are not speciﬁc to Cushing’s syndrome and, because spontaneous Cushing’s syndrome is rare, the positive predictive value of any single clinical feature alone is low. Moreover, some common disorders can be confused with Cushing’s syndrome because they are associated with alterations in cortisol secretion, e.g. obesity and depression (Box 18.38). Features that favour Cushing’s syndrome in an obese patient are bruising, myopathy and thin skin. Any clinical suspicion of cortisol excess is best resolved by further investigation. It is vital to exclude iatrogenic causes in all patients with Cushing’s syndrome since even inhaled or topical glucocorticoids can induce the syndrome in susceptible individuals. A careful drug history must therefore be taken before embarking on complex investigations. An 0800–0900-hr serum cortisol of < 100 nmol/L (3.6 μg/dL) in a patient with a normal sleep–wake pattern and Cushingoid appearance is consistent with exogenous synthetic glucocorticoid use (common) or cyclical secretion of cortisol from endogenous Cushing’s (uncommon). Some clinical features are more common in ectopic ACTH syndrome. While ACTH-secreting pituitary tumours retain some negative feedback sensitivity to cortisol, this is absent in tumours that produce ectopic ACTH, typically resulting in higher levels of both ACTH and cortisol than are observed in pituitary-driven disease. The high ACTH levels are associated with marked Fig. 18.19 The major pathways of synthesis of steroid hormones. (DHEAS = dehydroepiandrosterone sulphate; HSD = hydroxysteroid dehydrogenase) Cholesterol Pregnenolone 17-OHpregnenolone DHEAS Progesterone 17-OHprogesterone Androstenedione Oestrone 11-deoxycorticosterone 11-deoxycortisol Testosterone Oestradiol Corticosterone Cortisol Dihydrotestosterone Aldosterone 3β-HSD 17-hydroxylase 17,20-lyase 21-hydroxylase 17β-HSD Aromatase 11β-hydroxylase Aldo synthase 5α-reductase Enzymes outside the adrenal Enzymes in the adrenal Glucocorticoids Key Mineralocorticoids Androgens Oestrogens Progesterone 18.38 Classiﬁcation of endogenous Cushing’s syndrome ACTH-dependent – 80% • Pituitary adenoma secreting ACTH (Cushing’s disease) – 70% • Ectopic ACTH syndrome (bronchial carcinoid, small-cell lung carcinoma, other neuro-endocrine tumour) – 10% Non-ACTH-dependent – 20% • Adrenal adenoma – 15% • Adrenal carcinoma – 5% • ACTH-independent macronodular hyperplasia; primary pigmented nodular adrenal disease; McCune–Albright syndrome (together < 1%) Hypercortisolism due to other causes (also referred to as pseudo-Cushing’s syndrome) • Alcohol excess (biochemical and clinical features) • Major depressive illness (biochemical features only, some clinical overlap) • Primary obesity (mild biochemical features, some clinical overlap) (ACTH = adrenocorticotrophic hormone)

668 • ENDOCRINOLOGY measured following administration of 0.5 mg dexamethasone 4 times daily for 48 hours. For either test, a normal response is a serum cortisol of < 50 nmol/L (1.8 μg/dL). It is important for any oestrogens to be stopped for 6 weeks prior to investigation to allow corticosteroid-binding globulin (CBG) levels to return to normal and to avoid false-positive responses, as most cortisol assays measure total cortisol, including that bound to CBG. Cyclicity of cortisol secretion is a feature of all types of Cushing’s syndrome and, if very variable, can confuse diagnosis. Use of multiple salivary cortisol samples over weeks or months can be helpful in diagnosis but an elevated salivary cortisol alone should not be taken as proof of diagnosis. In iatrogenic Cushing’s syndrome, cortisol levels are low unless the patient is taking a glucocorticoid (such as prednisolone) that cross-reacts in immunoassays with cortisol. Determining the underlying cause Once the presence of Cushing’s syndrome is confirmed, measurement of plasma ACTH is the key to establishing the differential diagnosis; it is best measured in the morning around 0900 hrs. In the presence of excess cortisol secretion, an undetectable ACTH (< 1.1 pmol/L (5 ng/L)) indicates an adrenal cause, while ACTH levels of > 3.3 pmol/L (15 ng/L) suggest a pituitary cause or ectopic ACTH. ACTH levels between these values represent a ‘grey area’ and further evaluation by a specialist is required. Tests to discriminate pituitary from ectopic sources of ACTH rely on the fact that pituitary tumours, but not ectopic tumours, retain some features of normal regulation of Fig. 18.20 Cushing’s syndrome. A Clinical features common to all causes. B A patient with Cushing’s disease before treatment. C The same patient 1 year after the successful removal of an ACTH-secreting pituitary microadenoma by trans-sphenoidal surgery. Psychosis Cataracts Mild exophthalmos Hair thinning Hirsutism Acne Plethora Moon face Peptic ulcer Hyperglycaemia Menstrual disturbance May have exuberant callus with fractures Osteoporosis Tendency to infections with poor wound healing and little inflammatory response Hypertension Centripetal obesity Striae Wasting and weakness of proximal thigh muscles Bruising Loss of height and back pain from compression fracture Decreased skin thickness A B C in isolation. Accordingly, several tests are usually combined to establish the diagnosis. Testing for Cushing’s syndrome should be avoided under conditions of stress, such as an acute illness, because this activates the HPA axis, causing potentially spurious results. The diagnosis of Cushing’s is a two-step process:

to establish whether the patient has Cushing’s syndrome (Fig. 18.21)
to deﬁne its cause (Fig. 18.22). Some additional tests are useful in all cases of Cushing’s syndrome, including plasma electrolytes, glucose, glycosylated haemoglobin and bone mineral density measurement. Establishing the presence of Cushing’s syndrome In patients where there is appropriate clinical suspicion, Cushing’s syndrome is conﬁrmed by using two of three main tests:
failure to suppress serum cortisol with low doses of oral dexamethasone
loss of the normal circadian rhythm of cortisol, with inappropriately elevated late-night serum or salivary cortisol
increased 24-hour urine free cortisol (see Fig. 18.21). Dexamethasone is used for suppression testing because it does not cross-react in immunoassays for cortisol. An overnight dexamethasone suppression test (ONDST) involves administration of 1 mg dexamethasone at 2300 hrs and measurement of serum cortisol at 0900 hrs the following day. In a low-dose dexamethasone suppression test (LDDST), serum cortisol is

The adrenal glands • 669

with approximately 70% of patients going into immediate remission. Around 20% of patients suffer a recurrence, often years later, emphasising the need for life-long follow-up. Laparoscopic bilateral adrenalectomy performed by an expert surgeon effectively cures ACTH-dependent Cushing’s syndrome, but in patients with pituitary-dependent Cushing’s syndrome this can result in Nelson’s syndrome. In Nelson’s syndrome, the loss of negative feedback from endogenous cortisol results in growth of the pituitary tumour, often leading to an invasive pituitary macroadenoma (which causes local mass effects) and very high ACTH levels (which cause pigmentation). The risk of Nelson’s syndrome is reported as being reduced by pituitary irradiation in some series, but not all. The somatostatin analogue pasireotide is also licensed for the treatment of Cushing’s disease and works by suppressing ACTH secretion by the tumour. It may cause tumour shrinkage but cortisol levels are likely to return to pre-treatment levels following cessation of therapy. Pasireotide has to be administered by twice-daily subcutaneous injection and is relatively expensive. It is an alternative to drugs that inhibit glucocorticoid biosynthesis in patients who are not suitable for a surgical approach. Adrenal tumours Laparoscopic adrenal surgery is the treatment of choice for adrenal adenomas. Surgery offers the only prospect of cure for adrenocortical carcinomas but, in general, prognosis is poor with high rates of recurrence, even in patients with localised disease at presentation. Radiotherapy to the tumour bed reduces ACTH secretion. Thus, in pituitary-dependent Cushing’s disease, ACTH secretion is suppressed by high-dose dexamethasone and ACTH is stimulated by corticotrophin-releasing hormone (CRH). In a high-dose dexamethasone suppression test (HDDST), serum cortisol is measured before and after administration of 2 mg of dexamethasone 4 times daily for 48 hours. Techniques for localisation of tumours secreting ACTH or cortisol are listed in Figure 18.22. MRI detects around 60% of pituitary microadenomas secreting ACTH. If available, bilateral inferior petrosal sinus sampling (BIPSS) with measurement of ACTH is the best means of conﬁrming Cushing’s disease, unless MRI shows a tumour bigger than 6 mm, in which case it may not be needed. CT or MRI detects most adrenal tumours; adrenal carcinomas are usually large (> 5 cm) and have other features of malignancy (p. 673). Management Untreated severe Cushing’s syndrome has a 50% 5-year mortality. Most patients are treated surgically, but medical therapy may be given in severe cases for a few weeks prior to operation to improve the clinical state. A number of drugs are available that inhibit glucocorticoid biosynthesis, including metyrapone and ketoconazole. The dose of these agents is best titrated against serum cortisol levels or 24-hour urine free cortisol. Cushing’s disease Trans-sphenoidal surgery carried out by an experienced surgeon with selective removal of the adenoma is the treatment of choice, Fig. 18.21 Sequence of investigations in suspected spontaneous Cushing’s syndrome. A serum cortisol of 50 nmol/L is equivalent to 1.8 μg/dL. (LDDST = low-dose dexamethasone suppression test; ONDST = overnight dexamethasone suppression test; UFC = urinary free cortisol) Cushing’s syndrome suspected Exclude exogenous glucocorticoid exposure Perform one of the following tests Any abnormal result Suggest additional evaluation, repeat testing at interval or seek further opinion Normal result Cushing’s syndrome unlikely Perform 1 or 2 other studies shown above and consider repeating abnormal study At least two concordant abnormal tests Discrepant test results Cushing’s syndrome Normal result Cushing’s syndrome unlikely 24-UFC (≥ 2 tests) – Elevated if above reference range for assay Late-night salivary cortisol – Abnormal if above local reference range ONDST or LDDST – Abnormal if serum cortisol > 50 nmol/L

670 • ENDOCRINOLOGY Adverse effects of glucocorticoids The clinical features of glucocorticoid excess are illustrated in Figure 18.20. Adverse effects are related to dose, duration of therapy, and pre-existing conditions that might be worsened by glucocorticoid therapy, such as diabetes mellitus or osteoporosis. Osteoporosis is a particularly important problem because, for a given bone mineral density, the fracture risk is greater in glucocorticoid-treated patients than in post-menopausal osteoporosis. Therefore, when systemic glucocorticoids are prescribed and the anticipated duration of steroid therapy is more than 3 months, bone-protective therapy should be considered, as detailed on page 1005. Rapid changes in glucocorticoid levels can also lead to marked mood disturbances, including depression, mania and insomnia. Glucocorticoid use also increases the white blood cell count (predominantly neutrophils), which must be taken into account when assessing patients with possible infection. the risk of local recurrence; systemic therapy consists of the adrenolytic drug mitotane and chemotherapy, but responses are often poor. Ectopic ACTH syndrome Localised tumours, such as bronchial carcinoid, should be removed surgically. In patients with incurable malignancy, it is important to reduce the severity of the Cushing’s syndrome using medical therapy (see above) or, if appropriate, bilateral adrenalectomy. Therapeutic use of glucocorticoids The remarkable anti-inﬂammatory properties of glucocorticoids have led to their use in a wide variety of clinical conditions but the hazards are signiﬁcant. Equivalent doses of commonly used glucocorticoids are listed in Box 18.39. Topical preparations (dermal, rectal and inhaled) can also be absorbed into the systemic circulation, and although this rarely occurs to a sufﬁcient degree to produce clinical features of Cushing’s syndrome, it can result in signiﬁcant suppression of endogenous ACTH and cortisol secretion. Severe Cushing’s syndrome can result if there is concomitant administration of inhaled glucocorticoids and strong inhibitors of the liver enzyme CYP450 3A4, such as the antiretroviral drug ritonavir (p. 324). Fig. 18.22 Determining the cause of conﬁrmed Cushing’s syndrome. To convert pmol/L to ng/L, multiply by 4.541. (ACTH = adrenocorticotrophic hormone; AIMAH = ACTH-independent macronodular adrenal hyperplasia; BIPSS = bilateral inferior petrosal sinus sampling; hCRH = human corticotrophinreleasing hormone; HDDST = high-dose dexamethasone suppression test; PPNAD = primary pigmented nodular adrenal disease) BIPSS: ACTH central to peripheral gradient > 2:1 at baseline or > 3:1 at 5–10 mins after 100 mg CRH IV Cushing’s syndrome confirmed Measure plasma ACTH

3.3 pmol/L ACTH-independent Cushing’s syndrome Adrenal imaging with CT Adrenal lesion No adrenal lesion Adenoma Carcinoma AIMAH PPNAD Exogenous glucocorticoid Ectopic ACTH Cushing’s disease ACTH-dependent Cushing’s syndrome Pituitary MRI: adenoma > 6 mm Positive CRH test: after 100 mg hCRH IV (> 20% rise of cortisol; or 50% rise ACTH) HDDST: > 50% suppression in serum cortisol from baseline CT/MRI thorax and abdomen ± somatostatin scintigraphy < 1.1 pmol/L on more than two occasions Yes Yes Yes Yes No No No No 18.39 Approximate equivalent doses of glucocorticoids • Hydrocortisone: 20 mg • Cortisone acetate: 25 mg • Prednisolone: 5 mg • Dexamethasone: 0.5 mg

The adrenal glands • 671

dexamethasone per day), then serum cortisol can be measured at 0900 hrs before the next dose. If this is < 100 nmol/L (3.6 μg/ dL), slow reduction should be continued with a repeat 0900 hrs serum cortisol when the dose of prednisolone is 3 mg per day. Once 0900 hrs serum cortisol is > 100 nmol/L, then an ACTH stimulation test should be performed (see Box 18.43) to conﬁrm if glucocorticoids can be withdrawn completely. Even when glucocorticoids have been successfully withdrawn, short-term replacement therapy is often advised during signiﬁcant intercurrent illness occurring in subsequent months, as the HPA axis may not be able to respond fully to severe stress. Adrenal insufﬁciency Adrenal insufﬁciency results from inadequate secretion of cortisol and/or aldosterone. It is potentially fatal and notoriously variable in its presentation. A high index of suspicion is therefore required in patients with unexplained fatigue, hyponatraemia or hypotension. Causes are shown in Box 18.41. The most common is ACTH deﬁciency (secondary adrenocortical failure), usually because of inappropriate withdrawal of chronic glucocorticoid therapy or a pituitary tumour (p. 683). Congenital adrenal hyperplasia and Addison’s disease (primary adrenocortical failure) are rare causes. Clinical assessment The clinical features of adrenal insufficiency are shown in Box 18.42. In Addison’s disease, either glucocorticoid or mineralocorticoid deﬁciency may come ﬁrst, but eventually all patients fail to secrete both classes of corticosteroid. Patients may present with chronic features and/or in acute circulatory shock. With a chronic presentation, initial symptoms are often misdiagnosed as chronic fatigue syndrome or depression. In primary adrenal insufﬁciency, weight loss is a uniform presenting feature. Adrenocortical insufﬁciency should also be considered in patients with hyponatraemia, even in the absence of symptoms (p. 357). Features of an acute adrenal crisis include circulatory shock with severe hypotension, hyponatraemia, hyperkalaemia and, in some instances, hypoglycaemia and hypercalcaemia. Muscle cramps, nausea, vomiting, diarrhoea and unexplained fever The anti-inﬂammatory effect of glucocorticoids may mask signs of disease. For example, perforation of a viscus may be masked and the patient may show no febrile response to an infection. Although there is debate about whether or not glucocorticoids increase the risk of peptic ulcer when used alone, they act synergistically with NSAIDs, including aspirin, to increase the risk of serious gastrointestinal adverse effects. Latent tuberculosis may be reactivated and patients on glucocorticoids are at risk of severe varicella zoster virus infection, so should avoid contact with chickenpox or shingles if they are non-immune. Management of glucocorticoid withdrawal All glucocorticoid therapy, even if inhaled or applied topically, can suppress the HPA axis. In practice, this is likely to result in a crisis due to adrenal insufﬁciency on withdrawal of treatment only if glucocorticoids have been administered orally or systemically for longer than 3 weeks, if repeated courses have been prescribed within the previous year, or if the dose is higher than the equivalent of 7.5 mg prednisolone per day. In these circumstances, the drug, when it is no longer required for the underlying condition, must be withdrawn slowly at a rate dictated by the duration of treatment. If glucocorticoid therapy has been prolonged, then it may take many months for the HPA axis to recover. All patients must be advised to avoid sudden drug withdrawal. They should be issued with a steroid card and/or wear an engraved bracelet (Box 18.40). Recovery of the HPA axis is aided if there is no exogenous glucocorticoid present during the nocturnal surge in ACTH secretion. This can be achieved by giving glucocorticoid in the morning. Giving ACTH to stimulate adrenal recovery is of no value, as the pituitary remains suppressed. In patients who have received glucocorticoids for longer than a few weeks, especially if the period is months to years, it is often valuable to conﬁrm that the HPA axis is recovering during glucocorticoid withdrawal. Withdrawal has to be very slow, usually by a dose reduction equivalent of prednisolone 1 mg per month or slower. Once the dose of glucocorticoid is reduced to a minimum (e.g. 5 mg prednisolone or 0.5 mg 18.40 Advice to patients on glucocorticoid replacement therapy Intercurrent stress • Febrile illness: double dose of hydrocortisone Surgery • Minor operation: hydrocortisone 100 mg IM with pre-medication • Major operation: hydrocortisone 100 mg 4 times daily for 24 hrs, then 50 mg IM 4 times daily until ready to take tablets Vomiting • Patients must have parenteral hydrocortisone if unable to take it by mouth Steroid card • Patient should carry this at all times; it should give information regarding diagnosis, steroid, dose and doctor Bracelet and emergency pack • Patients should be encouraged to buy a bracelet and have it engraved with the diagnosis, current treatment and a reference number for a central database • Patients should be given a hydrocortisone emergency pack and trained in the self-administration of hydrocortisone 100 mg IM; they should be advised to take the pack on holidays/trips abroad 18.41 Causes of adrenocortical insufﬁciency Secondary (↓ACTH) • Withdrawal of suppressive glucocorticoid therapy • Hypothalamic or pituitary disease Primary (↑ACTH) Addison’s disease Common causes • Autoimmune: Sporadic Polyglandular syndromes (p. 688) • Tuberculosis • HIV/AIDS • Metastatic carcinoma • Bilateral adrenalectomy Rare causes • Lymphoma • Intra-adrenal haemorrhage (Waterhouse–Friderichsen syndrome following meningococcal sepsis) • Amyloidosis • Haemochromatosis Corticosteroid biosynthetic enzyme defects • Congenital adrenal hyperplasias • Drugs: metyrapone, ketoconazole, etomidate (ACTH = adrenocorticotrophic hormone)

672 • ENDOCRINOLOGY is circulatory compromise. Investigations should be performed before treatment is given in patients who present with features suggestive of chronic adrenal insufﬁciency. Assessment of glucocorticoids Random plasma cortisol is usually low in patients with adrenal insufﬁciency but it may be within the reference range, yet inappropriately low, for a seriously ill patient. Random measurement of normal levels of plasma cortisol cannot therefore be used to conﬁrm or refute the diagnosis, unless the value is above 500 nmol/L (> 18 μg/dL), which effectively excludes adrenal insufﬁciency. More useful is the short ACTH stimulation test (also called the tetracosactrin or short Synacthen test) described in Box 18.43. Cortisol levels fail to increase in response to exogenous ACTH in patients with primary or secondary adrenal insufﬁciency. These can be distinguished by measurement of ACTH (which is low in ACTH deﬁciency and high in Addison’s disease). Assessment of mineralocorticoids Mineralocorticoid secretion in patients with suspected Addison’s disease cannot be adequately assessed by electrolyte measurements since hyponatraemia occurs in both aldosterone and cortisol deﬁciency (see Box 18.42 and p. 357). Hyperkalaemia is common, but not universal, in aldosterone deﬁciency. Plasma renin and aldosterone should be measured in the supine position. In mineralocorticoid deﬁciency, plasma renin activity is high, with plasma aldosterone being either low or in the lower part of the reference range. Assessment of adrenal androgens This is not necessary in men because testosterone from the testes is the principal androgen. In women, dehydroepiandrosterone sulphate (DHEAS) and androstenedione may be measured in a random specimen of blood, though levels are highest in the morning. Other tests to establish the cause Patients with unexplained secondary adrenocortical insufﬁciency should be investigated as described on page 680. In patients with elevated ACTH, further tests are required to establish may be present. The crisis is often precipitated by intercurrent disease, surgery or infection. Vitiligo occurs in 10–20% of patients with autoimmune Addison’s disease (p. 630). Investigations Treatment should not be delayed to wait for results in patients with suspected acute adrenal crisis. Here, a random blood sample should be stored for subsequent measurement of serum cortisol and, if possible, plasma ACTH; if the patient’s clinical condition permits, it may be appropriate to spend 30 minutes performing a short ACTH stimulation test (Box 18.43) before administering hydrocortisone, but delays must be avoided if there The exact cortisol concentration depends on the cortisol assay being used. 18.43 How and when to do an ACTH stimulation test Use • Diagnosis of primary or secondary adrenal insufﬁciency • Assessment of HPA axis in patients taking suppressive glucocorticoid therapy • Relies on ACTH-dependent adrenal atrophy in secondary adrenal insufﬁciency, so may not detect acute ACTH deﬁciency (e.g. in pituitary apoplexy, p. 683) Dose • 250 μg ACTH1–24 (Synacthen) by IM injection at any time of day Blood samples • 0 and 30 mins for plasma cortisol • 0 mins also for ACTH (on ice) if Addison’s disease is being considered (patient not known to have pituitary disease or to be taking exogenous glucocorticoids) Results • Normal subjects: plasma cortisol > 500 nmol/L (approximately 18 μg/dL) either at baseline or at 30 mins • Incremental change in cortisol is not a criterion (ACTH = adrenocorticotrophic hormone; HPA = hypothalamic–pituitary–adrenal) 18.42 Clinical and biochemical features of adrenal insufﬁciency Glucocorticoid insufﬁciency Mineralocorticoid insufﬁciency ACTH excess Adrenal androgen insufﬁciency Withdrawal of exogenous glucocorticoid + – – + Hypopituitarism + – – + Addison’s disease + + + + Congenital adrenal hyperplasia (21-hydroxylase deﬁciency) + + + – Clinical features Weight loss, anorexia Malaise, weakness Nausea, vomiting Diarrhoea or constipation Postural hypotension Shock Hypoglycaemia Hyponatraemia (dilutional) Hypercalcaemia Hypotension Shock Hyponatraemia (depletional) Hyperkalaemia Pigmentation of: Sun-exposed areas Pressure areas (e.g. elbows, knees) Palmar creases, knuckles Mucous membranes Conjunctivae Recent scars Decreased body hair and loss of libido, especially in females (ACTH = adrenocorticotrophic hormone)

The adrenal glands • 673

Androgen replacement Androgen replacement with DHEAS (50 mg/day) is occasionally given to women with primary adrenal insufﬁciency who have symptoms of reduced libido and fatigue, but the evidence in support of this is not robust and treatment may be associated with side-effects such as acne and hirsutism. Incidental adrenal mass It is not uncommon for a mass in the adrenal gland to be identiﬁed on a CT or MRI scan of the abdomen that has been performed for another indication. Such lesions are known as adrenal ‘incidentalomas’. The prevalence increases with age and they are present in up to 10% of adults aged 70 years and older. Eighty-five per cent of adrenal incidentalomas are nonfunctioning adrenal adenomas. The remainder includes functional tumours of the adrenal cortex (secreting cortisol, aldosterone or androgens), phaeochromocytomas, primary and secondary carcinomas, hamartomas and other rare disorders, including granulomatous inﬁltrations. Clinical assessment and investigations There are two key questions to be resolved: is the lesion secreting hormones, and is it benign or malignant? Patients with an adrenal incidentaloma are usually asymptomatic. However, clinical signs and symptoms of excess glucocorticoids (p. 665), mineralocorticoids (see below), catecholamines (p. 666) and, in women, androgens (p. 666) should be sought. Investigations should include a dexamethasone suppression test, urine or plasma metanephrines and, in virilised women, measurement of serum testosterone, DHEAS and androstenedione. Patients with hypertension should be investigated for mineralocorticoid excess, as described below. In bilateral masses consistent with adrenocortical lesions, 17-OH-progesterone should also be measured. CT and MRI are equally effective in assessing the malignant potential of an adrenal mass, using the following parameters: • Size. The larger the lesion, the greater the malignant potential. Around 90% of adrenocortical carcinomas are over 4 cm in diameter, but speciﬁcity is poor since only approximately 25% of such lesions are malignant. • Conﬁguration. Homogeneous and smooth lesions are more likely to be benign. The presence of metastatic lesions elsewhere increases the risk of malignancy, but as many as two-thirds of adrenal incidentalomas in patients with cancer are benign. • Presence of lipid. Adenomas are usually lipid-rich, resulting in an attenuation of below 10 Hounsﬁeld units (HU) on the cause of Addison’s disease. Adrenal autoantibodies are frequently positive in autoimmune adrenal failure. If antibody tests are negative, imaging of the adrenal glands with CT or MRI is indicated. Tuberculosis causes adrenal calciﬁcation, visible on plain X-ray or ultrasound scan. A human immunodeﬁciency virus (HIV) test should be performed if risk factors for infection are present (p. 310). Adrenal metastases are a rare cause of adrenal insufﬁciency. Patients with evidence of autoimmune adrenal failure should be screened for other organ-speciﬁc autoimmune diseases, such as thyroid disease, pernicious anaemia and type 1 diabetes. Management Patients with adrenocortical insufficiency always need glucocorticoid replacement therapy and usually, but not always, mineralocorticoid therapy. There is some evidence that adrenal androgen replacement may also be beneﬁcial in women. Other treatments depend on the underlying cause. The emergency management of adrenal crisis is described in Box 18.44. Glucocorticoid replacement Adrenal replacement therapy consists of oral hydrocortisone (cortisol) 15–20 mg daily in divided doses, typically 10 mg on waking and 5 mg at around 1500 hrs. These are physiological replacement doses that should not cause Cushingoid side-effects. The dose may need to be adjusted for the individual patient but this is subjective. Excess weight gain usually indicates overreplacement, while persistent lethargy or hyperpigmentation may be due to an inadequate dose or lack of absorption. Measurement of serum cortisol levels is not usually helpful. Advice to patients dependent on glucocorticoid replacement is given in Box 18.40. Mineralocorticoid replacement Fludrocortisone (9α-ﬂuoro-hydrocortisone) is administered at the usual dose of 0.05–0.15 mg daily, and adequacy of replacement may be assessed by measurement of blood pressure, plasma electrolytes and plasma renin. It is indicated for virtually every patient with primary adrenal insufﬁciency but is not needed in secondary adrenal insufﬁciency. 18.44 Management of adrenal crisis Correct volume depletion • IV saline as required to normalise blood pressure and pulse • In severe hyponatraemia (< 125 mmol/L) avoid increases of plasma Na > 10 mmol/L/day to prevent pontine demyelination (p. 358) • Fludrocortisone is not required during the acute phase of treatment Replace glucocorticoids • IV hydrocortisone succinate 100 mg stat, and 100 mg 4 times daily for ﬁrst 12–24 hrs • Continue parenteral hydrocortisone (50–100 mg IM 4 times daily) until patient is well enough for reliable oral therapy Correct other metabolic abnormalities • Acute hypoglycaemia: IV 10% glucose • Hyperkalaemia: should respond to volume replacement but occasionally requires speciﬁc therapy (see Box 14.17, p. 363) Identify and treat underlying cause • Consider acute precipitant, such as infection • Consider adrenal or pituitary pathology (see Box 18.41) 18.45 Glucocorticoids in old age • Adrenocortical insufﬁciency: often insidious and may present with tiredness, drowsiness, delirium, falls, immobility and orthostatic hypotension. • Glucocorticoid therapy: especially hazardous in older people, who are already relatively immunocompromised and susceptible to osteoporosis, diabetes, hypertension and other complications. • ‘Physiological’ glucocorticoid replacement therapy: increased risk of adrenal crisis because adherence may be poor and there is a greater incidence of intercurrent illness. Patient and carer education, with regular reinforcement of the principles described in Box 18.40, is crucial.

674 • ENDOCRINOLOGY hyperaldosteronism, which is usually a consequence of enhanced activity of renin in response to inadequate renal perfusion and hypotension. Most individuals with primary hyperaldosteronism have bilateral adrenal hyperplasia (idiopathic hyperaldosteronism), while only a minority have an aldosterone-producing adenoma (APA; Conn’s syndrome). Glucocorticoid-suppressible hyperaldosteronism is a rare autosomal dominant condition in which aldosterone is secreted ‘ectopically’ from the adrenal zonae fasciculata/reticularis in response to ACTH. Rarely, the mineralocorticoid receptor pathway in the distal nephron is activated, even though aldosterone concentrations are low. Clinical features Individuals with primary hyperaldosteronism are usually asymptomatic but may have features of sodium retention or potassium loss. Sodium retention may cause oedema, while hypokalaemia may cause muscle weakness (or even paralysis, especially in South-east Asian populations), polyuria (secondary to renal tubular damage, which produces nephrogenic diabetes insipidus) and occasionally tetany (because of associated metabolic alkalosis and low ionised calcium). Blood pressure is elevated but accelerated phase hypertension is rare. Investigations Biochemical Routine blood tests may show a hypokalaemic alkalosis. Sodium is usually at the upper end of the reference range in primary hyperaldosteronism, but is characteristically low in secondary hyperaldosteronism (because low plasma volume stimulates vasopressin (antidiuretic hormone, ADH) release and high angiotensin II levels stimulate thirst). The key measurements are plasma renin and aldosterone (Box 18.46), and in many centres the aldosterone : renin ratio (ARR) is employed as a screening test for primary hyperaldosteronism in hypertensive patients. Almost all antihypertensive drugs interfere with this ratio (β-blockers inhibit while diuretics stimulate renin secretion). Thus, individuals with an elevated ARR require further testing after stopping antihypertensive drugs for at least 4 weeks. If necessary, antihypertensive agents that have minimal effects on the renin–angiotensin system, such as calcium antagonists and α-blockers, may be substituted. Oral potassium supplementation may also be required, as hypokalaemia itself suppresses renin activity. If, on repeat testing, plasma renin is low and aldosterone concentrations are elevated, then further investigation under specialist supervision may include suppression tests (sodium loading) and/or stimulation tests (captopril or furosemide administration) to differentiate angiotensin II-dependent aldosterone secretion in idiopathic hyperplasia from autonomous aldosterone secretion typical of an APA. Imaging and localisation Imaging with CT or MRI will identify most APAs (Fig. 18.23) but it is important to recognise the risk of false positives (non-functioning adrenal adenomas are common) and false negatives (imaging may have insufﬁcient resolution to identify adenomas with a diameter of less than 0.5 cm). If the imaging is inconclusive and there is an intention to proceed with surgery on the basis of strong biochemical evidence of an APA, then adrenal vein catheterisation with measurement of aldosterone (and cortisol to conﬁrm positioning of the catheters) is required. In some centres, this is performed even in the presence of a unilateral ‘adenoma’, to avoid inadvertent removal of an incidental non-functioning adenoma contralateral to a radiologically inapparent cause of aldosterone excess. an unenhanced CT, and in signal dropout on chemical shift MRI. • Enhancement. Benign lesions demonstrate rapid washout of contrast, whereas malignant lesions tend to retain contrast. Histology in a sample obtained by CT-guided biopsy is rarely indicated, and is not useful in distinguishing an adrenal adenoma from an adrenocortical carcinoma. Biopsy is occasionally helpful in conﬁrming adrenal metastases from other cancers, but should be avoided if either phaeochromocytoma or primary adrenal cancer is suspected in order to avoid precipitation of a hypertensive crisis or seeding of tumour cells, respectively. Management In patients with radiologically benign, non-functioning lesions of less than 4 cm in diameter, surgery is required only if serial imaging suggests tumour growth. Functional lesions and tumours of more than 4 cm in diameter should be considered for surgery, though many centres will not operate on tumours of more than 4 cm if all other characteristics suggest benign disease. Optimal management of patients with low-grade cortisol secretion, as demonstrated by the dexamethasone suppression test, remains to be established. Primary hyperaldosteronism Estimates of the prevalence of primary hyperaldosteronism vary according to the screening tests employed, but it may occur in as many as 10% of people with hypertension. Indications to test for mineralocorticoid excess in hypertensive patients include hypokalaemia (including hypokalaemia induced by thiazide diuretics), poor control of blood pressure with conventional therapy, a family history of early-onset hypertension, or presentation at a young age. Causes of excessive activation of mineralocorticoid receptors are shown in Box 18.46. It is important to differentiate primary hyperaldosteronism, caused by an intrinsic abnormality of the adrenal glands resulting in aldosterone excess, from secondary 18.46 Causes of mineralocorticoid excess With renin high and aldosterone high (secondary hyperaldosteronism) • Inadequate renal perfusion (diuretic therapy, cardiac failure, liver failure, nephrotic syndrome, renal artery stenosis) • Renin-secreting renal tumour (very rare) With renin low and aldosterone high (primary hyperaldosteronism) • Adrenal adenoma secreting aldosterone (Conn’s syndrome) • Idiopathic bilateral adrenal hyperplasia • Glucocorticoid-suppressible hyperaldosteronism (rare) With renin low and aldosterone low (non-aldosterone-dependent activation of mineralocorticoid pathway) • Ectopic ACTH syndrome • Liquorice misuse (inhibition of 11β-HSD2) • Liddle’s syndrome • 11-deoxycorticosterone-secreting adrenal tumour • Rare forms of congenital adrenal hyperplasia and 11β-HSD2 deﬁciency (11β-HSD2 = 11β-hydroxysteroid dehydrogenase type 2; ACTH = adrenocorticotrophic hormone)

The adrenal glands • 675

dehydrogenase B, C and D genes. Other genetic causes include mutations in SDHA, SDHAF2, TMEN127 and MAX. Clinical features These depend on the pattern of catecholamine secretion and are listed in Box 18.47. Some patients present with hypertension, although it has been estimated that phaeochromocytoma accounts for less than 0.1% of cases of hypertension. The presentation may be with a complication of hypertension, such as stroke, myocardial infarction, left ventricular failure, hypertensive retinopathy or accelerated phase hypertension. The apparent paradox of postural hypotension between episodes is explained by ‘pressure natriuresis’ during hypertensive episodes so that intravascular volume is reduced. There may also be features of the familial syndromes associated with phaeochromocytoma. Paragangliomas are often non-functioning. Investigations Excessive secretion of catecholamines can be conﬁrmed by measuring metabolites in plasma and/or urine (metanephrine and normetanephrine). There is a high ‘false-positive’ rate, as misleading metanephrine concentrations may be seen in stressed patients (during acute illness, following vigorous exercise or severe pain) and following ingestion of some drugs such as tricyclic antidepressants. For this reason, a repeat sample should usually be requested if elevated levels are found, although, as a rule, the higher the concentration of metanephrines, the more likely the diagnosis of phaeochromocytoma/paraganglioma. Serum chromogranin A is often elevated and may be a useful tumour marker in patients with non-secretory tumours and/or metastatic disease. Genetic testing should be considered in individuals with other features of a genetic syndrome, in those with a family history of phaeochromocytoma/paraganglioma, and in those presenting under the age of 50 years. Localisation Phaeochromocytomas are usually identiﬁed by abdominal CT or MRI (Fig. 18.24). Localisation of paragangliomas may be more difﬁcult. Scintigraphy using meta-iodobenzyl guanidine (MIBG) can be useful, particularly if combined with CT, for adrenal phaeochromocytoma but is often negative in paraganglioma. 18F-deoxyglucose PET is especially useful for detection of malignant disease and for conﬁrming an imaging abnormality as a paraganglioma in an individual with underlying risk due to genetic mutation. Less widely available, 68gallium dotatate PET/ CT imaging has high sensitivity for paraganglioma. Management In functioning tumours, medical therapy is required to prepare the patient for surgery, preferably for a minimum of 6 weeks, Management Mineralocorticoid receptor antagonists (spironolactone and eplerenone) are valuable in treating both hypokalaemia and hypertension in all forms of mineralocorticoid excess. Up to 20% of males develop gynaecomastia on spironolactone. Amiloride (10–40 mg/day), which blocks the epithelial sodium channel regulated by aldosterone, is an alternative. In patients with an APA, medical therapy is usually given for a few weeks to normalise whole-body electrolyte balance before unilateral adrenalectomy. Laparoscopic surgery cures the biochemical abnormality but, depending on the pre-operative duration, hypertension remains in as many as 70% of cases, probably because of irreversible damage to the systemic microcirculation. Phaeochromocytoma and paraganglioma These are rare neuro-endocrine tumours that may secrete catecholamines (adrenaline/epinephrine, noradrenaline/ norepinephrine). Approximately 80% of these tumours occur in the adrenal medulla (phaeochromocytomas), while 20% arise elsewhere in the body in sympathetic ganglia (paragangliomas). Most are benign but approximately 15% show malignant features. Around 40% are associated with inherited disorders, including neurofibromatosis (p. 1131), von Hippel–Lindau syndrome (p. 1132), MEN 2 and MEN 3 (p. 688). Paragangliomas are particularly associated with mutations in the succinate Fig. 18.23 Aldosterone-producing adenoma causing Conn’s syndrome. A CT scan of left adrenal adenoma (arrow). B The tumour is ‘canary yellow’ because of intracellular lipid accumulation. A B 18.47 Clinical features of phaeochromocytoma • Hypertension (usually paroxysmal; often postural drop of blood pressure) • Paroxysms of: Pallor (occasionally ﬂushing) Palpitations, sweating Headache Anxiety (angor animi) • Abdominal pain, vomiting • Constipation • Weight loss • Glucose intolerance

676 • ENDOCRINOLOGY such as ambiguous genitalia in girls. In the other two-thirds, mineralocorticoid secretion is adequate but there may be features of cortisol insufﬁciency and/or ACTH and androgen excess, including precocious pseudo-puberty, which is distinguished from ‘true’ precocious puberty by low gonadotrophins. Sometimes the mildest enzyme defects are not apparent until adult life, when females may present with amenorrhoea and/or hirsutism (pp. 762 and 763). This is called ‘non-classical’ or ‘late-onset’ congenital adrenal hyperplasia. Defects of all the other enzymes in Figure 18.19 are rare. Both 17-hydroxylase and 11β-hydroxylase deﬁciency may produce hypertension due to excess production of 11-deoxycorticosterone, which has mineralocorticoid activity. Investigations Circulating 17-OH-progesterone levels are raised in 21-hydroxylase deficiency but this may be demonstrated only after ACTH administration in late-onset cases. To avoid salt-wasting crises in infancy, 17-OH-progesterone can be routinely measured in heelprick blood spot samples taken from all infants in the ﬁrst week of life. Assessment is otherwise as described for adrenal insufﬁciency on page 672. In siblings of affected children, antenatal genetic diagnosis can be made by amniocentesis or chorionic villus sampling. This allows prevention of virilisation of affected female fetuses by administration of dexamethasone to the mother to suppress ACTH levels. Management The aim is to replace deﬁcient corticosteroids and to suppress ACTH-driven adrenal androgen production. A careful balance is required between adequate suppression of adrenal androgen excess and excessive glucocorticoid replacement resulting in features of Cushing’s syndrome. In children, growth velocity is an important measurement, since either under- or over-replacement with glucocorticoids suppresses growth. In adults, there is no uniformly agreed adrenal replacement regime, and clinical features (menstrual cycle, hirsutism, weight gain, blood pressure) and biochemical proﬁles (plasma renin, 17-OH-progesterone and testosterone levels) provide a guide. Women with late-onset 21-hydroxylase deﬁciency may not require corticosteroid replacement. If hirsutism is the main problem, anti-androgen therapy may be just as effective (p. 659). The endocrine pancreas and gastrointestinal tract A series of hormones are secreted from cells distributed throughout the gastrointestinal tract and pancreas. Functional anatomy and physiology are described on pages 723 and 848. Diseases associated with abnormalities of these hormones are listed in Box 18.48. Most are rare, with the exception of diabetes mellitus (Ch. 20). Presenting problems in endocrine pancreas disease Spontaneous hypoglycaemia Hypoglycaemia most commonly occurs as a side-effect of treatment with insulin or sulphonylurea drugs in people with to allow restoration of normal plasma volume. The most useful drug in the face of very high circulating catecholamines is the α-blocker phenoxybenzamine (10–20 mg orally 3–4 times daily) because it is a non-competitive antagonist, unlike prazosin or doxazosin. If α-blockade produces a marked tachycardia, then a β-blocker such as propranolol can be added. On no account should a β-blocker be given before an α-blocker, as this may cause a paradoxical rise in blood pressure due to unopposed α-mediated vasoconstriction. During surgery, sodium nitroprusside and the short-acting α-antagonist phentolamine are useful in controlling hypertensive episodes, which may result from anaesthetic induction or tumour mobilisation. Post-operative hypotension may occur and require volume expansion and, very occasionally, noradrenaline (norepinephrine) infusion, but is uncommon if the patient has been prepared with phenoxybenzamine. Metastatic tumours may behave in an aggressive or a very indolent fashion. Management options include debulking surgery, radionuclide therapy with 131I-MIBG, chemotherapy and (chemo) embolisation of hepatic metastases; some may respond to tyrosine kinase and angiogenesis inhibitors. Congenital adrenal hyperplasia Pathophysiology and clinical features Inherited defects in enzymes of the cortisol biosynthetic pathway (see Fig. 18.19) result in insufﬁciency of hormones downstream of the block, with impaired negative feedback and increased ACTH secretion. ACTH then stimulates the production of steroids upstream of the enzyme block. This produces adrenal hyperplasia and a combination of clinical features that depend on the severity and site of the defect in biosynthesis. All of these enzyme abnormalities are inherited as autosomal recessive traits. The most common enzyme defect is 21-hydroxylase deﬁciency. This results in impaired synthesis of cortisol and aldosterone, and accumulation of 17-OH-progesterone, which is then diverted to form adrenal androgens. In about one-third of cases, this defect is severe and presents in infancy with features of glucocorticoid and mineralocorticoid deﬁciency (see Box 18.42) and androgen excess, Fig. 18.24 CT scan of abdomen showing large left adrenal phaeochromocytoma. The normal right adrenal (white arrow) contrasts with the large heterogeneous phaeochromocytoma arising from the left adrenal gland (black arrow).

The endocrine pancreas and gastrointestinal tract • 677

always be conﬁrmed by a laboratory-based glucose measurement. At the same time, a sample should be taken for later measurement of alcohol, insulin, C-peptide, cortisol and sulphonylurea levels, if hypoglycaemia is conﬁrmed. Taking these samples during an acute presentation prevents subsequent unnecessary dynamic tests and is of medico-legal importance in cases where poisoning is suspected. Patients who attend the outpatient clinic with episodic symptoms suggestive of hypoglycaemia present a more challenging problem. The main diagnostic test is the prolonged (72-hour) fast. If symptoms of hypoglycaemia develop during the fast, then blood samples should be taken to conﬁrm hypoglycaemia and for later measurement of insulin and C-peptide. Hypoglycaemia is then corrected with oral or intravenous glucose and Whipple’s triad completed by conﬁrmation of the resolution of symptoms. The absence of clinical and biochemical evidence of hypoglycaemia during a prolonged fast effectively excludes the diagnosis of a hypoglycaemic disorder. What is the cause of the hypoglycaemia? In the acute setting, the underlying diagnosis is often obvious. In non-diabetic individuals, alcohol excess is the most common cause of hypoglycaemia in the UK but other drugs – e.g. salicylates, quinine and pentamidine – may also be implicated. Hypoglycaemia is one of many metabolic derangements that occur in patients with hepatic failure, renal failure, adrenal insufﬁciency, sepsis or malaria. Hypoglycaemia in the absence of insulin, or any insulin-like factor, in the blood indicates impaired gluconeogenesis and/or availability of glucose from glycogen in the liver. Hypoglycaemia associated with high insulin and low C-peptide concentrations is indicative of administration of exogenous insulin, either factitiously or feloniously. Adults with high insulin and C-peptide concentrations during an episode of hypoglycaemia are most likely to have an insulinoma but sulphonylurea ingestion should also be considered (particularly in individuals with access to such medication, such as health-care professionals or family members of someone with type 2 diabetes). Suppressed plasma β-hydroxybutyrate helps conﬁrm inappropriate insulin secretion during fasting. Usually, insulinomas in the pancreas diabetes mellitus. In non-diabetic individuals, symptomatic hypoglycaemia is rare, but it is not uncommon to detect venous blood glucose concentrations below 3.0 mmol/L (54 mg/dL) in asymptomatic patients. For this reason, and because the symptoms of hypoglycaemia are non-speciﬁc, a hypoglycaemic disorder should be diagnosed only if all three conditions of Whipple’s triad are met (Fig. 18.25). There is no speciﬁc blood glucose concentration at which spontaneous hypoglycaemia can be said to occur, although the lower the blood glucose concentration, the more likely it is to have pathological signiﬁcance. Investigations are unlikely to be needed unless glucose concentrations below 3.0 mmol/L are observed, many patients with true hypoglycaemia demonstrating glucose levels below 2.2 mmol/L (40 mg/dL). Clinical assessment The clinical features of hypoglycaemia are described in the section on insulin-induced hypoglycaemia on page 738. Individuals with chronic spontaneous hypoglycaemia often have attenuated autonomic responses and ‘hypoglycaemia unawareness’, and may present with a wide variety of features of neuroglycopenia, including odd behaviour and convulsions. The symptoms are usually episodic and relieved by consumption of carbohydrate. Symptoms occurring while fasting (such as before breakfast) or following exercise are much more likely to be representative of pathological hypoglycaemia than those that develop after food (post-prandial or ‘reactive’ symptoms). Hypoglycaemia should be considered in all comatose patients, even if there is an apparently obvious cause, such as hemiplegic stroke or alcohol intoxication. Investigations Does the patient have a hypoglycaemic disorder? Patients who present acutely with delirium, coma or convulsions should be tested for hypoglycaemia at the bedside with a capillary blood sample and an automated meter. While this is sufﬁcient to exclude hypoglycaemia, blood glucose meters are relatively inaccurate in the hypoglycaemic range and the diagnosis should 18.48 Classiﬁcation of endocrine diseases of the pancreas and gastrointestinal tract Primary Secondary Hormone excess Insulinoma Gastrinoma (Zollinger– Ellison syndrome, p. 802) Carcinoid syndrome (secretion of 5-HT) Glucagonoma VIPoma Somatostatinoma Hypergastrinaemia of achlorhydria Hyperinsulinaemia after bariatric surgery Hormone deﬁciency Diabetes mellitus Hormone resistance Insulin resistance syndromes (e.g. type 2 diabetes mellitus, lipodystrophy, Donohue’s syndrome) Non-functioning tumours Pancreatic carcinoma Pancreatic neuro-endocrine tumour (5-HT = 5-hydroxytryptamine, serotonin) Fig. 18.25 Differential diagnosis of spontaneous hypoglycaemia. Measurement of insulin and C-peptide concentrations during an episode is helpful in determining the underlying cause. Whipple’s triad confirmed Patient had symptoms of hypoglycaemia Low blood glucose measured at the time of symptoms Symptoms resolved on correction of hypoglycaemia ↑ Insulin ↓ C-peptide ↓ Insulin ↓ C-peptide ↑ Insulin ↑ C-peptide Alcohol Drugs Critical illnesses Hypopituitarism (rare) Primary adrenocortical failure (rare in adults) Non-islet cell tumour (e.g. sarcoma) Inborn errors of metabolism Exogenous insulin Insulinoma Sulphonylureas Other drugs Hyperinsulinism of infancy

678 • ENDOCRINOLOGY Clinical features Patients with gastroenteropancreatic NETs often have a history of abdominal pain over many years prior to diagnosis and usually present with local mass effects, such as small-bowel obstruction, appendicitis, and pain from hepatic metastases. Thymic and bronchial carcinoids occasionally present with ectopic ACTH syndrome (p. 667). Pancreatic NETs can also cause hormone excess (Box 18.50) but most are non-functional. The classic ‘carcinoid syndrome’ (Box 18.51) occurs when vasoactive hormones reach the systemic circulation. In the case of gastrointestinal carcinoids, this invariably means that the tumour has metastasised to the liver or there are peritoneal deposits, which allow secreted hormones to gain access to the systemic circulation; hormones secreted by the primary tumour into the portal vein are metabolised and inactivated in the liver. The features of Zollinger–Ellison syndrome are described on page 802. Investigations A combination of imaging with ultrasound, CT, MRI and/or radio-labelled somatostatin analogue (Fig. 18.26) will usually identify the primary tumour and allow staging, which is crucial for determining prognosis. Biopsy of the primary tumour or a metastatic deposit is required to conﬁrm the histological type. NETs demonstrate immunohistochemical staining for the proteins chromogranin A and synaptophysin, and the histological grade provides important prognostic information: the higher the Ki67 proliferation index, the worse the prognosis. Carcinoid syndrome is confirmed by measuring elevated concentrations of 5-hydroxyindoleacetic acid (5-HIAA), a metabolite of serotonin, in a 24-hour urine collection. False positives can occur, particularly if the individual has been eating certain foods, such as avocado and pineapple. Plasma chromogranin A can be measured in a fasting blood sample, along with the hormones listed in Box 18.50. All of these can be useful as tumour markers. are small (< 5 mm diameter) but can be identiﬁed by CT, MRI or ultrasound (endoscopic or laparoscopic). Imaging should include the liver since around 10% of insulinomas are malignant and may metastasise to the liver. Rarely, large non-pancreatic tumours, such as sarcomas, may cause recurrent hypoglycaemia because of their ability to produce excess pro-insulin-like growth factor-2 (pro-IGF-2), which has considerable structural homology to insulin. Management Treatment of acute hypoglycaemia should be initiated as soon as laboratory blood samples have been taken and should not be deferred until formal laboratory conﬁrmation has been obtained. Intravenous dextrose (5% or 10%) is effective in the short term in the obtunded patient and should be followed on recovery with oral unreﬁned carbohydrate (starch). Continuous dextrose infusion may be necessary, especially in sulphonylurea poisoning. Intramuscular glucagon (1 mg) stimulates hepatic glucose release but is ineffective in patients with depleted glycogen reserves, such as in alcohol excess or liver disease. Chronic recurrent hypoglycaemia in insulin-secreting tumours can be treated by regular consumption of oral carbohydrate combined with agents that inhibit insulin secretion (diazoxide or somatostatin analogues). Insulinomas are resected when benign, providing the individual is ﬁt enough to undergo surgery. Metastatic malignant insulinomas may be incurable and are managed along the same lines as other metastatic neuro-endocrine tumours (see below). Gastroenteropancreatic neuro-endocrine tumours Neuro-endocrine tumours (NETs) are a heterogeneous group derived from neuro-endocrine cells in many organs, including the gastrointestinal tract, lung, adrenals (phaeochromocytoma, p. 675) and thyroid (medullary carcinoma, p. 650). Most NETs occur sporadically but a proportion are associated with genetic cancer syndromes, such as MEN 1, 2 and 3 and neuroﬁbromatosis type 1 (pp. 688 and 1131). NETs may secrete hormones into the circulation. Gastroenteropancreatic NETs arise in organs that are derived embryologically from the gastrointestinal tract. Most commonly, they occur in the small bowel but they can also arise elsewhere in the bowel, pancreas, thymus and bronchi. The term ‘carcinoid’ is often used when referring to non-pancreatic gastroenteropancreatic NETs because, when initially described, they were thought to behave in an indolent fashion compared with conventional cancers. It is now recognised that there is a wide spectrum of malignant potential for all NETs; some are benign (most insulinomas and appendiceal carcinoid tumours), while others have an aggressive clinical course with widespread metastases (small-cell carcinoma of the lung). The majority of gastroenteropancreatic NETs behave in an intermediate manner, with relatively slow growth but a propensity to invade and metastasise to remote organs, especially the liver. 18.50 Pancreatic neuro-endocrine tumours Tumour Hormone Effects Gastrinoma Gastrin Peptic ulcer and steatorrhoea (Zollinger– Ellison syndrome, p. 802) Insulinoma Insulin Recurrent hypoglycaemia (see above) VIPoma Vasoactive intestinal peptide (VIP) Watery diarrhoea and hypokalaemia Glucagonoma Glucagon Diabetes mellitus, necrolytic migratory erythema Somatostatinoma Somatostatin Diabetes mellitus and steatorrhoea 18.49 Spontaneous hypoglycaemia in old age • Presentation: may present with focal neurological abnormality. Blood glucose should be checked in all patients with acute neurological symptoms and signs, especially stroke, as these will reverse with early treatment of hypoglycaemia. 18.51 Clinical features of the carcinoid syndrome • Episodic ﬂushing, wheezing and diarrhoea • Facial telangiectasia • Cardiac involvement (tricuspid regurgitation, pulmonary stenosis, right ventricular endocardial plaques) leading to heart failure

The hypothalamus and the pituitary gland • 679

carotid arteries. The gland is composed of two lobes, anterior and posterior, and is connected to the hypothalamus by the infundibular stalk, which has portal vessels carrying blood from the median eminence of the hypothalamus to the anterior lobe and nerve ﬁbres to the posterior lobe. Management Treatment of solitary tumours is by surgical resection. If metastatic or multifocal primary disease is present, then surgery is usually not indicated, unless there is a complication such as gastrointestinal obstruction. Diazoxide can reduce insulin secretion in insulinomas, and high doses of proton pump inhibitors suppress acid production in gastrinomas. Somatostatin analogues are effective in reducing the symptoms of carcinoid syndrome and of excess glucagon and vasoactive intestinal peptide (VIP) production. The slow-growing nature of NETs means that conventional cancer therapies, such as chemotherapy and radiotherapy, have limited efﬁcacy, but use of somatostatin analogues is associated with improved progressionfree survival. Other treatments, such as interferon, targeted radionuclide therapy with 131I-MIBG and radio-labelled somatostatin analogues (which may be taken up by NET metastases), and resection/embolisation/ablation of hepatic metastases, may have a role in the palliation of symptoms but debate exists as to whether this prolongs life. The tyrosine kinase inhibitor sunitinib and the mammalian target of rapamycin (mTOR) inhibitor everolimus have shown signiﬁcant improvements in progression-free survival in patients with advanced and progressive pancreatic and lung NETS that are not poorly differentiated, and should be considered as part of standard therapy. The hypothalamus and the pituitary gland Diseases of the hypothalamus and pituitary have an annual incidence of approximately 3:100 000 and a prevalence of 30–70 per 100 000. The pituitary plays a central role in several major endocrine axes, so that investigation and treatment invariably involve several other endocrine glands. Functional anatomy, physiology and investigations The anatomical relationships of the pituitary are shown in Figure 18.27 and its numerous functions are shown in Figure 18.2 (p. 633). The pituitary gland is enclosed in the sella turcica and bridged over by a fold of dura mater called the diaphragma sellae, with the sphenoidal air sinuses below and the optic chiasm above. The cavernous sinuses are lateral to the pituitary fossa and contain the 3rd, 4th and 6th cranial nerves and the internal Fig. 18.26 Octreotide scintigraphy in a metastatic neuro-endocrine tumour. A Coronal CT scan showing hepatomegaly and a mass inferior to the liver (at the intersection of the horizontal and vertical red lines). B Octreotide scintogram showing patches of increased uptake in the upper abdomen. C When the octreotide and CT scans are superimposed, it shows that the areas of increased uptake are in hepatic metastases and in the tissue mass, which may be lymph nodes or a primary tumour. B C A Fig. 18.27 Anatomical relationships of the normal pituitary gland and hypothalamus. See also Figure 18.2 (p. 633). A Sagittal MRI. B Coronal MRI. (AP = anterior pituitary; CS = cavernous sinus; H = hypothalamus; IC = internal carotid artery; OC = optic chiasm; PP = posterior pituitary; PS = pituitary stalk; SS = sphenoid sinus; TV = third ventricle) SS PP H TV OC AP A B OC IC TV PS CS AP

680 • ENDOCRINOLOGY Diseases of the hypothalamus and pituitary are classiﬁed in Box 18.52. By far the most common disorder is an adenoma of the anterior pituitary gland. Investigation of patients with pituitary disease Although pituitary disease presents with diverse clinical manifestations (see below), the approach to investigation is similar in all cases (Box 18.53). The approach to testing for hormone deﬁciency is outlined in Box 18.53. Details are given in the sections on individual glands elsewhere in this chapter. Tests for hormone excess vary according to the hormone in question. For example, prolactin is not secreted in pulsatile fashion, although it rises with signiﬁcant psychological stress. Assuming that the patient was not distressed by venepuncture, a random measurement of serum prolactin is sufﬁcient to diagnose hyperprolactinaemia. In contrast, growth hormone is secreted in a pulsatile fashion. A high random level does not conﬁrm acromegaly; the diagnosis is conﬁrmed only by failure of growth hormone to be suppressed during an oral glucose tolerance test, and a high serum insulin-like growth factor-1 (IGF-1). Similarly, in suspected ACTH-dependent Cushing’s disease (p. 666), random measurement of plasma cortisol is unreliable and the diagnosis is usually made by a dexamethasone suppression test. The most common local complication of a large pituitary tumour is compression of the optic pathway. The resulting visual ﬁeld defect can be documented using a Goldman’s perimetry chart. MRI reveals ‘abnormalities’ of the pituitary gland in as many as 10% of ‘healthy’ middle-aged people. It should therefore be performed only if there is a clear biochemical abnormality or if a patient presents with clinical features of pituitary tumour (see below). A pituitary tumour may be classiﬁed as either a macroadenoma (> 10 mm diameter) or a microadenoma (< 10 mm diameter). Surgical biopsy is usually only performed as part of a therapeutic operation. Conventional histology identiﬁes tumours as chromophobe (usually non-functioning), acidophil (typically prolactin- or growth hormone-secreting) or basophil (typically ACTH-secreting); immunohistochemistry may confirm their secretory capacity but is poorly predictive of growth potential of the tumour. 18.52 Classiﬁcation of diseases of the pituitary and hypothalamus Primary Secondary Non-functioning tumours Pituitary adenoma Craniopharyngioma Metastatic tumours Hormone excess Anterior pituitary Prolactinoma Acromegaly Cushing’s disease Rare TSH-, LH- and FSH-secreting adenomas Disconnection hyperprolactinaemia Hypothalamus and posterior pituitary Syndrome of inappropriate antidiuretic hormone (SIADH, p. 357) Hormone deﬁciency Anterior pituitary Hypothalamus and posterior pituitary Hypopituitarism Cranial diabetes insipidus GnRH deﬁciency (Kallmann’s syndrome) Hormone resistance Growth hormone resistance (Laron dwarﬁsm) Nephrogenic diabetes insipidus (FSH = follicle-stimulating hormone; GnRH = gonadotrophin-releasing hormone; LH = luteinising hormone; TSH = thyroid-stimulating hormone) 18.53 How to investigate patients with suspected pituitary hypothalamic disease Identify pituitary hormone deﬁciency ACTH deﬁciency • Short ACTH stimulation test (see Box 18.43) • Insulin tolerance test (see Box 18.56): only if there is uncertainty in interpretation of short ACTH stimulation test (e.g. acute presentation) LH/FSH deﬁciency • In the male, measure random serum testosterone, LH and FSH • In the pre-menopausal female, ask if the menses are regular • In the post-menopausal female, measure random serum LH and FSH (FSH normally > 30 IU/L and LH > 20 IU/L) TSH deﬁciency • Measure random serum T4 • Note that TSH is often detectable in secondary hypothyroidism Growth hormone deﬁciency Only investigate if growth hormone replacement therapy is being contemplated (p. 682) • Measure immediately after exercise • Consider other stimulatory tests (see Box 18.55) Cranial diabetes insipidus Only investigate if patient complains of polyuria/polydipsia, which may be masked by ACTH or TSH deﬁciency • Exclude other causes of polyuria with blood glucose, potassium and calcium measurements • Water deprivation test (see Box 18.61) or 5% saline infusion test Identify hormone excess • Measure random serum prolactin • Investigate for acromegaly (glucose tolerance test) or Cushing’s syndrome (p. 667) if there are clinical features Establish the anatomy and diagnosis • Consider visual ﬁeld testing • Image the pituitary and hypothalamus by MRI or CT (ACTH = adrenocorticotrophic hormone; FSH = follicle-stimulating hormone; LH = luteinising hormone; TSH = thyroid-stimulating hormone)

The hypothalamus and the pituitary gland • 681

Presenting problems in hypothalamic and pituitary disease The clinical features of pituitary disease are shown in Figure 18.28. Younger women with pituitary disease most commonly present with secondary amenorrhoea (p. 654) or galactorrhoea (in hyperprolactinaemia). Post-menopausal women and men of any age are less likely to report symptoms of hypogonadism and so are more likely to present late with larger tumours causing visual ﬁeld defects. Nowadays, many patients present with the incidental ﬁnding of a pituitary tumour on a CT or MRI scan. Hypopituitarism Hypopituitarism describes combined deﬁciency of any of the anterior pituitary hormones. The clinical presentation is variable and depends on the underlying lesion and the pattern of resulting hormone deﬁciency. The most common cause is a pituitary macroadenoma but other causes are listed in Box 18.54. Clinical assessment The presentation is highly variable. For example, following radiotherapy to the pituitary region, there is a characteristic sequence of loss of pituitary hormone secretion. Growth hormone secretion is often the earliest to be lost. In adults, this produces lethargy, muscle weakness and increased fat mass but these features are not obvious in isolation. Next, gonadotrophin (LH and FSH) secretion becomes impaired with loss of libido in the male and oligomenorrhoea or amenorrhoea in the female. Later, in the male there may be gynaecomastia and decreased frequency of shaving. In both sexes, axillary and pubic hair eventually become Fig. 18.28 Common symptoms and signs to consider in a patient with suspected pituitary disease. (ACTH = adrenocorticotrophic hormone; TSH = thyroid-stimulating hormone) Macroadenoma (arrows)

10 mm diameter Local complications • Headache • Visual field defect • Disconnection hyperprolactinaemia • Diplopia (cavernous sinus involvement) • Acute infarction/expansion (pituitary apoplexy) Hormone excess Hyperprolactinaemia • Galactorrhoea • Amenorrhoea • Hypogonadism Acromegaly • Headache • Sweating • Change in shoe and ring size Cushing’s disease • Weight gain • Bruising • Myopathy • Hypertension • Striae • Depression Hypopituitarism Growth hormone • Lethargy Gonadotrophins • Lethargy •Loss of libido • Hair loss • Amenorrhoea ACTH • Lethargy • Postural hypotension • Pallor • Hair loss TSH • Lethargy Vasopressin (usually post-surgical) • Thirst and polyuria Microadenoma (arrow) < 10 mm diameter 18.54 Causes of anterior pituitary hormone deﬁciency Structural • Primary pituitary tumour • Adenoma* • Carcinoma (exceptionally rare) • Craniopharyngioma* • Meningioma* • Secondary tumour (including leukaemia and lymphoma) • Chordoma • Germinoma (pinealoma) • Arachnoid cyst • Rathke’s cleft cyst • Haemorrhage (apoplexy) Inﬂammatory/inﬁltrative • Sarcoidosis • Infections, e.g. pituitary abscess, tuberculosis, syphilis, encephalitis • Lymphocytic hypophysitis • Haemochromatosis • Langerhans cell histiocytosis Congenital deﬁciencies • GnRH (Kallmann’s syndrome)* • GHRH* • TRH • CRH Functional* • Chronic systemic illness • Anorexia nervosa • Excessive exercise Other • Head injury* • (Para)sellar surgery* • (Para)sellar radiotherapy* • Post-partum necrosis (Sheehan’s syndrome) • Opiate analgesia *The most common causes of pituitary hormone deﬁciency. (CRH = corticotrophin-releasing hormone; GHRH = growth hormone-releasing hormone; GnRH = gonadotrophin-releasing hormone; TRH = thyrotrophinreleasing hormone)

682 • ENDOCRINOLOGY TSH is not helpful in adjusting the replacement dose because patients with hypopituitarism often secrete glycoproteins that are measured in the TSH assays but are not bioactive. The aim is to maintain serum T4 in the upper part of the reference range. It is dangerous to give thyroid replacement in adrenal insufﬁciency without ﬁrst giving glucocorticoid therapy, since this may precipitate adrenal crisis. Sex hormone replacement This is indicated if there is gonadotrophin deﬁciency in women under the age of 50 and in men to restore normal sexual function and to prevent osteoporosis (p. 1044). Growth hormone replacement Growth hormone (GH) is administered by daily subcutaneous self-injection to children and adolescents with GH deﬁciency and, until recently, was discontinued once the epiphyses had fused. However, although hypopituitary adults receiving ‘full’ replacement with hydrocortisone, levothyroxine and sex steroids are usually much improved by these therapies, some individuals remain lethargic and unwell compared with a healthy population. Some of these patients feel better, and have objective improvements in their fat:muscle mass ratio and other metabolic parameters, if they are also given GH replacement. Treatment with GH may also help young adults to achieve a higher peak bone mineral density. The principal side-effect is sodium retention, manifest as peripheral oedema or carpal tunnel syndrome if given in excess. For this reason, GH replacement should be started at a low dose, with monitoring of the response by measurement of serum IGF-1. sparse or even absent and the skin becomes characteristically ﬁner and wrinkled. Chronic anaemia may also occur. The next hormone to be lost is usually ACTH, resulting in symptoms of cortisol insufﬁciency (including postural hypotension and a dilutional hyponatraemia). In contrast to primary adrenal insufﬁciency (p. 671), angiotensin II-dependent zona glomerulosa function is not lost and hence aldosterone secretion maintains normal plasma potassium. In contrast to the pigmentation of Addison’s disease due to high levels of circulating ACTH acting on the skin melanocytes, a striking degree of pallor is usually present. Finally, TSH secretion is lost with consequent secondary hypothyroidism. This contributes further to apathy and cold intolerance. In contrast to primary hypothyroidism, frank myxoedema is rare, presumably because the thyroid retains some autonomous function. The onset of all of the above symptoms is notoriously insidious. However, patients sometimes present acutely unwell with glucocorticoid deﬁciency. This may be precipitated by a mild infection or injury, or may occur secondary to pituitary apoplexy (p. 683). Other features of pituitary disease may be present (Fig. 18.28). Investigations The strategy for investigation of pituitary disease is described in Box 18.53. In acutely unwell patients, the priority is to diagnose and treat cortisol deficiency (p. 672). Other tests can be undertaken later. Speciﬁc dynamic tests for diagnosing hormone deﬁciency are described in Boxes 18.43 and 18.55. More specialised biochemical tests, such as insulin tolerance tests (Box 18.56), GnRH and TRH tests, are rarely required. All patients with biochemical evidence of pituitary hormone deﬁciency should have an MRI or CT scan to identify pituitary or hypothalamic tumours. If a tumour is not identiﬁed, then further investigations are indicated to exclude infectious or inﬁltrative causes. Management Treatment of acutely ill patients is similar to that described for adrenocortical insufﬁciency on page 673, except that sodium depletion is not an important component to correct. Chronic hormone replacement therapies are described below. Once the cause of hypopituitarism is established, speciﬁc treatment – of a pituitary macroadenoma, for example (see below) – may be required. Cortisol replacement Hydrocortisone should be given if there is ACTH deﬁciency. Suitable doses are described in the section on adrenal disease on page 672. Mineralocorticoid replacement is not required. Thyroid hormone replacement Levothyroxine 50–150 μg once daily should be given as described on page 640. Unlike in primary hypothyroidism, measuring 18.55 Tests of growth hormone secretion GH levels are commonly undetectable, so a choice from the range of ‘stimulation’ tests is required: • Insulin-induced hypoglycaemia • Arginine (may be combined with GHRH) • Glucagon • Clonidine (in children) (GH = growth hormone; GHRH = growth hormone-releasing hormone) The precise cut-off ﬁgure for a satisfactory cortisol and GH response depends on the assay used and so varies between centres. 18.56 How and when to do an insulin tolerance test Use • Assessment of the HPA axis • Assessment of GH deﬁciency • Indicated when there is doubt after the other tests in Box 18.53 • Usually performed in specialist centres, especially in children • IV glucose and hydrocortisone must be available for resuscitation Contraindications • Ischaemic heart disease • Epilepsy • Severe hypopituitarism (0800 hrs plasma cortisol < 180 nmol/L (6.6 μg/dL)) Dose • 0.15 U/kg body weight soluble insulin IV Aim • To produce adequate hypoglycaemia (tachycardia and sweating with blood glucose < 2.2 mmol/L (40 mg/dL)) Blood samples • 0, 30, 45, 60, 90, 120 mins for blood glucose, plasma cortisol and growth hormone Results • Normal subjects: GH > 6.7 μg/L (20 mIU/L) • Normal subjects: cortisol > 550 nmol/L (approximately 20.2 μg/dL)* (GH = growth hormone; HPA = hypothalamic–pituitary–adrenal)

The hypothalamus and the pituitary gland • 683

Management Modalities of treatment of common pituitary and hypothalamic tumours are shown in Box 18.57. Associated hypopituitarism should be treated as described above. Urgent treatment is required if there is evidence of pressure on visual pathways. The chances of recovery of a visual ﬁeld defect are proportional to the duration of symptoms, with full recovery unlikely if the defect has been present for longer than 4 months. In the presence of a sellar mass lesion, it is crucial that serum prolactin is measured before emergency surgery is performed. If the prolactin is over 5000 mIU/L (236 ng/mL), then the lesion is likely to be a macroprolactinoma and should respond to a dopamine agonist with shrinkage of the lesion, making surgery unnecessary (see Fig. 18.29). Most operations on the pituitary are performed using the trans-sphenoidal approach via the nostrils, while transfrontal surgery via a craniotomy is reserved for suprasellar tumours and is much less frequently needed. It is uncommon to be able to resect lateral extensions into the cavernous sinuses, although with modern endoscopic techniques this is more feasible. All operations on the pituitary carry a risk of damaging normal endocrine function; this risk increases with the size of the primary lesion. Pituitary function (see Box 18.53) should be retested 4–6 weeks following surgery, primarily to detect the development of any new hormone deﬁcits. Rarely, the surgical treatment of a sellar lesion can result in recovery of hormone secretion that was deﬁcient pre-operatively. Following surgery, usually after 3–6 months, imaging should be repeated. If there is a signiﬁcant residual mass and the histology conﬁrms an anterior pituitary tumour, external radiotherapy may be given to reduce the risk of recurrence but the risk:beneﬁt ratio needs careful individualised discussion. Radiotherapy is not useful in patients requiring urgent therapy because it takes many months or years to be effective and there is a risk of acute swelling of the mass. Fractionated radiotherapy carries a life-long risk of hypopituitarism (50–70% in the ﬁrst 10 years) and annual pituitary function tests are obligatory. There is also concern that radiotherapy might impair cognitive function, cause vascular changes and even induce primary brain tumours, but these side-effects have not been quantiﬁed reliably and are likely Pituitary tumour Pituitary tumours produce a variety of mass effects, depending on their size and location, but also present as incidental ﬁndings on CT or MRI, or with hypopituitarism, as described above. A wide variety of disorders can present as mass lesions in or around the pituitary gland (see Box 18.54). Most intrasellar tumours are pituitary macroadenomas (most commonly non-functioning adenomas; see Fig. 18.28), whereas suprasellar masses may be craniopharyngiomas (see Fig. 18.31). The most common cause of a parasellar mass is a meningioma. Clinical assessment Clinical features are shown in Figure 18.28. A common but non-speciﬁc presentation is with headache, which may be the consequence of stretching of the diaphragma sellae. Although the classical abnormalities associated with compression of the optic chiasm are bitemporal hemianopia (see Fig. 18.29) or upper quadrantanopia, any type of visual ﬁeld defect can result from suprasellar extension of a tumour because it may compress the optic nerve (unilateral loss of acuity or scotoma) or the optic tract (homonymous hemianopia). Optic atrophy may be apparent on ophthalmoscopy. Lateral extension of a sellar mass into the cavernous sinus with subsequent compression of the 3rd, 4th or 6th cranial nerve may cause diplopia and strabismus, but in anterior pituitary tumours this is an unusual presentation. Occasionally, pituitary tumours infarct or there is bleeding into cystic lesions. This is termed ‘pituitary apoplexy’ and may result in sudden expansion with local compression symptoms and acute-onset hypopituitarism. Non-haemorrhagic infarction can also occur in a normal pituitary gland; predisposing factors include catastrophic obstetric haemorrhage (Sheehan’s syndrome), diabetes mellitus and raised intracranial pressure. Investigations Patients suspected of having a pituitary tumour should undergo MRI or CT. While some lesions have distinctive neuro-radiological features, the deﬁnitive diagnosis is made on histology after surgery. All patients with (para)sellar space-occupying lesions should have pituitary function assessed as described in Box 18.53. 18.57 Therapeutic modalities for functioning and non-functioning hypothalamic and pituitary tumours Surgery Radiotherapy Medical Comment Non-functioning pituitary macroadenoma 1st line 2nd line – Prolactinoma 2nd line 2nd line 1st line Dopamine agonists Dopamine agonists usually cause macroadenomas to shrink Acromegaly 1st line 2nd line 2nd line Somatostatin analogues Dopamine agonists GH receptor antagonists Medical therapy does not reliably cause macroadenomas to shrink Radiotherapy and medical therapy are used in combination for inoperable tumours Cushing’s disease 1st line 2nd line 2nd line Steroidogenesis inhibitors Pasireotide Radiotherapy may take many years to reduce ACTH excess and medical therapies may be used as a bridge. Bilateral adrenalectomy may also be considered if the pituitary tumour is not completely resectable Craniopharyngioma 1st line 2nd line – (ACTH = adrenocorticotrophic hormone; GH = growth hormone)

684 • ENDOCRINOLOGY to be rare. Stereotactic radiosurgery allows speciﬁc targeting of residual disease in a more focused fashion. Non-functioning tumours should be followed up by repeated imaging at intervals that depend on the size of the lesion and on whether or not radiotherapy has been administered. For smaller lesions that are not causing mass effects, therapeutic surgery may not be indicated and the lesion may simply be monitored by serial neuroimaging without a clear-cut diagnosis having been established. Hyperprolactinaemia/galactorrhoea Hyperprolactinaemia is a common abnormality that usually presents with hypogonadism and/or galactorrhoea (lactation in the absence of breastfeeding). Since prolactin stimulates milk secretion but not breast development, galactorrhoea rarely occurs in men and only does so if gynaecomastia has been induced by hypogonadism (p. 655). The differential diagnosis of hyperprolactinaemia is shown in Box 18.58. Many drugs, especially dopamine antagonists, elevate prolactin concentrations. Pituitary tumours can cause hyperprolactinaemia by directly secreting prolactin (prolactinomas, see below), or by compressing the infundibular stalk and thus interrupting the tonic inhibitory effect of hypothalamic dopamine on prolactin secretion (‘disconnection’ hyperprolactinaemia). Prolactin usually circulates as a free (monomeric) hormone in plasma but, in some individuals, prolactin becomes bound to an IgG antibody. This complex is known as macroprolactin and such patients have macroprolactinaemia (not to be confused with macroprolactinoma, a prolactin-secreting pituitary tumour of more than 1 cm in diameter). Since macroprolactin cannot cross blood-vessel walls to reach prolactin receptors 18.58 Causes of hyperprolactinaemia Physiological • Stress (e.g. post-seizure) • Pregnancy • Lactation • Nipple stimulation • Sleep • Coitus • Exercise • Baby crying Drug-induced Dopamine antagonists • Antipsychotics (phenothiazines and butyrophenones) • Antidepressants • Antiemetics (e.g. metoclopramide, domperidone) Dopamine-depleting drugs • Reserpine • Methyldopa Oestrogens • Oral contraceptive pill Pathological Common • Disconnection hyperprolactinaemia (e.g. non-functioning pituitary macroadenoma) • Prolactinoma (usually microadenoma) • Primary hypothyroidism • Polycystic ovarian syndrome • Macroprolactinaemia Uncommon • Pituitary tumour secreting prolactin and growth hormone • Hypothalamic disease • Renal failure Rare • Chest wall reﬂex (e.g. post herpes zoster) in target tissues, it is of no pathological signiﬁcance. Some commercial prolactin assays do not distinguish prolactin from macroprolactin and so macroprolactinaemia is a cause of spurious hyperprolactinaemia. Identiﬁcation of macroprolactin requires gel ﬁltration chromatography or polyethylene glycol precipitation techniques, and one of these tests should be performed in all patients with hyperprolactinaemia if the prolactin assay is known to cross-react. Clinical assessment In women, in addition to galactorrhoea, hypogonadism associated with hyperprolactinaemia causes secondary amenorrhoea and anovulation with infertility (p. 654). Important points in the history include drug use, recent pregnancy and menstrual history. The quantity of milk produced is variable and it may be observed only by manual expression. In men there is decreased libido, reduced shaving frequency and lethargy (p. 655). Unilateral galactorrhoea may be confused with nipple discharge, and breast examination to exclude malignancy or ﬁbrocystic disease is important. Further assessment should address the features in Figure 18.28. Investigations Pregnancy should ﬁrst be excluded before further investigations are performed in women of child-bearing potential. The upper limit of normal for many assays of serum prolactin is approximately 500 mIU/L (24 ng/mL). In non-pregnant and non-lactating patients, monomeric prolactin concentrations of 500–1000 mIU/L (24–47 ng/mL) are likely to be induced by stress or drugs, and a repeat measurement is indicated. Levels between 1000 and 5000 mIU/L (47–236 ng/mL) are likely to be due to either drugs, a microprolactinoma or ‘disconnection’ hyperprolactinaemia. Levels above 5000 mIU/L (236 ng/mL) are highly suggestive of a macroprolactinoma. Patients with prolactin excess should have tests of gonadal function (p. 651), and T4 and TSH should be measured to exclude primary hypothyroidism causing TRH-induced prolactin excess. Unless the prolactin falls after withdrawal of relevant drug therapy, a serum prolactin consistently above the reference range is an indication for MRI or CT scan of the hypothalamus and pituitary. Patients with a macroadenoma also need tests for hypopituitarism (see Box 18.53). Management If possible, the underlying cause should be corrected (e.g. cessation of offending drugs and giving levothyroxine replacement in primary hypothyroidism). If dopamine antagonists are the cause, then dopamine agonist therapy is contraindicated; if gonadal dysfunction is the primary concern, sex steroid replacement therapy may be indicated. Troublesome physiological galactorrhoea can also be treated with dopamine agonists (see Box 18.59). Management of prolactinomas is described below. Prolactinoma Most prolactinomas in pre-menopausal women are microadenomas because the symptoms of prolactin excess usually result in early presentation. Prolactin-secreting cells of the anterior pituitary share a common lineage with GH-secreting cells, so occasionally prolactinomas can secrete excess GH and cause acromegaly. In prolactinomas there is a relationship between prolactin concentration and tumour size: the higher the level, the bigger the tumour. Some macroprolactinomas can elevate prolactin concentrations above 100 000 mIU/L

The hypothalamus and the pituitary gland • 685

patients with a microadenoma. Also, after the menopause, suppression of prolactin is required in microadenomas only if galactorrhoea is troublesome, since hypogonadism is then physiological and tumour growth unlikely. In patients with macroadenomas, drugs can be withdrawn only after curative surgery or radiotherapy and under close supervision. Ergot-derived dopamine agonists (bromocriptine and cabergoline) can bind to 5-HT2B receptors in the heart and elsewhere and have been associated with ﬁbrotic reactions, particularly tricuspid valve regurgitation, when used in high doses in patients with Parkinson’s disease. At the relatively low doses used in prolactinomas most data suggest that systematic screening for cardiac ﬁbrosis is unnecessary, but if dopamine agonist therapy is prolonged, periodic screening by echocardiography or use of non-ergot agents (quinagolide) may be indicated. Surgery and radiotherapy Surgical decompression is usually necessary only when a macroprolactinoma has failed to shrink sufﬁciently with dopamine agonist therapy, and this may be because the tumour has a signiﬁcant cystic component. Surgery may also be performed in patients who are intolerant of dopamine agonists. Microadenomas can be removed selectively by trans-sphenoidal surgery with a cure rate of about 80%, but recurrence is possible; the cure rate for surgery in macroadenomas is substantially lower. External irradiation may be required for some macroadenomas to prevent regrowth if dopamine agonists are stopped. Pregnancy Hyperprolactinaemia often presents with infertility, so dopamine agonist therapy may be followed by pregnancy. Patients with microadenomas should be advised to withdraw dopamine agonist therapy as soon as pregnancy is conﬁrmed. In contrast, macroprolactinomas may enlarge rapidly under oestrogen stimulation and these patients should continue dopamine agonist therapy and need measurement of prolactin levels and visual ﬁelds during pregnancy. All patients should be advised to report headache or visual disturbance promptly. Acromegaly Acromegaly is caused by growth hormone (GH) secretion from a pituitary tumour, usually a macroadenoma, and carries an approximate twofold excess mortality when untreated. (4700 ng/mL). The investigation of prolactinomas is the same as for other pituitary tumours (see above). Management As shown in Box 18.57, several therapeutic modalities can be employed in the management of prolactinomas. Medical Dopamine agonist drugs are ﬁrst-line therapy for the majority of patients (Box 18.59). They usually reduce serum prolactin concentrations and cause signiﬁcant tumour shrinkage after several months of therapy (Fig. 18.29), but visual ﬁeld defects, if present, may improve within days of ﬁrst administration. It is possible to withdraw dopamine agonist therapy without recurrence of hyperprolactinaemia after a few years of treatment in some 18.59 Dopamine agonist therapy: drugs used to treat prolactinomas Drug Oral dose* Advantages Disadvantages Bromocriptine 2.5–15 mg/day 2–3 times daily Available for parenteral use Short half-life; useful in treating infertility Proven long-term efﬁcacy Ergotamine-like side-effects (nausea, headache, postural hypotension, constipation) Frequent dosing so poor adherence Rare reports of ﬁbrotic reactions in various tissues Cabergoline 250–1000 μg/week 2 doses/week Long-acting, so missed doses less important Reported to have fewer ergotamine-like side-effects Limited data on safety in pregnancy Associated with cardiac valvular ﬁbrosis in Parkinson’s disease Quinagolide 50–150 μg/day Once daily A non-ergot with few side-effects in patients intolerant of the above Limited data on safety in pregnancy *Tolerance develops for the side-effects. All of these agents, especially bromocriptine, must be introduced at low dose and increased slowly. If several doses of bromocriptine are missed, the process must start again. Fig. 18.29 Shrinkage of a macroprolactinoma following treatment with a dopamine agonist. A MRI scan showing a pituitary macroadenoma (T) compressing the optic chiasm (C). B MRI scan of the same tumour following treatment with a dopamine agonist. The macroadenoma, which was a prolactinoma, has decreased in size substantially and is no longer compressing the optic chiasm. A B T C T C

686 • ENDOCRINOLOGY Surgical Trans-sphenoidal surgery is usually the ﬁrst line of treatment and may result in cure of GH excess, especially in patients with microadenomas. More often, surgery serves to debulk the tumour and further second-line therapy is required, according to post-operative imaging and glucose tolerance test results. Radiotherapy External radiotherapy is usually employed as second-line treatment if acromegaly persists after surgery, to stop tumour growth and lower GH levels. However, GH levels fall slowly (over many years) and there is a risk of hypopituitarism. Medical If acromegaly persists after surgery, medical therapy is usually employed to lower GH levels to below 1.0 μg/L (approximately 3 mIU/L) and to normalise IGF-1 concentrations. Medical therapy may be discontinued after several years in patients who have received radiotherapy. Somatostatin analogues (such as octreotide, lanreotide or pasireotide) can be administered as slow-release injections every few weeks. Somatostatin analogues can also be used as primary therapy for acromegaly either as an alternative or in advance of surgery, given evidence that they can induce modest tumour shrinkage in some patients. Dopamine agonists are less effective at lowering GH but may sometimes be helpful, especially with associated prolactin excess. Clinical features If GH hypersecretion occurs before puberty, then the presentation is with gigantism. More commonly, GH excess occurs in adult life and presents with acromegaly. If hypersecretion starts in adolescence and persists into adult life, then the two conditions may be combined. The clinical features are shown in Figure 18.30. The most common complaints are headache and sweating. Additional features include those of any pituitary tumour (see Fig. 18.28). Investigations The clinical diagnosis must be conﬁrmed by measuring GH levels during an oral glucose tolerance test and measuring serum IGF-1. In normal subjects, plasma GH suppresses to below 0.5 μg/L (approximately 2 mIU/L). In acromegaly, GH does not suppress and in about 30% of patients there is a paradoxical rise; IGF-1 is also elevated. The rest of pituitary function should be investigated as described in Box 18.53. Prolactin concentrations are elevated in about 30% of patients due to co-secretion of prolactin from the tumour. Additional tests in acromegaly may include screening for colonic neoplasms with colonoscopy. Management The main aims are to improve symptoms and to normalise serum GH and IGF-1 to reduce morbidity and mortality. Treatment is summarised in Box 18.57. Fig. 18.30 Clinical features of acromegaly. (IGT = impaired glucose tolerance) Skull growth – prominent supraorbital ridges with large frontal sinuses Prognathism (growth of lower jaw) Enlargement of lips, nose and tongue Headache Hypertension Increased sweating Cardiomyopathy Cardiovascular disease (2–3 × ↑) Enlargement of liver Thickened skin IGT (25%)/type 2 diabetes (10%) Colonic cancer (2–3 × ↑) Enlargement of hands Arthropathy Carpal tunnel syndrome Myopathy Enlargement of feet Increased heel pad thickness

The hypothalamus and the pituitary gland • 687

tumour has a large cystic component, it may be safer to place in the cyst cavity a drain that is attached to a subcutaneous access device, rather than attempt a resection. Whatever form it takes, surgery is unlikely to be curative and radiotherapy may often be given to reduce the risk of relapse. Unfortunately, craniopharyngiomas often recur, requiring repeated surgery. They often cause considerable morbidity, usually from hypothalamic obesity, water balance problems and/or visual failure. Diabetes insipidus This uncommon disorder is characterised by the persistent excretion of excessive quantities of dilute urine and by thirst. It is classiﬁed into two types: • cranial diabetes insipidus, in which there is deﬁcient production of vasopressin by the hypothalamus • nephrogenic diabetes insipidus, in which the renal tubules are unresponsive to vasopressin. The underlying causes are listed in Box 18.60. Clinical features The most marked symptoms are polyuria and polydipsia. The patient may pass 5–20 L or more of urine in 24 hours. This is of low speciﬁc gravity and osmolality. If the patient has an intact thirst mechanism, is conscious and has access to oral ﬂuids, then he or she can maintain adequate ﬂuid intake. However, in an unconscious patient or a patient with damage to the hypothalamic thirst centre, diabetes insipidus is potentially lethal. If there is associated cortisol deﬁciency, then diabetes insipidus may not be manifest until glucocorticoid replacement therapy is given. The most common differential diagnosis is primary polydipsia, caused by drinking excessive amounts of ﬂuid in the absence of a defect in vasopressin or thirst control. Pegvisomant is a peptide GH receptor antagonist administered by daily self-injection and may be indicated in some patients whose GH and IGF-1 concentrations fail to suppress sufﬁciently following somatostatin analogue therapy. Craniopharyngioma Craniopharyngiomas are benign tumours that develop in cell rests of Rathke’s pouch, and may be located within the sella turcica, or commonly in the suprasellar space. They are often cystic, with a solid component that may or may not be calciﬁed (Fig. 18.31). In young people, they are diagnosed more commonly than pituitary adenomas. They may present with pressure effects on adjacent structures, hypopituitarism and/or cranial diabetes insipidus. Other clinical features directly related to hypothalamic damage may also occur. These include hyperphagia and obesity, loss of the sensation of thirst and disturbance of temperature regulation, and these features can be signiﬁcant clinical challenges to manage. Craniopharyngiomas can be treated by the trans-sphenoidal route but surgery may also involve a craniotomy, with a relatively high risk of hypothalamic damage and other complications. If the Fig. 18.31 Craniopharyngioma. A This developmental tumour characteristically presents in younger patients; it is often cystic and calciﬁed, as shown in this MRI scan (arrows). B Pathology specimen. A B 18.60 Causes of diabetes insipidus Cranial Structural hypothalamic or high stalk lesion • See Box 18.54 Idiopathic Genetic defect • Dominant (AVP gene mutation) • Recessive (DIDMOAD syndrome – association of diabetes insipidus with diabetes mellitus, optic atrophy, deafness) Nephrogenic Genetic defect • V2 receptor mutation • Aquaporin-2 mutation • Cystinosis Metabolic abnormality • Hypokalaemia • Hypercalcaemia Drug therapy • Lithium • Demeclocycline Poisoning • Heavy metals Chronic kidney disease • Polycystic kidney disease • Sickle-cell anaemia • Inﬁltrative disease

688 • ENDOCRINOLOGY of serum sodium concentrations and/or osmolality. The principal hazard is excessive treatment, resulting in water intoxication and hyponatraemia. Conversely, inadequate treatment results in thirst and polyuria. The ideal dose prevents nocturia but allows a degree of polyuria from time to time before the next dose (e.g. DDAVP nasal dose 5 μg in the morning and 10 μg at night). The polyuria in nephrogenic diabetes insipidus is improved by thiazide diuretics (e.g. bendroﬂumethiazide 5–10 mg/day), amiloride (5–10 mg/day) and NSAIDs (e.g. indometacin 15 mg 3 times daily), although the last of these carries a risk of reducing glomerular ﬁltration rate. Disorders affecting multiple endocrine glands Multiple endocrine neoplasia Multiple endocrine neoplasias (MEN) are rare autosomal dominant syndromes characterised by hyperplasia and formation of adenomas or malignant tumours in multiple glands. They fall into four groups, as shown in Box 18.63. Some other genetic diseases also have an increased risk of endocrine tumours; for example, phaeochromocytoma is associated with von Hippel–Lindau syndrome (p. 1132) and neuroﬁbromatosis type 1 (p. 1131). The MEN syndromes should be considered in all patients with two or more endocrine tumours and in patients with solitary tumours who report other endocrine tumours in their family. Inactivating mutations in MEN 1 (MENIN), a tumour suppressor gene on chromosome 11, cause MEN 1, whereas MEN 2 and 3 (also known as MEN 2a and 2b, respectively) are caused by gain-of-function mutations in the RET proto-oncogene on chromosome 10. These cause constitutive activation of the membrane-associated tyrosine kinase RET, which controls the development of cells that migrate from the neural crest. In contrast, loss-of-function mutations of the RET kinase cause Hirschsprung’s disease (p. 834). MEN 4 is extremely rare and is associated with loss-of-function mutations in the CDNK1B gene on chromosome 12; this gene codes for the protein p27, which has putative tumour suppressor activity. Predictive genetic testing can be performed on relatives of individuals with MEN syndromes, after appropriate counselling (p. 59). Individuals who carry mutations associated with MEN should be entered into a surveillance programme. In MEN 1, this typically involves annual history, examination and measurements of serum calcium and prolactin, and MRI of the pituitary and pancreas every 2 years; some centres also perform regular CT or MRI scans Investigations Diabetes insipidus can be conﬁrmed if serum vasopressin is undetectable (although the assay for this is not widely available) or the urine is not maximally concentrated (i.e. < 600 mmol/kg) in the presence of increased plasma osmolality (i.e. > 300 mOsmol/kg). Sometimes, the diagnosis can be conﬁrmed or refuted by random simultaneous samples of blood and urine, but more often a dynamic test is required. The water deprivation test described in Box 18.61 is widely used, but an alternative is to infuse hypertonic (5%) saline and measure vasopressin secretion in response to increasing plasma osmolality. Thirst can also be assessed during these tests on a visual analogue scale. Anterior pituitary function and suprasellar anatomy should be assessed in patients with cranial diabetes insipidus (see Box 18.53). In primary polydipsia, the urine may be excessively dilute because of chronic diuresis, which ‘washes out’ the solute gradient across the loop of Henle, but plasma osmolality is low rather than high. DDAVP (see below) should not be administered to patients with primary polydipsia, since it will prevent excretion of water and there is a risk of severe water intoxication if the patient continues to drink ﬂuid to excess. In nephrogenic diabetes insipidus, appropriate further tests may include plasma electrolytes, calcium, ultrasound of the kidneys and urinalysis. Management Treatment of cranial diabetes insipidus is with des-amino-desaspartate-arginine vasopressin (desmopressin, DDAVP), an analogue of vasopressin that has a longer half-life. For chronic replacement therapy DDAVP may be administered intranasally and orally, although the latter formulation has variable bioavailability. In sick patients, DDAVP should be given by intramuscular injection. The dose of DDAVP should be adjusted on the basis 18.61 How and when to do a water deprivation test Use • To establish a diagnosis of diabetes insipidus and to differentiate cranial from nephrogenic causes Protocol • No coffee, tea or smoking on the test day • Free ﬂuids until 0730 hrs on the morning of the test, but discourage patients from ‘stocking up’ with extra ﬂuid in anticipation of ﬂuid deprivation • No ﬂuids from 0730 hrs • Attend at 0830 hrs for measurement of body weight and plasma and urine osmolality • Record body weight, urine volume, urine and plasma osmolality and thirst score on a visual analogue scale every 2 hrs for up to 8 hrs • Stop the test if the patient loses 3% of body weight • If plasma osmolality reaches > 300 mOsmol/kg and urine osmolality < 600 mOsmol/kg, then administer DDAVP (see text) 2 μg IM Interpretation • Diabetes insipidus is conﬁrmed by a plasma osmolality

300 mOsmol/kg with a urine osmolality < 600 mOsmol/kg • Cranial diabetes insipidus is conﬁrmed if urine osmolality rises by at least 50% after DDAVP • Nephrogenic diabetes insipidus is conﬁrmed if DDAVP does not concentrate the urine • Primary polydipsia is suggested by low plasma osmolality at the start of the test 18.62 The pituitary and hypothalamus in old age • Late presentation: often with large tumours causing visual disturbance, because early symptoms such as amenorrhoea and sexual dysfunction do not occur or are not recognised. • Coincidentally discovered pituitary tumours: may not require surgical intervention if the visual apparatus is not involved, because of slow growth. • Hyperprolactinaemia: less impact in post-menopausal women who are already ‘physiologically’ hypogonadal. Macroprolactinomas, however, require treatment because of their potential to cause mass effects.

Further information • 689

of the chest. In individuals with MEN 2 and 3, annual history, examination and measurement of serum calcium, calcitonin and urinary or plasma catecholamine metabolites should be performed. Because the penetrance of medullary carcinoma of the thyroid approaches 100% in individuals with a RET mutation, prophylactic thyroidectomy should be performed in early childhood in most patients. The precise timing of surgery in childhood should be guided by the speciﬁc mutation in the RET gene. Autoimmune polyendocrine syndromes Two distinct autoimmune polyendocrine syndromes are known: APS types 1 and 2. The most common is APS type 2 (Schmidt’s syndrome), which typically presents in women between the ages of 20 and 60. It is usually deﬁned as the occurrence in the same individual of two or more autoimmune endocrine disorders, some of which are listed in Box 18.64. The mode of inheritance is autosomal dominant with incomplete penetrance and there is a strong association with HLA-DR3 and CTLA-4. Much less common is APS type 1, which is also termed autoimmune poly-endocrinopathy-candidiasis-ectodermal 18.63 Multiple endocrine neoplasia (MEN) syndromes MEN 1 (Wermer’s syndrome) • Primary hyperparathyroidism • Pituitary tumours • Pancreatic neuro-endocrine tumours (e.g. non-functioning, insulinoma, gastrinoma) • Bronchial and thymic carcinoids • Adrenal tumours • Cutaneous lesions (e.g. lipomas, collagenomas, angioﬁbromas) MEN 2 (also known as MEN 2a or Sipple’s syndrome) • Primary hyperparathyroidism • Medullary carcinoma of thyroid • Phaeochromocytoma MEN 3 (also known as MEN 2b) • As for MEN 2 above (though medullary thyroid cancer occurs earlier, even within the ﬁrst year of life) • Marfanoid habitus • Skeletal abnormalities (e.g. craniosynostosis) • Abnormal dental enamel • Multiple mucosal neuromas MEN 4 • Primary hyperparathyroidism • Pituitary tumours • Possible tumours in the adrenals, reproductive organs, kidneys • Possible pancreatic, gastric, bronchial and cervical neuro-endocrine tumours 18.64 Autoimmune polyendocrine syndromes (APS)* Type 1 (APECED) • Addison’s disease • Hypoparathyroidism • Type 1 diabetes • Primary hypothyroidism • Chronic mucocutaneous candidiasis • Nail dystrophy • Dental enamel hypoplasia Type 2 (Schmidt’s syndrome) • Addison’s disease • Primary hypothyroidism • Graves’ disease • Pernicious anaemia • Primary hypogonadism • Type 1 diabetes • Vitiligo • Coeliac disease • Myasthenia gravis *In both types of APS, the precise pattern of disease varies between affected individuals. (APECED = autoimmune poly-endocrinopathy-candidiasis-ectodermal dystrophy) dystrophy (APECED). This is inherited in an autosomal recessive fashion and is caused by loss-of-function mutations in the autoimmune regulator gene AIRE, which is responsible for the presentation of self-antigens to thymocytes in utero. This is essential for the deletion of thymocyte clones that react against self-antigens and hence for the development of immune tolerance (p. 82). The most common clinical features are described in Box 18.64, although the pattern of presentation is variable and other autoimmune disorders are often observed. Late effects of childhood cancer therapy The therapies used to treat cancers in children and adolescents, including radiotherapy and chemotherapy, may cause long-term endocrine dysfunction (p. 1298). Further information Websites british-thyroid-association.org British Thyroid Association: provider of guidelines, e.g. treatment of hypothyroidism and the investigation and management of thyroid cancer. btf-thyroid.org British Thyroid Foundation: a resource for patient leaﬂets and support for patients with thyroid disorders. endocrinology.org British Society for Endocrinology: useful online education resources and links to patient support group. endo-society.org American Endocrine Society: provider of clinical practice guidelines. pituitary.org.uk Pituitary Foundation: a resource for patient and general practitioner leaﬂets and further information. thyroid.org American Thyroid Association: provider of clinical practice guidelines.

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01-1 Clinical decision-making

02-2 Clinical therapeutics and good prescribing

03-3 Clinical genetics

04-4 Clinical immunology

05-5 Population health and epidemiology

06-6 Principles of infectious disease

01-7 Poisoning

02-8 Envenomation

03-9 Environmental medicine

04-10 Acute medicine and critical illness

01-11 Infectious disease

02-12 HIV infection and AIDS

03-13 Sexually transmitted infections

04-14 Clinical biochemistry and metabolic medicine

05-15 Nephrology and urology

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25-35 Laboratory reference ranges

08-18 Endocrinology

18 Endocrinology