733

20 Clinical examination in endocrine  

disease 734

An overview of endocrinology 736Functional anatomy and physiology 736Endocrine pathology 736Investigation of endocrine disease 737Presenting problems in endocrine disease 737

The thyroid gland 738Functional anatomy, physiology and

investigations 738Presenting problems in thyroid disease 740

Thyrotoxicosis 740Hypothyroidism 743Asymptomatic abnormal thyroid function

tests 745Thyroid lump or swelling 746

Autoimmune thyroid disease 747Transient thyroiditis 751Iodine-associated thyroid disease 752Simple and multinodular goitre 752Thyroid neoplasia 754Congenital thyroid disease 755

The reproductive system 756Functional anatomy, physiology and

investigations 756Presenting problems in reproductive

disease 758Delayed puberty 758Amenorrhoea 759Male hypogonadism 760Infertility 761Gynaecomastia 762Hirsutism 763

Polycystic ovarian syndrome 764Turner’s syndrome 765Klinefelter’s syndrome 766

Endocrine disease

The hypothalamus and the pituitary  gland 785Functional anatomy, physiology and

investigations 786Presenting problems in hypothalamic and

pituitary disease 787Hypopituitarism 787Pituitary tumour 789Hyperprolactinaemia/galactorrhoea 790

Prolactinoma 791Acromegaly 792Craniopharyngioma 793Diabetes insipidus 794

Disorders affecting multiple endocrine glands 795Multiple endocrine neoplasia 795Autoimmune polyendocrine syndromes 795Late effects of childhood cancer therapy 796

M.W.J. StrachanJ. Newell-Price

The parathyroid glands 766Functional anatomy, physiology and

investigations 766Presenting problems in parathyroid

disease 767Hypercalcaemia 767Hypocalcaemia 768

Primary hyperparathyroidism 769Familial hypocalciuric hypercalcaemia 770Hypoparathyroidism 770

The adrenal glands 771Functional anatomy and physiology 771Presenting problems in adrenal

disease 773Cushing’s syndrome 773Therapeutic use of glucocorticoids 776Adrenal insufficiency 777Incidental adrenal mass 779

Primary hyperaldosteronism 780Phaeochromocytoma and paraganglioma 781Congenital adrenal hyperplasia 782

The endocrine pancreas and gastrointestinal tract 782Presenting problems in endocrine pancreas

disease 783Spontaneous hypoglycaemia 783

Gastroenteropancreatic neuro-endocrine tumours 784

EndocrinE disEasE

734

CLINICAL EXAMINATION IN ENDOCRINE DISEASE

Observation

HandsPalmar erythema

TremorAcromegaly

Carpal tunnel syndrome

SkinHair distribution

Dry/greasyPigmentation/pallor

BruisingVitiligoStriae

Thickness

PulseAtrial fibrillation

Sinus tachycardiaBradycardia

BreastsGalactorrhoeaGynaecomastia

NeckVoice Hoarse, e.g. hypothyroid VirilisedThyroid gland (see opposite) Goitre Nodules

8

7

2

3

4

5

• 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 fatCentral obesity inCushing’s syndrome andgrowth hormone deficiency

9

Height and weight

BonesFragility fractures (e.g. ofvertebrae, neck of femur ordistal radius)

10

GenitaliaVirilisationPubertal developmentTesticular volume

11

LegsProximal myopathyMyxoedema

12

Blood pressureHypertension in Cushing’s

and Conn’s syndromes,phaeochromocytoma

Hypotension in adrenalinsufficiency

HeadEyes Graves’ disease (see opposite) Diplopia Visual field defect (see opposite)Hair Alopecia Frontal balding

6Facial features Hypothyroid Hirsutism Acromegaly Cushing’sMental state Lethargy Depression Confusion Libido

1

Prognathism in acromegaly

Acromegalic hands. Note softtissue enlargement causing

‘spade-like’ changes

Pigmentation of creasesdue to high ACTH levels

in Addison’s disease

Vitiligo in organ-specificautoimmune disease

Multinodular goitre

Pretibial myxoedemain Graves' disease

Clinical examination in endocrine disease

735

Endocrine disease causes clinical syndromes with symptoms and signs involving many organ systems, reflecting the diverse effects of

hormone deficiency and excess. 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. 21) and thyroid disease are the most common endocrine disorders.

• 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 theclassical finding in pituitarymacroadenomas (p. 789)

6 Examination of the visual fields by confrontation

6 Examination in Graves’ ophthalmopathy

• Inspect from front and side Periorbital oedema (Fig. 20.7) 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 26.28)

• 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

Lidretraction

Normal

Normaldescent

Lid lagdescent

7 Examination of the thyroid gland

Abnormal findingsDiffuse soft goitre with bruit Graves’ disease (p. 747) Diffuse firm goitre Hashimoto’s thyroiditis (p. 751)Diffuse tender goitre Subacute thyroiditis (p. 751)

Multinodular goitre (p. 752) ± Retrosternal extension, tracheal compression

Solitary nodule (p. 746) Adenoma, cyst or carcinomaCervical lymphadenopathy Suggests carcinoma

• Inspect from front to side

• Palpate from behind Thyroid moves on swallowing 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 20.7) incl. tremor, palmar erythema, warm peripheries, tachycardia, lid lag

• Consider signs of Graves’ disease incl. ophthalmopathy, pretibial myxoedema

EndocrinE disEasE

20

736

response elements on DNA to regulate gene expression (p. 42).

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. 20.1). However, additional levels of regulation are now recognised. Many other organs secrete hormones or contribute to the peripheral metabolism and activation of pro-hormones. 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 to affect adjacent cells, or act in an autocrine way to affect behaviour of the cell that pro-duces the hormone.

Endocrine pathology

For each endocrine axis or major gland, diseases can be classified as shown in Box 20.1. Pathology arising within the gland is often called ‘primary’ disease (for example, primary hypothyroidism in Hashimoto’s thyroiditis), while abnormal stimulation of the gland is often called ‘secondary’ disease (for example, secondary hypo-thyroidism in patients with a pituitary tumour and thyroid-stimulating hormone deficiency). Some patho-logical processes can affect multiple endocrine glands (p. 795); these may have a genetic basis (such as organ-specific autoimmune endocrine disorders and the mul-tiple endocrine neoplasia (MEN) syndromes) or be a consequence of therapy for another disease (for example, following treatment of childhood cancer with chemo-therapy and/or radiotherapy).

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. 21). 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. Some endocrine diseases are becoming more common in association with emerging diseases; HIV infection is associated in particular with adrenal insufficiency. Less common endocrine syndromes are described later in the chapter.

Few endocrine therapies have been evaluated by ran-domised controlled trials, in part because hormone replacement therapy (for example, with levothyroxine) has obvious clinical benefits and placebo-controlled trials would be unethical, and in part because many endocrine diseases are rare, making trials difficult to perform. Recommendations for ‘evidence-based medi-cine’ are, therefore, relatively scarce. They relate mainly to use of therapy that is ‘optional’ and/or recently avail-able, 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 control-led in turn by substances produced in the hypothalamus and released into portal blood, which drains directly down the pituitary stalk (Fig. 20.1). Posterior pituitary hormones are synthesised in the hypothalamus and transported down nerve axons, to be released from the posterior pituitary. Hormone release in the hypothala-mus 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 20.2.

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 signal-ling molecules on the cytosolic side of the plasma mem-brane to affect cell function, usually through changes in gene expression (p. 48). Some hormones, most notably steroids, triiodothyronine and vitamin D, bind to spe-cific intracellular receptors, which directly bind to

Fig. 20.1  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. 

Feedbackregulation

Trophichormone

Hormone Bindingprotein

Target organ

Metabolism

Endocrinegland

Pituitary

Neuralcontrol

Action

Receptor

Directregulation

An overview of endocrinology

20

737

Fig. 20.2  The principal endocrine ‘axes’. Some major endocrine glands are not controlled by the pituitary. These include the parathyroid glands (regulated by calcium concentrations, p. 766), the adrenal zona glomerulosa (regulated by the renin–angiotensin system, p. 771) and the endocrine pancreas (Ch. 21). Italics show negative regulation. (ACTH = adrenocorticotrophic hormone; ADH = antidiuretic hormone, arginine vasopressin; CRH = corticotrophin-releasing hormone; FSH = follicle-stimulating 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). 

Regulation

CircadianrhythmStress

Cortisol

OsmolalityIntravascular

volume

OestrogenProgesterone

AndrogenProlactinInhibin

T3 IGF-1

GnRH TRH Dopamine GHRHSomatostatin

CRH ADH OxytocinHypothalamus

TSH Prolactin GH ACTH

Posterior

PituitaryLH

FSH

Gonads:testes orovaries

Thyroid Breast Liver Adrenalcortex

Distalnephron

UterusBreast

OestrogenProgesterone

Androgen

T4T3

IGF-1IGF-BP3

CortisolAndrogen

Glands/targets

Targethormones

Function Reproduction Metabolism Lactation Growth Stress Waterbalance

ParturitionLactation

OestrogenStress

Anterior

Hormone excess• Primaryglandover-production• SecondarytoexcesstrophicsubstanceHormone deficiency• Primaryglandfailure• SecondarytodeficienttrophichormoneHormone hypersensitivity• Failureofinactivationofhormone• Targetorganover-activity/hypersensitivityHormone resistance• Failureofactivationofhormone• TargetorganresistanceNon-functioning tumours

20.1 Classification of endocrine disease

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. 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 20.2. The choice of test is often pragmatic, taking local access to reliable sampling facilities and laboratory measurements into account.

Timing of measurement

• Releaseofmanyhormonesisrhythmical(pulsatile,circadianormonthly),sorandommeasurementmaybeinvalidandsequentialordynamictestsmayberequired

Choice of dynamic biochemical tests

• Abnormalitiesareoftencharacterisedbylossofnormalregulationofhormonesecretion

• Ifhormonedeficiencyissuspected,chooseastimulationtest• Ifhormoneexcessissuspected,chooseasuppressiontest• Themoreteststherearetochoosefrom,thelesslikelyitis

thatanysingletestisinfallible,soavoidinterpretingoneresultinisolation

Imaging

• Secretorycellsalsotakeupsubstrates,whichcanbelabelled

• Mostendocrineglandshaveahighprevalenceof‘incidentalomas’,sodonotscanunlessthebiochemistryconfirmsendocrinedysfunctionortheprimaryproblemisatumour

Biopsy

• Manyendocrinetumoursaredifficulttoclassifyhistologically(e.g.adrenalcarcinomaandadenoma)

20.2 Principles of endocrine investigation

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

EndocrinE disEasE

20

738

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 which 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 pro-hormone, since it has a longer half-life in blood than T3 (approxi-mately 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 inac-tive 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 which diffuse into tissues and exert diverse metabolic actions. Some laboratories use assays which measure total T4 and T3 in plasma, but it is increasingly common to measure free T4 and free T3. The advantage of the free hormone measurements is that they are not influenced by changes in the concentration of binding proteins; in pregnancy, for example, TBG levels are increased and total T3 and T4 may be raised, but 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 stimula-tion 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

presentation is with non-specific symptoms (Box 20.3) or with asymptomatic biochemical abnormalities. In addition, endocrine diseases are encountered in the differential diagnosis of common complaints discussed in other chapters of this book, including electrolyte abnormalities (Ch. 16), hypertension (Ch. 18), obesity (Ch. 5) and osteoporosis (Ch. 25). 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 com-plaints, so it is important that clinicians are familiar with their key features.

THE THYROID GLAND

Diseases of the thyroid predominantly affect females and are common, occurring in about 5% of the popula-tion. 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. Diseases of the thyroid are summarised in Box 20.4.

Functional anatomy, physiology and investigations

Thyroid physiology is illustrated in Figure 20.3. 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

Primary Secondary

Hormone excess Graves’diseaseMultinodulargoitreAdenomaSubacutethyroiditis

TSHoma

Hormone deficiency

Hashimoto’sthyroiditisAtrophichypothyroidism

Hypopituitarism

Hormone hypersensitivity

–

Hormone resistance

Thyroidhormoneresistancesyndrome5′-monodeiodinasedeficiency

Non-functioning tumours

DifferentiatedcarcinomaMedullarycarcinomaLymphoma

20.4 Classification of thyroid disease

Symptom Most likely endocrine disorder(s)

Lethargy and depression

Hypothyroidism,diabetesmellitus,hyperparathyroidism,hypogonadism,adrenalinsufficiency,Cushing’ssyndrome

Weight gain Hypothyroidism,Cushing’ssyndrome

Weight loss Thyrotoxicosis,adrenalinsufficiency,diabetesmellitus

Polyuria and polydipsia

Diabetesmellitus,diabetesinsipidus,hyperparathyroidism,hypokalaemia(Conn’ssyndrome)

Heat intolerance Thyrotoxicosis,menopause

Palpitations Thyrotoxicosis,phaeochromocytoma

Headache Acromegaly,pituitarytumour,phaeochromocytoma

Muscle weakness (usually proximal)

Thyrotoxicosis,Cushing’ssyndrome,hypokalaemia(e.g.Conn’ssyndrome),hyperparathyroidism,hypogonadism

Coarsening of features

Acromegaly,hypothyroidism

20.3 Examples of non-specific presentations of endocrine disease

The thyroid gland

20

739

Fig. 20.3  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) 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

Follicularcell

Extracellularfluid

T4

MITDIT

T4

T3

Stimulates allsteps

+ hyperplasia

IodideTSHT3 T4

MIT Tg

DIT

T3

Iodide

MIT Tg

DIT

Tg

1 8 7

8

2

4

13

6

5

Protein-boundT4, T3 ( > 99%)

Increased metabolic rateMimic β-adrenergic action,e.g. on heart rate, gut motilityCNS activationBone demineralisationCellular differentiationetc.

rT3

T4

T3

8

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) Negativefeedback

3

4

HO CH2 COOH

NH2

CH

HO CH2 COOH

NH2

CH

Parafollicular (C) cells

ColloidFollicularepithelium

Red blood cells

Free T4,T3( < 1%)

TSH T4 T3 Most likely interpretation(s)

U.D. Raised Raised Primarythyrotoxicosis

U.D. Normal1 Raised PrimaryT3-toxicosis

U.D. Normal1 Normal1 Subclinicalthyrotoxicosis

U.D.orlow Raised Lowornormal Non-thyroidalillness,amiodaronetherapy

U.D. Low Low Secondaryhypothyroidism4

Transientthyroiditisinevolution

Normal Low Low2 Secondaryhypothyroidism4

Mildlyelevated5–20mU/L Low Low2 PrimaryhypothyroidismSecondaryhypothyroidism4

Elevated>20mU/L Low Low2 Primaryhypothyroidism

Mildlyelevated5–20mU/L Normal3 Normal2 Subclinicalhypothyroidism

Elevated20–500mU/L Normal Normal ArtefactEndogenousIgGantibodieswhichinterferewithTSHassay

Elevated Raised Raised Non-compliancewithT4replacement–recent‘loading’doseSecondarythyrotoxicosis4

Thyroidhormoneresistance

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.

20.5 How to interpret thyroid function test results

(U.D. = undetectable)

EndocrinE disEasE

20

740

circulating TSH levels. The anterior pituitary is very sen-sitive to minor changes in thyroid hormone levels within the reference range. Although the reference range for free T4 is 9–21 pmol/L (700–1632 pg/dL), a rise or fall of 5 pmol/L in an individual in whom the level is usually 15 pmol/L 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 consid-ering thyroid hormone levels may be misleading in patients with pituitary disease (see Box 20.58, p. 787). Moreover, TSH may take several weeks to ‘catch up’ with T4 and T3 levels, for example, when prolonged suppression of TSH in thyrotoxicosis is relieved by anti thyroid therapy. Heterophilic antibodies can also interfere with the TSH assay and cause a spuriously high measurement. Common patterns of abnormal thyroid function test results and their interpretation are shown in Box 20.5.

Other modalities commonly employed in the inves-tigation of thyroid disease include measurement of anti-bodies against the TSH receptor or other thyroid antigens (see Box 20.8, p. 741), 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 are either asymptomatic or have non-specific complaints such as tiredness and weight gain.

ThyrotoxicosisThyrotoxicosis describes a constellation of clinical fea-tures 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 20.6). Thyroiditis is more common in parts of the world where relevant viral infections occur, such as North America.

Clinical assessmentThe clinical manifestations of thyrotoxicosis are shown in Box 20.7 and an approach to differential diagnosis is given in Figure 20.4. 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 expe-rienced 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, con-junctival irritation, exophthalmos and diplopia. Pretibial myxoedema (p. 751) and the rare thyroid acropachy (a

Cause Frequency1 (%)

Graves’ disease 76

Multinodular goitre 14

Solitary thyroid adenoma 5

ThyroiditisSubacute(deQuervain’s)2 3Post-partum2 0.5

Iodide-inducedDrugs(amiodarone)2 1Radiographiccontrastmedia2 –Iodineprophylaxisprogramme2 –

Extrathyroidal source of thyroid hormoneFactitiousthyrotoxicosis2 0.2Strumaovarii2,3 –

TSH-induced

TSH-secreting pituitary adenoma 0.2Choriocarcinomaandhydatidiformmole4 –

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 radio-isotope uptake.3i.e. Ovarian teratoma containing thyroid tissue.4Human chorionic gonadotrophin has thyroid-stimulating activity.

20.6 Causes of thyrotoxicosis and their relative frequencies

periosteal hypertrophy, indistinguishable from finger clubbing) are also specific to Graves’ disease.

InvestigationsThe 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 raised (T3 toxicosis) in about 5%. Serum TSH is undetect-able in primary thyrotoxicosis, but values can be raised in the very rare syndrome of secondary thyrotoxicosis caused by a TSH-producing pituitary adenoma. When bio chemical thyrotoxicosis has been confirmed, further investigations should be undertaken to determine the underlying cause, including measurement of TSH recep-tor antibodies (TRAb, elevated in Graves’ disease, Box 20.8) and isotope scanning, as shown in Figure 20.4. Other non-specific abnormalities are common (Box 20.9). An 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. 751). Occa-sionally, patients induce ‘factitious thyrotoxicosis’ by consuming excessive amounts of a thyroid hormone preparation, most often levothyroxine. The exogenous thyroxine suppresses pituitary TSH secretion and hence iodine uptake, serum thyroglobulin and release of endogenous thyroid hormones. The T4:T3 ratio (typically

The thyroid gland

20

741

Thyrotoxicosis Hypothyroidism

Symptoms Signs Symptoms Signs

CommonWeightlossdespitenormalorincreasedappetiteHeatintolerance,sweatingPalpitations,tremorDyspnoea,fatigueIrritability,emotionallability

WeightlossTremorPalmarerythemaSinustachycardiaLidretraction,lidlag

WeightgainColdintoleranceFatigue,somnolenceDryskinDryhairMenorrhagia

Weightgain

Less commonOsteoporosis(fracture,lossofheight)Diarrhoea,steatorrhoeaAnginaAnkleswellingAnxiety,psychosisMuscleweaknessPeriodicparalysis(predominantlyinChinese)Pruritus,alopeciaAmenorrhoea/oligomenorrhoeaInfertility,spontaneousabortionLossoflibido,impotenceExcessivelacrimation

Goitrewithbruit1

Atrialfibrillation2

Systolichypertension/increasedpulsepressureCardiacfailure2

Hyper-reflexiaIll-sustainedclonusProximalmyopathyBulbarmyopathy2

ConstipationHoarsenessCarpaltunnelsyndromeAlopeciaAchesandpainsMusclestiffnessDeafnessDepressionInfertility

HoarsevoiceFacialfeatures:

PurplishlipsMalarflushPeriorbitaloedema

LossoflateraleyebrowsAnaemiaCarotenaemiaErythemaabigneBradycardiahypertensionDelayedrelaxationofreflexesDermalmyxoedema

RareVomitingApathyAnorexiaExacerbationofasthma

GynaecomastiaSpidernaeviOnycholysisPigmentation

Psychosis(myxoedemamadness)GalactorrhoeaImpotence

Ileus,ascitesPericardialandpleuraleffusionsCerebellarataxiaMyotonia

1ln Graves’ disease only. 2Features found particularly in elderly patients.

20.7 Clinical features of thyroid dysfunction

Antibodies to:

Thyroid peroxidase1 Thyroglobulin

TSH receptor2

Normal population

8–27 5–20 0

Graves’ disease 50–80 50–70 80–95

Autoimmune hypothyroidism

90–100 80–90 10–20

Multinodular goitre

∼30–40 ∼30–40 0

Transient thyroiditis

∼30–40 ∼30–40 0

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

20.8 Prevalence of thyroid autoantibodies (%)

30 : 1 in conventional thyrotoxicosis) is increased to above 70 : 1 because circulating T3 in factitious thyro-toxicosis is derived exclusively from the peripheral mon-odeiodination 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

Thyrotoxicosis

• Serumenzymes:raisedalanineaminotransferase,γ-glutamyltransferase(GGT),andalkalinephosphatasefromliverandbone

• Raisedbilirubin• Mildhypercalcaemia• Glycosuria:associateddiabetesmellitus,‘lagstorage’

glycosuria

Hypothyroidism

• Serumenzymes:raisedcreatinekinase,aspartateaminotransferase,lactatedehydrogenase(LDH)

• Hypercholesterolaemia• Anaemia:normochromicnormocyticormacrocytic• Hyponatraemia

20.9 Non-specific laboratory abnormalities in thyroid dysfunction*

*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.

EndocrinE disEasE

20

742

revert to sinus rhythm in about 50% of patients, but cardioversion may be required in the remainder.

Thyrotoxic crisis (‘thyroid storm’)This is a rare but life-threatening complication of thyro-toxicosis. The most prominent signs are fever, agitation, confusion, tachycardia or atrial fibrillation and, in the older patient, cardiac failure. It is a medical emergency, which has a mortality of 10% despite early recognition and treatment. Thyrotoxic crisis is most commonly pre-cipitated by infection in a patient with previously unrec-ognised or inadequately treated thyrotoxicosis. It may also develop shortly after subtotal thyroidectomy in an ill-prepared patient or within a few days of 131I therapy, when acute irradiation 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

Fig. 20.4  Establishing the differential diagnosis in thyrotoxicosis. (1) Graves’ ophthalmopathy refers to clinical features of exophthalmos and periorbital and conjunctival oedema, not simply the lid lag and lid retraction which can occur in all forms of thyrotoxicosis. (2) TSH receptor antibodies  are very rare in patients without autoimmune thyroid disease, but only occur in 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 which cause thyrotoxicosis. (3) Scintigraphy 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 resolvedPossible sick euthyroidism

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

Toxicmultinodular goitre

Graves’disease

Toxicadenoma

No

(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 treatment of thyrotoxicosis but are extremely useful in the short term, whilst patients are awaiting hospital con-sultation or following 131I therapy.

Atrial fibrillation in thyrotoxicosisAtrial 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. 745) is a risk factor for atrial fibrillation. Characteristi-cally, the ventricular rate is little influenced by digoxin, but responds to the addition of a β-blocker. Thromboem-bolic vascular complications are particularly common in thyrotoxic atrial fibrillation so that anticoagulation with warfarin is required, unless contraindicated. Once thyroid hormone and TSH concentrations have been returned to normal, atrial fibrillation will spontaneously

The thyroid gland

20

743

48–72 hours. This is a radiographic contrast medium which not only inhibits the release of thyroid hormones, but also reduces the conversion of T4 to T3 and is, there-fore, more effective than potassium iodide or Lugol’s solution. Dexamethasone (2 mg 4 times daily) and amio-darone have similar effects. Oral carbimazole 40–60 mg daily (p. 748) 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.

HypothyroidismHypothyroidism is a common condition with vari-ous causes (Box 20.10), 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 defi-ciency is endemic. Women are affected approximately six times more frequently than men.

Clinical assessmentThe clinical presentation depends on the duration and severity of the hypothyroidism. Those in whom com-plete thyroid failure has developed insidiously over

months or years may present with many of the clinical features listed in Box 20.7. A consequence of prolonged hypothyroidism is the infiltration of many body tissues by the mucopolysaccharides, hyaluronic acid and chon-droitin sulphate, resulting in a low-pitched voice, poor hearing, slurred speech due to a large tongue, and com-pression 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 com-bined 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 20.5. Care must be taken to identify patients with transient hypo-thyroidism, in whom life-long levothyroxine therapy is inappropriate. This is often observed during the first 6 months after subtotal thyroidectomy or 131I treatment of Graves’ disease, in the post-thyrotoxic phase of sub-acute thyroiditis and in post-partum thyroiditis. In these conditions, levothyroxine treatment is not always neces-sary, as the patient may be asymptomatic during the short period of thyroid failure.

InvestigationsIn 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 mU/L. Mea-surements of serum T3 are unhelpful since they do not discriminate reliably between euthyroidism and hypothyroidism. Secondary hypothyroidism is rare and is caused by failure of TSH secretion in an individual with hypothalamic or anterior pituitary disease. Other non-specific abnormalities are shown in Box 20.9. In severe, prolonged hypothyroidism, the electrocardio-gram (ECG) classically demonstrates sinus bradycardia with low-voltage complexes and ST segment and T-wave abnormalities. Measurement of thyroid peroxidase anti-bodies is helpful but further investigations are rarely required (see Fig. 20.5).

ManagementTreatment is with levothyroxine replacement. It is cus-tomary 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 (for example, 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 and adjusting the dose, usually by 25 µg per day. Patients feel better within 2–3 weeks. Reduction in weight and periorbital puffiness occurs quickly, but the restoration of skin and hair texture and

CausesAnti-TPO antibodies1 Goitre2

AutoimmuneHashimoto’sthyroiditis ++ ±Spontaneousatrophichypothyroidism – –Graves’diseasewithTSHreceptor-blockingantibodies

+ ±

IatrogenicRadioactiveiodineablation + ±Thyroidectomy + –Drugs Carbimazole,methimazole,

propylthiouracil+ ±

Amiodarone + ± Lithium – ±Transient thyroiditisSubacute(deQuervain’s)thyroiditis + ±Post-partumthyroiditis + ±Iodine deficiency,e.g.inmountainousregions

– ++

CongenitalDyshormonogenesis – ++Thyroidaplasia – –

InfiltrativeAmyloidosis,Riedel’sthyroiditis,sarcoidosisetc.

+ ++

Secondary hypothyroidismTSHdeficiency – –

1As shown in Box 20.8, 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.

20.10 Causes of hypothyroidism

EndocrinE disEasE

20

744

resolution of any effusions may take 3–6 months. As illustrated in Figure 20.5, most patients do not require specialist review but will require 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 or even slightly raised, because the T3 required for receptor activation is derived exclu-sively from conversion of T4 within the target tissues, without the usual contribution from thyroid secretion. Some physicians advocate combined replacement with T4 and T3 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 osteo-porosis and atrial fibrillation (p. 745; subclinical thyro-toxicosis), 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 patient compliance with therapy and allows adjustment for variable underlying thyroid activ-ity and other changes in levothyroxine requirements

Fig. 20.5  An approach to adults with suspected primary hypothyroidism. This scheme ignores congenital causes of hypothyroidism (see Box 20.10), such as thyroid aplasia and dyshormonogenesis (associated with nerve deafness in Pendred’s syndrome), which are usually diagnosed in childhood. (1) Immunoreactive 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 mU/L to confirm the diagnosis of primary hypothyroidism. (2) The usual abnormality in sick euthyroidism is a low TSH but any pattern can occur. (3) Thyroid peroxidase antibodies are highly sensitive but not very specific for autoimmune thyroid disease (see Boxes 20.8 and 20.10). (4) Specialist 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. 789). Rare causes of hypothyroidism with goitre include dyshormonogenesis and infiltration of the thyroid (see Box 20.10). 

↑TSH and ↓T4

Scenario?TSH < 20 mU/L1 Repeat when acute

illness has resolvedPossible sick euthyroidism2

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 secondaryhypothyroidism? 4

Thyroid ablation?• > 6 months since 131I or thyroidectomy

NoPositive

antithyroidperoxidase

antibodies?3

No No

TSH > 20 mU/L

Considerrare causesand refer tospecialist4

Spontaneousatrophic

hypothyroidism

Hashimoto’sthyroiditis

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 foras long as otherdrug is required

Yes

Yes No Yes

No

Goitre?

(Box 20.11). Some patients have a persistent elevation of serum TSH despite an ostensibly adequate replacement dose of levothyroxine; most commonly, this is a conse-quence of suboptimal compliance with therapy. There may be differences in bioavailability between the numer-ous generic preparations of levothyroxine and so, if an individual is experiencing marked changes in serum TSH despite optimal compliance, the prescription of a branded preparation of levothyroxine could be consid-ered. Levothyroxine absorption is maximal when the medication is taken before bed and may be further opti-mised by taking a vitamin C supplement.

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 20.5, p. 739).

Levothyroxine replacement in ischaemic heart diseaseHypothyroidism and ischaemic heart disease are common conditions that often occur together. Although angina may remain unchanged in severity or paradoxi-cally disappear with restoration of metabolic rate, exacerbation of myocardial ischaemia, infarction and

The thyroid gland

20

745

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 treat-ment must begin before biochemical confirmation of the diagnosis. Suspected cases should be treated with an intravenous injection of 20 µg triiodothyronine, fol-lowed 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 hypo-thyroidism, 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. 787). Other measures include slow rewarming (p. 105), cautious use of intravenous fluids, broad-spectrum antibiotics and high-flow oxygen. Occa-sionally, assisted ventilation may be necessary.

Symptoms of hypothyroidism with normal thyroid function testsThe classic symptoms of hypothyroidism are, by their very nature, non-specific (see Box 20.3). 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 indi-vidual’s thyroid hormone status. However, some indi-viduals believe that they have hypothyroidism despite normal serum TSH concentrations. There are a large number of websites which 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 con-version, 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 absorp-tion, and levels of selenium in blood and urine. Indi-viduals 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, then referral to a team specialising in medically unexplained symptoms should be considered.

Asymptomatic abnormal thyroid function testsOne 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 thyrotoxicosisSerum TSH is undetectable, and serum T3 and T4 are at the upper end of the reference range. This combina-tion is most often found in older patients with multi-nodular goitre. These patients are at increased risk of

Increased dose required

Use of other medication• IncreaseT4clearance:phenobarbital,phenytoin,

carbamazepine,rifampicin,sertraline*,chloroquine*• InterferewithintestinalT4absorption:colestyramine,

sucralfate,aluminiumhydroxide,ferroussulphate,dietaryfibresupplements,calciumcarbonate

Pregnancy or oestrogen therapy• Increasesconcentrationofserumthyroxine-bindingglobulin

After surgical or 131I ablation of Graves’ disease• Reducesthyroidalsecretionwithtime

Malabsorption

Decreased dose required

Ageing• DecreasesT4clearance

Graves’ disease developing in patient with long-standing primary hypothyroidism• SwitchfromproductionofblockingtostimulatingTSH

receptorantibodies

*Mechanism not fully established.

20.11 Situations in which an adjustment of the dose of levothyroxine may be necessary

sudden death are recognised complications of levo-thyroxine replacement, even using doses as low as 25 µg per day. In patients with known ischaemic heart disease, thyroid hormone replacement should be introduced at low dose and increased very slowly under specialist supervision. It has been suggested that T3 has an advan-tage 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 angioplasty or bypass surgery may be required if angina is exacerbated by levothyrox-ine replacement therapy.

Hypothyroidism in pregnancyMost pregnant women with primary hypothyroidism require an increase in the dose of levothyroxine of approximately 25–50 µg daily to maintain normal TSH levels. This may reflect increased metabolism of thyrox-ine by the placenta and increased serum thyroxine-binding globulin during pregnancy, resulting in an increase in the total thyroid hormone pool to maintain the same free T4 and T3 concentrations. Inadequate maternal T4 therapy may be associated with impaired cognitive development in an unborn child and so women are usually advised to increase their daily levothyroxine dose by 25 µg when pregnancy is confirmed. Serum TSH and free T4 should be measured during each trimester and the dose of levothyroxine adjusted to maintain a normal TSH. See also Box 20.20 (p. 756).

Myxoedema comaThis is a very rare presentation of hypothyroidism in which there is a depressed level of consciousness, usually in an elderly patient who appears myxoedema-tous. Body temperature may be as low as 25°C, convul-sions are not uncommon and cerebrospinal fluid (CSF) pressure and protein content are raised. The mortality

EndocrinE disEasE

20

746

childhood or adolescence, particularly if there is a past history of head and neck irradiation, or one presenting in the elderly should heighten suspicion of a primary thyroid malignancy (p. 754). The presence of cervical lymphadenopathy also increases the likelihood of malig-nancy. 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 investigationsSwellings in the anterior part of the neck most com-monly originate in the thyroid and this can be confirmed by demonstrating that the swelling moves on swallow-ing (p. 735). 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 aetiol-ogy 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 hypo-thyroidism (both of which may be subclinical) should lead to investigations, as already described on pages 740 and 743.

Thyroid scintigraphyThyroid scintigraphy with 99mtechnetium should be per-formed in an individual with a low serum TSH and a nodular thyroid to confirm the presence of an autono-mously functioning (‘hot’) nodule (see Fig. 20.4, p. 742). In such circumstances, further evaluation by fine needle aspiration is not necessary. ‘Cold nodules’ on scintigra-phy have a much higher likelihood of malignancy, but the majority are benign and so scintigraphy is not rou-tinely used in the evaluation of thyroid nodules when TSH is normal.

atrial fibrillation and osteoporosis, and hence the con-sensus view is that they have mild thyrotoxicosis and require therapy, usually with 131I. Otherwise, annual review is essential, as the conversion rate to overt thyro-toxicosis with elevated T4 and/or T3 concentrations is 5% each year.

Subclinical hypothyroidismSerum 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 mU/L. In patients with non-specific symptoms, a trial of levothyroxine therapy may be appropriate. In those with positive autoantibodies or TSH greater than 10 mU/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, 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, treat-ment should only be given with specialist advice and the diagnosis should be re-evaluated after recovery.

Thyroid lump or swellingA 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 20.12). 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 angiogra-phy. Increasingly, thyroid nodules are identified during staging of patients with cancer with computed tomog-raphy (CT), magnetic resonance imaging (MRI) or posi-tron 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. Multi-nodular goitres 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 solitary nodule presenting in

Diffuse goitre• Simplegoitre• Hashimoto’sthyroiditis1• Graves’disease• Drugs

Iodine,amiodarone,lithium

• Iodinedeficiency(endemicgoitre)1

• Suppurativethyroiditis2

• Transientthyroiditis2

• Dyshormonogenesis1

• InfiltrativeAmyloidosis,sarcoidosisetc.

• Riedel’sthyroiditis2

Multinodular goitre

Solitary nodule• Colloidcyst• Hyperplasticnodule• Follicularadenoma• Papillarycarcinoma• Follicularcarcinoma

• Medullarycellcarcinoma• Anaplasticcarcinoma• Lymphoma• Metastasis

1Goitre likely to shrink with levothyroxine therapy. 2Usually tender.

20.12 Causes of thyroid enlargement

The thyroid gland

20

747

individuals with an indeterminate biopsy (Box 20.13). Nodules in which malignancy is confirmed by formal histology are treated as described on page 754. Those which have benign cytology and a reassuring ultra-sound appearance may by observed by interval ultra-sound scans. 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.

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). Levothyroxine therapy may shrink the goitre of Hashimoto’s disease, particularly if serum TSH is elevated.

Autoimmune thyroid disease

Thyroid diseases are amongst the most prevalent antibody-mediated autoimmune diseases and are asso-ciated with other organ-specific autoimmunity (Ch. 4 and p. 795). Autoantibodies may produce inflammation and destruction of thyroid tissue, resulting in hypo-thyroidism, goitre (in Hashimoto’s thyroiditis) or some-times even transient thyrotoxicosis (‘Hashitoxicosis’), or they may stimulate the TSH receptor to cause thyrotoxi-cosis (in Graves’ disease). There is overlap between these conditions, since some patients have multiple autoantibodies.

Graves’ diseaseGraves’ 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 740. Graves’ disease also causes ophthalmo-pathy and, rarely, pretibial myxoedema (p. 734). These extrathyroidal features usually occur in thyrotoxic patients, but can occur in the absence of thyroid dysfunction.

Graves’ thyrotoxicosisPathophysiologyThe thyrotoxicosis results from the production of 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

Thyroid ultrasoundIf thyroid function tests are normal, an ultrasound scan will determine the nature of the thyroid swelling. Ultra-sound can establish whether there is generalised or localised swelling of the thyroid. Inflammatory disor-ders 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 autoanti-bodies 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 func-tion suggests a diagnosis of ‘simple goitre’ (p. 752).

Ultrasound can also readily determine the size and number of nodules within the thyroid and can distin-guish solid nodules from those with a cystic element. It cannot reliably distinguish benign from malignant nodules but, in experienced hands, there are some ultrasound characteristics which are associated with a higher likelihood of malignancy. These include: hyper-vascularity of the nodule, the presence of microcalcifica-tion and irregular, infiltrative margins. A pure cystic nodule is highly unlikely to be malignant and a ‘spongi-form’ appearance is also highly predicative of a benign aetiology.

Fine needle aspirationCytological examination of a thyroid nodule, following fine needle aspiration, is recommended for most thyroid nodules over 1 cm in size. Smaller nodules should be aspirated if there is a high suspicion of malignancy on clinical or ultrasound grounds, while some clinicians will be happy to observe a nodule up to 2 cm in size with a spongiform appearance. Individuals with a multinodular goitre have the same risk of malignancy as those with a solitary nodule. Sometimes, one of the nodules in a multinodular goitre is much larger than any other (a ‘dominant’ nodule), but ultimately the choice of nodule to biopsy should be based on ultra-sound characteristics.

Fine needle aspiration of a thyroid nodule can be performed in the outpatient clinic using a standard 21-gauge needle and a 20 mL syringe, usually making several passes through different parts of the lesion. Ultrasound-guided needle aspiration is necessary for impalpable nodules and to permit targeting of the solid component of a mixed cystic/solid nodule. Aspiration may be therapeutic in the small proportion of patients in whom the swelling is a cyst, although recurrence on more than one occasion is an indication for surgery. Cytological examination can differentiate benign (80%) from definitely malignant or indeterminate nodules (20%), of which 25–50% are confirmed as cancers at surgery. The limitations of fine needle aspiration are that it cannot differentiate between follicular adenoma and carcinoma, and that in 10–20% of cases an inadequate specimen is obtained.

ManagementSolitary nodules with a solid component in which cytol-ogy either is inconclusive or shows malignant cells are treated by surgical excision. Molecular techniques may, in the future, improve the diagnostic accuracy of thyroid cytology and allow a more conservative strategy for

‘Between60and70%ofdifferentiatedthyroidcancershaveatleastonesomaticgenemutation.UsingamicroarrayofmessengerRNAtranscriptsfrom167genesoncytologicallyindeterminatethyroidnodules,thenegativepredictivevalueforlesionswithalowlikelihoodforcancerwas94–95%.Useofthistechnologycould,intheory,avoidunnecessarysurgery.’

• AlexanderEK,etal.NEnglJMed2012;367:705–715.

Forfurtherinformation: www.thyroid.org

20.13 Molecular techniques in cytologically indeterminate thyroid nodules

EndocrinE disEasE

20

748

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. 20.6). The 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.

Fig. 20.6  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 years0 1 2 3 4 5

Thyrotoxic Euthyroid Hypothyroid

A

B

C

Management Common indications Contraindications Disadvantages/complications

Antithyroid drugs(carbimazole,propylthiouracil)

Firstepisodeinpatients<40yrs Breastfeeding(propylthiouracilsuitable)

Hypersensitivityrash2%Agranulocytosis0.2%Hepatotoxicity(withpropylthiouracil)–veryrarebutpotentiallyfatal>50%relapserateusuallywithin2yrsofstoppingdrug

Subtotal thyroidectomy1

LargegoitrePoordrugcompliance,especiallyinyoungpatientsRecurrentthyrotoxicosisaftercourseofantithyroiddrugsinyoungpatients

PreviousthyroidsurgeryDependenceonvoice,e.g.operasinger,lecturer2

Hypothyroidism(~25%)Transienthypocalcaemia(10%)Permanenthypoparathyroidism(1%)Recurrentlaryngealnervepalsy2(1%)

Radio-iodine Patients>40yrs3

RecurrencefollowingsurgeryirrespectiveofageOtherseriouscomorbidity

Pregnancyorplannedpregnancywithin6mthsoftreatmentActiveGraves’ophthalmopathy4

Hypothyroidism,~40%infirstyear,80%after15yrsMostlikelytreatmenttoresultinexacerbationofophthalmopathy4

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 which 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.

20.14 Comparison of treatments for the thyrotoxicosis of Graves’ disease

Graves’ disease has a strong genetic component. There is 50% concordance for thyrotoxicosis between monozygotic twins but only 5% concordance between dizygotic twins. Genome-wide association studies have identified polymorphisms at the MHC, CTLA4, PTPN22, TSHR1 and FCRL3 loci as predisposing genetic vari-ants. Many of these loci have been implicated in the pathogenesis of other autoimmune diseases.

A suggested trigger for the development of thyrotoxi-cosis in genetically susceptible individuals may be infec-tion 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. 752), iodine supplementation can precipitate thyro-toxicosis, 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.

ManagementSymptoms of thyrotoxicosis respond to β-blockade (p. 741) but definitive treatment requires control of thyroid hormone secretion. The different options are compared in Box 20.14. For patients under 40 years of age, most clinicians adopt the empirical approach of prescribing a course of carbimazole and recommending surgery if relapse occurs, while 131I is employed as first- or second-line treatment in those aged over 40. 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 magni-tude of the effect, if any, is small. Experience from the

The thyroid gland

20

749

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. 20.3, p. 739). Although 131I 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 MBq (10 mCi) is given orally. 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’ ophthalmo-pathy and evidence of significant active orbital inflam-mation. It can be administered with caution in those with mild or ‘burnt-out’ eye disease, when it is custom-ary 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 pregnancyThe coexistence of pregnancy and thyrotoxicosis is unusual, as anovulatory cycles are common in thyro-toxic patients and autoimmune disease tends to remit during pregnancy, when the maternal immune response is suppressed. Thyroid function tests must be inter-preted in the knowledge that thyroid-binding globulin, and hence total T4 and T3 levels, are increased in preg-nancy and that TSH reference ranges may be lower (see Box 20.20, p. 756); a fully suppressed TSH with elevated free thyroid hormone levels indicates thyrotoxicosis. The thyrotoxicosis is almost always caused by Graves’ disease. Both mother and fetus must be considered, since maternal thyroid hormones, TRAb and antithyroid drugs can all cross the placenta to some degree, expos-ing the fetus to the risks of thyrotoxicosis, iatrogenic hypothyroidism and goitre. Poorly controlled maternal thyrotoxicosis can result in fetal tachycardia, intra-uterine growth retardation, prematurity, stillbirth and possibly even congenital malformations.

Antithyroid drugs are the treatment of choice for thyrotoxicosis in pregnancy. Carbimazole has been associated with rare cases of embryopathy, particularly a skin defect known as aplasia cutis, and should be avoided in the first trimester. Propylthiouracil should be used in its place but, because of its potential hepato-toxicity, should be replaced with carbimazole from the beginning of the second trimester. Both drugs cross the placenta and will effectively treat thyrotoxicosis in the fetus caused by transplacental passage of TRAb. To avoid fetal hypothyroidism (which could affect brain development) and a resultant goitre, it is important to use the smallest dose of antithyroid drug (optimally, less than 150 mg propylthiouracil or 15 mg carbimazole per

Chernobyl disaster suggests that younger people are more sensitive to radiation-induced thyroid cancer. In many centres, however, 131I is used extensively, even in young patients.Antithyroid drugs. The most commonly used are carbi-mazole and its active metabolite, methimazole (not available in the UK). Propylthiouracil is equally effec-tive. These drugs reduce the synthesis of new thyroid hormones by inhibiting the iodination of tyrosine (see Fig. 20.3, p. 739). Carbimazole also has an immunosup-pressive 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 3–4 weeks. At this point, the dose can be reduced and titrated to main-tain 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. Patients with thyrotoxicosis relapse in at least 50% of cases, usually within 2 years of stopping treatment. Rarely, T4 and TSH levels fluctuate between those of thyrotoxicosis and hypothyroidism at successive review appointments, despite good drug compliance, presum-ably 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 poten-tially 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 whilst on treatment. Propylthiouracil is associ-ated 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 only be used during pregnancy or breastfeeding (see below), or if an adverse reaction to carbimazole has occurred.Thyroid surgery. Patients should be rendered euthyroid with antithyroid drugs before operation. Potassium iodide, 60 mg 3 times daily orally, is often added for 2 weeks before surgery to inhibit thyroid hormone release and reduce the size and vascularity of the gland, making surgery technically easier. Traditionally, a ‘sub-total’ 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 post-operatively. While complications of surgery are rare and 80% of patients are euthyroid, 15% are permanently hypo-thyroid 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 hypo-thyroidism and is probably associated with a higher risk

EndocrinE disEasE

20

750

control of thyroid function, especially hypothyroidism. The most frequent presenting symptoms are related to increased exposure of the cornea, resulting from prop-tosis and lid retraction. There may be excessive lacrima-tion 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 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. 735 and 1169). 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 sele-nium (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 (Box 20.16). More severe inflammatory episodes are treated with glucocorticoids (e.g. daily oral prednisolone or pulsed IV methylprednisolone) and sometimes orbital radiotherapy. There is also an increasing trend to use immunosuppressant therapies, such as ciclosporin, in combination with glucocorticoids. Loss of visual acuity

Fig. 20.7  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

• Presentation:maypresentwithadeteriorationinschoolperformanceorsymptomssuggestiveofattentiondeficithyperactivitydisorder.

• Anti-thyroid drug therapy:prolongedcoursesmayberequiredbecauseremissionratesfollowingan18-monthcourseoftherapyaremuchlowerthaninadults.

• Compliance:compliancewithanti-thyroiddrugtherapyisoftensuboptimal,resultinginpoordiseasecontrolwhichmayadverselyaffectperformanceatschool.

• Radio-iodine therapy:usuallyavoidedinadolescentsbecauseofconcernsaboutriskoffuturemalignancy.

20.15 Thyrotoxicosis in adolescence

day) that will maintain maternal (and presumably fetal) free T4, T3 and TSH within their respective reference ranges. Frequent review of mother and fetus (monitor-ing heart rate and growth) is important. TRAb levels can be measured in the third trimester to predict the likeli-hood of neonatal thyrotoxicosis. When TRAb levels are not elevated, the antithyroid drug can be discontinued 4 weeks before the expected date of delivery to minimise the risk of fetal hypothyroidism at the time of maximum brain development. After delivery, if antithyroid drug is required and the patient wishes to breastfeed, then propylthiouracil is the drug of choice, as it is excreted in the milk to a much lesser extent than carbimazole. Thyroid function should be monitored periodically in the breastfed child.

If thyroid surgery is necessary because of poor drug compliance or drug hypersensitivity, it is most safely performed in the second trimester. Radioactive iodine is absolutely contraindicated, as it invariably induces fetal hypothyroidism.

Thyrotoxicosis in adolescenceThyrotoxicosis can occasionally occur in adolescence and is almost always due to Graves’ disease. The pres-entation may be atypical and management challenging, as summarised in Box 20.15.

Graves’ ophthalmopathyThis condition is immunologically mediated but the autoantigen has not been identified. Within the orbit (and the dermis) there is cytokine-mediated prolifer-ation of fibroblasts which secrete hydrophilic glycos-aminoglycans. 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. 20.7) and a rise in retro-bulbar pressure. The eye is displaced forwards (propto-sis, exophthalmos; p. 735) and in severe cases there is optic nerve compression.

Ophthalmopathy, like thyrotoxicosis (see Fig. 20.6), typically follows an episodic course and it is helpful to distinguish patients with active inflammation (peri-orbital oedema and conjunctival inflammation with changing orbital signs) from those in whom the inflam-mation 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 thyro-toxic episodes (exophthalmic Graves’ disease). It is more common in cigarette smokers and is exacerbated by poor

The thyroid gland

20

751

Transient thyroiditis

Subacute (de Quervain’s) thyroiditisIn 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 thy-roiditis 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. 20.8). 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 sedimenta-tion rate (ESR) is usually raised. High-titre autoantibod-ies 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

is an indication for urgent surgical decompression of the orbit. In ‘burnt-out’ disease, surgery to the eyelids and/or ocular muscles may improve conjunctival expo-sure, cosmetic appearance and diplopia.

Pretibial myxoedemaThis infiltrative dermopathy occurs in fewer than 10% of patients with Graves’ disease and has similar patho-logical 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. 734). 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 thyroiditisHashimoto’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. 755), although this is exceedingly rare. The nomenclature of autoimmune hypothyroidism is confusing. Some authorities reserve the term ‘Hashimoto’s thyroiditis’ for 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 hypothyroid patients without a goitre in whom TSH receptor-blocking antibodies may be more important than antiperoxidase 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 characteris-tically firm or rubbery in consistency. The goitre may be soft, however, and impossible to differentiate from simple goitre (p. 752) by palpation alone. 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. 743), and also to shrink an associ-ated goitre. In this context, the dose of thyroxine should be sufficient to suppress serum TSH to low but detect-able levels.

Fig. 20.8  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

Referencerange

0 2 4 6Months

T4, T3

TSH

‘Seleniumtherapyfor6monthswasassociatedwithimprovementofboththeappearancescoreandthevisual-functioningscore.Thebenefitspersisted6monthsfollowingcessationoftherapy.’

• MarcocciC,etal.NEnglJMed2012;364:1920–1931.

Forfurtherinformation: www.thyroid.org

20.16 Effects of selenium supplementation in mild Graves’ ophthalmopathy

EndocrinE disEasE

20

752

levothyroxine can be prescribed temporarily in the hypothyroid phase. Care must be taken to identify patients presenting with hypothyroidism who are in the later stages of a transient thyroiditis, since they are unlikely to require life-long levothyroxine therapy (see Fig. 20.5, p. 744).

Post-partum thyroiditisThe 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 distur-bances of thyroid function occur in 5–10% of women within 6 months of delivery (see Box 20.20, p. 756). Those affected are likely to have anti-thyroid peroxidase anti-bodies 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 child-birth 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 preg-nancies, and eventually patients progress over a period of years to permanent hypothyroidism.

Iodine-associated thyroid disease

Iodine deficiencyThyroid enlargement is extremely common in certain mountainous parts of the world, such as the Andes, the Himalayas and central Africa, where there is dietary iodine deficiency (endemic goitre). Most patients are euthyroid with normal or raised TSH levels, although hypothyroidism can occur with severe iodine deficiency. Iodine supplementation programmes have abolished this condition in most developed countries.

Iodine-induced thyroid dysfunctionIodine has complex effects on thyroid function. Very high concentrations of iodine inhibit thyroid hormone release and this forms the rationale for iodine treatment of thyroid storm (p. 742) and prior to thyroid surgery for thyrotoxicosis (p. 748). Iodine administration initially enhances, but then inhibits, iodination of tyrosine and thyroid hormone synthesis (see Fig. 20.3, p. 739). The resulting effect of iodine on thyroid function varies according to whether the patient has an iodine-deficient diet or underlying thyroid disease. In iodine-deficient parts of the world, transient thyrotoxicosis may be pre-cipitated by prophylactic iodinisation programmes. In iodine-sufficient areas, thyrotoxicosis can be precipi-tated by radiographic contrast medium or expectorants in individuals who have underlying thyroid disease pre-disposing to thyrotoxicosis, such as multinodular goitre or Graves’ disease in remission. Induction of thyrotoxi-cosis by iodine is called the Jod–Basedow effect. Chronic excess iodine administration can, however, result in hypothyroidism. Increased iodine within the thyroid gland down-regulates iodine trapping, so that uptake is low in all circumstances.

Fig. 20.9  The structure of amiodarone. Note the similarities to T4 (see Fig. 20.3, p. 739). 

C4H9O I

C CH2 CH2 NO

C2H5

C2H5

I

O

AmiodaroneThe anti-arrhythmic agent amiodarone has a structure that is analogous to that of T4 (Fig. 20.9) and contains huge amounts of iodine; a 200 mg dose contains 75 mg iodine, compared with a daily dietary requirement of just 125 µg. Amiodarone also has a cytotoxic effect on thyroid follicular cells and inhibits conversion of T4 to 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. The ratio of T4:T3 is elevated and 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 nodular goitre or latent Graves’ disease

• type II: thyroiditis due to a direct cytotoxic effect if amiodarone administration results in a transient thyrotoxicosis.These patterns can overlap and can 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 radio-iodine. 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 combina-tion therapy with an antithyroid drug and glucocorti-coid 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, when antithyroid drugs may be continued and pred-nisolone withdrawn. Potassium perchlorate can also be used to inhibit iodine trapping in the thyroid. If the cardiac state allows, amiodarone should be discontin-ued, 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 levo-thyroxine, which can be given while amiodarone is continued.

Simple and multinodular goitre

These terms describe diffuse or multinodular enlarge-ment of the thyroid, which occurs sporadically and is of unknown aetiology.

The thyroid gland

20

753

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 thyrotoxi-cosis, p. 745) but sometimes elevated (toxic multinodu-lar goitre; see Fig. 20.4, p. 742).

Clinical features and investigationsMultinodular goitre is usually diagnosed in patients presenting with thyrotoxicosis, a large goitre with or without tracheal compression, or sudden painful swell-ing 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 may cause mediastinal compression with stridor (Fig. 20.11), dysphagia and obstruction of the superior vena cava. Hoarseness due to recurrent laryn-geal 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. 20.4, p. 742). In patients with large goitres, a flow-volume loop is a good screening test for significant tracheal compression (see Fig. 20.11). 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 754.

ManagementIf 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 which cause mediastinal compression or which are cosmetically unattractive. 131I can result in a significant reduction in thyroid size and may be of value in

Simple diffuse goitreThis 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, lymphaden-opathy 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 goitreThe natural history is shown in Figure 20.10. Patients with thyroid enlargement in the absence of thyroid

Fig. 20.10  Natural history of simple goitre. 

Age (in years)

Goitre

Trachealcompression/deviation

T3, T4

TSH

15–25 35–55 > 55

Diffuse Nodular Nodular

No Minimal Yes

Normal Normal Raised

Normal Normal orundetectable

Undetectable

Fig. 20.11  Multinodular goitre with tracheal compression.  A  A flow-volume loop (p. 653) showing a square-shaped inspiratory curve indicating extrathoracic airflow obstruction.  B  A CT scan of the neck showing a large retrosternal goitre (black arrows) with marked deviation and compression of the trachea (white arrow). 

02 4

Volume (L)

Exp

iratio

n (L

/sec

)In

spira

tion

(L/s

ec)

6

2

4

–4

–2

–6

A B

EndocrinE disEasE

20

754

(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. A surgi-cal hemithyroidectomy is an alternative.

Differentiated carcinomaPapillary carcinomaThis is the most common of the malignant thyroid tumours and accounts for 90% of irradiation-induced thyroid cancer. It may be multifocal and spread is ini-tially 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 carcinomaThis is always 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.

ManagementThis is usually by total thyroidectomy followed by a large dose of 131I (3700 MBq (approximately 100 mCi)) in order to ablate any remaining thyroid tissue, normal or malignant. Recent data indicate that a 131I dose of 1100 MBq (approximately 30 mCi) may be equally as effective at thyroid ablation (Box 20.18). Thereafter, long-term treatment with levothyroxine in a dose sufficient to suppress TSH (usually 150–200 µg daily) is important, as there is evidence that growth of differ-entiated thyroid carcinomas is TSH-dependent. Follow- up is by measurement of serum thyroglobulin, which should be undetectable in patients whose normal thyroid has been ablated and who are taking a sup-pressive dose of levothyroxine. Detectable thyroglobu-lin is suggestive of tumour recurrence or metastases, which may be localised by ultrasound, CT, MRI or whole-body scanning with 131I, and may respond to further radio-iodine therapy. Radio-iodine treatment in thyroid cancer and isotope scanning both require serum TSH concentrations to be elevated (> 20 mU/L). This may be achieved by stopping levothyroxine for 4–6 weeks, inducing symptomatic hypothyroidism, or by administering intramuscular injections of recom-binant human TSH. Patients usually find the latter approach preferable but it is more expensive. Clinical

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 hypo-thyroidism 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.

Asymptomatic patients with subclinical thyrotoxico-sis (p. 745) 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. 746). Most are benign and a few of these, called ‘toxic adenomas’, secrete excess thyroid hormones. Primary thyroid malignancy is rare, account-ing for less than 1% of all carcinomas, and has an inci-dence of 25 per million per annum. As shown in Box 20.17, 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 adenomaA 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. 20.4, p. 742). The thyrotoxicosis is usually mild and in almost 50% of patients the plasma T3 alone is elevated

‘Ablativeradioactiveiodinehasbeenassociatedwithanincreasedriskofsecondmalignancies.Tworandomisedcontrolledclinicaltrialshaveshownthat1100MBqradio-iodine(30mCi)isaseffectiveatablatingthyroidtissueas3700MBq(100mCi).Bothtrialsalsoshowedthatpreparationofpatientsforradio-iodinetreatmentwithrecombinantTSHwasaseffectiveaslevothyroxinewithdrawal.’

• SchlumbergerM,etal.NEnglJMed2012;366:1663–1673.• MallickU,etal.NEnglJMed2012;366:1674–1685.

Forfurtherinformation: www.thyroid.org

20.18 Ablative radio-iodine following thyroidectomy for differentiated thyroid cancer

Type of tumourFrequency (%)

Age at presentation (years)

10-year survival (%)

Follicular cellsDifferentiatedcarcinoma Papillary 75–85 20–40 98 Follicular 10–20 40–60 94Anaplastic <5 >60 9

Parafollicular C cellsMedullarycarcinoma 5–8 >40* 78

LymphocytesLymphoma <5 >60 45

*Patients with medullary carcinoma as part of MEN type 2 (p. 795) may present in childhood.

20.17 Malignant thyroid tumours

The thyroid gland

20

755

trials are currently ongoing with novel anti-cancer agents, such as tyrosine kinase inhibitors, in patients with advanced papillary and follicular carcinoma that is refractive to radio-iodine.

PrognosisMost patients with papillary and thyroid cancer will be cured with appropriate treatment. Adverse prognostic factors include older age at presentation, the presence of distant metastases, male sex and the identification of certain histological subtypes. However, radio-iodine therapy can be effective in treating even those with distant metastases, particularly small-volume disease in the lungs, and so prolonged survival is quite common.

Anaplastic carcinoma and lymphomaThese two conditions are difficult to distinguish clini-cally 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 anaplas-tic 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 pre-existing Hashimoto’s thyroiditis, is better (p. 1041), with a median survival of 9 years. Some 98% are non-Hodgkin’s lymphomas, usually the diffuse large B-cell subtype. Treatment is with combination chemotherapy, such as the CHOP regime (p. 1045), and external beam radiotherapy.

Medullary carcinomaThis 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, adrenocortico-trophic hormone (ACTH) and prostaglandins. As a con-sequence, carcinoid syndrome (p. 784) and Cushing’s syndrome (p. 773) 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, a tyrosine kinase inhibitor, is licensed for patients with advanced medullary cancer. The prognosis is less good than for papillary and follicular carcinoma, but individuals can live for many decades with persistent disease which behaves in an indolent fashion.

Thyrotoxicosis

• Causes:commonlyduetomultinodulargoitre.• Clinical features:apathy,anorexia,proximalmyopathy,

atrialfibrillationandcardiacfailurepredominate.• Non-thyroidal illness:thyroidfunctiontestsareperformed

morefrequentlyintheelderly,butinterpretationmaybealteredbyintercurrentillness.

Hypothyroidism

• Clinical features:non-specificfeatures,suchasphysicalandmentalslowing,areoftenattributedtoincreasingageandthediagnosisisdelayed.

• Myxoedema coma(p.745):morelikelyintheelderly.• Levothyroxine dose:toavoidexacerbatinglatentor

establishedheartdisease,thestartingdoseshouldbe25µgdaily.Levothyroxinerequirementsfallwithincreasingageandfewpatientsneedmorethan100µgdaily.

• Other medication(seeBox20.11,p.745):mayinterferewithabsorptionormetabolismoflevothyroxine,necessitatinganincreaseindose.

20.19 The thyroid gland in old age

Medullary carcinoma of the thyroid may occur sporadically, or in families as part of the MEN type 2 syndrome (p. 795).

Riedel’s thyroiditisThis is not a form of thyroid cancer, but the presentation is similar and the differentiation can usually only be made 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 which is irregular and stony-hard. There is usually tracheal and oesophageal compression necessitating partial thyroidectomy. Other recognised complications include recurrent laryn-geal nerve palsy, hypoparathyroidism and eventually hypothyroidism.

Congenital thyroid disease

Early treatment with levothyroxine is essential to prevent irreversible brain damage in children (cretin-ism) with congenital hypothyroidism. Routine screening of TSH levels in heelprick blood samples obtained 5–7 days after birth (as part of the Guthrie test) has revealed an incidence of approximately 1 in 3000, result-ing 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 thyroid replacement therapy within 2 weeks of birth. Developmental assessment of infants treated at this early stage has revealed no differ-ences between cases and controls in most children.

DyshormonogenesisSeveral autosomal recessive defects in thyroid hormone synthesis have been described; the most common results from deficiency of the intrathyroidal peroxidase

EndocrinE disEasE

20

756

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. tachycar-dia). This condition can be difficult to distinguish from an equally rare TSH-producing pituitary tumour (see Box 20.5, p. 739); administration of TRH results in eleva-tion of TSH in thyroid hormone resistance and not in TSHoma, but an MRI scan of the pituitary may be neces-sary 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.

Functional anatomy, physiology and investigations

The physiology of male and female reproductive func-tion is illustrated in Figures 20.12 and 20.13 respectively.

enzyme. Homozygous individuals present with con-genital 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 which transports iodide to the luminal surface of the follicular cell (see Fig. 20.3, p. 739).

Thyroid hormone resistanceThis 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 mono-deiodinase activity. The result is high levels of TSH, T4 and T3, often with a moderate goitre which may not be noted until adulthood. Thyroid hormone signalling is highly complex and involves different isozymes of both monodeiodinases and thyroid hormone receptors in

Fig. 20.12  Male reproductive physiology. (FSH = follicle-stimulating hormone; LH = luteinising hormone). 

Negativefeedback

LH FSH

Interstitial(Leydig)

cells

Sertoli cellsin 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

Normal pregnancy

• Trimester-specific reference ranges:shouldbeusedtointerpretthyroidfunctiontestresultsinpregnancy.Inthefirsttrimester,TSHislowerandfreeT4andT3higher,inpartduetothyroidstimulationbyhumanchorionicgonadotrophin(hCG).Inlaterpregnancy,freeT4andT3arelower.Bindingglobulinlevelsareinducedbyoestrogen,sototalT4andT3levelsareinvariablyhigh.

• Iodine requirements:increasedinpregnancy.TheWorldHealthOrganization(WHO)recommendsminimumintakeof200µg/day.

• Screening of thyroid function and autoantibodies:notrecommendedforeverywoman,butshouldbeperformedinthefirsttrimesterinthosewithapersonalorfamilyhistoryofthyroiddisease,goitre,otherautoimmunediseaseincludingtype1diabetes,orwhenthereisclinicalsuspicionofthyroiddysfunction.

Thyrotoxicosis

• Hyperemesis gravidarum:associatedwiththyrotoxicbiochemistry,sometimesrequiringantithyroiddrugs.

• Subclinical thyrotoxicosis:notusuallytreated,toavoidfetalhypothyroidism.

• Antithyroid drugs:propylthiouracilshouldbeusedinthefirsttrimester,withcarbimazolesubstitutedinthesecondandthirdtrimesters.

Hypothyroidism

• Preterm labour and impaired cognitive development in the offspring:maybeassociatedwithevensubclinicalhypothyroidism.

• Levothyroxine replacement therapy dose requirements:increaseby30–50%fromearlyinpregnancy.MonitoringtomaintainTSHresultswithinthetrimester-specificreferencerangeisrecommendedinearlypregnancyandatleastonceineachtrimester.

Post-partum thyroiditis

• Screening:notrecommendedforeverywoman,butthyroidfunctionshouldbetested4–6weekspost-partuminthosewithapersonalhistoryofthyroiddisease,goitreorotherautoimmunediseaseincludingtype1diabetes,thoseknowntohavepositiveanti-thyroidperoxidaseantibodies,orwhenthereisclinicalsuspicionofthyroiddysfunction.

20.20 Thyroid disease in pregnancy

The reproductive system

20

757

Fig. 20.13  Female reproductive physiology and the normal menstrual cycle. 

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

0 7 14 21 28Days after start of last menstrual period

FSHLH

OestradiolProgesterone

OvulationLuteal phaseFollicular phase

Primary Dominantvesicular

Mature Haemorrhagic Mature Regressing

Oestradiol OestradiolOestradiol

ProgesteroneOestradiol

Progesterone

Corpus luteum

Ovary

Menses

Follicle

Pathways for synthesis of sex steroids are shown in Figure 20.18 (p. 772).

The maleIn the male, the testis subserves 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 there-fore, if testosterone is marginally low, sampling should be repeated in the early morning (0900 hrs). Testoster-one 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’ testoster-one. 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.

The femaleIn the female, physiology varies during the normal men-strual 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 differ-entiates into a corpus luteum, which secretes proges-terone. 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 (typically to levels above 30 U/L (3.3 µg/L)).

The pathophysiology of male and female reproduc-tive dysfunction is summarised in Box 20.21.

EndocrinE disEasE

20

758

• Aetiology:inboysthemostcommoncauseisconstitutionaldelay,whereasingirlsthereisinvariablyanunderlyingstructuralorfunctionalcause.

• Psychological effects:whatevertheunderlyingcause,delayedpubertyisoftenassociatedwithsubstantialpsychologicaldistress.

• Investigations:akaryotypeshouldbeperformedinalladolescentswithhypergonadotrophichypogonadism,toexcludeTurner’sandKlinefelter’ssyndromes,unlessthereisanobviousprecipitatingcause.

• Medical induction of puberty:ifthisisbeingconsidered,itneedstobemanagedcarefullyandbecarriedoutinacontrolledfashion,toavoidprematurefusionoftheepiphyses.

20.23 Delayed puberty

Primary Secondary

Hormone excess PolycysticovariansyndromeGranulosacelltumourLeydigcelltumourTeratoma

Pituitarygonadotrophinoma

Hormone deficiency

MenopauseHypogonadism(seeBox20.22)Turner’ssyndromeKlinefelter’ssyndrome

HypopituitarismKallmann’ssyndrome(isolatedGnRHdeficiency)Severesystemicillness,includinganorexianervosa

Hormone hypersensitivity

Idiopathichirsutism

Hormone resistance

AndrogenresistancesyndromesComplete(‘testicularfeminisation’)Partial(Reifenstein’ssyndrome)5α-reductasetype2deficiency

Non-functioning tumours

OvariancystsCarcinomaTeratomaSeminoma

20.21 Classification of diseases of the reproductive system

Presenting problems in reproductive disease

Delayed pubertyPuberty 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. 110).

Clinical assessmentThe differential diagnosis is shown in Box 20.22. The key issue is to determine whether the delay in puberty is simply because the ‘clock is running slow’ (con-stitutional delay of puberty) or because there is pathol-ogy in the hypothalamus/pituitary (hypogonadotrophic hypogonadism) or the gonads (hypergonadotrophic hypogonadism). A general history and physical exami-nation should be performed with particular reference to previous or current medical disorders, social cir-cumstances and family history. Body proportions, sense of smell and pubertal stage should be carefully docu-mented 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

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 associ-ated with acquired disease. Issues that are commonly encountered in the management of adolescents with delayed puberty are summarised in Box 20.23.

Constitutional delay of pubertyThis is the most common cause of delayed puberty. Affected children are healthy and have usually been more than 2 SD below the mean height for their age

Constitutional delayHypogonadotrophic hypogonadism• Structuralhypothalamic/pituitarydisease(seeBox20.59,

p.787)• Functionalgonadotrophindeficiency

Chronicsystemicillness(e.g.asthma,malabsorption,coeliacdisease,cysticfibrosis,renalfailure)PsychologicalstressAnorexianervosaExcessivephysicalexerciseHyperprolactinaemiaOtherendocrinedisease(e.g.Cushing’ssyndrome,primaryhypothyroidism)

• Isolatedgonadotrophindeficiency(Kallmann’ssyndrome)Hypergonadotrophic hypogonadism• Acquiredgonadaldamage

Chemotherapy/radiotherapytogonadsTrauma/surgerytogonadsAutoimmunegonadalfailureMumpsorchitisTuberculosisHaemochromatosis

• Developmental/congenitalgonadaldisordersSteroidbiosyntheticdefectsAnorchidism/cryptorchidisminmalesKlinefelter’ssyndrome(47XXY,malephenotype)Turner’ssyndrome(45XO,femalephenotype)

20.22 Causes of delayed puberty and hypogonadism

The reproductive system

20

759

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 chil-dren can experience significant psychological distress because of their lack of physical development, particu-larly when compared with their peers.

Hypogonadotrophic hypogonadismThis may be due to structural, inflammatory or infiltra-tive disorders of the pituitary and/or hypothalamus (see Box 20.59, p. 787). 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 pro-found 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 gynaeco-mastia are commonly observed in all forms of hypo-gonadotrophic hypogonadism.

Hypergonadotrophic hypogonadismHypergonadotrophic hypogonadism associated with delayed puberty is usually due to Klinefelter’s syn-drome in boys and Turner’s syndrome in girls (pp. 765 and 766). Other causes of primary gonadal failure are shown in Box 20.22.

InvestigationsKey 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 constitu-tional 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. 880) 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. 786).

ManagementPuberty can be induced using low doses of oral oestrogen in girls (for example, ethinylestradiol 2 µg daily) or testo-sterone 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.

AmenorrhoeaPrimary amenorrhoea describes the condition of a female patient 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. The causes of this common presentation are shown in Box 20.24. 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 (Asher-man’s syndrome) can form after uterine curettage, surgery or infection with tuberculosis or schistosomia-sis, preventing endometrial proliferation and shedding.

Clinical assessmentThe 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 meno-pause (Box 20.25). 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 syndrome (PCOS, p. 764). The presence of other autoimmune disease raises the possibility of auto-immune premature ovarian failure.

InvestigationsPregnancy should be excluded in women of reproduc-tive age by measuring urine or serum human chorionic

Physiological• Pregnancy • Menopause

Hypogonadotrophic hypogonadism (see Box 20.22)

Ovarian dysfunction• Hypergonadotrophic

hypogonadism(seeBox20.22)

• Polycysticovariansyndrome

• Androgen-secretingtumours

Uterine dysfunction• Asherman’ssyndrome

20.24 Causes of secondary amenorrhoea

EndocrinE disEasE

20

760

of endometrial cancer. Cyclical hormone replacement therapy (HRT) regimens typically involve giving oestro-gen 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 frac-tures but is associated with adverse effects, which are related to the duration of therapy and to the patient’s age (Box 20.26). In patients with premature menopause, HRT should be continued up to the age of around 50 years, but only continued beyond this age if there are continued symptoms of oestrogen deficiency on discontinuation.

Management of infertility in oestrogen-deficient women is described on page 760.

Male hypogonadismThe clinical features of both hypo- and hypergonado-trophic 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 20.22.

InvestigationsMale hypogonadism is confirmed by demonstrating a low serum testosterone level. The distinction between hypo- and hypergonadotrophic hypogonadism is by measurement of random LH and FSH. Patients with hypogonadotrophic hypogonadism should be investi-gated as described for pituitary disease on page 786. Biochemical hypogonadism is associated with central obesity and the metabolic syndrome (p. 805); postulated mechanisms are complex and include reduction in sex hormone binding 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 20.34, p. 766) and this is associated with gonadotrophin levels that are low or inappropri-ately within the ‘normal’ range. There is an increasing trend to measure testosterone in older men, typically as part of an assessment of erectile dysfunction. Patients with hypergonadotrophic hypogonadism should have the testes examined for cryptorchidism or atrophy,

Vasomotor effects

• Hotflushes • Sweating

Psychological

• Anxiety• Irritability

• Emotionallability

Genitourinary

• Dyspareunia• Urgencyofmicturition

• Vaginalinfections

20.25 Symptoms of oestrogen deficiency

gonadotrophin (hCG). Serum LH, FSH, oestradiol, pro-lactin, 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 791. 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, pro-lactin and testosterone levels with normal oestradiol are common in PCOS. Low levels of LH, FSH and oestra-diol suggest hypothalamic or pituitary disease, and a pituitary MRI is indicated.

There is some overlap in gonadotrophin and oestro-gen concentrations between women with hypogonado-trophic 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 pro-gestogen (e.g. medroxyprogesterone acetate 10 mg twice daily) can be assessed. In women with PCOS, the pro-gestogen will cause maturation of the endometrium and menstruation will occur a few days after the progestogen is stopped. In women with hypogonadotrophic hypo-gonadism, 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 energy X-ray absorptiometry (DEXA, p. 1065) may be appropri-ate in patients with low androgen and oestrogen levels.

ManagementWhere possible, the underlying cause should be treated. For example, women with functional amenorrhoea due to excessive exercise and low weight should be encour-aged to reduce their exercise and regain some weight. The management of structural pituitary and hypo-thalamic disease is described on page 790 and that of PCOS on page 764.

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

‘AdministeringHRTfor5yearsto10000womenaged50–79yearsprevents5hipfracturesand6casesofcolorectalcancer,whileinducing8extracasesofbreastcancer,8ofpulmonaryembolism,7ofcoronaryheartdiseaseand8ofstroke.Therisksincreasewithage.’

• WritingGroupfortheWomen’sHealthInitiativeInvestigators.JAMA2002:288:321–333.

20.26 Hormone replacement therapy (HRT) in post-menopausal women

The reproductive system

20

761

causing subfertility is present, and in a large proportion no cause can be identified.

Clinical assessmentA 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

Route of administration Preparation Dose Frequency Comments

Intramuscular Testosteroneenantate

50–250mg Every3–4wks Producespeaksandtroughsoftestosteronelevelswhichareoutsidethephysiologicalrangeandmaybesymptomatic

Testosteroneundecanoate

1000mg Every3mths Smootherprofilethantestosteroneenantate,lessfrequentinjections

Subcutaneous Testosteronepellets

600–800mg Every4–6mths Smootherprofilethantestosteroneenantatebutimplantationcausesscarringandinfection

Transdermal Testosteronepatch

5–10mg Daily Stabletestosteronelevelsbuthighincidenceofskinhypersensitivity

Testosteronegel 50–100mg Daily Stabletestosteronelevels;transferofgelcanoccurfollowingskin-to-skincontactwithanotherperson

Oral Testosteroneundecanoate

40–120mg Twicedaily Veryvariabletestosteronelevels;riskofhepatotoxicity

20.27 Options for androgen replacement therapy

Female factor (35–40%)• Ovulatorydysfunction

PolycysticovariansyndromeHypogonadotrophichypogonadism(seeBox20.22)Hypergonadotrophichypogonadism(seeBox20.22)

• TubulardysfunctionPelvicinflammatorydisease(chlamydia,gonorrhoea)EndometriosisPrevioussterilisationPreviouspelvicorabdominalsurgery

• Cervicaland/oruterinedysfunctionCongenitalabnormalitiesFibroidsTreatmentforcervicalcarcinomaAsherman’ssyndrome

Male factor (35–40%)• Reducedspermqualityorproduction

YchromosomemicrodeletionsVaricocoeleHypergonadotrophichypogonadism(seeBox20.22)Hypogonadotrophichypogonadism(seeBox20.22)

• TubulardysfunctionVaricocoeleCongenitalabnormalityofvasdeferens/epididymisPrevioussexuallytransmittedinfection(chlamydia,gonorrhoea)Previousvasectomy

Unexplained or mixed factor (20–35%)

20.28 Causes of infertilityand a karyotype performed (to identify Klinefelter’s syndrome).

ManagementTestosterone replacement is clearly indicated in younger men with significant hypogonadism to prevent osteo-porosis 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 obesity, particularly in the absence of struc-tural pituitary/hypothalamic disease or other pituitary hormone deficiency. In such instances, a therapeutic trial of testosterone therapy may be considered if symp-toms are present, but the benefits of therapy must be carefully weighed against the potential for harm.

Routes of testosterone administration are shown in Box 20.27. First-pass hepatic metabolism of testosterone is highly efficient, so bioavailability of ingested prepara-tions 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 (see Box 20.27). 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 poly-cythaemia. Testosterone replacement inhibits spermato-genesis; treatment for fertility is described below.

InfertilityInfertility affects around 1 in 7 couples of reproductive age, often causing psychological distress. The main causes are listed in Box 20.28. In women, it may result from anovulation or abnormalities of the reproductive tract that prevent fertili sation or embryonic implanta-tion, often damaged fallopian tubes from previous infec-tion. In men, infertility may result from impaired sperm quality (for example, reduced motility) or reduced sperm number. Azoospermia or oligospermia is usually idiopathic, but may be a consequence of hypo gonadism (see Box 20.22). Microdeletions of the Y chromosome are increasingly recognised as a cause of severely abnormal spermatogenesis. In many couples, more than one factor

EndocrinE disEasE

20

762

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 varicocoele 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.

GynaecomastiaGynaecomastia 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 20.29. The most common are physiological: for example, in the newborn baby (due to maternal and placental oestrogens), in pubertal boys (in whom oestra-diol concentrations reach adult levels before testoster-one) and in elderly men (due to decreasing testosterone concentrations). Prolactin excess alone does not cause gynaecomastia (p. 790).

Clinical assessmentA drug history is important. Gynaecomastia is often asymmetrical and palpation may allow breast tissue to be distinguished from the prominent adipose tissue around the nipple that is often observed in obesity. Fea-tures of hypogonadism should be sought (see above) and the testes examined for evidence of cryptorchidism, atrophy or a tumour.

InvestigationsIf a clinical distinction between gynaecomastia and adipose tissue cannot be made, then ultrasonography or mammography is required. A random blood sample

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 varicocoele.

InvestigationsInvestigations should generally be performed after a couple has failed to conceive despite unprotected inter-course for 12 months, unless there is an obvious abnor-mality 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, tempera-ture measurement, or assessment of cervical mucus) is not recommended, as the information is often counter-balanced by increased anxiety if interpretation is incon-clusive. In women with regular periods, ovulation can be confirmed by an elevated serum progesterone con-centration on day 21 of the menstrual cycle. Transvagi-nal ultrasound can be used to assess uterine and ovarian anatomy. Tubal patency may be examined at laparos-copy 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.

ManagementCouples should be advised to have regular sexual inter-course, 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. 764), 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 gonado-trophin deficiency or in whom anti-oestrogen therapy is unsuccessful, ovulation may be induced by direct stimu-lation of the ovary by daily injection of FSH and an injection of hCG to 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 secre-tion). Whatever method of ovulation induction is employed, monitoring of response is essential to avoid multiple ovulation. For clomifene, ultrasound monitor-ing 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 hyperstimula-tion 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 effec-tive but in vitro fertilisation (IVF) is normally recom-mended. IVF is widely used for many causes of infertility and in unexplained cases of prolonged (> 3 years)

IdiopathicPhysiologicalDrug-induced• Cimetidine• Digoxin• Anti-androgens(cyproteroneacetate,spironolactone)• Someexogenousanabolicsteroids(diethylstilbestrol)• CannabisHypogonadism (see Box 20.22)Androgen resistance syndromesOestrogen excess• Liverfailure(impairedsteroidmetabolism)• Oestrogen-secretingtumour(forexample,oftestis)• hCG-secretingtumour(forexample,oftestisorlung)

20.29 Causes of gynaecomastia

The reproductive system

20

763

Clinical assessmentThe severity of hirsutism is subjective. Some women suffer profound embarrassment from a degree of hair growth which 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 vul-garis or Cushing’s syndrome (p. 773). Hirsutism of recent onset associated with virilisation is suggestive of an androgen-secreting tumour but this is rare.

InvestigationsA random blood sample should be taken for testoster-one, prolactin, LH and FSH. If there are clinical features of Cushing’s syndrome, further investigations should be performed (p. 774).

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 circumstances, other causes of andro-gen excess should be sought. Congenital adrenal hyper-plasia due to 21-hydroxylase deficiency is diagnosed by a short ACTH stimulation test with measurement of 17OH-progesterone (p. 782). In patients with androgen-secreting tumours, serum testosterone does not sup-press following dexamethasone (either as an overnight or a 48-hour low-dose suppression test) or oestrogen

should be taken for testosterone, LH, FSH, oestradiol, prolactin and hCG. Elevated oestrogen concentrations are found in testicular tumours and hCG-producing neoplasms.

ManagementAn 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 in a harmonious manner, then there may be an underlying abnormality that requires investigation (p. 758). 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.

HirsutismHirsutism refers to the excessive growth of thick termi-nal hair in an androgen-dependent distribution in women (upper lip, chin, chest, back, lower abdomen, thigh, forearm) and is one of the most common presenta-tions of endocrine disease. It should be distinguished from hypertrichosis, which is generalised excessive growth of vellus hair. The aetiology of androgen excess is shown in Box 20.30.

Cause Clinical features Investigation findings Treatment

Idiopathic OftenfamilialMediterraneanorAsianbackground

Normal CosmeticmeasuresAnti-androgens

Polycystic ovarian syndrome

ObesityOligomenorrhoeaorsecondaryamenorrhoeaInfertility

LH:FSHratio>2.5:1Minorelevationofandrogens*Mildhyperprolactinaemia

WeightlossCosmeticmeasuresAnti-androgens(Metformin,glitazonesmaybeuseful)

Congenital adrenal hyperplasia(95%21-hydroxylasedeficiency)

PigmentationHistoryofsalt-wastinginchildhood,ambiguousgenitalia,oradrenalcrisiswhenstressedJewishbackground

Elevatedandrogens*whichsuppresswithdexamethasoneAbnormalrisein17OH-progesteronewithACTH

GlucocorticoidreplacementadministeredinreverserhythmtosuppressearlymorningACTH

Exogenous androgen administration

AthletesVirilisation

LowLHandFSHAnalysisofurinaryandrogensmaydetectdrugofmisuse

Stopsteroidmisuse

Androgen-secreting tumour of ovary or adrenal cortex

RapidonsetVirilisation:clitoromegaly,deepvoice,balding,breastatrophy

Highandrogens*whichdonotsuppresswithdexamethasoneoroestrogenLowLHandFSHCTorMRIusuallydemonstratesatumour

Surgicalexcision

Cushing’s syndrome ClinicalfeaturesofCushing’ssyndrome(p.773)

Normalormildelevationofadrenalandrogens*Seeinvestigations(p.774)

Treatthecause(p.775)

*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.

20.30 Causes of hirsutism

EndocrinE disEasE

20

764

Menstrual irregularity and infertilityMost women with PCOS have oligomenorrhoea, with irregular, heavy menstrual periods. This may not require treatment unless fertility is desired. Metformin (p. 821), by reducing insulin resistance, may restore regular ovu-latory cycles in overweight women, although it is less effective than clomifene (p. 762) at restoring fertility as measured by successful pregnancy (Box 20.32). Thiazo-lidinediones (p. 823) also enhance insulin sensitivity and restore menstrual regularity in PCOS, but are contra-indicated 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 hyperpla-sia. Progestogens can be administered on a cyclical basis to induce regular shedding of the endometrium and a withdrawal bleed, or a progestogen-impregnated intra-uterine coil can be fitted.

HirsutismFor hirsutism, most patients will have used cosmetic measures, such as shaving, bleaching and waxing, before consulting a 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.

(30 µg daily for 7 days). The tumour should then be sought by CT or MRI of the adrenals and ovaries.

ManagementThis depends on the cause (see Box 20.30). 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 heterogenous dis-order (Box 20.31), 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 fea-tures of PCOS vary markedly between individual patients but diagnosis is usually made during the inves-tigation of hirsutism (p. 763) or amenorrhoea/oligo-menorrhoea (p. 759). Infertility may also be present (p. 761). 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. 20.14).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. 805).

ManagementThis should be directed at the presenting complaint, but all PCOS patients who are overweight should be encour-aged to lose weight, as this can improve several symp-toms, including menstrual irregularity, and reduces the risk of type 2 diabetes.

Fig. 20.14  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. 

Mechanisms* Manifestations

Pituitary dysfunction HighserumLHHighserumprolactin

Anovulatory menstrual cycles

OligomenorrhoeaSecondaryamenorrhoeaCysticovariesInfertility

Androgen excess HirsutismAcne

Obesity HyperglycaemiaElevatedoestrogens

Insulin resistance DyslipidaemiaHypertension

*These mechanisms are interrelated; it is not known which, if any, is primary. PCOS probably represents the common end point of several different pathologies.

20.31 Features of polycystic ovarian syndrome

‘Inonerandomisedcontrolledclinicaltrial,626infertilewomenwithPCOSwererandomisedtoreceiveclomifene,metforminorcombinationtherapy.After6months,thelivebirthrateswere22.5%,7.2%and26.8%respectively.Multiplebirthsoccurredin6%ofwomenreceivingclomifeneandnoneofthosereceivingmetformin.’

• RSLegro,etal.NewEnglJMed2008;356:551–566.

20.32 Treatment of infertility in women with PCOS

The reproductive system

20

765

Mechanism of action Drug Dose Hazards

Androgen receptor antagonists Cyproteroneacetate 2,50or100mgondays1–11of28-daycyclewithethinylestradiol30µgondays1–21

HepaticdysfunctionFeminisationofmalefetusProgesteronereceptoragonistDysfunctionaluterinebleeding

Spironolactone 100–200mgdaily ElectrolytedisturbanceFlutamide Notrecommended Hepaticdysfunction

5α-reductase inhibitors(preventconversionoftestosteronetoactivedihydrotestosterone)

Finasteride 5mgdaily Limitedclinicalexperience;possiblylessefficaciousthanothertreatments

Suppress ovarian steroid production and elevate sex hormone-binding globulin

Oestrogen SeecombinationwithcyproteroneacetateaboveorConventionaloestrogen-containingcontraceptive

VenousthromboembolismHypertensionWeightgainDyslipidaemiaIncreasedbreastandendometrialcarcinoma

20.33 Anti-androgen therapy

If conservative measures are unsuccessful, anti-androgen therapy is given (Box 20.33). 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 regular-ity. 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 featuresThese are shown in Figure 20.15.

Fig. 20.15  Clinical features of Turner’s syndrome (45XO). (IGT = impaired glucose tolerance). 

Psychological problemsImpaired visuospatial processingReduced IQ (ring chromosome X)

Low-set earsSensorineural/conductionhearing loss

Webbing of neck (25–40%)

Widely spaced nipples

Shield chest

Type 2 diabetes/IGT (10–30%)

Wide carrying angle of elbows

Lymphoedema of handsand feet ( 30%)

Reduced bone mineral density

Inflammatory boweldisease (0.2–0.3%)

Horseshoe kidneys and otherrenal and collecting systemabnormalities

Bicuspid aortic valveAortic root dilatation

Coronary artery disease

Autoimmune thyroid disease (20%)

Streak gonadsGonadoblastoma (XY mosaic)

Abnormal LFTs (30 – 80%)

Short stature

Fish-like mouthHigh-arched palate

Coarctation of aorta

Hypertension

EndocrinE disEasE

20

766

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 haploinsuf-ficiency 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 gesta-tion, 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 associ-ated somatic abnormalities. The severity of the pheno-type is, in part, related to the underlying cytogenetic abnormality. Mosaic individuals may have only mild short stature and may enter puberty spontaneously before developing gonadal failure.

Diagnosis and managementThe 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 gonad-ectomy is recommended for individuals with 45XO/46XY mosaicism because there is an increased risk of gonado-blastoma. Pubertal development can be induced with oestrogen therapy but causes fusion of the epiphyses and cessation of growth. Therefore, the timing of puber-tal induction needs to be carefully planned. Adults with Turner’s syndrome require long-term oestrogen replace-ment 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 ado-lescence, hyalinisation and fibrosis are present within the semini ferous tubules and Leydig cell function is impaired, resulting in hypogonadism.

Clinical featuresThe 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 those with 46XY/47XXY mosaicism, may pass through puberty normally and be identified only during investigation for infertility.

Diagnosis and managementKlinefelter’s syndrome is suggested by the typical pheno-type in a patient with hypergonadotrophic hypo-gonadism and can be confirmed by karyotype analysis. Individuals with clinical and biochemical evidence of androgen deficiency require androgen replacement (see Box 20.27, p. 761).

THE PARATHYROID GLANDS

Parathyroid hormone (PTH) plays a key role in the regu-lation of calcium and phosphate homeostasis and vitamin D metabolism, as shown in Figure 25.55 (p. 1125). The consequences of altered function of this axis in gut and renal disease are covered in Chapters 22 and 17, respectively. Other metabolic bone diseases are explored in Chapter 25. Here, the investigation of hyper-calcaemia and hypocalcaemia and disorders of the para-thyroid 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 conversion of 25-hydroxycholecalciferol to the active metabolite 1,25-dihydroxycholecalciferol; the 1,25- dihydroxycholecalciferol, in turn, enhances calcium absorption from the gut.

• Post-menopausal osteoporosis:amajorpublichealthissueduetothehighincidenceofassociatedfragilityfractures,especiallyofhip.

• Hormone replacement therapy:shouldonlybeprescribedabovetheageof50fortheshort-termreliefofsymptomsofoestrogendeficiency.

• Sexual activity:manyolderpeopleremainsexuallyactive.• ‘Male menopause’:doesnotoccur,althoughtestosterone

concentrationsdofallwithage.Testosteronetherapyinmildlyhypogonadalmenmaybeofbenefitforbodycomposition,muscleandbone.Largerandomisedtrialsarerequiredtodeterminewhetherbenefitsoutweighpotentiallyharmfuleffectsontheprostateandcardiovascularsystem.

• Androgens in older women:hirsutismandbaldingoccur.Intherarepatientsinwhomandrogenlevelsareelevated,thismaybepathological,e.g.fromanovariantumour.

20.34 Gonadal function in old age

The parathyroid glands

20

767

More than 99% of total body calcium is in bone. Pro-longed exposure of bone to high levels of PTH is associ-ated 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 treat-ment of osteoporosis (p. 1124).

The differential diagnosis of disorders of calcium metabolism requires measurement of calcium phos-phate, alkaline phosphatase, renal function, PTH and 25(OH)D. Although the parathyroid glands detect and respond to ionised calcium levels, most clinical labora-tories only measure total serum calcium levels and 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 adjust-ing the value for calcium upwards by 0.02 mmol/L (0.4 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. 755) and can be given therapeutically in Paget’s disease of bone (p. 1129), its release from the thyroid is of no clinical relevance to calcium homeostasis in humans.

Disorders of the parathyroid glands are summarised in Box 20.35.

(CASR = calcium-sensing receptor)

Primary Secondary

Hormone excess

Primaryhyperparathyroidism

ParathyroidadenomaParathyroidcarcinoma1

Parathyroidhyperplasia2

Tertiaryhyperparathyroidism

Followingprolongedsecondaryhyperparathyroidism

Secondaryhyperparathyroidism

ChronickidneydiseaseMalabsorptionVitaminDdeficiency

Hormone deficiency

HypoparathyroidismPost-surgicalAutoimmuneInherited

Hormone hypersensitivity

Autosomaldominanthypercalciurichypocalcaemic(CASR-activatingmutation)

Hormone resistance

PseudohypoparathyroidismFamilialhypocalciurichypercalcaemia

Non-functioning tumours

Parathyroidcarcinoma1

1Parathyroid carcinomas may or may not produce PTH. 2ln multiple endocrine neoplasia (MEN) syndromes (p. 794)

20.35 Classification of diseases of the parathyroid glands

With normal or elevated PTH levels

• Primaryortertiaryhyperparathyroidism• Lithium-inducedhyperparathyroidism• Familialhypocalciurichypercalcaemia

With low PTH levels

• Malignancy(lung,breast,myeloma,renal,lymphoma,thyroid)

• Elevated1,25(OH)2vitaminD(vitaminDintoxication,sarcoidosis,HIV,othergranulomatousdisease)

• Thyrotoxicosis• Paget’sdiseasewithimmobilisation• Milk-alkalisyndrome• Thiazidediuretics• Glucocorticoiddeficiency

20.36 Causes of hypercalcaemia

Presenting problems in parathyroid disease

HypercalcaemiaHypercalcaemia is one of the most common biochemical abnormalities and is often detected during routine bio-chemical 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.

Causes of hypercalcaemia are listed in Box 20.36. Of these, primary hyperparathyroidism and malignant hypercalcaemia are by far the most common. Familial hypocalciuric hypercalcaemia (FHH) is a rare but impor-tant cause that needs differentiation from primary hyperparathyroidism (HPT). Lithium may cause hyper-parathyroidism by reducing the sensitivity of the calcium-sensing receptor.

Clinical assessmentSymptoms and signs of hypercalcaemia include poly-uria 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 hyperpara-thyroidism 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 hyperpara-thyroidism 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 5% of first stone formers and 15% of recurrent stone formers have primary hyperpara thyroidism (p. 769). Hypertension is a common feature of hyperparathyroidism. Parathyroid tumours are almost never palpable.

A family history of hypercalcaemia raises the possi-bility of FHH or MEN (p. 794).

EndocrinE disEasE

20

768

InvestigationsThe most discriminant investigation is measurement of PTH. If PTH levels are detectable or elevated in the presence of hypercalcaemia, then primary hyperpara-thyroidism 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 bio-chemical 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 a 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 spe-cific 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. 1046) and CT as appropriate.

ManagementTreatment of severe hypercalcaemia and primary hyper-parathyroidism is described on pages 273 and 769, respectively. FHH does not require any specific intervention.

HypocalcaemiaAetiologyHypocalcaemia is much less common than hypercalcae-mia. The differential diagnosis is shown in Box 20.37.

Total serum calcium

lonised serum calcium

Serum phosphate Serum PTH Comments

Hypoalbuminaemia ↓ ↔ ↔ ↔ Adjustcalciumupwardsby0.02mmol/L(0.1mg/dL)forevery1g/Lreductioninalbuminbelow40g/L

Alkalosis ↔ ↓ ↔ ↔or↑ Ch.16

Vitamin D deficiency ↓ ↓ ↓ ↑ Ch.25

Chronic renal failure ↓ ↓ ↑ ↑ DuetoimpairedvitaminDhydroxylationSerumcreatinine↑

Hypoparathyroidism ↓ ↓ ↑ ↓ Seetext

Pseudohypoparathyroidism ↓ ↓ ↑ ↑ Characteristicphenotype(seetext)

Acute pancreatitis ↓ ↓ ↔or↓ ↑ UsuallyclinicallyobviousSerumamylase↑

Hypomagnesaemia ↓ ↓ Variable ↓or↔ Treatmentofhypomagnesaemiamaycorrecthypocalcaemia

(↑ = levels increased; ↓ = levels reduced; ↔ = levels normal)

20.37 Differential diagnosis of hypocalcaemia

The most common cause of hypocalcaemia is a low serum albumin with normal ionised calcium concentra-tion. 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 mag-nesium depletion and should be considered in patients with malabsorption, on diuretic or proton pump inhibi-tor therapy, and/or with a history of alcohol excess. Magnesium deficiency causes hypocalcaemia by impair-ing the ability of the parathyroid glands to secrete PTH (resulting in PTH concentrations that are low or inap-propriately in the reference range) and may also impair the actions of PTH on bone and kidney.

Clinical assessmentMild 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 carpo-pedal 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 associa-tion with tingling of the hands and feet and around the mouth, but stridor and fits are rare.

Latent tetany may be detected by eliciting Trous-seau’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 spe-cific 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.

The parathyroid glands

20

769

Immediate management

• 10–20mL10%calciumgluconateIVover10–20mins• ContinuousIVinfusionmayberequiredforseveralhours

(equivalentof10mL10%calciumgluconate/hr)• Cardiacmonitoringisrecommended

If associated hypomagnesaemia

• 50mmolmagnesiumchlorideIVover24hours• Mostparenteralmagnesiumwillbeexcretedintheurine,so

furtherdosesmayberequiredtoreplenishbodystores

20.38 Management of severe hypocalcaemia

Type Serum calcium PTH

Primary Raised NotsuppressedSingleadenoma(90%)Multipleadenomas(4%)Nodularhyperplasia(5%)Carcinoma(1%)

Secondary Low RaisedChronicrenalfailureMalabsorptionOsteomalaciaandrickets

Tertiary Raised Notsuppressed

20.39 Hyperparathyroidism

(p. 1090). 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 sub-periosteal 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 hyperpara-thyroidism. This is usually not evident radiographically and requires assessment by DEXA (p. 1065).

In nephrocalcinosis, scattered opacities may be visible within the renal outline. There may be soft tissue calci-fication in arterial walls and hands and in the cornea.

InvestigationsThe diagnosis can be confirmed by finding a raised PTH level in the presence of hypercalcaemia, provided that FHH is excluded (p. 770). Parathyroid scanning by 99mTc-sestamibi scintigraphy (Fig. 20.16) and/or ultrasound examination can be performed prior to surgery, in an attempt to localise an adenoma and allow a targeted resection. However, negative imaging does not exclude the diagnosis.

ManagementThe treatment of choice for primary hyperpara-thyroidism is surgery, with excision of a solitary para-thyroid 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 cor-recting 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 peptic ulceration, renal stones, renal impairment or osteoporosis), and (in asympto-matic 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 medi-cally with intravenous fluids and bisphosphonates, as

Hypocalcaemia can cause papilloedema and prolon-gation 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 asso-ciated with hypophosphataemia, as in vitamin D defi-ciency, causes rickets in children and osteomalacia in adults (p. 1125).

ManagementEmergency management of hypocalcaemia associated with tetany is described in Box 20.38. Treatment of chronic hypocalcaemia is described on page 770.

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 mil-limetres to several centimetres. It should be distin-guished 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. 1126), and from tertiary hyper-parathyroidism, in which continuous stimulation of the parathyroids over a prolonged period of time results in adenoma formation and autonomous PTH secretion (Box 20.39). This is most commonly seen in individuals with advanced chronic kidney disease (p. 483).

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. 795), in which case hyperplasia or multiple adenomas of all four parathyroid glands are more likely than a solitary adenoma.

Clinical and radiological featuresThe clinical presentation of primary hyperpara-thyroidism is described on page 769. Parathyroid bone disease is now rare due to earlier diagnosis and treat-ment. 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

EndocrinE disEasE

20

770

A B

Fig. 20.16  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. 

described on page 273. If this is not effective, then urgent parathyroidectomy should be considered.

Cinacalcet is a calcimimetic which enhances the sensitivity of the calcium-sensing receptor, so reducing PTH levels, and is licensed for tertiary hyperpara-thyroidism 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 concentra-tions. As a result, higher than normal calcium levels are required to suppress PTH secretion. The typical presen-tation is with mild hypercalcaemia with PTH concentra-tions 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. The hypercalcaemia of FHH is always asymptomatic and complications do not occur. The main risk of FHH is of the patient being subjected to an unnec-essary (and ineffective) parathyroidectomy if misdiag-nosed as having primary hyperparathyroidism. Testing of family members for hypercalcaemia is helpful in con-firming 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; post-operative hypocalcaemia develops in 5.5% of patients overall but 9% of patients undergoing total thyroidectomy. Rarely, hypopara-thyroidism can occur as a result of infiltration of the glands with iron in haemochromatosis (p. 972) or copper in Wilson’s disease (p. 973).

There are a number of rare congenital or inherited forms of hypoparathyroidism. One form is associated with autoimmune polyendocrine syndrome type 1 (p. 795) and another with DiGeorge syndrome (p. 56). Autosomal dominant hypoparathyroidism (ADH) is the mirror image of familial hypocalciuric hypercalcae-mia (see above), in that an activating mutation in the calcium-sensing receptor reduces PTH levels, resulting in hypocalcaemia and hypercalciuria.

• Osteoporosis:alwaysexcludeosteomalaciaandhyperparathyroidismbycheckingvitaminDandcalciumconcentrations.

• Primary hyperparathyroidism:morecommonwithageing.Olderpeoplecanoftenbeobservedwithoutsurgicalintervention.

• Hypercalcaemia:maycauseconfusion.• Vitamin D deficiency:commonbecauseofpoordietand

limitedexposuretothesun.

20.40 The parathyroid glands in old age

PseudohypoparathyroidismIn this disorder, the individual is functionally hypopara-thyroid but, instead of PTH deficiency, there is tissue resistance to the effects of PTH, such that PTH con-centrations 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 (pseudohypopara-thyroidism 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 pseudo-hypoparathyroidism occurs only when the GNAS1 mutation is inherited on the maternal chromosome.

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 disor-ders is an example of genetic imprinting (p. 52). 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 hypocal-caemia and resistance to PTH (which regulates 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 hypoparathyroidismPersistent hypoparathyroidism and pseudohypopara-thyroidism are treated with oral calcium salts and

The adrenal glands

20

771

rather than synapses. Most of the adrenal cortex is made up of cells which 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 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 syn-dromes of adrenal hormone deficiency and excess are relatively rare.

Functional anatomy and physiology

Adrenal anatomy and function are shown in Figure 20.17. Histologically, the cortex is divided into three zones, but these function as two units (zona glomeru-losa and zonae fasciculata/reticularis) which produce

vitamin D analogues, either 1α-hydroxycholecalciferol (alfacalcidol) or 1,25-dihydroxycholecalciferol (calci-triol). 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. 1120) and, although not currently licensed, has been used in hypoparathyroidism (but not in pseudo-hypoparathyroidism). 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.

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 which secretes catecholamines into capillaries

Fig. 20.17  Structure and function of the adrenal glands. (ACE = angiotensin-converting enzyme; ACTH = adrenocorticotrophic hormone; JGA = juxtaglomerular apparatus; MR = mineralocorticoid receptor). 

Sympathetic nervoussystem

Medulla

Adrenaline(epinephrine)

Noradrenaline(norepinephrine)

β-adrenoceptor α-adrenoceptor

VasodilatationTachycardia

Insulin resistance

Vasoconstriction

Sympathetic nervous system

Adrenal medulla

ACTH

CortexZonae fasciculata

and reticularis

Hypothalamic – pituitary– adrenal axis

Adrenal cortexZonae fasciculata

and reticularis

Androgens Cortisol

Androgenreceptor

Glucocorticoidreceptor

Pubic andaxillary hair

Libido, especiallyfemales

Protein catabolismInsulin resistanceImmune response

HypertensionIncreased appetite

Memory

Na retentionK wastingMetabolicalkalosis

Low renal perfusionLow filtered NaSympatheticactivation

Angiotensin II

CortexZona

glomerulosa

Aldosterone

Renin – angiotensin – aldosterone axis

Adrenal cortexZona glomerulosa

Angiotensin I

Angiotensinogen

Renin

ACE

MR

JGA

Adrenalgland

Negative feedback

EndocrinE disEasE

20

772

Fig. 20.18  The major pathways of synthesis of steroid hormones. (DHEA = dehydroepiandrosterone; HSD = hydroxysteroid dehydrogenase; OHase = hydroxylase) 

Cholesterol

Pregnenolone

17OHPregnenolone

DHEA

Progesterone

17OHProgesterone

Androstenedione

Oestrone

11-Deoxy-corticosterone

11-Deoxy-cortisol

Testosterone

Oestradiol

Corticosterone

Cortisol

Dihydro-testosterone

Aldosterone

3β-H

SD

17 OHase

17,20 lyase

21 O

Has

e17

-βH

SD

Aromatase

11β

OH

ase

Ald

o sy

ntha

se

5α-r

educ

tase

Enzymes outside the adrenal

Enzymes in the adrenal

Glucocorticoids

Mineralocorticoids

Androgens

Oestrogens

Progesterone

corticosteroids in response to humoral stimuli. Path-ways for the biosynthesis of corticosteroids are shown in Figure 20.18. Investigation of adrenal function is described under specific diseases below. The different types of adrenal disease are shown in Box 20.41.

GlucocorticoidsCortisol 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 poten-tially 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 mineralo-corticoid receptors also express an enzyme called 11 β-hydroxysteroid dehydrogenase type 2 (11 β-HSD2), which inactivates cortisol by converting it to cortisone. Inhibitors of 11 β-HSD2 (such as liquorice) or mutations in the gene that encodes 11 β-HSD2 cause cortisol to act as a mineralocorticoid, resulting in sodium retention and hypertension (see Box 20.50, p. 780).

MineralocorticoidsAldosterone is the most important mineralocorticoid. It binds to mineralocorticoid receptors in the kidney and causes sodium retention and increased excretion of potassium and protons (Ch. 16). The principal stimulus to aldosterone secretion is angiotensin II, a peptide pro-duced by activation of the renin–angiotensin system (see Fig. 20.17). Renin activity in the juxtaglomerular appa-ratus of the kidney is stimulated by low perfusion pres-sure 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.

CatecholaminesIn humans, only a small proportion of circulating noradrenaline (norepinephrine) is derived from the adrenal medulla; much more is released from sympa-thetic nerve endings. Conversion of noradrenaline to adrenaline (epinephrine) is catalysed by catechol-o-methyltransferase (COMT), which is induced by gluco-corticoids. Blood flow in the adrenal is centripetal, so that the medulla is bathed in high concentrations of cor-tisol and is the major source of circulating adrenaline. However, after surgical removal of the adrenal medul-lae, there appear to be no clinical consequences attribut-able to deficiency of circulating catecholamines.

Primary Secondary

Hormone excess

Non-ACTH-dependentCushing’ssyndromePrimaryhyperaldosteronismPhaeochromocytoma

ACTH-dependentCushing’ssyndromeSecondaryhyperaldosteronism

Hormone deficiency

Addison’sdiseaseCongenitaladrenalhyperplasia

Hypopituitarism

Hormone hypersensitivity

11β-hydroxysteroiddehydrogenasetype2deficiencyLiddle’ssyndrome

Hormone resistance

PseudohypoaldosteronismGlucocorticoidresistancesyndrome

Non-functioning tumours

AdenomaCarcinoma(usuallyfunctioning)Metastatictumours

20.41 Classification of diseases of the adrenal glands

The adrenal glands

20

773

Adrenal androgensAdrenal 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 syndromeCushing’s syndrome is caused by excessive activation of glucocorticoid receptors. It is most commonly iatro-genic, due to prolonged administration of synthetic glucocorticoids such as prednisolone. Endogenous Cushing’s syndrome is uncommon but is due to chronic over-production of cortisol by the adrenal glands, either as the result of an adrenal tumour or because of exces-sive production of ACTH by a pituitary tumour or ectopic ACTH production by other tumours.

AetiologyThe causes are shown in Box 20.42. Amongst endo-genous 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

ACTH-dependent – 80%

• PituitaryadenomasecretingACTH(Cushing’sdisease)–70%• EctopicACTHsyndrome(bronchialcarcinoid,small-celllung

carcinoma,otherneuro-endocrinetumour)–10%

Non-ACTH-dependent – 20%

• Adrenaladenoma–15%• Adrenalcarcinoma–5%• ACTH-independentmacronodularhyperplasia;primary

pigmentednodularadrenaldisease;McCune–Albrightsyndrome(together<1%)

Hypercortisolism due to other causes (also referred to as pseudo-Cushing’s syndrome)

• Alcoholexcess(biochemicalandclinicalfeatures)• Majordepressiveillness(biochemicalfeaturesonly,some

clinicaloverlap)• Primaryobesity(mildbiochemicalfeatures,someclinical

overlap)

20.42 Classification of endogenous Cushing’s syndrome

syndrome (often due to a small-cell carcinoma of the bronchus) is more common in men.

Clinical assessmentThe diverse manifestations of glucocorticoid excess are shown in Figure 20.19. Many of these are not specific to Cushing’s syndrome and, because spontaneous Cushing’s syndrome is rare, the positive predictive

Fig. 20.19  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

CataractsMild exophthalmos

Hair thinningHirsutism

AcnePlethora

Moon face

Peptic ulcer

Hyperglycaemia

Menstrualdisturbance

May haveexuberantcallus with

fractures

Osteoporosis

Tendency toinfections

with poor woundhealing and little

inflammatoryresponse

Hypertension

Centripetal obesity

Striae

Wasting and weakness of proximal thigh muscles

Bruising

Loss of heightand back pain

from compressionfracture

Decreased skinthickness

A B

C

EndocrinE disEasE

20

774

value of any single clinical feature alone is low. More-over, some common disorders can be confused with Cushing’s syndrome because they are associated with alterations in cortisol secretion: for example, obesity and depression (see Box 20.42). Features which 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.

Some clinical features are more common in ectopic ACTH syndrome. Whilst 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 pigmentation because of binding to melano-cortin 1 receptors on melanocytes in the skin. The high cortisol levels also overcome the capacity of 11 β-HSD2 to inactivate cortisol in the kidney (p. 772), causing hypokalaemic alkalosis which aggravates myopathy and hyperglycaemia (by inhibiting insulin secretion).

Cushing’s syndrome suspected

Exclude exogenousglucocorticoid exposure

Perform one of the following tests

Any abnormal result

Suggest additional evaluation,repeat testing at intervalor seek further opinion

Normal result

Cushing’s syndromeunlikely

Perform 1 or 2 other studies shown aboveand consider repeating abnormal study

At least two concordantabnormal tests

Discrepant test results

Cushing’s syndrome

Normal result

Cushing’s syndromeunlikely

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

Fig. 20.20  Sequence of investigations in suspected spontaneous Cushing’s syndrome. A serum cortisol of 50 nmol/L is equivalent to 1.81 μg/dL. (LDDST = low-dose dexamethasone suppression test; ONDST = overnight dexamethasone suppression test; UFC = urinary free cortisol) 

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. 787) are rare.

InvestigationsThe large number of tests available for Cushing’s syn-drome reflects the fact that each one has limited specifi-city and sensitivity 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:1. to establish whether the patient has Cushing’s

syndrome (Fig. 20.20)2. to define its cause (Fig. 20.21).

The adrenal glands

20

775

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 syndromeCushing’s syndrome is confirmed by using two of three main tests:1. failure to suppress serum cortisol with low doses

of oral dexamethasone2. loss of the normal circadian rhythm of cortisol,

with inappropriately elevated late-night serum or salivary cortisol

3. increased 24-hour urine free cortisol (see Fig. 20.20).

Dexamethasone is used for suppression testing because it does not cross-react in radioimmunoassays for cortisol. An overnight dexamethasone suppression test (ONDST) involves administration of 1 mg dexa-methasone at 2300 hrs and measuring serum cortisol at 0900 hrs the following day. In a low-dose dexametha-sone suppression test (LDDST), serum cortisol is meas-ured following administration of 0.5 mg dexamethasone

4 times daily for 48 hours. It is important for any oestro-gens 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 res-ponses, as most cortisol assays measure total cortisol, including that bound to CBG. Cyclicity of cortisol secre-tion is a feature of all types of Cushing’s syndrome and, if very variable, can confuse diagnosis. Use of mul-tiple salivary cortisol samples over weeks or months can be of use 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 corticosteroid (such as prednisolone) that cross-reacts in immunoassays with cortisol.

Determining the underlying causeOnce the presence of Cushing’s syndrome is confirmed, measurement of plasma ACTH is the key to establishing the differential diagnosis. In the presence of excess cortisol secretion, an undetectable ACTH (below 1.1 pmol/L (5 pg/mL)) indicates an adrenal cause, while ACTH levels greater than 3.3 pmol/L (15 pg/mL) suggest a pituitary cause or ectopic ACTH. ACTH

BIPSS: ACTH central toperipheral gradient > 2:1 at

baseline or > 3:1 at 5–10 minsafter 100 mg CRH IV

Cushing’s syndrome confirmed

Measure plasma ACTH

> 3.3 pmol/L

ACTH-independentCushing’s syndrome

Adrenal imagingwith CT

Adrenallesion

No adrenallesion

AdenomaCarcinomaAIMAH

PPNADExogenousglucocorticoid

Ectopic ACTHCushing’s disease

ACTH-dependentCushing’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% suppressionin serum cortisol from baseline

CT/MRI thoraxand abdomen ±

somatostatinscintigraphy

< 1.1 pmol/L on morethan two occasions

Yes

Yes

Yes

Yes

No

No

No

No

Fig. 20.21  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; CRH = corticotrophin-releasing hormone; HDDST = high-dose dexamethasone suppression test; PPNAD = primary pigmented nodular adrenal disease) 

EndocrinE disEasE

20

776

Therapeutic use of glucocorticoidsThe remarkable anti-inflammatory properties of gluco-corticoids have led to their use in a wide variety of clini-cal conditions but the hazards are significant. Equivalent doses of commonly used glucocorticoids are listed in Box 20.43. Topical preparations (dermal, rectal and inhaled) can also be absorbed into the systemic circula-tion, and although this rarely occurs to a sufficient degree to produce clinical features of Cushing’s syn-drome, it can result in significant suppression of endogenous ACTH and cortisol secretion. Severe Cush-ing’s syndrome can result if there is concomitant admin-istration of inhaled glucocorticoids and inhibitors of the liver enzyme CYP450 3A4, such as the antiretroviral drug ritonavir (p. 407).

Adverse effects of glucocorticoidsThe clinical features of glucocorticoid excess are illus-trated in Figure 20.19. Adverse effects are related to dose, duration of therapy, and pre-existing conditions that might be worsened by corticosteroid 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 1102. Rapid changes in glucocorticoid levels can also lead to marked mood disturbances, including depression, mania and insomnia.

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 corticosteroids 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 tubercu-losis may be re-activated and patients on corticosteroids should be advised to avoid contact with varicella zoster virus if they are not immune.

Management of glucocorticoid withdrawalAll glucocorticoid therapy, even if inhaled or applied topically, can suppress the HPA axis. In practice, this is only likely to result in a crisis due to adrenal insuffi-ciency on withdrawal of treatment 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

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 ACTH secretion. Thus, in pituitary-dependent Cush-ing’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 corti-sol 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 20.21. MRI detects around 60% of pituitary microadenomas secreting ACTH. If available, bilateral inferior petrosal sinus sam-pling (BIPSS) with measurement of ACTH is the best means of confirming Cushing’s disease, unless MRI shows a tumour bigger than 6 mm. CT or MRI detects most adrenal tumours; adrenal carcinomas are usually large (> 5 cm) and have other features of malignancy (p. 779).

ManagementUntreated 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 used to inhibit corticosteroid bio-synthesis, including metyrapone and ketoconazole. The dose of these agents is best titrated against serum corti-sol levels or 24-hour urine free cortisol.

Cushing’s diseaseTrans-sphenoidal surgery carried out by an experienced surgeon with selective removal of the adenoma is the treatment of choice, 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, with an invasive pituitary macro-adenoma and very high ACTH levels causing pigmenta-tion. The risk of Nelson’s syndrome may be reduced by pituitary irradiation.

Adrenal tumoursLaparoscopic 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. Radio-therapy to the tumour bed reduces the risk of local recurrence, and systemic therapy consists of the adreno-lytic drug mitotane and chemotherapy, but responses are often poor.

Ectopic ACTH syndromeLocalised tumours, such as bronchial carcinoid, should be removed surgically. In patients with incurable malig-nancy, it is important to reduce the severity of the Cushing’s syndrome using medical therapy (see above) or, if appropriate, bilateral adrenalectomy.

• Hydrocortisone:20mg• Cortisoneacetate:25mg• Prednisolone:5mg• Dexamethasone:0.5mg

20.43 Approximate equivalent doses of glucocorticoids

The adrenal glands

20

777

Congenital adrenal hyperplasias and Addison’s disease (primary adrenocortical failure) are rare causes.

Clinical assessmentThe clinical features of adrenal insufficiency are shown in Box 20.46. 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 presenta-tion, initial symptoms are often misdiagnosed as chronic fatigue syndrome or depression. Adrenocortical insufficiency should also be considered in patients with hyponatraemia, even in the absence of symptoms (p. 437).

Features of an acute adrenal crisis include circulatory shock with severe hypotension, hyponatraemia, hyper-kalaemia and, in some instances, hypoglycaemia and hypercalcaemia. Muscle cramps, nausea, vomiting, diar-rhoea and unexplained fever may be present. The crisis is often precipitated by intercurrent disease, surgery or infection.

Vitiligo occurs in 10–20% of patients with auto-immune Addison’s disease (p. 734).

InvestigationsTreatment 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 cortisol and, if the patient’s clinical condition permits, it may be appropriate to spend 30 minutes performing a short ACTH stimulation test (Box 20.47) before administering hydrocortisone. Inves-tigations should be performed before treatment is given in patients who present with features suggestive of chronic adrenal insufficiency.

Assessment of glucocorticoidsRandom plasma cortisol is usually low in patients with adrenal insufficiency but it may be within the reference

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 with-drawal. They should be issued with a steroid card and/or wear an engraved bracelet (Box 20.44).

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 stimu-late adrenal recovery is of no value, as the pituitary remains suppressed.

In patients who have received glucocorticoids for longer than a few weeks, it is often valuable to confirm that the HPA axis is recovering during glucocorticoid withdrawal. Once the dose of glucocorticoid is reduced to a minimum (e.g. 4 mg prednisolone or 0.5 mg dexa-methasone per day), then measure plasma cortisol at 0900 hrs before the next dose. If this is detectable, then perform an ACTH stimulation test (see Box 20.47) to confirm that glucocorticoids can be withdrawn com-pletely. Even once glucocorticoids have been success-fully 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 insufficiencyAdrenal 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 unex-plained fatigue, hyponatraemia or hypotension. Causes are shown in Box 20.45. The most common is ACTH deficiency (secondary adrenocortical failure), usually because of inappropriate withdrawal of chronic gluco-corticoid therapy or a pituitary tumour (p. 789).

Intercurrent stress

• Febrileillness:doubledoseofhydrocortisone

Surgery

• Minoroperation:hydrocortisone100mgIMwithpre-medication

• Majoroperation:hydrocortisone100mg4timesdailyfor24hrs,then50mgIM4timesdailyuntilreadytotaketablets

Vomiting

• Patientsmusthaveparenteralhydrocortisoneifunabletotakeitbymouth

Steroid card

• Patientshouldcarrythisatalltimes;itshouldgiveinformationregardingdiagnosis,steroid,doseanddoctor

Bracelet and emergency pack

• Patientsshouldbeencouragedtobuyoneoftheseandhaveitengravedwiththediagnosis,currenttreatmentandareferencenumberforacentraldatabase

• Patientsshouldbegivenahydrocortisoneemergencypackandtrainedintheself-administrationofhydrocortisone100mgIM;theyshouldbeadvisedtotakethepackonholidays/tripsabroad

20.44 Advice to patients on glucocorticoid replacement therapy

Secondary (↓ACTH)

• Withdrawalofsuppressiveglucocorticoidtherapy• Hypothalamicorpituitarydisease

Primary (↑ACTH)

Addison’s diseaseCommon causes• Autoimmune

SporadicPolyglandularsyndromes(p.795)

• Tuberculosis• HIV/AIDS• Metastaticcarcinoma• Bilateraladrenalectomy

Rare causes• Lymphoma• Intra-adrenalhaemorrhage

(Waterhouse–Friedrichsensyndromefollowingmeningococcalsepticaemia)

• Amyloidosis• Haemochromatosis

Corticosteroid biosynthetic enzyme defects• Congenitaladrenalhyperplasias• Drugs

Metyrapone,ketoconazole,etomidate

20.45 Causes of adrenocortical insufficiency

EndocrinE disEasE

20

778

Glucocorticoid insufficiency

Mineralocorticoid insufficiency ACTH excess

Adrenal androgen insufficiency

Withdrawal of exogenous glucocorticoid

+ – – +

Hypopituitarism + – – +Addison’s disease + + + +Congenital adrenal hyperplasia(21 OHase deficiency)

+ + + –

Clinical features Weightloss,anorexiaMalaise,weaknessNausea,vomitingDiarrhoeaorconstipationPosturalhypotensionShockHypoglycaemiaHyponatraemia(dilutional)Hypercalcaemia

HypotensionShockHyponatraemia(depletional)Hyperkalaemia

Pigmentationof:Sun-exposedareasPressureareas(e.g.elbows,knees)Palmarcreases,knucklesMucousmembranesConjunctivaeRecentscars

Decreasedbodyhairandlossoflibido,especiallyinfemale

20.46 Clinical and biochemical features of adrenal insufficiency

range, yet inappropriately low, for a seriously ill patient. Random measurement of plasma cortisol cannot there-fore 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 20.47. Cortisol levels fail to increase in response to exogenous ACTH in patients with primary or secondary adrenal insufficiency. These can be distin-guished by measurement of ACTH (which is low in ACTH deficiency and high in Addison’s disease).

Assessment of mineralocorticoidsMineralocorticoid 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 20.46 and p. 437). Hyperkalaemia is common, but not univer-sal, in aldosterone deficiency. Plasma renin and aldo-sterone 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 androgensThis is not necessary in men because testosterone from the testes is the principal androgen. In women, dehydro-epiandrosterone (DHEA) and androstenedione may be measured in a random specimen of blood, though levels are highest in the morning.

Other tests to establish the causePatients with unexplained secondary adrenocortical insufficiency should be investigated as described on page 786. In patients with elevated ACTH, further tests are required to establish the cause of Addison’s disease. Adrenal autoantibodies are frequently positive in autoimmune adrenal failure. If antibody tests are nega-tive, imaging of the adrenal glands with CT or MRI is indicated. Tuberculosis causes adrenal calcification, visible on plain X-ray or ultrasound scan. An HIV test should be performed if risk factors for infection are present (p. 391). Adrenal metastases are a rare cause of adrenal insufficiency. Patients with evidence of auto-immune adrenal failure should be screened for other organ-specific autoimmune diseases, such as thyroid disease, pernicious anaemia and type 1 diabetes.

ManagementPatients with adrenocortical insufficiency always need glucocorticoid replacement therapy and usually, but

Use

• Diagnosisofprimaryorsecondaryadrenalinsufficiency• AssessmentofHPAaxisinpatientstakingsuppressive

glucocorticoidtherapy• ReliesonACTH-dependentadrenalatrophyinsecondary

adrenalinsufficiency,somaynotdetectacuteACTHdeficiency(forexample,inpituitaryapoplexy,p.789)

Dose

• 250µgACTH1–24(Synacthen)byIMinjectionatanytimeofday

Blood samples

• 0and30minsforplasmacortisol• 0minsalsoforACTH(onice)ifAddison’sdiseaseisbeing

considered(patientnotknowntohavepituitarydiseaseortobetakingexogenousglucocorticoids)

Results

• Normalsubjects:plasmacortisol>500nmol/L(~18µg/dL)*eitheratbaselineorat30mins

• Incrementalchangeincortisolisnotacriterion

20.47 How and when to do an ACTH stimulation test

*The exact cortisol concentration depends on the cortisol assay being used.

The adrenal glands

20

779

Correct volume depletion

• IVsalineasrequiredtonormalisebloodpressureandpulse• Inseverehyponatraemia(<125mmol/L)avoidincreases

ofplasmaNa>10mmol/L/daytopreventpontinedemyelination(p.437)

• Fludrocortisoneisnotrequiredduringtheacutephaseoftreatment

Replace glucocorticoids

• IVhydrocortisonesuccinate100mgstat,and100mg4timesdailyforfirst12–24hours

• Continueparenteralhydrocortisone(50–100mgIM4timesdaily)untilpatientiswellenoughforreliableoraltherapy

Correct other metabolic abnormalities

• Acutehypoglycaemia:IV10%glucose• Hyperkalaemia:shouldrespondtovolumereplacementbut

occasionallyrequiresspecifictherapy(seeBox16.17,p.443)

Identify and treat underlying cause

• Consideracuteprecipitant,suchasinfection• Consideradrenalorpituitarypathology(seeBox20.45)

20.48 Management of adrenal crisis

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 20.48.

Glucocorticoid replacementAdrenal replacement therapy consists of oral hydrocor-tisone (cortisol) 15–20 mg daily in divided doses, typi-cally 10 mg on waking and 5 mg at around 1500 hrs. These are physiological replacement doses which 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 over-replacement, whilst persistent lethargy or hyperpigmen-tation may be due to an inadequate dose or lack of absorption. Measurement of plasma cortisol levels is not usually helpful. Advice to patients dependent on gluco-corticoid replacement is given in Box 20.44.

Mineralocorticoid replacementFludrocortisone (9α-fluoro-hydrocortisone) is adminis-tered at the usual dose of 0.05–0.15 mg daily, and ade-quacy of replacement may be assessed by measurement of blood pressure, plasma electrolytes and plasma renin.

Androgen replacementAndrogen replacement with DHEA (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 massIt 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’. They are present in up to 10% of adults and the prevalence increases with age.

Eighty-five per cent of adrenal incidentalomas are non-functioning adrenal adenomas. The remainder includes functional tumours of the adrenal cortex (secreting cortisol, aldosterone or androgens), phaeo-chromocytomas, primary and secondary carcinomas, hamartomas and other rare disorders, including granu-lomatous infiltrations.

Clinical assessment and investigationsThere 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. 772), mineralocorticoids (see below), catecholamines (p. 781) and, in women, andro-gens (p. 763) should be sought. Investigations should include a dexamethasone suppression test, urine or plasma metanephrines and, in virilised women, meas-urement of serum testosterone, DHEA and androstene-dione. Patients with hypertension should be investigated for mineralocorticoid excess, as described below.

CT and MRI are equally effective in assessing the malignant potential of an adrenal mass, using the fol-lowing 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 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 adrenal carcinoma. Biopsy is

• Adrenocortical insufficiency:ofteninsidiousanddifficulttospot.

• Glucocorticoid therapy:especiallyhazardousinolderpeople,whoarealreadyrelativelyimmunocompromisedandsusceptibletoosteoporosis,diabetes,hypertensionandothercomplications.

• ‘Physiological’ glucocorticoid replacement therapy:increasedriskofadrenalcrisisbecausecompliancemaybepoorandthereisagreaterincidenceofintercurrentillness.Patientandcarereducation,withregularreinforcementoftheprinciplesdescribedinBox20.44,iscrucial.

20.49 Glucocorticoids in old age

EndocrinE disEasE

20

780

occasionally helpful in confirming adrenal metastases from other cancers, but should be avoided if either phaeochromocytoma or primary adrenal cancer is sus-pected in order to avoid precipitation of a hypertensive crisis or seeding of tumour cells, respectively.

ManagementFunctional lesions and tumours of more than 4 cm in diameter should be considered for removal by adrenal surgery. In patients with radiologically benign, non-functioning lesions of less than 4 cm in diameter, surgery is only required if serial imaging suggests tumour growth. Optimal management of patients with low-grade cortisol secretion, as demonstrated by the dexa-methasone suppression test, remains to be established.

Primary hyperaldosteronism

Estimates of the prevalence of primary hyperaldo-steronism vary according to the screening tests employed, but it may occur in as many as 10% of people with hypertension. Indications to test for mineralocorti-coid excess in hypertensive patients include hypokalae-mia (including hypokalaemia induced by thiazide diuretics), poor control of blood pressure with conven-tional therapy, a family history of early-onset hyperten-sion, or presentation at a young age.

Causes of excessive activation of mineralocorticoid receptors are shown in Box 20.50. It is important to differentiate primary hyperaldosteronism, caused by an intrinsic abnormality of the adrenal glands resulting in aldosterone excess, from secondary hyperaldo-steronism, which is usually a consequence of enhanced activity of renin in response to inadequate renal per-fusion 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 hyperaldo-steronism is a rare autosomal dominant condition in

which aldosterone is secreted ‘ectopically’ from the adrenal fasciculata/reticularis in response to ACTH. Rarely, the mineralocorticoid receptor pathway in the distal nephron is activated, even though aldosterone concentrations are low.

Clinical featuresIndividuals 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 weak-ness (or even paralysis, especially in Chinese), 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 acceler-ated phase hypertension is rare.

InvestigationsBiochemicalRoutine blood tests may show a hypokalaemic alkalosis. Sodium is usually at the upper end of the reference range in primary hyperaldosteronism, but is character-istically low in secondary hyperaldosteronism (because low plasma volume stimulates antidiuretic hormone (ADH) release and high angiotensin II levels stimulate thirst). The key measurements are plasma renin and aldosterone (see Box 20.50), and in many centres, the aldosterone : renin ratio (ARR) is employed as a screen-ing test for primary hyperaldosteronism in hypertensive patients. Almost all antihypertensive drugs interfere with this ratio (β-blockers inhibit whilst thiazide diuret-ics stimulate renin secretion). Thus, individuals with an elevated ARR require further testing after stopping anti-hypertensive drugs for at least 2 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 sup-plementation 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 furo-semide administration) to differentiate angiotensin II-dependent aldosterone secretion in idiopathic hyper-plasia from autonomous aldosterone secretion typical of an APA.

Imaging and localisationImaging with CT or MRI will identify most APAs (Fig. 20.22), but it is important to recognise the risk of false-positives (non-functioning adrenal adenomas are common) and false-negatives (imaging may have insuf-ficient resolution to identify adenomas with 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 the inapparent cause of aldosterone excess.

With renin high and aldosterone high (secondary hyperaldosteronism)

• Inadequaterenalperfusion(diuretictherapy,cardiacfailure,liverfailure,nephroticsyndrome,renalarterystenosis)

• Renin-secretingrenaltumour(veryrare)

With renin low and aldosterone high (primary hyperaldosteronism)

• Adrenaladenomasecretingaldosterone(Conn’ssyndrome)• Idiopathicbilateraladrenalhyperplasia• Glucocorticoid-suppressiblehyperaldosteronism(rare)

With renin low and aldosterone low (non-aldosterone-dependent activation of mineralocorticoid pathway)

• EctopicACTHsyndrome• Liquoricemisuse(inhibitionof11β-HSD2)• Liddle’ssyndrome• 11-deoxycorticosterone-secretingadrenaltumour• Rareformsofcongenitaladrenalhyperplasiaand11β-HSD2

deficiency

20.50 Causes of mineralocorticoid excess

The adrenal glands

20

781

• Hypertension(usuallyparoxysmal;oftenposturaldropofbloodpressure)

• Paroxysmsof:Pallor(occasionallyflushing)Palpitations,sweatingHeadacheAnxiety(angoranimi)

• Abdominalpain,vomiting• Constipation• Weightloss• Glucoseintolerance

20.51 Clinical features of phaeochromocytoma

Fig. 20.22  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

ManagementMineralocorticoid receptor antagonists (spironolactone and eplerenone) are valuable in treating both hypo-kalaemia and hypertension in all forms of mineralocor-ticoid excess. Up to 20% of males develop gynaecomastia on spironolactone. Amiloride (10–40 mg/day), which blocks the epithelial sodium channel regulated by aldo-sterone, is an alternative.

In patients with an APA, medical therapy is usually given for a few weeks to normalise whole-body electro-lyte balance before unilateral adrenalectomy. Laparo-scopic 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 approxi-mately 15% show malignant features. Around 30% are associated with inherited disorders, including neuro-fibromatosis (p. 1215), von Hippel–Lindau syndrome

(p. 1216) and MEN 2 (p. 795). Paragangliomas are par-ticularly associated with mutations in the succinate dehydrogenase B, C and D genes.

Clinical featuresThese depend on the pattern of catecholamine secretion and are listed in Box 20.51.

Some patients present with hypertension, although it has been estimated that phaeochromocytoma accounts for less than 0.1% of cases of hypertension. The presenta-tion may be with a complication of hypertension, such as stroke, myocardial infarction, left ventricular failure, hypertensive retinopathy or accelerated phase hyperten-sion. 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 phaeochromo-cytoma. Paragangliomas are often non-functioning.

InvestigationsExcessive secretion of catecholamines can be con-firmed 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 concentra-tion of metanephrines, the more likely is the diagnosis of phaeochromocytoma/paraganglioma. Serum chromo-granin 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 consid-ered in individuals with other features of a genetic syn-drome, with a family history of phaeochromocytoma/paraganglioma, and in those presenting under the age of 50 years.

LocalisationPhaeochromocytomas are usually identified by abdomi-nal CT or MRI (Fig. 20.23). Localisation of paragan-gliomas may be more difficult. Scintigraphy using meta-iodobenzyl guanidine (MIBG) can be useful, par-ticularly if combined with CT. 18F-deoxyglucose PET is especially useful for detection of malignant disease and for confirming an imaging abnormality as a paragan-glioma in an individual with underlying risk due to genetic mutation.

EndocrinE disEasE

20

782

Fig. 20.23  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). 

ManagementMedical therapy is required to prepare the patient for surgery, preferably for a minimum of 6 weeks 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 antago-nist, unlike prazosin or doxazosin. If α-blockade pro-duces 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 featuresInherited defects in enzymes of the cortisol biosynthetic pathway (see Fig. 20.18, p. 772) 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 17OH-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 glucocor-ticoid and mineralocorticoid deficiency (see Box 20.46, p. 778) and androgen excess, such as ambiguous genita-lia in girls. In the other two-thirds, mineralocorticoid secretion is adequate but there may be features of corti-sol insufficiency and/or ACTH and androgen excess, including precocious pseudo-puberty, which is distin-guished from ‘true’ precocious puberty by low gonado-trophins. Sometimes the mildest enzyme defects are not apparent until adult life, when females may present with amenorrhoea and/or hirsutism (p. 763). This is called ‘non-classical’ or ‘late-onset’ congenital adrenal hyperplasia.

Defects of all the other enzymes in Figure 20.18 (p. 772) are rare. Both 17-hydroxylase and 11 β- hydroxylase deficiency may produce hypertension due to excess production of 11-deoxycorticosterone, which has mineralocorticoid activity.

InvestigationsCirculating 17OH-progesterone levels are raised in 21-hydroxylase deficiency, but this may only be demon-strated after ACTH administration in late-onset cases. To avoid salt-wasting crises in infancy, 17OH- 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 778.

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 dexametha-sone to the mother to suppress ACTH levels.

ManagementThe aim is to replace deficient corticosteroids and to suppress ACTH-driven adrenal androgen production. A careful balance is required between adequate sup-pression 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 replace-ment regime, and clinical features (menstrual cycle, hir-sutism, weight gain, blood pressure) and biochemical profiles (plasma renin, 17OH-progesterone and testo-sterone 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. 764).

THE ENDOCRINE PANCREAS AND GASTROINTESTINAL TRACT

A series of hormones are secreted from cells dis-tributed throughout the gastrointestinal tract and pancreas. Functional anatomy and physiology are

The endocrine pancreas and gastrointestinal tract

20

783

Primary Secondary

Hormone excess

InsulinomaGastrinoma(Zollinger–Ellisonsyndrome)Carcinoidsyndrome(secretionof5-HT)GlucagonomaVIPomaSomatostatinoma

HypergastrinaemiaofachlorhydriaHyperinsulinaemiaafterbariatricsurgery

Hormone deficiency

Diabetesmellitus

Hormone resistance

Insulinresistancesyndromes(e.g.type2diabetesmellitus,lipodystrophy,leprechaunism)

Non-functioning tumours

PancreaticcarcinomaPancreaticneuro-endocrinetumour

20.52 Classification of endocrine diseases of the pancreas and gastrointestinal tract

Fig. 20.24  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 confirmedPatient had symptoms of hypoglycaemia

Low blood glucose measured at the time of symptomsSymptoms resolved on correction of hypoglycaemia

↑ Insulin↓ C-peptide

↓ Insulin↓ C-peptide

↑ Insulin↑ C-peptide

AlcoholDrugsCritical illnessesHypopituitarism (rare)Primary adrenocortical failure (rare in adults)Non-islet cell tumour (e.g. sarcoma)Inborn errors of metabolism

Exogenousinsulin

InsulinomaSulphonylureasOther drugsHyperinsulinism of infancy

described in Chapters 21 and 22. Diseases associated with abnormalities of these hormones are listed in Box 20.52. Most are rare, with the exception of diabetes mellitus (Ch. 21).

Presenting problems in endocrine pancreas disease

Spontaneous hypoglycaemiaHypoglycaemia most commonly occurs as a side-effect of treatment with insulin or sulphonylurea drugs in people with diabetes mellitus. In non-diabetic individu-als, symptomatic hypoglycaemia is rare, but it is not

uncommon to detect venous blood glucose concentra-tions below 3.0 mmol/L in asymptomatic patients. For this reason, and because the symptoms of hypoglycae-mia are non-specific, a hypoglycaemic disorder should only be diagnosed if all three conditions of Whipple’s triad are met (Fig. 20.24). There is no specific blood glucose concentration at which spontaneous hypo-glycaemia can be said to occur, although the lower the blood glucose concentration, the more likely it is to have pathological significance.

Clinical assessmentThe clinical features of hypoglycaemia are described in the section on insulin-induced hypoglycaemia on page 814. Individuals with chronic spontaneous hypoglycae-mia often have attenuated autonomic responses and ‘hypoglycaemia unawareness’, and may present with a wide variety of features of neuro-glycopenia, including odd behaviour and convulsions. The symptoms are usually episodic and relieved by consumption of carbo-hydrate. Symptoms occurring while fasting (such as before breakfast) or following exercise are much more likely to be representative of pathological hypoglycae-mia than those which develop after food (post-prandial or ‘reactive’ symptoms). Hypoglycaemia should be con-sidered in all comatose patients, even if there is an apparently obvious cause, such as hemiplegic stroke or alcohol intoxication.

InvestigationsDoes the patient have a hypoglycaemic disorder?Patients who present acutely with confusion, coma or convulsions should be tested for hypoglycaemia at the bedside with a capillary blood sample and an auto-mated meter. While this is sufficient to exclude hypo-glycaemia, blood glucose meters are relatively inaccurate in the hypoglycaemic range and the diagnosis should always be confirmed by a laboratory-based glucose measurement. At the same time, a sample should be taken for later measurement, if necessary, of alcohol, insulin, C-peptide, cortisol and sulphonylurea levels. Taking these samples during an acute presentation

EndocrinE disEasE

20

784

secretion (diazoxide or somatostatin analogues). Insuli-nomas are resected when benign, providing the indi-vidual is fit enough to undergo surgery. Metastatic malignant insulinomas are 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. 781) and thyroid (medullary carcinoma, p. 755). Most NETs occur sporadically, but a proportion are associated with genetic cancer syndromes, such as MEN 1, MEN 2 and neurofibromatosis type 1 (pp. 795 and 1215). 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 conven-tional 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 carci-noma of the lung). The majority of gastroenteropancre-atic NETs behave in an intermediate manner, with relatively slow growth but a propensity to invade and metastasise to remote organs, especially the liver.

Clinical featuresPatients with gastroenteropancreatic NETs often have a history of abdominal pain over many years prior to diag-nosis 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. 774). Pancreatic NETs can also cause hormone excess (Box 20.54) but most are non-functional. The classic ‘car-cinoid syndrome’ (Box 20.55) 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.

prevents subsequent unnecessary dynamic tests and is of medico-legal importance in cases where poisoning is suspected.

Patients who attend the outpatient clinic with epi-sodic symptoms suggestive of hypoglycaemia present a more challenging problem. The main diagnostic test is the prolonged (72-hour) fast. If symptoms of hypo-glycaemia 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 reso-lution of symptoms. The absence of clinical and bio-chemical evidence of hypoglycaemia during a prolonged fast effectively excludes the diagnosis of a hypoglycae-mic 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 – for example, salicylates, quinine and pentamidine – may also be implicated. Hypoglycaemia is one of many metabolic derangements which occur in patients with hepatic failure, renal failure, 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 indica-tive of administration of exogenous insulin, either facti-tiously or feloniously. Adults with high insulin and C-peptide concentrations during an episode of hypo-glycaemia are most likely to have an insulinoma, but sulphonylurea ingestion should also be considered (par-ticularly 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 are small (< 5 mm diameter) but can be identi-fied by CT, MRI or ultrasound (endoscopic or laparo-scopic). Imaging should include the liver since around 10% of insulinomas are malignant. Rarely, large non-pancreatic tumours, such as sarcomas, may cause recur-rent hypoglycaemia because of their ability to produce excess pro-insulin-like growth factor-2 (pro-IGF-2).

ManagementTreatment of acute hypoglycaemia should be initiated as soon as laboratory blood samples have been taken, and should not be deferred until formal laboratory con-firmation 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

• Presentation:maypresentwithfocalneurologicalabnormality.Bloodglucoseshouldbecheckedinallpatientswithacuteneurologicalsymptomsandsigns,especiallystroke,asthesewillreversewithearlytreatmentofhypoglycaemia.

20.53 Spontaneous hypoglycaemia in old age

The hypothalamus and the pituitary gland

20

785

Tumour Hormone Effects

Gastrinoma Gastrin Pepticulcerandsteatorrhoea(Zollinger–Ellisonsyndrome)

Insulinoma Insulin Recurrenthypoglycaemia(seeabove)

VIPoma Vasoactiveintestinalpeptide(VIP)

Waterydiarrhoeaandhypokalaemia

Glucagonoma Glucagon Diabetesmellitus,necrolyticmigratoryerythema

Somatostatinoma Somatostatin Diabetesmellitusandsteatorrhoea

20.54 Pancreatic neuro-endocrine tumours

• Episodicflushing,wheezinganddiarrhoea• Facialtelangiectasia• Cardiacinvolvement(tricuspidregurgitation,pulmonary

stenosis,rightventricularendocardialplaques)leadingtoheartfailure

20.55 Clinical features of the carcinoid syndrome

Fig. 20.25  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 CA

‘Tworandomisedcontrolledclinicaltrialsshowedsignificantimprovementsinprogression-freesurvivalinpatientswithadvancedandprogressivepancreaticneuro-endocrinetumours.’

• YaoJC,etal.NEnglJMed2011;364(6):514–523.• RaymondE,etal.NEnglJMed2011;364(6):501–513.

20.56 Tyrosine kinase/mTOR inhibitors in advanced pancreatic neuro-endocrine tumours

InvestigationsA combination of imaging with ultrasound, CT, MRI and/or radio-labelled somatostatin analogue (Fig. 20.25) 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 may also provide prognostic information.

Carcinoid syndrome is confirmed by measuring ele-vated 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 meas-ured in a fasting blood sample, along with the hormones listed in Box 20.54. All of these can be useful as tumour markers.

ManagementTreatment 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. Dia-zoxide can reduce insulin secretion in insulinomas, and high doses of proton pump inhibitors suppress acid pro-duction in gastrinomas. Somatostatin analogues are effective in reducing the symptoms of carcinoid syn-drome 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. Other treatments, such as interferon, targeted radio-nuclide therapy with 131I-MIBG and radio-labelled somatostatin analogues (which may be taken up by NET metastases), and resection/embolisation of hepatic metastases, may have a role in the palliation of symp-toms but there is little evidence that they prolong life. The tyrosine kinase inhibitor sunitinib and the mam-malian target of rapamycin (mTOR) inhibitor everolimus have shown benefit in progressive pancreatic NETS (Box 20.56), and should be considered as part of stand-ard therapy.

THE HYPOTHALAMUS AND THE PITUITARY GLAND

Diseases of the hypothalamus and pituitary have an annual incidence of approximately 3 : 100 000 and a

EndocrinE disEasE

20

786

prevalence of 30–40 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 20.26 and its numerous functions are shown in Figure 20.2 (p. 737). 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 cavern-ous sinuses are lateral to the pituitary fossa and contain the 3rd, 4th and 6th cranial nerves and the internal carotid arteries. The gland is composed of two lobes, anterior and posterior, and is connected to the hypotha-lamus by the infundibular stalk, which has portal vessels carrying blood from the median eminence of the hypo-thalamus to the anterior lobe and nerve fibres to the posterior lobe.

Diseases of the hypothalamus and pituitary are clas-sified in Box 20.57. By far the most common disorder is an adenoma of the anterior pituitary gland.

Fig. 20.26  Anatomical relationships of the normal pituitary gland and hypothalamus. See also Figure 20.2 (p. 737).  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

TVOC

AP

A

B

OC

IC

TV

PS

CS

AP

Primary Secondary

Non-functioning tumours

PituitaryadenomaCraniopharyngiomaMetastatictumours

Hormone excessAnteriorpituitary Prolactinoma

AcromegalyCushing’sdiseaseRareTSH-,LH-andFSH-secretingadenomas

Disconnectionhyperprolactinaemia

Hypothalamusandposteriorpituitary

Syndromeofinappropriateantidiuretichormone(SIADH;p.438)

Hormone deficiencyAnteriorpituitaryHypothalamusandposteriorpituitary

HypopituitarismCranialdiabetesinsipidus

GnRHdeficiency(Kallmann’ssyndrome)

Hormone resistance

Growthhormoneresistance(Larondwarfism)Nephrogenicdiabetesinsipidus

20.57 Classification of diseases of the pituitary and hypothalamus

Investigation of patients with pituitary diseaseAlthough pituitary disease presents with diverse clinical manifestations (see below), the approach to investiga-tion is similar in all cases (Box 20.58).

The approach to testing for hormone deficiency is outlined in Box 20.58. Details are given in the sections on individual glands elsewhere in this chapter. Tests for hormone excess vary according to the hormone in ques-tion. 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 prolac-tin is sufficient to diagnose hyperprolactinaemia. In con-trast, growth hormone is secreted in a pulsatile fashion. A high random level does not confirm acromegaly; the diagnosis is only confirmed by failure of growth hormone to be suppressed during an oral glucose toler-ance test, and a high serum insulin-like growth factor-1 (IGF-1). Similarly, in suspected ACTH-dependent Cush-ing’s disease (p. 773), 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 pitui-tary 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 in a patient who 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).

The hypothalamus and the pituitary gland

20

787

Identify pituitary hormone deficiency

ACTH deficiency• ShortACTHstimulationtest(seeBox20.47,p.778)• Insulintolerancetest(seeBox20.61,p.788):onlyif

uncertaintyininterpretationofshortACTHstimulationtest(e.g.acutepresentation)

LH/FSH deficiency• Inthemale,measurerandomserumtestosterone,LHand

FSH• Inthepre-menopausalfemale,askifmensesareregular• Inthepost-menopausalfemale,measurerandomserumLH

andFSH(whichwouldnormallybe>30mU/L)TSH deficiency• MeasurerandomserumT4

• NotethatTSHisoftendetectableinsecondaryhypothyroidism

Growth hormone deficiencyOnlyinvestigateifgrowthhormonereplacementtherapyisbeingcontemplated;p.789• Measureimmediatelyafterexercise• Considerotherstimulatorytests(seeBox20.60)Cranial diabetes insipidusOnlyinvestigateifpatientcomplainsofpolyuria/polydipsia,whichmaybemaskedbyACTHorTSHdeficiency• Excludeothercausesofpolyuriawithbloodglucose,

potassiumandcalciummeasurements• Waterdeprivationtest(seeBox20.66,p.795)or5%saline

infusiontest

Identify hormone excess

• Measurerandomserumprolactin• Investigateforacromegaly(glucosetolerancetest)or

Cushing’ssyndrome(p.774)ifthereareclinicalfeatures

Establish the anatomy and diagnosis

• Considervisualfieldtesting• ImagethepituitaryandhypothalamusbyMRIorCT

20.58 How to investigate patients with suspected pituitary hypothalamic disease

Surgical biopsy is usually only performed as part of a therapeutic operation. Conventional histology identi-fies 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.

Presenting problems in hypothalamic and pituitary disease

The clinical features of pituitary disease are shown in Figure 20.27 overleaf. Younger women with pituitary disease most commonly present with secondary amen-orrhoea (p. 759) or galactorrhoea (in hyperprolactin-aemia). 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.

HypopituitarismHypopituitarism describes combined deficiency of any of the anterior pituitary hormones. The clinical presenta-tion 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 20.59.

Clinical assessmentThe presentation is highly variable. For example, follow-ing radiotherapy to the pituitary region, there is a char-acteristic 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, in the male, loss of libido and, in the female, oligomenorrhoea or amenorrhoea. Later, in the male there may be gynaecomastia and decreased frequency of shaving. In both sexes, axillary and pubic hair eventually become 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 cor-tisol insufficiency (including postural hypotension and

Structural

• PrimarypituitarytumourAdenoma*Carcinoma(exceptionallyrare)

• Craniopharyngioma*• Meningioma*• Secondarytumour

(includingleukaemiaandlymphoma)

• Chordoma• Germinoma(pinealoma)• Arachnoidcyst• Rathke’scleftcyst• Haemorrhage(apoplexy)

Inflammatory/infiltrative

• Sarcoidosis• Infections,e.g.pituitary

abscess,tuberculosis,syphilis,encephalitis

• Lymphocytichypophysitis• Haemochromatosis• Langerhanscell

histiocytosis

Congenital deficiencies

• GnRH(Kallmann’ssyndrome)*–gonadotrophin-releasinghormone

• GHRH*–growthhormone-releasinghormone

• TRH–thyrotrophin-releasinghormone

• CRH–corticotrophin-releasinghormone

Functional*

• Chronicsystemicillness• Anorexianervosa

• Excessiveexercise

Other

• Headinjury*• (Para)sellarsurgery*• (Para)sellarradiotherapy*

• Post-partumnecrosis(Sheehan’ssyndrome)

• Opiateanalgesia

*The most common causes of pituitary hormone deficiency.

20.59 Causes of anterior pituitary hormone deficiency

EndocrinE disEasE

20

788

a dilutional hyponatraemia). In contrast to primary adrenal insufficiency (p. 777), angiotensin II-dependent zona glomerulosa function is not lost and hence aldos-terone 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 pre-cipitated by a mild infection or injury, or may occur secondary to pituitary apoplexy (p. 789).

Other features of pituitary disease may be present (see Fig. 20.27).

InvestigationsThe strategy for investigation of pituitary disease is described in Box 20.58. In acutely unwell patients, the priority is to diagnose and treat cortisol deficiency (p. 776). Other tests can be undertaken later. Specific dynamic tests for diagnosing hormone deficiency are described in Boxes 20.47 (p. 778) and 20.60. More spe-cialised biochemical tests, such as insulin tolerance tests (Box 20.61), 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

Fig. 20.27  Common symptoms and signs to consider in a patient with suspected pituitary disease. 

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 (ADH)(usually post-surgical)• Thirst and polyuria

Microadenoma (arrow)< 10 mm diameter

GHlevelsarecommonlyundetectable,soachoicefromtherangeof‘stimulation’testsisrequired:• Insulin-inducedhypoglycaemia• Arginine(maybecombinedwithGHRH)• Glucagon• Clonidine

20.60 Tests of growth hormone secretion

is not identified, then further investigations are indi-cated to exclude infectious or infiltrative causes.

ManagementTreatment of acutely ill patients is similar to that described for adrenocortical insufficiency on page 778, except that sodium depletion is not an important component to correct. Chronic hormone replacement therapies are described below. Once the cause of hypo-pituitarism is established, specific treatment – of a pitui-tary macroadenoma, for example (see below) – may be required.

Cortisol replacementHydrocortisone should be given if there is ACTH defi-ciency. Suitable doses are described in the section on adrenal disease on page 779. Mineralocorticoid replace-ment is not required.

Thyroid hormone replacementLevothyroxine 50–150 µg once daily should be given as described on page 743. Unlike in primary

The hypothalamus and the pituitary gland

20

789

started at a low dose, with monitoring of the response by measurement of serum IGF-1.

Pituitary tumourPituitary 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 hypo-pituitarism, as described above. A wide variety of dis-orders can present as mass lesions in or around the pituitary gland (see Box 20.59). Most intrasellar tumours are pituitary macroadenomas (most commonly non-functioning adenomas, see Fig. 20.27), whereas suprasel-lar masses may be craniopharyngiomas (see Fig. 20.30, p. 794). The most common cause of a parasellar mass is a meningioma.

Clinical assessmentClinical features are shown in Figure 20.27. 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. 20.28) 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 hypo-pituitarism. Non-haemorrhagic infarction can also occur in a normal pituitary gland; predisposing factors include catastrophic obstetric haemorrhage (Sheehan’s syn-drome), diabetes mellitus and raised intracranial pressure.

InvestigationsPatients suspected of having a pituitary tumour should undergo MRI or CT. Whilst some lesions have dis-tinctive neuro-radiological features, the definitive diag-nosis is made on histology after surgery. All patients with (para)sellar space-occupying lesions should have pituitary function assessed as described in Box 20.58 (p. 787).

ManagementModalities of treatment of common pituitary and hypothalamic tumours are shown in Box 20.62. Associ-ated 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 pres-ence of a sellar mass lesion, it is crucial that serum prolactin is measured before emergency surgery is per-formed. If the prolactin is over 5000 mU/L, then the lesion is likely to be a macroprolactinoma and to respond

*The precise cut-off figure for a satisfactory cortisol and GH response depends on the assay used and so varies between centres.

Use

• AssessmentoftheHPAaxis• Assessmentofgrowthhormonedeficiency• Indicatedwhenthereisdoubtaftertheothertestsin

Box20.58• Usuallyperformedinspecialistcentres,especiallyinchildren• IVglucoseandhydrocortisonemustbeavailablefor

resuscitation

Contraindications

• Ischaemicheartdisease• Epilepsy• Severehypopituitarism(0800hrsplasmacortisol

<180nmol/L(6.6µg/dL))

Dose

• 0.15U/kgbodyweightsolubleinsulinIV

Aim

• Toproduceadequatehypoglycaemia(tachycardiaandsweatingwithbloodglucose<2.2mmol/L(40mg/dL))

Blood samples

• 0,30,45,60,90,120minsforbloodglucose,plasmacortisolandgrowthhormone

Results

• Normalsubjects:GH>6.7µg/L(20mU/L)*• Normalsubjects:cortisol>550nmol/L(∼20.2µg/dL)*

20.61 How and when to do an insulin tolerance test

hypo thyroidism, measuring TSH is not helpful in adjust-ing the replacement dose because patients with hypo-pituitarism often secrete glycoproteins which are measured in the TSH assays but are not bioactive. The aim is to maintain serum T4 in the upper part of the refer-ence range. It is dangerous to give thyroid replacement in adrenal insufficiency without first giving glucocorti-coid therapy, since this may precipitate adrenal crisis.

Sex hormone replacementThis 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. 1120).

Growth hormone replacementGrowth hormone (GH) is administered by daily subcu-taneous self-injection to children and adolescents with GH deficiency and, until recently, was discontinued once the epiphyses had fused. However, although hypo-pituitary adults receiving ‘full’ replacement with hydro-cortisone, 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 ratios 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 syn-drome. For this reason, GH replacement should be

EndocrinE disEasE

20

790

to a dopamine agonist with shrinkage of the lesion, making surgery unnecessary (see Fig. 20.28).

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. It is uncommon to be able to resect lateral extensions into the cavernous sinuses. All opera-tions 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 20.58, p. 787) 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 and, 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. 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 obliga-tory. 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 to be rare. Stereotactic radiosurgery, best delivered by the ‘gamma knife’, 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/galactorrhoeaHyperprolactinaemia is a common abnormality which usually presents with hypogonadism and/or galactor-rhoea (lactation in the absence of breastfeeding). Since

Surgery Radiotherapy Medical Comment

Non-functioning pituitary macroadenoma

1stline 2ndline –

Prolactinoma 2ndline 2ndline 1stlineDopamineagonists

Dopamineagonistsusuallycausemacroadenomastoshrink

Acromegaly 1stline 2ndline 2ndlineSomatostatinanaloguesDopamineagonistsGHreceptorantagonists

MedicaltherapydoesnotreliablycausemacroadenomastoshrinkRadiotherapyandmedicaltherapyareusedincombinationforinoperabletumours

Cushing’s disease 1stline 2ndline – Radiotherapymaybemoreeffectiveinchildrenthaninadultsandappearstocauselesshypopituitarisminthelong-term

Craniopharyngioma 1stline 2ndline –

20.62 Therapeutic modalities for hypothalamic and pituitary tumours

prolactin stimulates milk secretion but not breast devel-opment, galactorrhoea rarely occurs in men and only does so if gynaecomastia has been induced by hypo-gonadism (p. 760). The differential diagnosis of hyper-prolactinaemia is shown in Box 20.63. Many drugs, especially dopamine antagonists, elevate prolactin con-centrations. Pituitary tumours can cause hyperprolacti-naemia by directly secreting prolactin (prolactinomas, see below), or by compressing the infundibular stalk

Physiological

• Stress(e.g.post-seizure)• Pregnancy• Lactation• Nipplestimulation

• Sleep• Coitus• Exercise• Babycrying

Drug-induced

Dopamine antagonists• Antipsychotics

(phenothiazinesandbutyrophenones)

• Antidepressants

• Antiemetics(e.g.metoclopramide,domperidone)

Dopamine-depleting drugs• Reserpine • Methyldopa

Oestrogens• Oralcontraceptivepill

Pathological

Common• Disconnection

hyperprolactinaemia(e.g.non-functioningpituitarymacroadenoma)

• Prolactinoma(usuallymicroadenoma)

• Primaryhypothyroidism• Polycysticovarian

syndrome• Macroprolactinaemia

Uncommon• Pituitarytumoursecreting

prolactinandgrowthhormone

• Hypothalamicdisease• Renalfailure

Rare• Chestwallreflex(e.g.post-herpeszoster)

20.63 Causes of hyperprolactinaemia

The hypothalamus and the pituitary gland

20

791

Levels above 5000 mU/L are highly suggestive of a macroprolactinoma.

Patients with prolactin excess should have tests of gonadal function (p. 757), 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 20.58).

ManagementIf possible, the underlying cause should be corrected (for example, cessation of offending drugs and giving levo-thyroxine replacement in primary hypothyroidism). If dopamine antagonists are the cause, then dopamine agonist therapy is contraindicated, and if gonadal dys-function is the primary concern, sex steroid replacement therapy may be indicated. Troublesome physiological galactorrhoea can also be treated with dopamine ago-nists (see Box 20.64). 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 prolac-tinomas 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 mU/L. The investigation of prolactinomas is the same as for other pituitary tumours (see above).

ManagementAs shown in Box 20.62, several therapeutic modalities can be employed in the management of prolactinomas.

MedicalDopamine agonist drugs are first-line therapy for the majority of patients (Box 20.64). They usually reduce

and thus interrupting the tonic inhibitory effect of hypothalamic dopamine on prolactin secretion (‘discon-nection’ 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 macro-prolactinoma, a prolactin-secreting pituitary tumour of more than 1 cm in diameter). Since macropro-lactin cannot cross blood-vessel walls to reach prolactin receptors 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 hyperpro-lactinaemia. 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 assessmentIn women, in addition to galactorrhoea, hypogonadism associated with hyperprolactinaemia causes secondary amenorrhoea and anovulation with infertility (p. 759). 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. 760). Uni-lateral galactorrhoea may be confused with nipple dis-charge, and breast examination to exclude malignancy or fibrocystic disease is important. Further assessment should address the features in Figure 20.27 (p. 788).

InvestigationsPregnancy should first be excluded before further inves-tigations are performed in women of child-bearing potential. The upper limit of normal for many assays of serum prolactin is approximately 500 mU/L (14 ng/mL). In non-pregnant and non-lactating patients, monomeric prolactin concentrations of 500–1000 mU/L are likely to be induced by stress or drugs, and a repeat measure-ment is indicated. Levels between 1000 and 5000 mU/L are likely to be due to either drugs, or a micro-prolactinoma or ‘disconnection’ hyperprolactinaemia.

Oral dose* Advantages Disadvantages

Bromocriptine 2.5–15mg/day2–3timesdaily

AvailableforparenteraluseShorthalf-life;usefulintreatinginfertilityProvenlong-termefficacy

Ergotamine-likeside-effects(nausea,headache,posturalhypotension,constipation)FrequentdosingsopoorcomplianceRarereportsoffibroticreactionsinvarioustissues

Cabergoline 250–1000µg/week2doses/week

Long-acting,somisseddoseslessimportantReportedtohavefewerergotamine-likeside-effects

LimiteddataonsafetyinpregnancyAssociatedwithcardiacvalvularfibrosisinParkinson’sdisease

Quinagolide 50–150µg/dayOncedaily

Anon-ergotwithfewside-effectsinpatientsintolerantoftheabove

Untestedinpregnancy

*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.

20.64 Dopamine agonist therapy: drugs used to treat prolactinomas

EndocrinE disEasE

20

792

serum prolactin concentrations and cause significant tumour shrinkage after several months of therapy (Fig. 20.28), but visual field defects, if present, may improve within days of first administration. It is possible to with-draw dopamine agonist therapy without recurrence of hyperprolactinaemia after a few years of treatment in some patients with a microadenoma. Also, after the menopause, suppression of prolactin is only required in microadenomas if galactorrhoea is troublesome, since hypogonadism is then physiological and tumour growth unlikely. In patients with macroadenomas, drugs can only be withdrawn after curative surgery or radio-therapy 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 regurgita-tion, 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 screen-ing by echocardiography or use of non-ergot agents (quinagolide) may be indicated.

Surgery and radiotherapySurgical decompression is usually only necessary 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 not unusual; the cure rate for surgery in macroadenomas is substantially lower.

External irradiation may be required for some macro-adenomas to prevent regrowth if dopamine agonists are stopped.

PregnancyHyperprolactinaemia often presents with infertility, so dopamine agonist therapy may be followed by preg-nancy. Patients with microadenomas should be advised to withdraw dopamine agonist therapy as soon as preg-nancy 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) secre-tion from a pituitary tumour, usually a macroadenoma, and carries an approximate two-fold excess mortality when untreated.

Clinical featuresIf 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 20.29. The most common complaints are headache and sweating. Addi-tional features include those of any pituitary tumour (see Fig. 20.27, p. 788).

InvestigationsThe 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 mU/L). In acromegaly, GH does not suppress and in about 30% of patients there is a paradoxical rise; IGF-1 is also ele-vated. The rest of pituitary function should be investi-gated as described in Box 20.58 (p. 787). 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.

ManagementThe main aims are to improve symptoms and to normal-ise serum GH and IGF-1 to reduce morbidity and mor-tality. Treatment is summarised in Box 20.62.

SurgicalTrans-sphenoidal surgery is usually the first line of treat-ment 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.

Fig. 20.28  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

The hypothalamus and the pituitary gland

20

793

Fig. 20.29  Clinical features of acromegaly. (IGT = impaired glucose tolerance) 

Skull growth – prominentsupraorbital ridges with largefrontal sinuses

Prognathism(growth of lower jaw)

Enlargement of lips,nose and tongue

Headache

Hypertension

Increased sweating

CardiomyopathyCardiovascular disease

(2–3 × ↑)

Enlargement of liver

Thickened skin

IGT (25%)/type 2diabetes (10%)

Colonic cancer(2–3 × ↑)

Enlargement of handsArthropathy

Carpal tunnel syndrome

Myopathy

Enlargement of feetIncreased heel pad thickness

RadiotherapyExternal 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.

MedicalIf acromegaly persists after surgery, medical therapy is usually employed to lower GH levels to below 1.5 µg/L (below approximately 5 mU/L) and to normal-ise IGF-1 concentrations. Medical therapy may be dis-continued after several years in patients who have received radiotherapy. Somatostatin analogues (such as octreotide or lanreotide) 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. Pegvisomant is a peptide GH receptor antagonist admin-istered 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. 20.30). In young people, they are diagnosed more commonly than pituitary ade-nomas. They may present with pressure effects on adja-cent 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.

Craniopharyngiomas can be treated by the trans-sphenoidal route but surgery may also involve a crani-otomy, with a relatively high risk of hypothalamic damage and other complications. If the tumour has a large cystic component, it may be safer to place in the cyst cavity a drain which is attached to a subcutaneous access device, rather than attempt a resection. Whatever form it takes, surgery is unlikely to be curative and radiotherapy is usually given to reduce the risk of relapse. Unfortunately, craniopharyngiomas often recur, requiring repeated surgery. They often cause consider-able morbidity, usually from hypothalamic obesity, water balance problems and/or visual failure.

EndocrinE disEasE

20

794

insipidus may not be manifest until glucocorticoid replacement therapy is given. The most common dif-ferential diagnosis is primary polydipsia, caused by drinking excessive amounts of fluid in the absence of a defect in ADH or thirst control.

InvestigationsDiabetes insipidus can be confirmed if serum ADH is undetectable (although the assay for this is not widely available) or the urine is not maximally concentrated (i.e. is below 600 mOsm/kg) in the presence of increased plasma osmolality (i.e. greater than 300 mOsm/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 depri-vation test described in Box 20.66 is widely used, but an alternative is to infuse hypertonic (5%) saline and measure ADH 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 20.58, p. 787).

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 include plasma electrolytes, calcium and investigation of the renal tract (Chs 16 and 17).

ManagementTreatment of cranial diabetes insipidus is with des-amino-des-aspartate-arginine vasopressin (desmo-pressin, DDAVP), an analogue of ADH which has a

Diabetes insipidus

This uncommon disorder is characterised by the per-sistent 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 ADH by the hypothalamus• nephrogenic diabetes insipidus, in which the renal

tubules are unresponsive to ADH.The underlying causes are listed in Box 20.65.

Clinical featuresThe most marked symptoms are polyuria and polydip-sia. 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

Fig. 20.30  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

Cranial

Structural hypothalamic or high stalk lesion• SeeBox20.59

Idiopathic

Genetic defect• Dominant(AVPgenemutation)• Recessive(DIDMOADsyndrome–associationofdiabetes

insipiduswithdiabetesmellitus,opticatrophy,deafness)

Nephrogenic

Genetic defect• V2receptormutation• Aquaporin-2mutation

• Cystinosis

Metabolic abnormality• Hypokalaemia • Hypercalcaemia

Drug therapy• Lithium • Demeclocycline

Poisoning• Heavymetals

Chronic kidney disease• Polycystickidneydisease• Sickle-cellanaemia

• Infiltrativedisease

20.65 Causes of diabetes insipidus

Disorders affecting multiple endocrine glands

20

795

Use

• Toestablishadiagnosisofdiabetesinsipidusandtodifferentiatecranialfromnephrogeniccauses

Protocol

• Nocoffee,teaorsmokingonthetestday• Freefluidsuntil0730hrsonthemorningofthetest,but

discouragepatientsfrom‘stockingup’withextrafluidinanticipationoffluiddeprivation

• Nofluidsfrom0730hrs• Attendat0830hrsforbodyweight,plasmaandurine

osmolality• Recordbodyweight,urinevolume,urineandplasma

osmolalityandthirstscoreonavisualanaloguescaleevery2hrsforupto8hrs

• Stopthetestifthepatientloses3%ofbodyweight• Ifplasmaosmolalityreaches>300mOsm/kgandurine

osmolality<600mOsm/kg,thenadministerDDAVP(seetext)2µgIM

Interpretation

• Diabetesinsipidusisconfirmedbyaplasmaosmolality>300mOsm/kgwithaurineosmolality<600mOsm/kg

• Cranialdiabetesinsipidusisconfirmedifurineosmolalityrisesbyatleast50%afterDDAVP

• NephrogenicdiabetesinsipidusisconfirmedifDDAVPdoesnotconcentratetheurine

• Primarypolydipsiaissuggestedbylowplasmaosmolalityatthestartofthetest

20.66 How and when to do a water deprivation test

longer half-life. DDAVP is usually administered intra-nasally. An oral formulation is also available but bio-availability is low and rather unpredictable. In sick patients, DDAVP should be given by intramuscular injection. The dose of DDAVP should be adjusted on the basis of serum sodium concentrations and/or osmolal-ity. The principal hazard is excessive treatment, result-ing in water intoxication and hyponatraemia. Conversely, inadequate treatment results in thirst and polyuria. The ideal dose prevents nocturia but allows a degree of poly-uria 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. bendroflumethia-zide 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.

• Late presentation:oftenwithlargetumourscausingvisualdisturbance,becauseearlysymptomssuchasamenorrhoeaandsexualdysfunctiondonotoccurorarenotrecognised.

• Coincidentally discovered pituitary tumours:maynotrequiresurgicalinterventionifthevisualapparatusisnotinvolved,becauseofslowgrowth.Radiotherapyaloneissometimesemployedsimplytopreventfurthergrowth.

• Hyperprolactinaemia:lessimpactinpost-menopausalwomenwhoarealready‘physiologically’hypogonadal.Macroprolactinomas,however,requiretreatmentbecauseoftheirpotentialtocausemasseffects.

20.67 The pituitary and hypothalamus in old age

MEN 1 (Wermer’s syndrome)

• Primaryhyperparathyroidism• Pituitarytumours• Pancreaticneuro-endocrinetumours(insulinoma,gastrinoma)

MEN 2 (Sipple’s syndrome)

• Primaryhyperparathyroidism• Medullarycarcinomaofthyroid• Phaeochromocytoma

Inaddition,inMEN2bsyndrome,therearephenotypicchanges(includingmarfanoidhabitus,skeletalabnormalities,abnormaldentalenamel,multiplemucosalneuromas)

20.68 Multiple endocrine neoplasia (MEN) syndromes

The MEN syndromes should be considered in all patients with two or more endocrine tumours and in patients with solitary tumours who report other endo-crine tumours in their family. Inactivating mutations in MENIN, a tumour suppressor gene on chromosome 11, cause MEN 1, whereas MEN 2 is caused by gain-of-function mutations in the RET proto-oncogene on chro-mosome 10. These cause constitutive activation of the membrane-associated tyrosine kinase RET, which con-trols 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. 917). Genetic testing can be performed on relatives of affected individuals, after appropriate counselling (p. 67).

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, gastrointestinal hormones (see Box 20.54, p. 785) and prolactin; MRI of the pituitary and pancreas is per-formed at less frequent intervals. In individuals with MEN 2, annual history, examination and measurement of serum calcium and urinary catecholamine metabolites should be performed. Because the penetrance of medul-lary carcinoma of the thyroid is 100% in individuals with a RET mutation, prophylactic thyroidectomy should be performed in early childhood.

Autoimmune polyendocrine syndromes

Two distinct autoimmune polyendocrine syndromes are known: APS types 1 and 2.

DISORDERS AFFECTING MULTIPLE ENDOCRINE GLANDS

Multiple endocrine neoplasia

Multiple endocrine neoplasias (MEN) are rare auto-somal dominant syndromes characterised by hyperpla-sia and formation of adenomas or malignant tumours in multiple glands. They fall into two groups, as shown in Box 20.68. Some other genetic diseases also have an increased risk of endocrine tumours; for example, phaeochromocytoma is associated with von Hippel–Lindau syndrome (p. 1216) and neurofibromatosis type 1 (p. 1215).

EndocrinE disEasE

20

796

The most common is APS type 2 (Schmidt’s syn-drome), 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 20.69. The mode of inheritance is autosomal dominant with incomplete penetrance and there is a strong asso-ciation with HLA-DR3 and CTLA-4.

Much less common is APS type 1, which is also termed autoimmune poly-endocrinopathy-candidiasis-ectodermal 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 tol-erance (Ch. 4). The most common clinical features are described in Box 20.69, although the pattern of presenta-tion is variable and other autoimmune disorders are often observed.

*In both types of APS, the precise pattern of disease varies between affected individuals.

Type 1 (APECED)

• Addison’sdisease• Hypoparathyroidism• Type1diabetes• Primaryhypothyroidism

• Chronicmucocutaneouscandidiasis

• Naildystrophy• Dentalenamelhypoplasia

Type 2 (Schmidt’s syndrome)

• Addison’sdisease• Primaryhypothyroidism• Graves’disease• Perniciousanaemia• Primaryhypogonadism

• Type1diabetes• Vitiligo• Coeliacdisease• Myastheniagravis

20.69 Autoimmune polyendocrine syndromes (APS)*

Late effects of childhood cancer therapy

Prolonged survival is increasingly common following successful treatment of cancers in children and ado-lescents. The therapies used to treat these diseases, including radiotherapy and chemotherapy, may cause long-term endocrine dysfunction. In many circum-stances this is predictable, such as cytotoxic chemo-therapy causing future infertility and pubertal delay (especially in boys), cranial irradiation causing long-term pituitary dysfunction, and radiotherapy to the neck causing hypothyroidism and thyroid cancer. Increasing recognition of these issues has resulted in active moni-toring programmes for survivors of childhood cancer, who are best seen in specialist ‘late effects’ multidiscipli-nary clinics where teams include endocrinologists, oncologists, reproductive medicine specialists, psychol-ogists and nurse specialists.

Further information

Websiteswww.british-thyroid-association.org British Thyroid

Association: provider of guidelines, e.g. for use of thyroid function tests.

www.btf-thyroid.org British Thyroid Foundation: a resource for patient leaflets and support for patients with thyroid disorders.

www.endocrinology.org British Society for Endocrinology: useful online education resources and links to patient support group.

www.endo-society.org American Endocrine Society: provider of clinical practice guidelines.

www.pituitary.org.uk Pituitary Foundation: a resource for patient and general practitioner leaflets and further information.

www.thyroid.org American Thyroid Association: provider of clinical practice guidelines.