Diabetes mellitus is becoming a major public health problem. This is particularly true for type 2 diabetes, the prevalence of which is increasing rapidly due to the association with obesity and physical inactivity. Much of the morbidity, and cost, of diabetes care is due to the associated complications, rather than directly to hyperglycaemia and its management.

Thyroid disease and polycystic ovarian syndrome are also prevalent conditions. Most other endocrine disorders are uncommon, although of considerable clinical interest and often associated with a wide range of symptoms and signs. The increasing sophistication and availability of biochemical testing means that the final diagnosis and management of endocrine disorders is now almost entirely dependent on the measurement of the concentrations of either hormones themselves, or metabolites influenced by those hormones. As biochemical testing has become progressively more reliable and straightforward, an increasing number of patients with endocrine or metabolic disorders are now diagnosed at an early, often pre-symptomatic stage, e.g. early type 2 diabetes, subclinical thyroid dysfunction and mild hypercalcaemia due to hyperparathyroidism.





The classic triad of symptoms associated with diabetes mellitus consists of:

  • thirst
  • polyuria (often nocturia)
  • weight loss.

Many patients will also experience pruritus or balanitis, fatigue and blurred vision. Some people, particularly those with newly presenting type 1 diabetes mellitus (T1DM) or with marked hyperglycaemia in type 2 diabetes mellitus (T2DM), may have a ‘full house’ of symptoms, in which case it is generally not difficult to suspect the diagnosis. However, other patients, particularly those with only modestly elevated blood glucose concentrations in T2DM, will have fewer, milder symptoms, and some may be entirely asymptomatic. Note that symptoms potentially suggestive of diabetes may have alternative causes, particularly in elderly people, for example, frequency and nocturia in an older man may be due to bladder outflow obstruction, and many medical disorders are associated with weight loss.

The symptom complex of thirst, polydipsia and polyuria most commonly suggests a diagnosis of uncontrolled diabetes mellitus but can occur in other settings. Some patients taking diuretics will experience similar symptoms. A dry mouth, perhaps associated with drug usage (e.g. tricyclic antidepressants) or certain medical conditions (e.g. Sjögren’s syndrome), may lead to increased fluid intake in an attempt at symptom relief. In addition, there are other metabolic disorders which can interfere with the concentrating ability of the renal medulla and hence cause increased urine output with compensatory thirst. Such conditions include diabetes insipidus, hypercalcaemia, hypokalaemia and (on occasions) renal failure.

Weight loss is a symptom that always requires further evaluation as this may have a serious underlying cause. Some patients do not appear to notice or to report weight change, and it can be helpful to obtain objective evidence from prior weights recorded in hospital or their general practitioner’s (GP’s) notes. In some patients with weight loss, particularly those who are elderly, it can be difficult to be certain whether their diabetes has been sufficiently uncontrolled to account for this, or whether the weight loss may be due to a second diagnosis. A pragmatic trial of improved diabetes management may be required to see if the weight loss resolves.


The rest of the history

When seeing a patient presenting with symptoms of possible diabetes, or where this is being re-evaluated, you should also ask relevant questions to try to establish the following.

1. If the patient already has complications of diabetes


30–50 per cent of patients with newly diagnosed T2DM will already have tissue complications at diagnosis due to the prolonged period of antecedent moderate and asymptomatic hyperglycaemia.


Complications will not be present in patients with new and recently diagnosed T1DM, but may occur in all others. The complications of diabetes are broadly divided into:

  • microvascular complications (often diabetes specific)
  • macrovascular complications.

The most important microvascular complications are retinopathy, nephropathy and neuropathy. When taking a history, you should therefore ask about these complications and specifically about any changes to vision and about neuropathic symptoms.

The most common form of a diabetic neuropathy is a ‘glove and stocking’ distal sensory (or sensorimotor) neuropathy, although in practice the hands are rarely affected. Such a sensory neuropathy may be painless, but note that numbness is sometimes not noticed or reported by the patient and is first identified on examination. Some patients experience a symptomatic painful neuropathy with added sensations such as burning, shooting pains or paraesthesiae, characteristically worse at rest and particularly at night.

Other forms of neuropathy can occur in diabetes including a mononeuropathy (e.g. an isolated cranial or individual peripheral nerve palsy), and an autonomic neuropathy, most commonly manifest as impotence in men, but more rarely causing postural hypotension or a gastrointestinal motility disorder with vomiting and a disturbed bowel habit.

Your evaluation of a patient with diabetes is not complete without obtaining a history of hypertension and symptomatic macrovascular disease (Fig. 15.1):

  • cardiovascular disease (angina, myocardial infarction, heart failure, revascularization procedures)
  • cerebrovascular disease (transient ischaemic attack or stroke)
  • peripheral vascular disease (claudication, foot ulceration or amputation).

As a corollary to the above, when you see a patient presenting with clinical problems which may possibly be associated with diabetes, you should determine whether that patient has diabetes or not. For example, all patients with newly diagnosed cardio-, cerebro- or peripheral vascular disease should be assessed for diabetes.


2. The type and cause of diabetes (see later; this will include full past medical, drug and family histories)

3. The effect of diabetes, and of its management and complications, in the social history
Ask the patient how they look after their diabetes and how this affects their daily life. Diabetes management may affect functioning or occupation – patients on insulin in particular may have problems with hypoglycaemia, or adapting to shift working, and are restricted from certain occupations and holding a vocational driving licence. Complications such as reduced vision or foot ulceration will affect daily activities and quality of life.


Physical examination

Patients with established diabetes should have an annual review. This consists of:

  • measurement of blood pressure
  • funduscopy or retinal photography for retinopathy
  • assessment of visual acuity
  • a check of the integrity of foot pulses and sensation
  • a urine test for (micro-) albuminuria, the hallmark of diabetic nephropathy.

When examining the eye, check visual acuity first. Then dilate the pupils with tropicamide (or equivalent) eye drops as it is generally much easier to look for signs of retinal disease using an ophthalmoscope through a dilated rather than an undilated pupil. Ophthalmoscopy takes a lot of practice to become competent.

First look for lens opacities. Then focus on the optic disc. Subsequently follow each of the superior and inferior temporal and nasal vascular arcades out to the periphery and back again to the disc. Finally, inspect the macula by asking the patient to look directly into the ophthalmoscope; if the patient finds the light painfully bright, reduce its intensity.

The signs and classification of retinopathy depend on the stage of the disease (Table 15.1, Fig. 15.2). Maculopathy is defined as any changes occurring within one optic disc diameter of the fovea. You may also see signs of previous laser therapy for retinopathy (Fig. 15.3).





Examine the foot, first looking for signs of ulceration, infection or deformity (Figs 15.4 and 15.5). Any deformity such as a prominent bunion or metatarsal heads, claw toes, a prior minor amputation or Charcot’s foot is a risk factor for subsequent ulceration. Thick callus can accumulate at pressure points and erode the underlying healthy skin.




Next, assess for peripheral vascular disease by palpating for the dorsalis pedis and tibialis anterior foot pulses – if these are absent or difficult to find, check for the popliteal and femoral pulses and listen for a femoral bruit.

Finally check for neuropathy by testing sensation and the ankle reflex. Look in particular for a ‘sock’ distribution of sensory loss; if there is loss of sensation in the feet, examine the hands as well.

There are frequently no abnormalities on physical examination in patients with T1DM, particularly those who are younger or who do not have long-standing disease. Those who have had T1DM for more than a few years and all of those with T2DM (even from first diagnosis) may have tissue complications of diabetes identified at annual review, and there may therefore be additional signs of cardiovascular or cerebrovascular disease.



Patients with a new diagnosis of what is apparently T2DM should have a full general examination as, occasionally, the diabetes may be the presenting feature of (but secondary to) another disorder e.g. acromegaly, haemochromatosis or Cushing’s syndrome.


The diagnosis of diabetes mellitus rests solely on laboratory blood glucose concentrations (see below). Further investigations may be required in occasional patients in whom it is thought that the diabetes may be secondary to another medical disorder. Tests essential in the further evaluation and longer-term assessment of patients with diabetes are:

  • HbA1c – as a marker of longer-term glycaemic control
  • serum lipid profile
  • urea, electrolytes and creatinine – as indicators of renal function (now generally converted to estimated glomerular filtration rate, eGFR)
  • liver function tests – in view of the association with non-alcoholic fatty liver disease (NAFLD).

Diagnosis and classification of diabetes mellitus

Diabetes mellitus is formally diagnosed solely using laboratory blood glucose tests. The presence of glycosuria, a raised HbA1c and elevated capillary blood glucose meter readings raise the possibility of diabetes but are insufficient for diagnosis.

In the great majority of patients, diabetes is diagnosed on the basis of symptoms and a random venous plasma glucose concentration above 11.1mmol/L. Other patients may require a fasting blood glucose or a 75g oral glucose tolerance test (OGTT), which is performed the morning after an overnight fast of 8–14 hours (water is permitted). After a baseline blood sample is taken for a venous plasma glucose level, an adult patient is given 75 g glucose in 300 mL water to drink over 5 minutes. A further blood sample is taken after 2 hours. Table 15.2 provides guidance on interpretation of the results of an OGTT.

Just one abnormal blood test is needed to make the diagnosis in patients with typical symptoms of diabetes, with two abnormal results required in those who are asymptomatic. The categories impaired glucose tolerance (IGT) and impaired fasting glycaemia (IFG) are defined as there is a significant rate of progression to T2DM. Impaired glucose tolerance in particular is associated with a considerably increased risk of macrovascular disease, almost to the degree seen in T2DM. The scheme for diagnosing diabetes is not entirely intuitive. It is, for instance, possible to have both IFG and IGT. In addition, a fasting plasma glucose consistent with IFG or even in the normal range does not fully exclude a possible diagnosis of diabetes.



Blood glucose meters are accurate enough for monitoring but should never be relied upon without laboratory back-up either for diagnosis or for evaluating patients who are unwell with decompensated diabetes (ketoacidosis or hyperosmolar state), or with reduced consciousness due to possible hypoglycaemia.


The blood glucose concentration at diagnosis is not useful as a guide to whether an individual patient has T1DM or T2DM. Patients with T1DM can be in severe ketoacidosis with a blood glucose less than 20mmol/L, and even below 10mmol/L on occasions, whereas T2DM can present with a hyperosmolar state with blood glucose levels over 50 mmol/L.

Diabetes mellitus is not a single disorder. In the UK, 85–90 per cent of patients will have T2DM (formerly non-insulin-dependent diabetes, NIDDM) and the majority of the remainder will have T1DM (formerly insulin-dependent diabetes, IDDM). It is important to make this distinction, as initial management from diagnosis is so different. Table 15.3 lists clinical features that are useful in distinguishing T1DM from T2DM, and many patients will clearly fit one or other pattern. In a small number of patients, it is not always possible to be certain whether they have T1DM or T2DM at the time of diagnosis. In particular, although age is a pointer to diabetes type, it is far from an absolute discriminator, as T2DM is now prevalent in obese younger people, even teenagers, and T1DM can occur in elderly people.



In addition to T1DM and T2DM, there is a small number of patients in whom diabetes can be monogenic, part of another disease or syndrome, secondary to another condition, drug-induced or due to primary disease of the exocrine pancreas. The classification of diabetes is summarized in Table 15.4 (note: only selected, more common ‘other’ causes of diabetes are given).




In normal physiology, a fall in blood glucose concentration below normal causes a reduction in endogenous insulin production and a counter-regulatory response with the release of glucagon, adrenaline, cortisol and growth hormone. There is also autonomic activation which, together with the increase in circulating adrenaline induces a variety of symptoms including:

  • anxiety
  • palpitations
  • tremor
  • sweating
  • hunger.

Many patients with diabetes recognize these symptoms as a ‘warning’ and know that they need to take additional carbohydrate to restore their blood glucose concentration. If warning symptoms are delayed, absent, not recognized or not acted on, progressive hypoglycaemia will lead to neuroglycopenia, with a variety of symptoms such as blurred or double vision, loss of concentration and difficulty word finding. A further fall in blood glucose will cause a reduction in conscious level and eventually fitting and/or coma.

It is generally not difficult to suspect an episode of hypoglycaemia in patients who are known to have diabetes, particularly if they are being treated with insulin or sulphonylureas. Significant hypoglycaemia not associated with diabetes is much more difficult to recognize. Hypoglycaemia should be considered in all patients who present with symptoms suggestive of intermittent sympatho-adrenal activation and/or neuroglycopenia (as described above) whether or not they are known to have diabetes.



Spontaneous hypoglycaemia, although clinically very significant, is rare.



Diabetes mellitus is much more than a disorder of glucose metabolism. The complications of diabetes can affect many of the organ systems leading to associated cardiac, vascular, renal, retinal, neurological and other disorders. The satisfactory evaluation and management of a patient with diabetes requires knowledge of the wider manifestations of the condition and an understanding of its impact on the individual as a whole.



Thyroid disease generally presents either as an endocrine disorder and/or as a thyroid swelling (nodule or goitre).

Thyroid dysfunction

There are two serum thyroid hormones. Both the total and free (non-protein bound) concentrations of thyroxine (T4) are higher than those of the more biologically active tri-iodothyronine (T3). The serum thyroid hormone concentrations determine the rate of metabolism. Thyroid-stimulating hormone (TSH) derives from the pituitary gland and, due to negative feedback, is generally suppressed in thyroid overactivity and increased in underactivity. In normal health, the serum levels of TSH, T4 and T3 show little diurnal or seasonal variation.

  • Thyrotoxicosis denotes any excess of thyroid hormones, whereas hyperthyroidism refers more specifically to overactivity of the thyroid gland per se.
  • Hypothyroidism denotes thyroid underactivity, and the term myxoedema is generally only used to describe clinically severe hypothyroidism.

The clinical features associated with thyroid over- and underactivity are fairly predictable and opposite.

Presenting symptoms

The principal and contrasting presenting symptoms of hyper- and hypothyroidism are given in Table 15.5.



Some patients with marked thyroid dysfunction will present with a ‘full house’ of clinical symptoms. However many patients will have only some, or less severe, symptoms. In addition, others may have some symptoms that are apparently paradoxical; in particular, on occasions, patients with thyroid overactivity can present with weight gain, rather than weight loss, if the increase in appetite is greater than that in the metabolic rate. Conversely, some elderly patients may have so-called ‘apathetic’ thyrotoxicosis, superficially more resembling hypothyroidism. Hypothyroidism, particularly if prolonged or severe, can on occasions cause additional clinical features. Nerve entrapment can result in carpal tunnel syndrome and pleural or pericardial effusions occasionally occur.

There is naturally a degree of correlation between the severity of symptoms in thyroid dysfunction and the degree of biochemical disturbance. However, some patients can become quite unwell with relatively minor changes in biochemistry, whereas others with gross biochemical disturbance may be relatively asymptomatic.

The descriptions hyper- and hypothyroidism do not provide a full diagnosis. Thyrotoxicosis, in particular, has several potential causes, the most common being:

  • autoimmune Graves’ disease
  • toxic multinodular goitre
  • thyroid adenoma
  • viral thyroiditis
  • post-partum thyroiditis
  • drug-associated – such as amiodarone.



Rarely, severe prolonged hypothyroidism can result in myxoedema coma presenting with inanition (lack of energy), hypothermia and a reduced conscious level due to a grossly suppressed metabolism.



Try to establish the aetiology of thyrotoxicosis, as this determines the natural history of the condition and also influences clinical management.


When undertaking an evaluation of a patient with thyroid disease, you should therefore not only elicit symptoms and signs directly related to thyroid dysfunction, but also seek for pointers towards the underlying cause (see Table 15.6). It is often helpful to ask about the duration of symptoms. The clinical severity of Graves’ disease in particular often changes with time and, in retrospect, patients may recall episodes months or even years previously where they had transient symptoms. By contrast, nodular thyroid disease is often fairly mild and more stable over time.



Remainder of the history

Thyrotoxicosis associated with a painful goitre strongly suggests a diagnosis of viral (de Quervain’s) thyroiditis. Graves’ disease is autoimmune in origin, and so if you suspect Graves’ disease, find out whether the patient has any associated autoimmune disease or whether any close relative is affected.

Hyper- or hypothyroidism first occurring within about 6 months of pregnancy is suggestive of postpartum thyroiditis, which is often self-limiting. A few drugs can cause thyroid dysfunction, most notably amiodarone (both hyperand hypothyroidism) and lithium, which causes hypothyroidism.

Some patients with Graves’ disease develop an associated eye problem variously described as thyroid eye disease (TED), Graves’ ophthalmopathy, or thyroid associated ophthalmopathy (TAO). Patients may describe a discomfort in their eyes, a bulging or prominent appearance, puffiness or swelling around the eyes, double vision or, very rarely, visual loss.



The severity of thyroid dysfunction and of thyroid-associated ophthalmopathy (TAO) may not follow a parallel course; TAO can first occur some time after thyrotoxicosis appears or be the initial feature of Graves’ disease occurring with normal thyroid function tests or even hypothyroidism.


Physical examination

Patients with thyrotoxicosis from any cause will often have signs compatible with the symptoms described above including:

  • tachycardia (irregular pulse if in atrial fibrillation) with increased pulse volume
  • finger tremor
  • warm and sweaty skin
  • brisk tendon reflexes
  • weight loss.

Rarely, patients with severe thyroid overactivity may be in heart failure. By contrast, those with hypothyroidism may have:

  • bradycardia with cool dry skin
  • slowly relaxing tendon reflexes
  • weight gain.

However, there may be no significant physical signs, particularly if the biochemical derangement is mild. All patients with thyroid dysfunction, and also those presenting with a neck swelling in the region of the thyroid, should be examined for the presence of a goitre or nodule. Examine the thyroid by standing behind the seated patient (Fig. 15.6). Place your thumbs behind the patient’s neck and rest the tips of your ring fingers on the ends of the patient’s clavicles. Use the index and middle fingers of each hand to palpate the thyroid.



  • If a goitre is present, note whether the gland is generally enlarged (both lobes and isthmus).
  • Is the gland tender (uncommon) and does it appear smooth or nodular?
  • Is there an abnormal consistency – is this hard (rare) or rubbery, suggestive of Hashimoto’s disease in hypothyroidism?
  • Ask the patient to swallow some water. A normal gland moves upwards on swallowing, but if tethered to surrounding structures, suspect a malignancy.
  • Assuming the gland does move up on swallowing, feel for the trachea in the suprasternal notch below it – if this is impalpable, the gland has a retrosternal extension and may cause tracheal compression.
  • Are the cervical lymph nodes enlarged?
  • Finally, in a thyrotoxic patient listen with a stethoscope over the goitre for a bruit, which is virtually diagnostic of Graves’ disease.

Common causes of a thyroid swelling and their clinical characteristics are given in Table 15.7.



Patients with thyrotoxicosis of any cause may have lid retraction and/or lid lag. The thyroid overactivity causes contraction of the levator palpebrae superioris, which has some sympathetic innervation, The upper lid may therefore retract sufficiently to expose an arc of white cornea above the upper border of the iris, producing a ‘staring’ appearance. This effect may be further demonstrated by eliciting ‘lid lag’. Gently hold the patient’s chin to keep the head steady, place your other hand above the eyeline so that the patient needs to look upwards. Then ask the patient to follow your hand, using their eyes only, as you lower this below the horizontal over a period of 3 seconds or so. In thyroid overactivity, movement of the upper lid may lag behind that of the eye, transiently exposing the cornea above the upper border of the iris.

Only patients with Graves’ disease develop additional symptoms and signs of TAO. Unequivocal changes of TAO, if present, are therefore diagnostic of Graves’ disease. TAO can result a variety of signs, which should be determined. The most common sign, which can be difficult to ascertain clinically, is proptosis, where the eyeball is pushed forward by retro-orbital inflammatory tissue. Patients with proptosis will have a staring appearance, but this should not be confused with simple lid retraction. Forward protrusion of the eye in proptosis may lead to exposure of the cornea below the lower arc of the iris, as well as above the upper border. True proptosis may also be recognized by prominence of the eyeballs when looking down from above the patient’s head.

The patient may also have periorbital oedema (see below) and abnormalities of movement of extraocular muscles which patients may describe as ‘double vision’; look for disconjugate gaze on examining eye movements (see examination of cranial nerves, Chapter 12). Rarely, TAO can lead to loss of vision through compression of the optic nerve, so check visual acuity. In severe proptosis, corneal exposure can lead to scarring – check that patients can voluntarily close their eyes fully.

It is important to assess for all features of TAO. Some patients have:

  • marked periorbital oedema, which causes a striking change in facial appearance and considerable distress, but is not medically serious
  • visual loss due to optic nerve compression without other apparent signs of TAO
  • changes which may be asymmetrical and occasionally even unilateral.

Full evaluation of TAO can be difficult and should be left to the expert, once it has been identified.



Occasional patients with Graves’ disease and TAO may have a thickening of the skin over the shin (pretibial myxoedema) and other areas and, very rarely, thyroid acropachy, with clubbing and pain and swelling in the hands and wrists due to periosteal new bone formation.




Adrenal cortex


Cushing’s syndrome

The term Cushing’s syndrome refers to the clinical state associated with excess endogenous cortisol production from any cause. Cushing’s disease refers specifically to cortisol overproduction secondary to excessive adrenocorticotropic hormone (ACTH) release from a pituitary adenoma, and excludes the other causes of Cushing’s syndrome, namely ectopic ACTH production and autonomous adrenocortical overactivity. The term ‘cushingoid’ variously refers to patients with clinical features resembling Cushing’s syndrome, either resulting from chronic exogenous corticosteroid use or spontaneously without biochemical disturbance.

The major clinical features of Cushing’s syndrome include:

  • increased and redistributed adiposity with loss of muscle bulk (myopathy), leading to a typical general appearance with central obesity, thin limbs (a ‘lemon on matchstick’ appearance), a moon face and a ‘buffalo’ hump due to expansion of the interscapular fat deposits. The myopathy may cause considerable weakness, such that the patient cannot easily get out of a low chair or a bath, and not be able to rise from a squatting position – a useful, simple clinical test for a proximal myopathy
  • loss of subcutaneous connective tissue leading to thin skin and easy bruising, and also to abdominal striae, which are typically purple
  • hyperandrogenism, which in women may lead to acne, hirsutes, frontal balding and amenorrhoea
  • systemic effects including hypertension and glucose intolerance
  • psychological effects (common) such as mood changes and depression.
  • Cushing’s syndrome can be difficult to recognize and diagnose because some of the associated clinical features are very common but the syndrome itself is rare. Hypertension, obesity, T2DM and hirsutes occur frequently, individually and collectively; it would be almost impossible to screen patients with these features alone for steroid overproduction as very few will have Cushing’s syndrome.



Select patients for screening for possible Cushing’s syndrome on the basis of more discriminatory clinical features including osteoporosis, myopathy, purple abdominal striae, thin skin and easy bruising.


Patients thought likely to have Cushing’s syndrome on clinical grounds should first be investigated with biochemical screening tests. The two tests most commonly used are:

  • overnight dexamethasone test – serum cortisol taken at 9am will not be suppressed by dexamethasone
  • 24-hour urinary collection for free cortisol.

Patients who have abnormal results on screening tests should be referred to a specialist endocrinologist for further confirmatory tests and investigation of the cause of the Cushing’s syndrome because the interpretation of these tests is fraught with difficulties and pitfalls.



Addison’s disease

Underproduction of corticosteroids can occur either as a result of failure of the adrenal glands (primary adrenocortical insufficiency, Addison’s disease), or secondary to pituitary failure.

Addison’s disease is rare, and the diagnosis is often delayed. Patients with marked primary adrenocortical insufficiency may have a classic collection of clinical features including:

  • weight loss
  • fatigue
  • weakness
  • dizziness on standing (due to postural hypotension)
  • brown skin pigmentation.

Pigmentation extends to areas not exposed to the sun and is often particularly marked in natural skin creases, established scars and inside the cheeks. Patients may also present with or describe episodes of extreme lethargy, abdominal pain, vomiting and hypotension, a so-called ‘addisonian crisis’, which can be fatal if not recognized and appropriately treated.

Patients with severe Addison’s disease, and particularly those in a crisis, will typically have hyponatraemia, hyperkalaemia and a raised serum urea due to dehydration, although electrolytes can be normal in early or mild disease. The short synacthen test, showing a subnormal stimulated serum cortisol concentration, is the ‘gold standard’ diagnostic investigation.



Other adrenal cortex disorders

  • Conn’s syndrome results from primary overproduction of aldosterone. It is an uncommon cause of hypertension, often in association with hypokalaemia, although the latter is generally not severe enough to cause symptomatic muscular weakness.
  • Excess androgen production – see hirsutes.


Adrenal medulla



Phaeochromocytoma is a disorder of the adrenal medulla or the sympathetic chain where there is overproduction and release of excess catecholamines. It is a cause of secondary hypertension, and may be suspected when there are additional associated features resulting from the variable catecholamine release, including:

  • fluctuating and sometimes severe hypertension
  • headache
  • fainting (from postural hypotension)
  • sweating
  • anxiety.



The commonest cause of pituitary gland dysfunction is an adenoma in the anterior part of the gland, but other disorders in adjacent structures (parapituitary lesions) can lead to a similar presentation. Pituitary disease is generally manifest as clinical problems associated with one or more of:

  • pituitary hormone overproduction
  • pituitary underfunction (hypopituitarism)
  • pressure effects from a large adenoma on other local structures.


Pituitary hormone overproduction



In premenopausal women, an increase in serum prolactin causes oligo- or amenorrhoea, infertility and galactorrhoea. An elevated serum prolactin concentration is most commonly due to a prolactinoma, but there are other causes, including pregnancy, breastfeeding, primary hypothyroidism and certain drugs. In men, a raised serum prolactin may or may not cause symptoms associated with hypogonadism, and there are usually no endocrine effects in older women. Prolactinomas in men and older women therefore usually present with pituitary gland failure or with local pressure effects from a large pituitary adenoma rather than with the endocrine manifestations of hyperprolactinaemia.


Acromegaly (literally ‘large extremities’) is due to excess growth hormone production from a pituitary adenoma. This results in a striking clinical syndrome with numerous manifestations. The most obvious changes are an alteration in appearance with enlarged supra-orbital ridges, deepened nasolabial folds, a prominent jaw and a ‘coarse’ facies (Fig. 15.7). The teeth become wide-spaced and there may be mandibular prognathism with the teeth in the lower jaw protruding in front of those in the upper jaw, leading to problems with occlusion, with either natural or artificial teeth. The hands and feet are broad, the former being described as ‘spade-like’ (Fig. 15.8), and patients may describe a change in ring or shoe size. The skin is thick and greasy. Patients also variously develop arthopathies, entrapment neuropathies (e.g. carpal tunnel syndrome), hypertension, glucose intolerance or diabetes and heart failure.



The change in appearance, although often eventually quite striking, is very gradual in onset, and it is not unusual for the diagnosis to be first suspected by a new GP, dentist or even medical student meeting the patient for the first time. Some people have constitutional physical features resembling acromegaly, for whom the term ‘acromegaloid’ is sometimes used. Biochemical confirmation of the diagnosis of acromegaly is made where there is failure of near complete suppression of serum growth hormone levels during a glucose tolerance test.

Cushing’s disease

See earlier in the chapter.


Pituitary underfunction (hypopituitarism)

Anterior pituitary gland failure leads to clinical features resulting from a combination of one or more of secondary adrenocortical, thyroid and gonadal dysfunction. Growth hormone deficiency may also occur and is the probable cause of the characteristically associated finely wrinkled skin. It is not difficult to identify patients with pituitary gland failure when they present with gonadal dysfunction (e.g. amenorrhoea, infertility or impotence) as, on testing, the relevant sex hormone (oestradiol or testosterone) concentration is reduced with low or inappropriately normal gonadotrophin (luteinizing hormone (LH) and follicle-stimulating hormone (FSH)) concentrations. However, other patients may present more insidiously with less definite symptoms such as fatigue, weakness, weight loss and faintness, and there may be little in the way of physical signs other than pale skin, conjunctival pallor due to anaemia and, in men, reduced facial and body hair growth. The diagnosis of hypopituitarism is consequently often delayed.


Pressure effects

A large pituitary adenoma or other para-pituitary lesion can cause and sometimes present with pressure effects on local structures with or without endocrine effects. The classic presentation is with a bitemporal hemianopia (loss of the temporal visual field in both eyes; Fig. 15.9), as a pituitary adenoma extends upwards to compress the optic chiasm. The visual field loss can be minor or extensive and, at a late stage, there can be loss of visual acuity or even blindness. Lateral extension of a pituitary or parapituitary lesion may cause pressure on one or more of the oculomotor nerves (cranial nerves III, IV, VI), and so patients may describe diplopia, and there may be abnormalities of eye movements on clinical testing.



All patients with known or suspected pituitary disease should have a clinical assessment of visual acuity, visual fields by confrontation, and of eye movements. These clinical tests should be backed up with a formal visual field test and with magnetic resonance imaging (preferred) or computed tomography.


Diabetes insipidus

Diabetes insipidus results from a deficiency in antidiuretic hormone (ADH) produced in the posterior lobe of the pituitary gland. It can occur either as an isolated condition or in association with, generally severe, anterior pituitary or para-pituitary disease. Classic presenting symptoms are thirst and polyuria (cf diabetes mellitus). The diagnosis is made by documenting a high urine volume output (generally exceeding 3 L/day), then excluding other potential causes for this, and finally establishing an inappropriately low urine concentration (osmolality) in the presence of a high serum osmolality during a water deprivation test.



Increased availability of hormone testing means that many patients are referred to endocrinologists with the diagnosis already made or suspected. Other patients are sometimes referred with one or more of a series of symptoms for evaluation which may or may not have an endocrine cause, such as those described below.


As a solitary complaint in the absence of other symptoms, weight change or abnormalities on physical examination, it is unusual to find a definite organic cause for fatigue. However, consider anaemia, thyroid dysfunction, Addison’s disease and hypopituitarism. A diagnosis of chronic fatigue syndrome should only be considered after reasonably excluding other possible medical conditions.


It is not uncommon for patients to self-diagnose ‘hypoglycaemia’ on the basis of intermittent symptoms of, for example, fatigue, weakness or tremor, particularly if the complaints appear to improve after ingesting carbohydrate. Home capillary blood glucose meter readings can be misleading and are not sufficiently accurate or reliable enough to diagnose spontaneous hypoglycaemia. Genuine fasting hypoglycaemia therefore needs to be established by laboratory testing but is rare. Endocrine causes include insulinoma, Addison’s disease and hypopituitarism, and also consider liver failure.


It is unusual to find a definite underlying medical cause in the absence of other symptoms and signs. Sweating can occur as a side effect of medication and also obesity. Endocrine causes include thyrotoxicosis, acromegaly and phaeochromocytoma.

Collapse/altered consciousness/funny turns

Such symptoms are much more likely to be due to cardiovascular or neurological disorders than endocrine disease, but consider hypoglycaemia, Addison’s disease, hypopituitarism and phaeochromocytoma.


Endocrine disorders are well recognized as important causes of secondary hypertension. Consider Conn’s syndrome (hypokalaemia), Cushing’s syndrome (somatic features) and phaeochromocytoma (additional symptoms – see above).


Excess hair growth in women is a common presenting complaint. Look for other evidence of hyperandrogenism such as acne and frontal balding, and also signs of virilization, which suggests the presence of grossly elevated androgen levels. Polycystic ovarian syndrome is very common, and is also associated with amenorrhoea/oligomenorrhoea and infertility. Congenital adrenal hyperplasia, Cushing’s syndrome and adrenal and ovarian androgen secreting tumours are all rarer causes of hirsutes. In many women, there is no clear underlying pathology – so-called ‘idiopathic’ hirsutes.


Weight gain and obesity rarely have a definable and treatable underlying endocrine disorder. Hypothyroidism is associated with weight gain, but this is often relatively modest. There will generally be additional clinical features in weight gain due to Cushing’s syndrome.



  • The diagnosis of diabetes mellitus can only be made on the basis of laboratory blood glucose measurements.
  • In most patients, diabetes mellitus is diagnosed with a random blood glucose concentration exceeding 11.1 mmol/L in the presence of typical symptoms, but pre-symptomatic diabetes is also common.
  • It is usually (but not invariably) possible to distinguish between T1DM and T2DM on initial presentation.
  • There is a high prevalence of vascular disease in patients with diabetes mellitus.
  • All patients with diabetes mellitus should have an annual review including screening for associated retinal, renal and foot complications.
  • Thyrotoxicosis is not an adequate diagnosis – try to establish the aetiology.
  • The clinical severity of thyroid dysfunction and associated ophthalmopathy often do not run in parallel in Graves’ disease.
  • Diabetes, hypertension, obesity and hirsutes are common – use more discriminatory clinical features to select patients for biochemical screening for Cushing’s syndrome.
  • Hypopituitarism can present insidiously.
  • Obesity and fatigue, as isolated symptoms, rarely have an endocrine cause.


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SA Bos, M.D.

Lead Author