Treatment method	Advantages	Disadvantages
Surgical
Trans-sphenoidal adenomectomy or hypophysectomy	Relatively minor procedure Potentially curative for micro- and smaller macro-adenomas	Some extrasellar extensions may not be accessible Risk of CSF leakage and meningitis
Trans-frontal	Good access to suprasellar region	Major procedure; danger of frontal lobe damage High chance of subsequent hypopituitarism
Radiotherapy
External (40–50 Gy)	Non-invasive Reduces recurrence rate after surgery	Slow action, often over many years Not always effective Possible late risk of tumour induction
Stereotactic	Precise administration of dose to lesion	Long-term follow-up data limited
Yttrium implantation	High local dose	Only used in few centres
Medical
Dopamine agonist (e.g. bromocriptine)	Non-invasive; reversible	Usually not curative; significant side-effects in minority
Somatostatin analogue (octreotide)	Non-invasive; reversible	Usually not curative; expensive
Growth hormone receptor antagonist (pegvisomant)	Highly selective	Usually not curative; very expensive

Hypopituitarism

Compression of the pituitary gland by a mass lesion results in progressive loss of function. Growth hormone and gonadotrophins are usually the first hormones to be affected, followed by TSH and finally ACTH (panhypopituitarism). Prolactin levels may rise due to compression of the pituitary stalk and loss of dopaminergic inhibitory control.

Clinical features

Secondary hypothyroidism (p. 571) and adrenal failure (p. 582) both lead to tiredness and general malaise:

• Hypothyroidism causes slowness of thought and action, dry skin and cold intolerance.

• Hypoadrenalism causes mild hypotension, hyponatraemia and ultimately cardiovascular collapse during severe intercurrent stressful illness.

• Gonadotrophin deficiency causes loss of libido, loss of secondary sexual hair, amenorrhoea and impotence.

• Hyperprolactinaemia causes galactorrhoea and hypogonadism.

Examination

• Fundoscopy (with dilatation) and visual acuity testing are carried out to exclude optic atrophy, retinal vein engorgement and papilloedema associated with expansion of a tumour mass.

• Visual field assessment, by formal perimetry or by confrontation using a red pin, is used to assess for optic chiasmal compression causing bitemporal hemianopia.

Investigation of pituitary function

Axis	Usual replacement therapies
Adrenal	Hydrocortisone 15–40 mg daily (starting dose 10 mg on rising/5 mg lunchtime/5 mg evening) (Normally no need for mineralocorticoid replacement)
Thyroid	Levothyroxine 100–150 mcg daily
Gonadal
Male	Testosterone IM, orally, transdermally or implant
Female	Cyclical oestrogen/progestogen orally or as patch
Fertility	HCG plus FSH (purified or recombinant) or pulsatile GnRH to produce testicular development, spermatogenesis or ovulation
Growth	Recombinant human growth hormone used routinely to achieve normal growth in children Also advocated for replacement therapy in adults where growth hormone has effects on muscle mass and well-being
Thirst	Desmopressin 10–20 mcg 1–3 times daily by nasal spray or orally 100–200 mcg 3 times daily Carbamazepine, thiazides and chlorpropamide are very occasionally used in mild diabetes insipidus
Breast (prolactin inhibition)	Dopamine agonist (e.g. cabergoline 500 mcg weekly)

FSH, follicle-stimulating hormone; GnRH, gonadotrophin-releasing hormone; HCG, human chorionic gonadotrophin.

Thyroid disorders

The thyroid hormones, T₄ and T₃, are produced within the thyroid gland. Synthesis and release are stimulated by TSH, which is released from the pituitary gland in response to the hypothalamic factor, TRH (thyrotrophin-releasing hormone) (Fig. 15.1). Predominantly, T₄ is produced, but this is converted in the peripheral tissues (liver, kidney, muscle) to the more active T₃. More than 99% of T₄ and T₃ circulate bound to plasma proteins, mainly thyroid-binding globulin (TBG).

Fig. 15.1 The hypothalamic–pituitary–thyroid axis. TRH, thyrotrophin-releasing hormone; TSH, thyroid-stimulating hormone.

Diagnosis of thyroid disease includes the clinical features, together with measurement of plasma TSH and thyroid hormones T₄ and T₃.

Thyroid function tests

• Measurement of plasma TSH is the single most useful assessment of thyroid function, even for the detection of mild disease. Levels will increase in response to falling levels of circulating active thyroid hormones and fall with high levels of thyroid hormone. Exceptions include pituitary disease and ‘sick euthyroid syndrome’, in which TSH may be low without hyperthyroidism.

• Measurement of plasma free T₄ and free T₃, along with TSH, has simplified the interpretation of thyroid function tests.

• Accurate diagnosis requires two tests, e.g.:

• TSH plus free T₄ or free T₃ for suspected hyperthyroidism

• TSH plus free T₄ for hypothyroidism.

Problems in interpreting thyroid function tests

• Serious acute or chronic illness. Failure of conversion of T₄ to T₃ (in favour of reverse T₃) causes a reduction in hypothalamic–pituitary production of TSH, resulting in low/normal measurements of all factors.

• Pregnancy or oral contraceptive use. Increased levels of TBG lead to higher levels of total T₄ and T₃. Levels of free hormone are unaffected. The TSH can be low.

• Heterophile antibodies. These interfere with assay measurements of hormone levels and lead to bizarre thyroid function tests that have no obvious clinical explanation. The laboratory should be able to confirm this with additional testing.

• Amiodarone. This prevents generation of T₃ from T₄, resulting in an increase in T₄ levels. Tissue perception of this is of ‘reduced’ active T₃ levels, and TSH levels may therefore increase. Amiodarone also provides a significant iodine load, up to 100 times the daily recommended amount. This can have two effects on thyroid function. The iodine load can:

• precipitate thyrotoxicosis by unmasking subclinical hyperthyroidism in an iodine-deplete individual (amiodarone-induced thyrotoxicosis type 1) or

• precipitate hypothyroidism due to blockade of intrathyroidal hormone production from excess iodine.

Alternatively, amiodarone results in a destructive thyroiditis with the release of thyroid hormone (amiodarone-induced thyrotoxicosis type 2).

Treatment

While amiodarone-induced hypothyroidism is relatively straightforward to treat, with thyroxine, hyperthyroidism is more difficult. The destructive thyroiditis is best managed with prednisolone 40 mg/day, while type 1 hyperthyroidism is best managed with antithyroid drugs. In practice it can be difficult to tell the two apart and both treatments may be offered in tandem.

Hypothyroidism

• Primary hypothyroidism is confirmed by high levels of TSH. ‘Compensated’ hypothyroidism comprises a slightly raised TSH (typically < 10 mU/L) with normal levels of T₄ and T₃. Further failure of the thyroid gland results in increasing TSH and falling levels of T₄ and T₃ below the normal range.

• Secondary hypothyroidism is due to pituitary–hypothalamic failure; there is no increase in TSH despite falling levels of thyroid hormone.

Clinical features

Hypothyroidism can produce the classic picture of a slow, dry-haired, thick-skinned, deep-voiced patient with weight gain, cold intolerance, bradycardia and constipation; however, symptoms are usually minimal and non-specific, and biochemical testing is essential in any suspected case.

Investigations

• There is raised TSH with low/normal T₄ and T₃.

• Thyroid antibodies may be positive.

• Additional features may include anaemia, typically normochromic normocytic, but possibly either microcytic due to menorrhagia or macrocytic due to autoimmune pernicious anaemia.

• There are raised serum aspartate aminotransferase (AST) levels from muscle and liver, raised creatine kinase (CK) levels, hypercholesterolaemia, hyponatraemia due to increased ADH and impaired free water clearance.

Treatment

• Thyroxine (T₄) replacement is lifelong, with the aim of reducing the TSH level to the lower half of the normal range. A typical replacement dose is levothyroxine between 100 and 150 mcg per day. Starting doses range between 25 mcg and 100 mcg, depending on existing co-morbidity.

• Patients with heart disease benefit from slow increments of thyroxine, and adjustments to anti-anginal therapy may be required. In severe cardiac disease treatment may be initiated with a small dose of T₃ (liothyronine) 2.5 mcg every 8 hours, doubling the dose every 48 hours until a maximal dose of 10 mcg 3 times daily is achieved. T₄ is then commenced at this point and the T₃ discontinued 5 days later.

• Fluctuating levels of TSH on replacement therapy typically reflect poor compliance but may result from malabsorption. Dose alterations should be reassessed after at least 6 weeks and then yearly.

Myxoedema coma

Myxoedema coma (rare) is profound hypothyroidism with a fall in core temperature, ECG changes (low voltage, prolonged QT interval, flat T waves and heart block), hypoglycaemia and altered mental status.

• General management includes maintenance of airway and body warmth (but not active rewarming, which risks peripheral vasodilatation and cardiovascular collapse), restriction of free water and glucose supplementation.

• IV hydrocortisone replacement 100 mg every 8 hours should be initiated, after blood tests have been taken for ACTH and cortisol.

• Thyroid hormone should be given without waiting for biochemical confirmation of hypothyroidism. There is no consensus on method of thyroid hormone replacement. Some advocate the use of 300–500 mcg levothyroxine IV followed by 50–100 mcg daily (either orally or IV). Others advocate a lower-dose regimen of 25 mcg levothyroxine daily, increasing on a weekly basis.

• Liothyronine (T₃) IV may be used if there are concerns regarding impaired conversion of T₄ to T₃, but this risks cardiac decompensation. Doses of T₃ range between 5 and 20 mcg daily.

Hypothyroidism and pregnancy

Maternal hypothyroidism impairs fertility and may lead to intellectual deficit in the developing child. An average increase of 50% in levothyroxine dose requirement is typical in pregnancy.

Hyperthyroidism

Hyperthyroidism is common and is characterized by high levels of T₃ and T₄ with suppression of plasma TSH. Nearly all cases are due to intrinsic thyroid disease.

Clinical features

Weight loss, increased appetite, irritability, tremor and heat intolerance are classic symptoms of hyperthyroidism. A tachycardia with or without atrial fibrillation is a frequent presentation, particularly in the elderly. A goitre with a bruit occurs. Apathetic thyrotoxicosis occurs in elderly patients, in whom the clinical picture is more like hypothyroidism with few clinical signs of thyrotoxicosis.

• Graves’ disease. This autoimmune disease is the commonest form of thyrotoxicosis. In addition to symptoms and signs of hyperthyroidism, there may be ocular changes (exophthalmos and ophthalmoplegia), pretibial myxoedema and thyroid acropachy. Other autoimmune diseases, such as pernicious anaemia and myasthenia gravis, are also associated. The degree of thyrotoxicosis may fluctuate and the typical picture is of relapses and remissions. Ultimately many patients become hypothyroid.

• Toxic solitary nodule/toxic multinodular goitre. Although typical thyrotoxicosis can occur, autonomy within a nodule may not cause complete suppression of TSH.

• De Quervain’s thyroiditis. A transient episode of hyperthyroidism can occur with acute inflammation of the thyroid, secondary to viral infections such as mumps, Coxsackie, influenza, adenoviruses and echoviruses. Toxicosis may last for some weeks and may be followed by a period of hypothyroidism. In its acute phase it is accompanied by fever, malaise and local thyroid tenderness, and the ESR is often raised. Symptomatic treatment is with NSAIDs or aspirin, with the option of short-term prednisolone starting at 40 mg per day, reducing over 6 weeks.

Treatment (Table 15.3)

Propranolol is used to gain rapid control of thyrotoxic symptoms. High doses (up to 160 mg 3 times daily) may be required due to increased metabolism of the drug.

Table 15.3 Drugs used in the treatment of hyperthyroidism

There are three main options and preference varies widely.

• Antithyroid medications. Carbimazole initially 20 mg 3 times daily is the drug most commonly used in the UK. Its active metabolite, methimazole, is used preferentially in the USA. These drugs inhibit the formation of thyroid hormone and the clinical benefits can take up to 2 weeks to become apparent. Propylthiouracil 300–600 mg daily is occasionally used as an alternative, particularly during pregnancy and breast feeding. It has additional theoretical benefits in that it prevents peripheral conversion of T₄ to T₃. The major side-effect of these medications is agranulocytosis, and prior to commencing treatment patients should be told to seek medical help should severe mouth ulcers, sore throat or febrile illness occur. A white blood cell count is then urgently required. Antithyroid medication also reduces the immune processes and thus a trial of therapy for up to 18–24 months may result in remission of autoimmune thyrotoxicosis. Initially doses of antithyroid medications are high. There is then the option of dose reduction as the thyroid tests normalize, or the option of adding thyroxine to high-dose anti-thyroid medication (‘block and replace regimen’). A fall of T₄ and T₃ in response to treatment guides initial dose reductions (gradually reduce dose to 5 mg over 6 to 24 months if hyperthyroidism is controlled), as the TSH may remain suppressed for some time. Antithyroid medications will never lead to remission in toxic nodular disease, and while long-term antithyroid medications are an option, more definitive treatment is required.

• Radioactive iodine. This is increasingly accepted as a safe treatment option in the management of adults with thyrotoxicosis. It provides definitive treatment for toxic nodular disease and can be used in Graves’ disease, although there are concerns that antibody levels rise following treatment and these can exacerbate dysthyroid eye disease. Patients should be made euthyroid prior to therapy but anti-thyroid medications should be discontinued at least 4 days before. A pregnancy test is performed in young females. Following treatment with ¹³¹iodine 200–550 MBq, patients must be monitored for a short-term ‘flare’ of thyrotoxicosis (transient hypothyroidism may also occur) and for longer-term development of hypothyroidism. The presence of a large goitre with potential for airway compromise is a contraindication. Radioactive iodine is contraindicated in pregnancy and lactation.

• Surgery. Subtotal thyroidectomy is performed when anti-thyroid medications are not tolerated, when radioactive iodine is contraindicated, or for cosmetic reasons. All patients must be rendered euthyroid, stopping the antithyroid drugs 1–2 weeks before surgery and giving 60 mg of potassium iodide 3 times daily to reduce the vascularity of the gland.

• Transient hypocalcaemia is relatively common following surgery due to trauma to the parathyroid glands and disruption to the blood supply. This resolves with oral or IV calcium supplementation. Long-term replacement with alfacalcidol 0.25–1 mcg/day is occasionally required. Damage to the recurrent nerve and permanent loss of parathyroid gland function can occur. Function from the residual gland may be sufficient to avoid thyroid hormone replacement.

Thyroid storm

Fever (> 38.5°C), liver dysfunction, confusion and delirium are seen in this rare disorder. Systolic hypertension and high-output cardiac failure are also present.

Treatment

• Corticosteroids. Hydrocortisone IV 100 mg is given since this will further inhibit peripheral conversion of T₄ to T₃. Any precipitant cause, e.g. infection, should be treated.

• High-dose anti-thyroid drugs. (e.g. propylthiouracil 250 mg 8-hourly) is given.

• Chlorpromazine. Chlorpromazine 50–10 mg IM is given for agitation and may help with hyperpyrexia as a result of its central action.

Goitre

Assessment is made of its pathological nature and the patient’s thyroid status. Acute pain within a goitre suggests an acute viral thyroiditis (de Quervain’s), which may be associated with transient hyperthyroidism. Pain may also herald bleeding into a cyst and is rarely associated with thyroid cancer.

Investigations

• Thyroid function tests and thyroid antibodies allow assessment of function and diagnosis of autoimmune thyroiditis.

• Ultrasound can help monitor gland size and nature, and identify whether any nodules are cystic or solid. US does not identify malignant lesions but calcification raises the suspicion of cancer. Multiple small nodules may be demonstrated within a goitre associated with Graves’ disease.

• Thyroid isotope scans can identify hot or cold nodules; a hot nodule reduces concerns of malignancy.

• Fine needle aspiration (FNA) of solitary nodules or of dominant nodules within a multinodular gland helps diagnose malignancy and has replaced isotope scans and reduced the necessity for surgery. There is, however, a 5% false negative rate and follow-up is essential.

Treatment

Surgery is only required in some cases:

• Possibility of malignancy. There may be a history of rapid growth, cervical lymphadenopathy or neck irradiation. The finding of a hard, craggy nodule should prompt referral for FNA but any dominant nodule within a gland may harbour a malignancy. Surgical resection is required if doubt persists.

• Local pressure symptoms. Retrosternal extension should be assessed by CT of the neck.

• Cosmetic reasons. If the patient is euthyroid and the goitre is small, simple reassurance may be all that is required. However, if surgery is needed, the patient is rendered euthyroid prior to it.

Reproduction and sexual disorders

Normal puberty in the male begins between 10 and 14 years with acceleration of growth velocity and development of secondary sexual characteristics. In girls sexual development starts a year earlier and normal menses begin between the ages of 11 and 15.

Investigation of gonadal function

• Serum LH, FSH, SHBG, oestrogen or testosterone. A low free testosterone or oestradiol indicates gonadal failure. If associated with high LH and FSH, this failure is primary. Low LH and FSH values indicate hypothalamic–pituitary failure.

• Serum prolactin. Hyperprolactinaemia is associated with reduced sexual function.

• Luteal phase progesterone. High levels of serum progesterone in the second phase (typically measured on day 21) of the menstrual cycle confirms ovulation.

• Semen analysis.

Male disorders

Hypogonadism

• Treatment. There are increasing options for testosterone replacement, including topical preparations, injections and tablets; IM depot preparations, e.g. testosterone mixed esters 250 mg every 3 weeks or testosterone propionate 50–100 mg 2–3 times per week are the preferred long-term therapy. Adequacy of replacement is assessed by return of normal libido and secondary sexual characteristics, such as a requirement to shave. Serum levels of testosterone, LH and FSH should also be monitored. Maintenance of bone density is a further goal of therapy. Haemoglobin and prostate surface antigen should also be measured on treatment. Fertility may be achieved with gonadotrophin injections, e.g. gonadorelin analogues, provided testicular maturity has been reached.

Erectile dysfunction

Psychogenic, vascular, neurogenic and endocrine factors, diabetic mellitus, drugs and alcohol may lead to erectile dysfunction.

• Treatment. Management requires avoidance of alcohol, withdrawal of drugs that may be compounding the problem, exclusion of endocrine causes and cardiovascular/neurological assessment. Drugs such as the phosphodiesterase inhibitors (e.g. sildenafil 50 mg) are the treatment of choice but must not be given with nitrates, as the combination causes severe hypotension. Intracavernosal injections, penile implants and vacuum expanders are less frequently used.

Female disorders

Hypogonadism

• Primary amenorrhoea is the failure of menarche by the age of 16.

• Secondary amenorrhoea is a cessation of menses for over 6 months.

• Oligomenorrhoea is defined as fewer than 9 menstrual cycles per year.

Symptoms of oestrogen deficiency include hot flushes, vaginal dryness and dyspareunia, mood changes and sleep disturbance.

Amenorrhoea

Pregnancy should be excluded in all cases as a cause of amenorrhoea.

Polycystic ovarian syndrome (PCOS)

PCOS consists of oligomenorrhoea, hirsutism, acne and weight gain. Hyperandrogenism, insulin resistance and features of the metabolic syndrome (p. 429) are frequently seen. The syndrome probably arises from a combination of environmental and genetic interactions. Increased numbers of ovarian follicles may be found on US, but this is also seen in women without the syndrome.

• Investigations

• Serum androgens — testosterone, dehydroepiandrosterone (DHEAS), androstenedione, SHBG. Testosterone levels may be within normal limits, but in the context of a low SHBG (reflecting an insulin-resistant state) the free testosterone ratio may be high. Androgens are secreted by the ovary, and the adrenal glands. If the androgen levels are very high, an adrenal or an ovarian tumour is the likely source. Suppression of testosterone with a low-dose dexamethasone suppression test should be undertaken in these cases. A reduction of testosterone by more than 40% helps exclude an androgen-secreting tumour. Suppression of cortisol during the same test excludes Cushing’s disease, another cause of menstrual disturbance, weight gain and hirsutism. If suspicion of adrenal or ovarian tumour is high, imaging of the adrenal glands and ovaries is indicated.

• Serum gonadotrophins. Raised LH : FSH ratio to > 2 is seen, but not always on a random sample.

• 17α hydroxyprogesterone. An elevated 17α hydroxyprogesterone (17 OHP) measured in the follicular phase of the menstrual cycle indicates late-onset congenital adrenal hyperplasia (CAH), particularly in the context of low cortisol levels and raised ACTH. A very high rise of 17 OHP in response to a short tetracosactide stimulation test confirms the diagnosis of CAH.

• Consensus/Rotterdam criteria 2003 for diagnosis of PCOS stipulate at least two of:

a) clinical or biochemical evidence of hyperandrogenism

b) evidence of oligo- or anovulation

c) presence of polycystic ovaries on US.

• Treatment. Weight loss, exercise and non-medical management of hirsutism, e.g. shaving, waxing, laser and electrolysis, are used. A topical cream, eflornithine (an antiprotozoal), has become available and reduces hair growth.

• Prevention of endometrial hyperplasia and the risk of malignancy. In order to avoid this, regular withdrawal bleeds with the oral contraceptive pill (OCP) or progesterone (e.g. medroxyprogesterone 5 mg for 10 days) are used.

• Reduction in insulin resistance. Weight loss and exercise help the metabolic features of the disorder and may improve ovulatory function and androgen excess. Metformin 500 mg 3 times daily is being increasingly used.

• Anti-androgen therapy. Suppression of ovarian function with the OCP reduces serum androgen levels, while the oestrogen component increases SHBG levels, thereby lowering free testosterone. A commonly used OCP is co–cyprindiol, which has additional benefits since it contains the long-acting progesterone cyproterone acetate 50–100 mg daily, which also possesses anti-androgen activity. Additional cyproterone acetate may be given for the first 10 days of each OCP cycle to maximize its effect. Other anti-androgens include 5α-reductase inhibitors, e.g. finasteride 5 mg/day or dutasteride 500 mcg daily. Spironolactone 200 mg daily also has anti-androgenic properties and can help hirsutism. Flutamide 250 mg 3 times daily is less commonly used because of hepatic side-effects. Risks of teratogenicity mean that anti-androgen treatments should only be offered with adequate contraception.

• Restoration of ovulation. Weight management alone may help restore ovulation and metformin has been beneficial in some women. Reverse circadian prednisolone (2–2.5 mg prednisolone taken on rising in the morning and 4–5 mg prednisolone on retiring) can help with anovulation by suppressing androgen release. Clomiphene 50–100 mg daily on days 2–6 of the cycle and low-dose gonadotrophins are used with US surveillance.

Menopause

Menopause is diagnosed with loss of menses for 12 months, occurring at an average age of 50 years.

Premature menopause occurs with loss of menses before the age of 40. Chromosomal abnormalities and autoimmune ovarian failure account for the majority of cases, while chemotherapy and radiotherapy can also result in early gonadal failure.

• Investigation of premature menopause. Serum LH, FSH and oestradiol are performed. A low oestrogen level with high gonadotrophins confirms ovarian failure. Autoimmune screen, thyroid function tests, prolactin and karyotype are required in selected cases.

• Treatment

• Premature menopause. Exogenous oestrogens with progestogen are required to alleviate symptoms and maintain bone strength. Replacement should continue until the woman reaches the average age at which natural menopause occurs (around 50 years).

• Hormone replacement therapy (HRT). Following natural menopause at or around the age of 50 years, HRT is controversial. Hot flushes and vaginal dryness are helped by HRT. There are increases in bone strength. However, HRT increases the risk of breast cancer, venous thrombosis, and cardiovascular and cerebrovascular disease. Endometrial cancer can be avoided by giving progesterone with oestrogen treatment in women with an intact uterus. If amenorrhoea has been present for some time, the starting dose of oestrogen should be low and titrated upwards. In patients with an intact uterus, progesterone should be offered for 10–14 days each month to prevent endometrial hyperplasia. Replacement options include implants and transdermal, intravaginal and oral preparations. Oral oestrogens undergo extensive first-pass metabolism and should be avoided in liver disease. For alternatives to HRT for prevention of osteoporosis, see p. 324.

• Examples of HRT

• Continuous oral preparations. Conjugated oestradiol 0.625 mg + medroxyprogesterone acetate 2.5 mg. Bleeding may be unpredictable but should reduce within the first year of use.

• Cyclical preparations. Conjugated oestradiol 0.625 mg + medroxyprogesterone acetate 5–10 mg on days 1–10 each month. A daily dose of between 0.3 and 2.5 mg conjugated oestradiol is required for symptom control. Medroxyprogesterone is the favoured progesterone, being the least androgenic.

Hyperprolactinaemia

Prolactin stimulates breast milk production and inhibits the gonadotrophin axis, resulting in oligomenorrhoea and reduced libido.

• Marginally raised serum levels of prolactin (400–600 mU/L) may be seen with stress (including phlebotomy) and drugs.

• Higher levels of prolactin may be associated with pituitary stalk compression and disinhibition of dopaminergic tone on lactotroph cells.

• Very high levels (> 5000 mU/L) suggest a prolactin-secreting adenoma.

Assay interference by ‘macroprolactin’, a prolactin–IgG complex that lacks biological activity, should be excluded.

• Investigations. Pituitary function tests are required:

• blood (09:00 h cortisol, thyroid function tests, LH/FSH, oestradiol/testosterone, prolactin)

• pregnancy test

• macroprolactin: should be excluded

• visual fields and MRI of pituitary.

• Treatment. The presence of a pituitary tumour with raised prolactin levels (> 5000 mU/L) is indicative of a prolactin-secreting tumour rather than disinhibition. Continuous medical therapy with a dopamine agonist is the treatment of choice rather than surgery. It not only reduces prolactin levels but may also achieve tumour shrinkage.

• Bromocriptine 2.5–15 mg in divided doses is well established but associated with gastrointestinal side-effects. Cabergoline 500 mcg taken once or twice each week or quinagolide 75–150 mcg daily is an alternative.

• Response to treatment is monitored by serum prolactin measurements and MRI of the pituitary.

• Side-effects of these dopamine agonists may include pulmonary, retroperitoneal and pericardial fibrotic reactions and patients should be constantly monitored.

Acromegaly

Growth hormone acts in the liver to synthesize and secrete insulin-like growth factor (IGF)-1, which promotes skeletal and soft tissue growth. Growth hormone excess will result in gigantism prior to epiphyseal fusion, and acromegaly following puberty.

Acromegaly is due to excess growth hormone release, usually from a benign pituitary adenoma.

Somatotroph tumours are frequently large (> 1 cm diameter) and are associated with local compression effects, including chiasmal compression causing visual field defects and ophthalmoplegia. Compromise of normal pituitary function can result initially, with loss of libido or oligomenorrhoea.

Excess growth hormone results in a change of bodily appearance with coarsening of the features and an increase in shoe, glove and in particular ring size. Increased sweating is a common symptom, as is generalized lethargy and weakness — which may result from loss of ACTH but may also reflect loss of intrinsic muscle power despite increasing muscle bulk.

Acromegaly is associated with increased mortality from cardiovascular, respiratory and metabolic complications, e.g. diabetes. Obstructive sleep apnoea is commonly recognized. The incidence of colorectal carcinoma is also higher.

Investigation of growth hormone levels

• IGF-1 levels. These are almost always raised. IGF-binding protein 3 (IGF-BP3) is less useful, as there is overlap with normal levels.

• Growth hormone day curve. Growth hormone release is pulsatile in nature, making single measurements difficult to interpret. The absence of undetectable levels of growth hormone at intervals of the day is abnormal and suggestive of growth hormone excess.

• Glucose tolerance test (GTT). Failure of suppression of growth hormone levels to < 1 mU/L supports a diagnosis of acromegaly.

• Further pituitary function tests. The presence of a pituitary tumour should prompt exclusion of functional deficits affecting the other pituitary hormones (see ‘panhypopituitarism’, p. 567). Prolactin should be measured, and if high, may reflect dual secretion from the tumour or disinhibition from pituitary stalk compression.

• Neuro-ophthalmological assessment. Visual field defects are common.

• Imaging. Pituitary MRI is the investigation of choice. Pituitary CT is also used.

Treatment

Trans-sphenoidal surgery remains the treatment of choice, with medical therapy used to optimize the patient for anaesthesia and to achieve a reduction in tumour bulk to facilitate removal. Normal growth hormone dynamics are rarely achieved with surgery and therefore disease control rather than cure is sought. Following surgery, medical therapy may once more be required to achieve satisfactory growth hormone control — patients with uncontrolled levels are offered radiotherapy, which should improve growth hormone levels over subsequent months and years. A nadir of growth hormone levels following a GTT of < 5 mU/L, and normalization of serum IGF-1 level are predictive of good outcome in the long term.

• Medical therapies

• Somatostatin analogues. Injectable octreotide 100–200 mcg SC 3 times daily and lanreotide 60 mg every 28 days are somatostatin analogues, which are the treatment of choice in resistant cases and employed as a short-term treatment, while other modalities, e.g. surgery/radiotherapy, become effective.

• Dopamine agonists. These agents are available for oral administration but have limited efficacy and dose requirements are large. Bromocriptine (doses up to 20–30 mg may be required) is frequently associated with side-effects, e.g. hypotension, headaches and dyskinesia, limiting its use. Longer-acting alternatives such as cabergoline may have a better side-effect profile, but again large doses are required (1 mg/day). Both drugs are associated with an increased incidence of gallstone disease.

• Growth hormone antagonists. Pegvisomant, a genetically modified analogue of growth hormone, prevents binding of growth hormone to its receptor. IGF-1 levels are normalized in 90% of cases. It is used after failure of other therapies.

Cushing’s syndrome

Cortisol, secreted from the adrenal cortex under the influence of pituitary ACTH, is the principle endogenous glucocorticoid. It enhances gluconeogenesis, fat deposition, protein catabolism, sodium retention and potassium loss, and attenuates the immune response.

Cushing’s syndrome is due to glucocorticoid excess, which is seen most frequently following the therapeutic administration of exogenous synthetic steroids.

Clinical features consist of weight gain, change of appearance, depression, lack of libido, excess hair growth, acne and psychosis. Signs include plethora, thin skin, bruising, hypertension, pathological fractures (particularly involving the vertebrae and ribs), striae (purple or red) and a proximal myopathy. Moon face is characteristic.

Diagnosis

Exogenous steroid use should be excluded. Medications such as oestrogen will increase cortisol-binding globulin and result in misleadingly high total cortisol measurements. Such medications should be stopped 6 weeks prior to investigations.

• Timed cortisol measurements. In health, cortisol levels fluctuate throughout the day; thus random measurements of cortisol are meaningless. Measurements are taken to coincide with the normal peak morning secretion, to exclude deficiency syndromes, while measurements taken during the natural trough at midnight exclude excess. Loss of the normal circadian rhythm of cortisol secretion with measurable levels, asleep at midnight, is indicative of Cushing’s syndrome. False positives occur in depression and intercurrent illness. Simultaneous measurement of ACTH aids interpretation; confirmation of reduced ACTH levels in the context of high cortisol values suggests adrenal disease, while raised ACTH levels result from pituitary disease or ectopic sources, and further investigation seeks to differentiate between all these.

• 24-hour urinary free cortisol measurements. This is a useful screening tool for outpatient investigation. Repeatedly normal values make the diagnosis of Cushing’s syndrome unlikely.

• Low-dose dexamethasone suppression test. Individuals with Cushing’s syndrome are resistant to suppression of the HPA axis seen with administration of exogenous steroid. Dexamethasone 0.5 mg, taken strictly every 6 hours (starting at 09:00 h following a baseline measurement of serum cortisol and ACTH) for 48 hours, should result in suppression of serum cortisol to < 50 nmol/L (sensitivity > 97%). Hepatic enzyme inducers, such as phenytoin, will reduce plasma dexamethasone levels, invalidating the test.

• High-dose dexamethasone test. Pituitary disease retains an element of feedback control that ectopic sources of ACTH will not have. Thus, excess cortisol from pituitary disease will tend to suppress with 2 mg dexamethasone given every 6 hours for 48 hours. Ectopic ACTH secretion or adrenal tumour will not be suppressed with dexamethasone.

• CXR or CT. This is done to exclude bronchial carcinoma or carcinoid as the source of ectopic ACTH.

• Adrenal CT or MRI. This is used to exclude adrenal adenoma or carcinoma. A unilateral cortisol-secreting adenoma may result in atrophy of the contralateral gland. Any adenoma > 5 cm in diameter must be viewed as potentially malignant and resected for histological examination. Bilateral nodular hyperplasia may reflect ACTH excess from either a pituitary or ectopic source, or may be ACTH-independent.

• Pituitary MRI. This is done to exclude corticotroph adenoma. Images must be interpreted in the context of biochemistry since roughly 10% of people harbour an incidental pituitary adenoma; adenomas associated with Cushing’s disease may only be a few millimetres in diameter, so are easily missed.

Treatment

• Control of cortisol levels. Uncontrolled cortisol levels lead in the long term to glucose intolerance, hypertension and cardiovascular disease. In the shorter term, high levels of cortisol compromise tissue healing and immune response, so levels are controlled medically prior to more definitive (surgical) therapy. The most commonly used agents inhibit steroid biosynthesis in the adrenal cortex. Serum levels of cortisol must be monitored at several time points through the day at the start of treatment to establish adequate control (cortisol 150–300 nmol/L) and to avoid over-treatment. Examples of adrenolytic agents include:

• metyrapone 750 mg–4 g daily in divided doses

• ketoconazole 200 mg 3 times daily

• mitotane 1 g 3 times daily is used for inoperable adrenocortical carcinoma.

Cushing’s disease (pituitary-dependent hyperadrenalism)

• Trans-sphenoidal surgery is the treatment of choice, with selective removal of the adenoma where a pituitary lesion has been identified on MRI. Lateralization with inferior petrosal sampling can guide the surgeon to a hemi-hypophysectomy while preserving pituitary function. Post-operative dependence on steroid replacement is indicative of good outcome, although such patients must remain under surveillance for both re-emergence of the suppressed HPA axis and for recurrence.

• External beam radiotherapy is unsatisfactory as primary therapy but is used following surgery where cortisol levels have not been controlled.

• Bilateral adrenalectomy may be used as a last resort to control pituitary-dependent Cushing’s disease.

Adrenal adenomas and carcinoma

Surgical resection of adenomas, and tumour debulking in the case of carcinoma, are primary management. Suppression of the contralateral adrenal gland may take years to recover.

Ectopic ACTH-secreting tumours

Surgery, chemotherapy or localized radiotherapy is indicated, depending on the nature of the tumour suppression.

Nelson’s syndrome

Enlargement of a pituitary corticotroph tumour can occur following bilateral adrenalectomy, resulting in pressure on residual normal pituitary, with loss of function and with high levels of α-melanocyte stimulating hormone (derived from the ACTH precursor peptide, pro-opimelanocortin, POMC), which causes darkening of the skin.

The incidence of Nelson’s syndrome has reduced as radiotherapy is now offered to patients with pituitary-dependent Cushing’s in whom surgery has failed to control cortisol burden.

Management is difficult and frequently unsuccessful. Options include surgery and radiotherapy.

Adrenal insufficiency

Adrenal insufficiency may result from primary adrenal disease, pituitary disease with failure of ACTH production or, very rarely, hypothalamic disease (failure of corticotrophin-releasing hormone (CRH)). In practice, adrenal insufficiency is most commonly seen in the context of stopping exogenous glucocorticoid therapy for inflammatory diseases such as rheumatoid arthritis or asthma.

Clinical features are often vague and non-specific, but include weight loss, anorexia, weakness, fever, depression, diarrhoea, abdominal pain and constipation. Signs include pigmentation (especially of new scars and palmar creases) and postural hypotension. Loss of body hair and vitiligo also occur.

Addison’s disease (primary adrenal failure)

Autoimmune destruction of the entire adrenal cortex leads to failure of glucocorticoid, mineralocorticoid and adrenal sex steroid production. Patients with autoimmune destruction of the adrenal gland are prone to other autoimmune endocrine disorders, including type 1 diabetes, thyroiditis and premature ovarian failure.

Secondary adrenal failure

Insufficient ACTH production from pituitary disease, or HPA axis suppression following long-term exogenous steroid therapy, leads to failure of adrenal glucocorticoid production. Adrenal mineralocorticoid function is mainly preserved, being stimulated predominantly by angiotensin II rather than ACTH.

Assessment of the HPA axis

• 09:00 h ACTH and cortisol measurement: the patient should be relaxed.

• Insulin tolerance test/glucagon stimulation test: see p. 568.

• Short tetracosactide test: see p. 568. Variations exist, which extend the test to last up to 2 days. These tests help differentiate between primary, secondary and tertiary (hypothalamic) failure. Primary adrenal failure will fail to respond to ACTH, while secondary and tertiary adrenal failure will exhibit a delayed response to exogenous ACTH.

Management of adrenal failure (Table 15.4)

In primary adrenal failure, both glucocorticoid and mineralocorticoid replacement is required.

• Hydrocortisone is the glucocorticoid of choice at a dose of 20 mg per day in 3 divided doses (e.g. 10 mg on waking, 5 mg at midday and 5 mg at 18:00 h). Hydrocortisone has some inherent mineralocorticoid activity, but additional fludrocortisone about 0.1 mg daily may be required to maintain intravascular volume and to prevent sodium loss and hyperkalaemia. In pituitary ACTH deficiency, replacement with mineralocorticoid agents is unnecessary. Adequacy of hydrocortisone dose is assessed by measurements of hydrocortisone through the day, while fludrocortisone is assessed by absence of postural hypotension and suppression of plasma renin levels to the upper half of the normal range.

• Alternatives to hydrocortisone include prednisolone 5–7.5 mg/day and dexamethasone 0.25–0.75 mg/day. These preparations are less physiological, being longer-acting, and therefore may be associated with signs of glucocorticoid excess.

Table 15.4 Replacement therapy for primary hypoadrenalism

Drug	Dose
Glucocorticoid
Hydrocortisone	20–30 mg daily e.g. 10 mg on waking, 5 mg at 12:00 h, 5 mg at 18:00 h
or
Prednisolone	7.5 mg daily 5 mg on waking, 2.5 mg at 18:00 h
rarely
Dexamethasone	0.75 mg daily 0.5 mg on waking, 0.25 mg at 18:00 h
Mineralocorticoid
Fludrocortisone	50–300 mcg daily

Emergency management of adrenal failure (Box 15.1) (also see Emergencies in Medicine p. 720)

• Fluid resuscitation with 0.9% saline is required, as sodium and water deficit is significant.

• Glucocorticoid replacement with hydrocortisone 100 mg IV is followed immediately with hydrocortisone 100 mg IM every 6 hours. At these doses, an additional mineralocorticoid agent is not required.

• IM hydrocortisone is also used perioperatively until the patient is eating and drinking normally. Over periods of illness or physical stress (e.g. minor operative procedures), the oral hydrocortisone dose is increased to double the normal dose.

• All patients dependent on adrenal replacement therapy should wear a ‘MedicAlert’ bracelet and carry with them a steroid alert card. They should also have immediate access to a single dose of 100 mg IM hydrocortisone and be trained in its use.

Box 15.1 Management of acute hypoadrenalism

• Clinical context: hypotension, hyponatraemia, hyperkalaemia, hypoglycaemia, dehydration, pigmentation often with precipitating infection, infarction, trauma or operation. The major deficiencies are of salt, steroid and glucose

• Assuming normal cardiovascular function, the following are required:

– 1 L of 0.9% saline should be given over 30–60 mins with 100 mg of IV bolus hydrocortisone

– Subsequent requirements are several litres of saline within 24 hours (assessing with central venous pressure line if necessary) plus hydrocortisone 100 mg IM 6-hourly, until the patient is clinically stable

– Glucose should be infused if there is hypoglycaemia

– Oral replacement medication is then started, unless the patient is unable to take oral medication: initially hydrocortisone 20 mg 8-hourly, reducing to 20–30 mg in divided doses over a few days (Table 15.4)

– Fludrocortisone is unnecessary acutely as the high cortisol doses provide sufficient mineralocorticoid activity — it should be introduced later

The incidental adrenal adenoma

The incidental finding on CT or MRI of an adrenal adenoma occurs with increasing frequency. Assessment of function should include a low-dose dexamethasone test, measurement of urinary catecholamines and, if the patient is hypertensive, measurement of serum potassium and plasma aldosterone/renin activity ratio. Patients with an adenoma > 5 cm should undergo surgery, since these tumours have a higher risk of malignancy. Adenomas of < 3 cm diameter and no evidence of function can be monitored.

Long-term steroid therapy

Long-term therapy with supra-physiological doses of exogenous steroids results in adrenal failure and compromise of the adrenal response to stress if the glucocorticoid therapy is abruptly withdrawn.

• Suppression. This may be seen with topical and inhaled steroid preparations, as well as oral therapy.

• Synthetic glucocorticoids. These vary in their relative glucocorticoid or mineralocorticoid potency — hydrocortisone possesses glucocorticoid and mineralocorticoid activity, prednisolone has predominantly glucocorticoid properties, and dexamethasone exclusively glucocorticoid effects.

• Side-effects. While steroid replacement therapy at physiological doses is not associated with side-effects (Box 15.2), high-dose treatment is frequently associated with unwanted effects. In the short term, high-dose steroid therapy may be associated with mood swings and sleep disturbance. Longer-term therapy may lead to adrenal suppression, osteoporosis and cushingoid appearance. Glucose intolerance can also be seen with high-dose steroid therapy, as can hypertension and hypokalaemia.

• Stopping long-term steroid therapy. A gradual dose reduction not only diminishes the risk of deterioration of the underlying disease, but also prevents adrenal crisis.

• Once physiological replacement dose has been reached (e.g. 7.5 mg prednisolone, 20 mg hydrocortisone and 0.75 mg dexamethasone), further reductions hold the risk of adrenal insufficiency so reduction in dose must be slow and carefully monitored.

• Options for assessing the adrenal axis include measurement of pre-dose 09:00 h cortisol levels, short tetracosactide testing and response to insulin-induced hypoglycaemia.