Endocrinology: The hypothalamic-pituitary axis and its assessment

The pituitary gland is the ‘conductor of the endocrine orchestra’, controlling all peripheral glands via trophic hormones.
It is approximately the size of a pea and sits in the pituitary fossa at the base of the brain (Figure 2.1). The anterior pituitary is derived embryologically from Rathke’s pouch, derived from primitive gut tissue. The posterior pituitary is derived from a down-growth of primitive brain tissue. The optic chiasm lies superior to the pituitary gland. Lateral is the cavernous sinus, which contains cranial nerves III, IV and Va and the internal carotid artery (Figure 2.1).

Physiology

Hypothalamic releasing and inhibiting factors are transported along the hypophyseal portal tract to the anterior pituitary. There are five pituitary axes: GH, ACTH, gonadotrophins (FSH and LH), TSH and prolactin (Table 2.1).

Growth hormone

GH is secreted in a pulsatile manner with peak pulses during REM sleep. GH acts on the liver to produce IGF-1, which is used as a marker of GH activity. GH exerts its action both by direct effects of GH and via IGF-1. GH causes musculoskeletal growth in children and has an important role in adults. Growth hormone releasing hormone (GHRH) stimulates GH, while somatostatin inhibits it.

ACTH

ACTH has a circadian rhythm, with peak pulses early in the morning and lowest activity at midnight. ACTH stimulates
cortisol release, and is itself stimulated by corticotrophin releasing hormone (CRH). Cortisol is the only hormone that inhibits ACTH.

Gonadotrophins (FSH and LH)

FSH leads to ovarian follicle development in women and spermatogenesis in men. In women, LH causes mid-cycle ovulation during the LH surge and formation of the corpus luteum.
In men, LH drives testosterone secretion from testicular Leydig cells. Gonadotrophin releasing hormone (GnRH) stimulates LH and FSH release. Testosterone and oestrogen inhibit LH and FSH, while prolactin also has a direct inhibitory effect.

TSH

TSH drives thyroxine release via stimulation of TSH receptors in the thyroid gland. TRH stimulates TSH secretion and is a weak stimulator of prolactin secretion. Thyroxine directly inhibits TSH.

Prolactin

Prolactin causes lactation and inhibits LH and FSH. It is under predominantly negative control by dopamine and weak stimulatory control by TRH. Anything that inhibits dopamine leads to an elevation in prolactin level.

Assessment of the pituitary gland

Pituitary tumours develop as a result of compression of local structures and/or the effects of endocrine hypo- or hypersecretion. Compression of the optic chiasm classically leads to a bi-temporal hemianopia. Assessment of visual fields with a red pin is a mandatory part of the clinical examination of patients with pituitary tumours. Automated visual field assessment has superseded Goldmann perimetry as the formal way of documenting visual field defects.

Basal tests

Prolactin and TSH do not have major circadian rhythms so can be checked at any time of day. Both free T4 (fT4) and TSH should be checked in pituitary disease because TSH is often normal in secondary hypothyroidism. In women, LH and FSH should be measured within the first 5 days of the menstrual cycle (follicular phase). In men, LH, FSH and basal testosterone should be checked at 09.00 in the fasting state. Basal cortisol should be checked at 09.00 to exclude deficiency, although a stimulatory (Synacthen) test is usually needed to confirm this. IGF-1 is a marker of GH activity: low or low–normal levels suggesting GH deficiency; high levels suggesting GH excess.

Dynamic pituitary tests

Dynamic endocrine tests are used to assess hormones that have a pulsatile secretion or circadian rhythm. If an endocrine deficiency is suspected, a stimulation test is used; if endocrine excess is suspected, a suppression test is used (Table 2.1). All endocrine tests should be interpreted in the clinical context.

Synacthen test

This is predominantly used to assess primary adrenal failure, but also to assess pituitary ACTH reserve. After 2 weeks of ACTH deficiency, atrophy of the adrenal cortex leads to an inadequate response to synthetic ACTH (Synacthen). This test should not be used in the acute situation, such as pituitary apoplexy, or immediately post-pituitary surgery.

Insulin tolerance test

The insulin tolerance test (ITT) is the gold standard test of ACTH and GH reserve. Insulin-induced hypoglycaemia (glucose <2.5 mmol/L) causes physiological stress, leading to a rise in ACTH and GH. A normal cortisol response to hypoglycaemia is >550 nmol/L whereas a GH value >3 μg/dL after hypoglycaemia excludes severe GH deficiency in adults.
The ITT is contraindicated in patients with ischaemic heart disease and epilepsy.

Other tests of GH reserve

The ITT is the gold standard assessment of GH reserve, but is an invasive and unpleasant test to undergo. Glucagon can be used instead of the ITT, although it is a less robust test of GH reserve; nausea is a common side effect. The GHRH–arginine test has particular use in patients who have had pituitary radiotherapy.
Common side effects of this are flushing, nausea and an unpleasant taste in the mouth.

Imaging

Magnetic resonance imaging (MRI) is the imaging modality of choice for the pituitary gland (Figure 2.1). Dedicated pituitary views with injection of contrast highlight the difference between tumour and normal gland. Pituitary tumours >1 cm are termed macro-adenomas, while lesions <1 cm are called microadenomas.
Computed tomography (CT) may be adequate in patients who are unable to undergo MRI. There is increasing interest in newer imaging modalities, including 11C-methionine positron emission tomography (PET).

Acromegaly – Sagittal MRI Showing Pituitary Macro-adenoma

Acromegaly, meaning ‘large extremities’ in Greek, is almost exclusively caused by a GH-secreting pituitary tumour.
Patients have often had acromegaly for many years before the diagnosis is considered. The increased detection of incidental pituitary tumours can lead to early diagnosis if appropriate tests are performed. Untreated acromegaly can lead to disfiguring features and premature death, predominantly from cardiovascular disease.

Clinical features

Acromegaly is associated with a classic constellation of clinical features (Figure 3.1). Increased size of hands and feet occur commonly, and rings may need to be cut off as they become too tight. Facial features become coarser over time, with frontal bossing of the forehead, protrusion of the chin (prognathism) and widely spaced teeth (Figure 3.2). The diagnosis is often made after the first consultation with a new healthcare professional. Soft tissue swelling leads to enlargement of the tongue and soft palate, snoring and sleep apnoea, and puffiness of the hands with carpal tunnel syndrome. Other specific features of GH hypersecretion include sweating, headaches, hypertension and diabetes mellitus, which may resolve after treatment.

Comparison with old photographs can show when acromegalic features started to develop (Figure 3.3). Patients
with large pituitary tumours may present with visual field disturbance resulting from optic chiasm compression and
hypopituitarism. If acromegaly occurs before puberty, gigantism occurs. Organomegaly, cardiomyopathy and increased risk of colon cancer can occur in association with acromegaly.

Investigation

Oral glucose tolerance test and IGF-1

It is relatively easy to confirm or refute a diagnosis of acromegaly once it is considered. An oral glucose tolerance test (OGTT) with 75 g glucose causes suppression of GH to <1 μg/L in patients who do not have acromegaly. Failure to suppress suggests autonomous GH secretion and a diagnosis of acromegaly. Typically, IGF-1 levels are elevated in acromegaly, reflecting increased GH activity. Some tumours co-secrete both GH and prolactin as they share the same cell origin, therefore prolactin may be simultaneously elevated.

Imaging

Pituitary MRI will reveal either a macro-adenoma or a microadenoma. Typically, large tumours are associated with higher GH and IGF-1 levels. Patients with cavernous sinus invasion are likely to need additional treatment because this area is relatively inaccessible surgically.

Management

Surgery is the most appropriate initial treatment for most patients as this is the only modality that offers the chance of permanent cure. With micro-adenomas, there is a high likelihood (>80%) of surgical remission, while remission is only achieved in approximately 60% of patients with macro-adenomas, hence additional treatment may be needed to achieve acceptable GH and IGF-1 levels.

Medical treatment

Somatostatin analogues (e.g. octreotide, lanreotide and pasireotide) can improve symptoms and control GH and IGF-1
levels. These drugs are usually given as monthly injections. GH receptor blockers (pegvisomant) can control IGF-1 levels
in patients with aggressive acromegaly although treatment is expensive and not widely available. Dopamine agonists can control GH in certain patients with acromegaly, although less effective in patients with very high levels of GH secretion.

Radiotherapy

In patients with significant residual tumour bulk and disease activity, additional treatment may be needed. External beam or stereotactic (‘gamma knife’ or radio-surgery) radiotherapy can be used. External beam radiotherapy is more established treatment with more published outcome data, but requires daily visits to hospital for administration over several weeks.
Stereotactic radiotherapy provides a more targeted treatment at higher dosage and is increasingly used, but is only suitable for lesions well away from the optic chiasm. Radiotherapy can take many years to lower GH. Long-term side effects of radiotherapy include gradual-onset hypopituitarism because of damage to the normal pituitary, and possible cerebrovascular disease.

Monitoring disease activity

After initial surgery, repeat OGTT will indicate if there is persistent disease. Long-term follow-up is important to ensure
adequate control of GH and IGF-1 levels, and exclude recurrence. Surveillance of disease status is by clinical assessment, IGF-1 measurement and a measure of GH activity (random GH, nadir GH to OGTT or mean GH from a GH day series). The target is GH <1 μg/L and normal IGF-1 although this is often difficult to achieve in practice. There may be a discrepancy between GH and IGF-1 levels in up to 30% of patients. Clinical assessment is important in such patients in deciding whether to treat or monitor. Because of the association of acromegaly with risk of neoplasia, periodic screening colonoscopy should also be considered.

Cushing’s syndrome

Cushing’s syndrome occurs as a result of increased endogenous or exogenous steroids. The diagnosis is considered
when the classic clinical features are recognised. There are several causes of Cushing’s syndrome, but Cushing’s disease specifically refers to an ACTH-secreting pituitary tumour, leading to bilateral adrenal hyperplasia and excess cortisol secretion. Systematic biochemical evaluation is essential to accurately confirm the presence of Cushing’s syndrome and determine the source of excess steroid. Cushing’s syndrome can be a challenging condition both in terms of diagnosis and treatment.

Clinical features

Cushing’s syndrome is characterised by the development of central obesity, a dorso-cervical fat pad and increased roundness of the face. Patients often have a flushed appearance (plethoric) and complain of thin skin, easy bruising and proximal myopathy (Figure 4.1). Patients may present with hypertension, premature osteoporosis and diabetes mellitus. Left untreated, Cushing’s syndrome is associated with significant morbidity and has a 5-year mortality approaching 50%.

Investigation

Biochemical screening tests

Before considering the differential diagnosis, it is important to confirm that true Cushing’s syndrome is present with the use of biochemical screening tests. Alcoholism and severe depression cause patients to look Cushingoid (pseudo-Cushing’s) but screening tests will usually be normal. Twenty-hour hour urine free cortisol (UFC), low dose dexamethasone suppression test (LDDST) and the overnight dexamethasone suppression test (DST) are used as screening tests. Twenty-four hour UFC levels will typically be elevated, and there is failure to suppress cortisol to <50 nmol/L after LDDST or overnight DST. The LDDST is more specific and sensitive than the overnight DST (Figure 4.1).
Most recently, late night salivary cortisol has emerged as a convenient outpatient screening test, whereby patients with Cushing’s syndrome fail to demonstrate the expected nocturnal fall in cortisol levels.

Differential diagnosis

Once Cushing’s syndrome has been confirmed, further assessment is needed to determine the cause (Figure 4.1). Cushing’s disease is more common than ectopic ACTH and has a higher prevalence in females. Hypokalaemia, a history of smoking and weight loss are suggestive of ectopic ACTH resulting from lung cancer or another malignancy. Significant and accelerated hirsutism suggests an adrenal tumour.
Imaging can lead to misleading information, because pituitary tumours may be too small to be seen on MRI, and ‘incidentalomas’ of the adrenal and pituitary are common. Therefore, biochemical assessment should be performed before imaging.

ACTH levels

If ACTH is low, an adrenal tumour is likely and adrenal imaging is indicated (CT or MRI). If ACTH is normal or high, Cushing’s disease or ectopic ACTH should be considered.

CRH and high dose DST

CRH injection causes an exaggerated rise in ACTH and cortisol in patients with Cushing’s disease, with a flat response observed in ectopic ACTH (CRH test). The high dose DST leads to some degree of cortisol suppression in Cushing’s disease but not in ectopic ACTH, although this test has largely been superseded by inferior petrosal sinus sampling (IPSS).

Imaging and inferior petrosal sinus sampling

If biochemical tests suggest Cushing’s disease, an MRI of the pituitary should be performed. If there is no clear pituitary lesion on MRI, IPSS can help to confirm central ACTH secretion by showing a clear gradient between central and peripheral ACTH levels after CRH injection. In suspected ectopic ACTH, a whole body CT scan, with or without PET imaging, may reveal a carcinoma.

Management

If an adrenal tumour is found, laparoscopic adrenalectomy is the treatment of choice. In ectopic ACTH, appropriate treatment of the underlying malignancy and medical control of cortisol levels are needed. In Cushing’s disease, trans-sphenoidal removal of the pituitary adenoma is indicated.

Medical treatment

Metyrapone blocks cortisol production and may improve symptoms. Other medical approaches include ketoconazole and pasireotide (a somatostatin analogue), which can be effective in some patients. Medical treatment can be used pre-operatively if symptoms are severe, or there is uncontrolled hypokalaemia, diabetes and hypertension.

Additional treatment

In large pituitary tumours, and those invading the cavernous sinus, external beam or stereotactic radiotherapy may be required. Bilateral adrenalectomy can be performed to normalise cortisol status in Cushing’s disease, although uncontrolled negative feedback can lead to uncontrolled residual pituitary tumour growth. In some cases, this has an aggressive course and may be associated with extreme pigmentation due to very high ACTH levels, with headache and cranial nerve palsies (Nelson’s syndrome).

Follow-up and monitoring

For Cushing’s disease, an early postoperative cortisol level of <50 nmol/L suggests biochemical remission. Positive confirmation of ACTH immunostaining of the tumour is helpful to confirm the correct diagnosis. Low cortisol levels result from ACTH suppression in the remaining normal corticotroph cells due to exposure to previously high corticosteroid levels. Hydrocortisone replacement may be needed for several years until the hypothalamic–pituitary–adrenal (HPA) axis recovers. Patients with Cushing’s disease should have long-term follow-up to ensure there is no recurrence.

Hypopituitarism and Non-Functioning Pituitary Adenomas

Non-functioning pituitary adenomas

Non-functioning pituitary adenomas (NFPAs) are biochemically inert tumours. They usually present with the physical effects of a pituitary mass lesion (e.g. visual field loss, headache and hypopituitarism) or, increasingly, when discovered incidentally on routine brain MRI (‘pituitary incidentalomas’). Surgical decompression is indicated if there is a visual field defect or if the lesion is close to the optic chiasm.
The usual route for removal is trans-sphenoidally, although trans-cranial surgery is occasionally needed. NFPAs can cause hypopituitarism by compressing the normal gland, which requires endocrine replacement. Histologically, NFPAs can have positive immunostaining for inactive LH and FSH, but they do not secret bioactive hormones. Patients with significant postoperative residual tumour may require radiotherapy.

Hypopituitarism

Causes

Hypopituitarism has several causes, either congenital (from pituitary transcription factor defects) or acquired. Acquired hypopituitarism is most commonly caused by the presence of a pituitary tumour. Other acquired causes include inflammatory and infiltrative disorders, traumatic brain injury and radiotherapy (Figure 5.1). In patients with hypopituitarism and a large empty pituitary fossa on MRI, it is important to enquire about a previous history of severe headache, as this may reflect missed pituitary apoplexy (Chapter 36).

Order of anterior pituitary hormone loss

In pituitary tumours, compression of the stalk usually leads to loss of pituitary hormones in the following order: GH, gonadotrophins, TSH then ACTH. Of these, ACTH deficiency is the most urgent problem as secondary hypoadrenalism has significant clinical implications requiring immediate hydrocortisone replacement. Pituitary stalk compression by NFPAs leads to mild hyperprolactinaemia, typically <5000 miU/L. Prolactin >5000 miU/L in the context of a large pituitary lesion suggests active prolactin secretion from a macroprolactinoma (Chapter 6) rather than NFPA. This is an important distinction because prolactinomas are managed medically, while NFPAs are managed surgically. Patients with pituitary adenomas hardly ever develop diabetes insipidus (in the absence of surgery), hence confirmed diabetes insipidus should lead to consideration of alternative diagnoses, such as inflammatory hypophysitis, craniopharyngioma or metastasis as a cause of the hypopituitarism (Chapter 7).

Clinical presentation

Visual field loss from pituitary tumours is a specific discriminatory clinical feature, but hypopituitarism often causes non-specific symptoms including lethargy, weight gain and sexual dysfunction (Figure 5.1). In adults, acquired hypopituitarism has often been present for many years prior to diagnosis, and symptoms can mimic common diseases such as depression. Hypopituitarism can present as an acute hypoadrenal crisis, with hyponatraemia and hypotension, which is a medical emergency (Chapter 13). In children, short stature may be a presenting feature (Chapter 24).

Investigation

In patients with suspected hypopituitarism, the priority is assessment of the adrenal axis. Patients with chronic ACTH deficiency (>4 weeks) will have a suboptimal response to Synacthen, as a result of adrenal atrophy. In acute hypopituitarism (e.g. pituitary apoplexy; Chapter 36), the Synacthen test is not a reliable test of ACTH reserve as the adrenals will not have had sufficient time to become atrophic and can give a falsely reassuring normal cortisol response.
Secondary hypothyroidism is demonstrated by a low (or low end of normal) T4 with inappropriately normal TSH.
Secondary hypogonadism is confirmed by low sex hormones with non-elevated LH and FSH. In postmenopausal females, LH and FSH levels are a good screening test for hypopituitarism, as gonadotrophins should be elevated at this stage of life. GH deficiency is suggested by low or low–normal IGF-1 levels; dynamic GH-stimulation tests are required to confirm this before starting treatment. The imaging investigation of choice in hypopituitarism is MRI, although CT can give reconstructed views of the pituitary fossa in patients who cannot undergo MRI.

Treatment

Patients with ACTH deficiency often feel immediately better with appropriate hydrocortisone replacement, reporting increased energy and appetite with a general improvement in symptoms.
In the acute situation, hydrocortisone can be life-saving (Figure 5.1). TSH deficiency is treated with standard thyroxine replacement, with dosage titrated according to symptomatic improvement and fT4 levels, as TSH cannot be used as a guide.
Patients with gonadotrophin deficiency need appropriate sex hormone replacement. Men with gonadotrophin deficiency may benefit from testosterone replacement, both for symptom control and protection from osteoporosis. Testosterone is given by gel or injection. Women with oestrogen deficiency are given oestrogen and progesterone replacement as appropriate, which can be given as the combined contraceptive pill or hormone replacement therapy (HRT).

Growth hormone deficiency

Growth hormone deficiency in adults can give rise to reduced quality of life, reduced muscle and bone mass, and increased fat mass with an adverse cardiovascular profile. GH deficiency should be considered in all patients with pituitary disease with impaired quality of life, as replacement has the potential to improve this significantly. Recombinant GH is administered as a daily subcutaneous injection. In order to qualify for treatment, GH deficiency should be established as severe through biochemical testing, and response to treatment should be documented using Adult Growth Hormone Deficiency Assessment (AGHDA) scores, according to National Institute for Health and Care Excellence (NICE) guidelines.

Prolactinoma and hyperprolactinaemia

Hyperprolactinaemia

Hyperprolactinaemia is common in clinical practice, occurring more commonly in women than men. Demonstration of persistent hyperprolactinaemia is important because repeat prolactin measurement may be normal. Pregnancy is a common cause of hyperprolactinaemia, and should be considered before further investigation. A full drug history is required because dopamine antagonists such as anti-emetics and antipsychotics commonly cause an elevation in prolactin. Classic features of hyperprolactinaemia include menstrual disturbance, reduced fertility and galactorrhoea. Profound hypothyroidism can cause hyperprolactinaemia by TRH-driven prolactin secretion.
Polycystic ovary syndrome is commonly associated with mild hyperprolactinaemia, with prolactin levels typically <1000 miU/L together with symptoms of androgen excess. In large pituitary tumours, a prolactin level >5000 iU/L suggests a macro-prolactinoma rather than a non-functioning adenoma.

Prolactinoma

Clinical presentation

Micro-prolactinoma

These are the most common pituitary tumours and are more frequently seen in women than men. Micro-prolactinomas are <1 cm, and typically present with menstrual disturbance and galactorrhoea, although infertility may be the only feature (Figure 6.1). Migrainous headaches can be a feature, probably because of endocrine disturbance in individuals predisposed to migraine, rather than mass effect. Polycystic ovary syndrome is distinguished from prolactinomas by the presence of androgenic symptoms, less elevated prolactin levels (typically <1000 miU/L) and the absence of a pituitary lesion on MRI.
Occasionally, micro-prolactinomas can be so small that they are not seen on MRI.

Macro-prolactinomas

By definition these are >1 cm and can be very large. They are more common in men than women, and patients typically present with mass symptoms of visual field loss and headache, particularly if there is cavernous sinus invasion. Prolactin levels are typically 5000 miU/L and can be in the hundreds of thousands, which is virtually diagnostic of a macro-prolactinoma (Figure 6.1). When levels of prolactin are extremely high, the immunoassay can give inaccurately low results for methodological reasons (called the hook effect) so it may be necessary to dilute the sample to achieve a more accurate result.

Treatment

Prolactinomas are treated with dopamine (D2) agonists, most commonly cabergoline and bromocriptine (Figure 6.1).
Cabergoline is given once or twice weekly and is better tolerated than bromocriptine, which is given daily. Common side effects include nausea and postural hypotension, and rarely psychiatric disturbance. Bromocriptine is preferable to cabergoline in women who are trying to conceive.
Macro-prolactinomas are treated medically even if they are very large, usually with good reduction in prolactin and tumour bulk (Figure 6.2). In 10% of macro-prolactinomas, cerebrospinal fluid (CSF) leak occurs as a result of the rapid reduction in the size of the lesion. This is important to recognise as it is a potential source of meningitis.

Surveillance and long-term follow-up

The aim of treatment is resolution of symptoms and normalisation of prolactin using the lowest possible dose of dopamine agonist medication. Micro-prolactinomas are usually treated with dopamine agonists for 2–3 years and then discontinued to see if there is remission. A convenient time for discontinuing treatment is after menopause, because prolactinomas are oestrogen-driven. Macro-prolactinomas require higher doses of dopamine agonists and commonly recur so treatment time is longer. A high cumulative dose of dopamine agonist can lead to cardiac valve abnormalities, although this is not a concern in the usual dosage needed to treat micro-prolactinomas.

Pituitary incidentaloma

Approximately 1 in 10 people have an incidental pituitary lesion, which may be of no clinical significance. Increased access to MRI scans has led to an increase in their detection. The majority of incidentalomas are micro-adenomas. Serum prolactin should be checked and if there are signs of acromegaly, Cushing’s or hypopituitarism, appropriate basal and dynamic tests should be performed. If there is thickening of the pituitary stalk on MRI, serum and urine osmolalities should be checked to exclude diabetes insipidus, especially if there is polyuria and polydipisia.
Local protocols will guide further imaging, but patients can often be reassured and eventually discharged if there is no growth detected on serial scans.