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Diagnosis of pituitary disease
PITUITARY
Diagnosis of pituitary disease
corticotrophs, which produce adrenocorticotrophic hormone (ACTH) and other fragments of the pro-opiomelanocortin molecule thyrotrophs, which produce thyroid-stimulating hormone (TSH) gonadotrophs, which produce follicle-stimulating hormone (FSH) and luteinizing hormone (LH). Portal vessels in the stalk connect the hypothalamus and the median eminence with the pituitary, and transmit releasing and inhibiting hormones to the anterior pituitary gland, which they regulate. The hormones of the posterior pituitary gland (vasopressin and oxytocin) and their carrier protein neurophysin are synthesized in the supra-optic and paraventricular nuclei of the hypothalamus and are transported along the stalk in unmyelinated nerve fibres, to be stored and then secreted from the posterior pituitary. Anatomically, the pituitary sits at the base of the brain close to some critically important structures (Figure 1).
Alan M McGregor
Abstract Pituitary adenomas are relatively uncommon and slow growing. The onset of symptoms and signs is often insidious, particularly with nonfunctioning adenomas, so patients tend to present late and there is often a delay in diagnosis. A high index of suspicion is therefore essential.
Keywords assessing pituitary function; craniopharyngioma; pituitary adenoma; pituitary apoplexy; pituitary disease presentation; pituitary imaging; pituitary incidentaloma; pituitary mass differentiation
Pituitary tumours Epidemiology Pituitary tumours (Table 1) are uncommon, accounting for about 10% of intracranial neoplasms, and have an annual incidence of about 25 per million population. They are generally benign, but up to 50% show histological evidence of capsule invasion. Less than 0.2% are malignant, with local spread into the CNS. The peak incidence is at age 30e60 years; presentation is earlier in women than in men.
Background Pituitary development Epithelial tissue in the oral ectoderm, situated in the roof of the primitive buccal cavity, thickens, invaginates and becomes pinched off to form a vesicle (Rathke’s pouch) that develops into the anterior pituitary gland. The absence of mesenchyme between Rathke’s pouch and the midline ventral diencephalon allows these two structures to approximate, and the subsequent interaction leads to the development of the downwards extension of neural tissue from the brain that becomes the infundibulum (stalk) and the posterior pituitary. The signalling pathways and transcription factors involved in pituitary gland development are being characterized. Of particular importance, and currently best characterized, are the transcription factors Pit-1 and Prop-1. Pit-1 is essential for the differentiation of cells secreting growth hormone, prolactin and thyroid stimulating hormone. Prop-1 is required for the expression of Pit-1, the critical lineage-determining transcription factor. Mutations in the genes of these transcription factors lead to hypopituitarism.
Aetiology Rarely, ectopic hypothalamic-releasing hormones induce pituitary disease. For example, GH-releasing hormone (GHRH) causes pituitary somatotroph hyperplasia, GH hypersecretion and acromegaly. It seems more likely that pituitary tumours arise as a result of abnormalities in the pituitary than in the hypothalamus. Characteristically, a pituitary adenoma is not associated with surrounding hyperplasia of the rest of the gland, lesions are
Anatomy of the pituitary gland Thalamus Hypothalamic sulcus
Pituitary structure The anterior pituitary comprises five hormone-secreting cell types: somatotrophs, which synthesize, store and secrete growth hormone (GH) lactotrophs, which produce prolactin
Hypothalamic area
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Neurohypophysis
Alan M McGregor MA MD FRCP FMedSci is Professor of Medicine at King’s College London and Honorary Consultant with a special interest in Endocrinology at King’s College Hospital NHS Foundation Trust, London, UK. He qualified from the University of Cambridge, and trained in London, Newcastle upon Tyne and Cardiff, UK. His research interests include pituitary disease and autoimmune thyroid disease. Competing interests: none declared.
Optic chiasm Adenohypophysis
Mamillary body
Hypophysial stalk
Cleft
Posterior lobe
Anterior lobe
Figure 1
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Ó 2009 Elsevier Ltd. All rights reserved.
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Pituitary adenomas
a b c d
Presenting features of pituitary adenoma
Cell type
Prevalence (%)
Lactotroph cell adenoma Null cell adenomaa Somatotroph adenoma Corticotroph adenomab Plurihormonal cell adenomac Oncocytomad Gonadotroph cell adenoma Thyrotroph cell adenoma
26 17 14 15 13 6 8 1
Functioning adenoma Prolactin secreting e infertility, amenorrhoea, galactorrhoea, impotence Growth hormone secreting e acromegaly Adrenocorticotrophic hormone secreting e Cushing’s disease; commonly also silent Luteinizing hormone and/or follicle-stimulating hormone synthesizing e secretion uncommon; hypogonadism Thyroid-stimulating hormone secreting e hyperthyroidism Consequences of tumour expansion/extension Hypopituitarism e most commonly luteinizing hormone deficiency, hypogonadism Neurological e headache Suprasellar extension C Optic chiasm involved e bitemporal hemianopia C Stalk displacement, involving hypothalamus e hyperprolactinaemia C Diabetes insipidus (rare) C Hypothalamic dysfunction C Obstruction of third ventricle e hydrocephalus, headache, vomiting, altered consciousness, papilloedema
No evidence of hormone excess; negative immunocytochemistry. Can be functioning or non-functioning (silent). Particularly growth hormone and prolactin secreting. Variant of null cell with marked mitochondrial accumulation.
Table 1
usually solitary, and cure can be achieved with complete removal of the adenoma e all factors favouring a pituitary origin for the disease. Allelic X-chromosome inactivation analysis has shown that almost all pituitary adenomas are monoclonal in origin, supporting the view that the abnormality is in the pituitary and not the hypothalamus, and confirming that these tumours are true neoplasms, although characteristically benign in nature. Research continues into identifying somatic mutations leading to neoplastic transformation in anterior pituitary gland cells. The best-studied examples of this phenomenon are the activating mutations of the alpha chain of the stimulatory G protein (Gsp), which links the somatotroph cell membrane GHRH receptor to adenylate cyclase and, by its activation, induces GH secretion. This Gsp-activating mutation has been identified in up to 40% of patients with somatotroph adenomas leading to acromegaly. Genetic predisposition to pituitary tumours can occur as part of familial multiple endocrine neoplasia type 1 (see the article on multiple endocrine neoplasia in the next issue of Medicine). A variety of novel genes and mutations in them have been identified which may play a role in pituitary tumour development. These include: the pituitary tumour transforming gene (PTTG), which is over-expressed in most human pituitary adenomas a truncated form of the fibroblast growth factor 4 receptor (FGF4R) the nuclear architectural protein HMGA2, which has the ability to initiate the cell cycle in pituitary cells the aryl hydrocarbon receptor interacting protein (AIP). Identification of such genes and their mutations are also helping to characterize the pathogenic basis of families with a familial predisposition to pituitary tumours.
Lateral extension Invading cavernous sinus e cranial nerve involvement, diplopia Inferior extension C Eroding sphenoid sinus e CSF rhinorrhoea C
Incidentaloma Pituitary apoplexy Usually a large pituitary tumour Acute, haemorrhagic infarction of adenoma Increased size e infarction, bleeding, oedema Consequences C Gland destruction C Compression of surrounding structures C Obstructive hydrocephalus Presentation C Acute, severe headache C Meningism C Visual impairment C Ophthalmoplegia C Altered consciousness Differential diagnosis C C
Subarachnoid haemorrhage Meningitis
NB: Silent bleeds into an adenoma are much more common. Sheehan’s syndrome e normal pituitary gland necrosis post-partum, caused by severe blood loss/hypovolaemic shock. CSF: cerebrospinal fluid.
Table 2
Pituitary hyperplasia It is important to distinguish physiological and pathological hyperplasia of the pituitary gland from a pituitary adenoma. Prolactin cell hyperplasia, which can lead to a doubling in size of the pituitary gland, occurs physiologically during pregnancy and lactation.
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In patients with long-standing primary hypothyroidism or primary gonadal failure, hyperplasia of TSH-producing cells or LH/FSH-producing cells, respectively, may result. GH cell hyperplasia may result from ectopic production of GHRH, although this is extremely rare.
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Up to 10% of patients with Cushing’s disease have pituitary hyperplasia caused by ectopic production of corticotrophinreleasing factor.
Functioning and non-functioning pituitary adenomas Functioning tumours of the anterior pituitary gland lead to several well-recognized clinical syndromes (Table 2). The more common conditions (GH hypersecretion leading to acromegaly, prolactin hypersecretion leading to infertility, hypogonadism and galactorrhoea, and ACTH hypersecretion leading to Cushing’s disease) are described in other contributions. In patients with hyperprolactinaemia and a pituitary mass, it is important to note that, although this may be caused by a prolactin-secreting pituitary adenoma, it can also reflect displacement of the pituitary stalk by a mass, resulting in interference with normal hypothalamic dopamine suppression of prolactin release. Prolactin levels of more than 5000 mU/litre are most likely to be caused by a prolactin-secreting adenoma. When evaluating prolactin levels, it is important to exclude macroprolactinaemia, caused by the presence of the predominant 23 kDa prolactin monomer in the circulation, together with ‘big, big prolactin’ (a complex of this monomer with IgG). Rarely in patients with extremely high levels of prolactin, an artefactually low test result (‘hook effect’) may be reported. If this is suspected, dilution of the sample is essential. Cerebrospinal fluid (CSF) rhinorrhoea, although extremely rare in patients with untreated pituitary adenomas, occurs more commonly (<10%) with invasive macroprolactinomas. Gonadotroph cell adenomas are seen most commonly in older patients and seldom manifest as functioning tumours endocrinologically; when they do, they are associated with hypogonadism. Functioning thyrotroph cell adenomas present with hyperthyroidism with or without a goitre and are characterized by detectable and even elevated levels of TSH, in contrast to the common primary thyroid diseases causing hyperthyroidism, in which TSH is suppressed. A spectrum of cell types contribute to the development of pituitary adenomas (Table 1).
Diagnosis Pituitary tumours can present clinically in various ways (Table 2), but particularly: as a consequence of hormone overproduction (functioning adenomas), with the associated resulting clinical syndrome because of the consequences of their large size (often nonfunctioning), which may lead to hypopituitarism (Table 3) through destruction of surrounding normal pituitary tissue neurologically, when the expanding mass compresses local structures following acute, haemorrhagic infarction and expansion of a macroadenoma (pituitary apoplexy) (Table 2) by chance, when detected radiologically (‘incidentalomas’). Pituitary adenomas can be classified radiologically, according to their size, as microadenomas (<1 cm) or macroadenomas (>1 cm). Clinicians faced with a patient with a possible pituitary adenoma must address several key questions. Does the patient have a functioning or a non-functioning pituitary adenoma? How large is the lesion and does it extend outside the sella turcica? Is the lesion a pituitary adenoma or another pathology? Is hypopituitarism present as a consequence of the extent of the lesion? What are the neurological consequences of the lesion extending outside the sella turcica? How should a pituitary incidentaloma be managed?
Size and extent of pituitary adenomas Plain radiographs of the skull are non-invasive and inexpensive, but provide only limited information on the bony sella, cannot
Signs and symptoms of pituitary insufficiency Growth hormone Fatigue, loss of energy, impaired psychological well-being, increased abdominal fat mass, reduced muscle strength and exercise capacity Luteinizing hormone and follicle-stimulating hormone
Empty sella syndrome Enlarged sella, filled with CSF (‘empty’) Primary C Defective, enlarged diaphragma sella opening C Herniation of subarachnoid space into sella C Caused by raised intracranial pressure/developmental anomaly C Compression and displacement of anterior pituitary posteriorly C Most patients are middle-aged women C Usually incidental and clinically irrelevant C Secondary hyperprolactinaemia (stalk effect) can occur C Intrasellar prolapse of optic chiasm (usually asymptomatic) can occur Secondary C Post-infarction, surgery, radiotherapy of pituitary adenoma/sella mass C Fibrosis and ischaemia of prolapsed optic chiasm e visual acuity may decline
Women Oligomenorrhoea/amenorrhoea, infertility, dyspareunia, breast atrophy, flushes Men Loss of libido, impotence, infertility, flushes, regression of secondary sexual characteristics, loss of body hair, soft testicles, fine wrinkles around the mouth Thyroid-stimulating hormone Fatigue, muscle weakness, sensitivity to cold, constipation, apathy, weight gain, dry skin Adrenocorticotrophic hormone Fatigue, anorexia, weight loss, weakness, nausea, vomiting, hypoglycaemia, apathy, loss of pubic and axillary hair in women Vasopressin Polyuria, polydipsia, nocturia
Table 4
Table 3
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define soft tissue changes (e.g. to distinguish a pituitary sella mass from an empty sella, Table 4) and have no role in the management of patients with pituitary disease. CT provides excellent visualization of the bony structure of the region and is much more sensitive than MRI in detecting calcification of soft tissues, but requires intravenous contrast agents and exposes the patient to radiation. Artefacts generated from dense bone in the skull base obscure soft tissue detail, and artefacts from metallic dental materials compromise characterization of soft tissues on direct coronal imaging.
body in the eye or spinal canal or near a major blood vessel; in such situations, CT is the only alternative. Bony structures are largely unidentified, except where fatty marrow produces high signal intensity on T1-weighted images. On T1-weighted images, the normal pituitary gland is iso-intense with white matter, whereas the posterior pituitary gives a higher signal intensity. With gadolinium, the pituitary gland and stalk enhance brightly. In patients with a suspected pituitary microadenoma, MRI is required both in the coronal plain and sagittally. Usually, the tumour enhances less than normal tissue and the lesion can be further clarified using gadolinium enhancement and dynamic imaging of the gland. In patients with suspected microadenomas in whom imaging with a conventional 1.5 Tesla magnet does not detect the lesion, the improved signal-to-noise ratio and spatial resolution of a 3 Tesla system may be helpful. Similarly perfusion-weighted imaging of functioning microadenomas allows identification of their increased vascularity as compared with normal pituitary tissue. In patients with a macroadenoma, MRI allows clear definition of the margin of the tumour and involvement of the optic chiasm (Figure 2), cavernous sinus, sphenoid sinus, orbit, temporal lobe and carotid arteries, and identifies haemorrhage.
Magnetic resonance imaging of the pituitary: magnetic resonance imaging (MRI) has become the most important imaging modality in the sella region, simultaneously and effectively characterizing soft tissues, CSF spaces and blood vessels. Multiplanar images can be acquired, ionizing radiation is not required, and the contrast agent used (gadolinium) is associated with fewer adverse events than those used in computed tomography (CT). MRI cannot be used in patients with a cardiac pacemaker, metallic clips on aneurysms (newer titanium clips are not a problem), or any kind of metallic foreign
Non-pituitary pathology involving the sella Pituitary adenomas are the most common cause of sella masses, but other disorders can present in this manner (Tables 5, 6). All of these lesions can present with headaches, visual impairment and the consequences of hydrocephalus and pituitary destruction, depending on the site in which they arise, their size and the extent of involvement with local tissues. Diabetes insipidus is present more commonly than in patients with a pituitary adenoma. Careful clinical and radiological assessment have a critical role in the diagnosis of non-pituitary pathologies involving the sella turcica and the suprasellar cistern, and in distinguishing these from primary pituitary pathology. It is
Mass lesions involving the sella turcica and suprasellar cistern C C C C C C C C C
Pituitary adenoma Craniopharyngioma Meningioma Metastasis Cysts e Rathke’s cleft, dermoid, epidermoid Aneurysm Germinoma Optic glioma Inflammatory disease
Abscess e bacterial, fungal, parasitic Granulomatous disease e sarcoidosis Histiocytosis X MRI scans in the coronal a and sagittal b plains, which demonstrate a pituitary macroadenoma extending superiority to the optic chiasm in a.
Lymphocytic hypophysitis
Figure 2
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Table 5
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Abscess formation in the pituitary gland arises from local spread (e.g. acute sphenoid sinusitis) or as a result of septicaemia. Hypopituitarism secondary to tuberculosis is usually followed by basilar meningitis. Sarcoidosis: clinically apparent CNS involvement by sarcoidosis is uncommon and has a predilection for the base of the brain. Involvement of the pituitary stalk or the hypothalamus can occur, with the resulting clinical consequences. Langerhans’ cell histiocytosis (histiocytosis X) is a group of conditions that are non-neoplastic but vary in organ involvement and clinical course. Usually, the lesions are solitary or multifocal eosinophilic granulomata, particularly of bone. They commonly involve the CNS, and particularly the hypothalamicepituitary axis. Involvement of the anterior pituitary is uncommon, but there may be hyperprolactinaemia from stalk involvement. The most common endocrine presentation is diabetes insipidus. Bony lesions are usually detectable elsewhere in the skeleton. Lymphocytic hypophysitis is a destructive, inflammatory lesion of the anterior pituitary gland that is thought to be autoimmune in origin. It occurs almost entirely in women and most commonly during pregnancy or postpartum. It may be associated with other autoimmune conditions of the endocrine system. The anterior pituitary initially undergoes extensive lymphocytic infiltration, and the gland becomes fibrotic. Pituitary failure may result.
Craniopharyngioma C C C C C C
C
C
Arises from remnants of Rathke’s pouch Most are suprasellar in location 20% originate in sella Histologically benign tumour Adherence to local structures e difficult to treat; often recurs Adamantinous subtype Cystic tumour of childhood Often partially calcified Oily, thick cystic fluid Papillary subtype Predominantly solid tumour of adulthood Usually suprasellar origin Unlike pituitary adenoma, commonly causes diabetes insipidus
Table 6
important to remember that the primary pathology may be in the infundibulum (stalk) (Table 7). Craniopharyngiomas (Table 6) can be cystic or solid. The signal obtained on MRI depends on the cyst fluid content. Cystic adamantinous lesions tend to be hyperintense, with encasement of local vessels by the tumour. Meningiomas usually arise in the parasellar region and are intimately associated with the dura. They may be calcified and on CT are hyperdense, with or without hyperostosis of the adjacent bone. On MRI, they tend to be iso-intense with grey matter, and become hyperintense with gadolinium contrast. Aneurysms tend to be of high density on non-enhanced CT and become hyperintense following administration of intravenous contrast. On spin-echo MRI, aneurysms exhibit very low signal intensity or signal void. Magnetic resonance angiography is diagnostic. Germ cell tumours, including germinomas, are often associated with simultaneous lesions in the pineal gland, and human chorionic gonadotropin-b is detected in the serum or CSF. Onehalf of these lesions are highly malignant and metastasize readily, but they are also extremely radiosensitive.
Traumatic brain injury Historically traumatic brain injury (TBI) has not been recognized as a significant contributor to anterior pituitary dysfunction, though post traumatic onset of diabetes insipidus is well recognized. Prospective studies with longer-term follow-up often demonstrate recovery of hypopituitarism with time but in a significant number of patients with severe TBI, the abnormalities may persist, particularly GH deficiency.
Tests of pituitary function As the assays for pituitary hormones have improved, there has been slightly less reliance on dynamic tests than in the past. This particularly applies to TSH; the assay can now detect such low
Pituitary stalk lesions (‘stalk thickening’) Classification and frequency Congenital/developmental pituitary hypoplasia, septo-optic dysplasia Inflammatory/infections Lymphocytic hypophysitis, histiocytosis, sarcoidosis, TB Neoplastic Germinoma, metastases, glioma, pituicytoma, leukaemia, lymphoma Presentation Incidental finding on MRI Varying degree of hypopituitarism Hyperprolactinaemia Diabetes insipidus MRI stalk enhancement with gadolinium suggests inflammatory/infections process
33% 30% 37%
Table 7
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loss. On formal testing, they may show the classic bitemporal hemianopia, but asymmetry is characteristic. With lateral spread of adenoma tissue into the cavernous sinus, compression of the oculomotor, trochlear and abducens nerves may cause double vision. Headaches are attributed to stretching or invasion of the dura. Large tumours with marked suprasellar extension may lead to obstructive hydrocephalus. In patients with hypothalamic damage, this may precipitate diabetes insipidus (see pp. 414e415 in this issue), but it may also be associated with changes in temperature regulation, food intake and behaviour.
Laboratory findings suggesting, and tests confirming, pituitary insufficiency Growth hormone C Low insulin-like growth factor I adjusted for sex and age C Insulin-induced hypoglycaemia test (glucose <2.2 mmol/litre, 40 mg/dl), maximal stimulated growth hormone <3.5 mg/litre, 10 mU/litre (N > 10 mU/litre) Luteinizing hormone and follicle-stimulating hormone In women C Reduced oestradiol with normal or reduced basal luteinizing hormone and follicle-stimulating hormone In men C Reduced testosterone with normal or reduced basal luteinizing hormone and follicle-stimulating hormone C Normochromic, normocytic anaemia Thyroid-stimulating hormone C Reduced thyroxine or free thyroxine with normal or reduced thyroid-stimulating hormone C Elevated cholesterol
Pituitary incidentalomas Incidentalomas are defined as mass lesions, usually pituitary adenomas, identified during radiological examination of the base of the skull for other reasons. In patients with a lesion that is intrasellar, non-functioning and a microadenoma, two-yearly assessment by MRI is all that is required; therapeutic intervention is required only if the lesion increases in size. Annual MRI is sufficient in patients with non-functioning pituitary adenomas of more than 1 cm in diameter in whom hypopituitarism has been excluded and when there is no threat to the optic chiasm. In this group of patients follow-up over 5 years demonstrates that up to half will show an increase in tumour size and therefore require surgical intervention. They must therefore not be lost to follow-up. A
Adrenocorticotrophic hormone Low or reduced basal cortisol (8e9 a.m.) <100 nmol/litre, with normal or reduced adrenocorticotrophic hormone C Hypoglycaemia (glucose <2.2 mmol/litre, 40 mg/dl) C Eosinophilia C Lymphocytosis C Hyponatraemia C Insulin-induced hypoglycaemia test (glucose <2.2 mmol/litre, 40 mg/dl), maximal stimulated cortisol <550 nmol/litre, 20 mg/dl (N > 550 nmol/litre) C
FURTHER READING Asa SL. Practical pituitary pathology. Arch Pathol Lab Med 2008; 132: 1231e40. Bonneville J-F, Bonneville F, Barrali E, et al. Magnetic resonance imaging of the pituitary area: pathological aspects. In: De Werder WW, ed. Functional and morphological imaging of the endocrine system. Norwell: Kluwer, 2001. Freda PU, Post KD. Differential diagnosis of sella masses. Endocrinol Metab Clin North Am 1999; 28: 81e117. Hamilton BE, Salzman KL, Osborn AG. Anatomic and pathologic spectrum of pituitary infundibulum lesions. Amer J. Roentgenol 2007; 188: W223e32. Kerr J, Wood W, Ridgway EC. Basic science and clinical research advances in the pituitary transcription factors: Pit-1 and Prop-1. Curr Opin Endocrinol Diabetes Obes 2008; 15: 359e63. Melmed S, ed. The pituitary. 2nd edn. Oxford: Blackwell, 2002. [An exhaustive text covering the whole field.] Pituitary tumours: recommendations for service provision and guidelines for management of patients. London: Royal College of Physicians, 1997. [An excellent guide to best practice in patient care.] Scully KM, Rosenfeld MG. Pituitary development: regulatory codes in mammalian organogenesis. Science 2002; 295: 2231e5.
Vasopressin C Reduced urine osmolality C Elevated serum osmolality and sodium C Water deprivation test Table 8
levels that the TRH test is unnecessary. However, concentrations of GH and cortisol are affected by stress, and deficiencies can be proved only by failure to respond to stimulation. Both are stimulated by an episode of hypoglycaemia (<2.2 mM), so the gold-standard test is to subject the patient to insulin-induced hypoglycaemia and then to measure cortisol and GH. Tests used to determine pituitary function are listed in Table 8.
Neurological consequences of pituitary expansion The optic chiasm, optic tracts and intracranial optic nerves are vulnerable to suprasellar extension of pituitary adenoma. Initially, patients often describe nonspecific patterns of visual
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Diagnosis of pituitary disease
corticotrophs, which produce adrenocorticotrophic hormone (ACTH) and other fragments of the pro-opiomelanocortin molecule thyrotrophs, which produce thyroid-stimulating hormone (TSH) gonadotrophs, which produce follicle-stimulating hormone (FSH) and luteinizing hormone (LH). Portal vessels in the stalk connect the hypothalamus and the median eminence with the pituitary, and transmit releasing and inhibiting hormones to the anterior pituitary gland, which they regulate. The hormones of the posterior pituitary gland (vasopressin and oxytocin) and their carrier protein neurophysin are synthesized in the supra-optic and paraventricular nuclei of the hypothalamus and are transported along the stalk in unmyelinated nerve fibres, to be stored and then secreted from the posterior pituitary. Anatomically, the pituitary sits at the base of the brain close to some critically important structures (Figure 1).
Alan M McGregor
Abstract Pituitary adenomas are relatively uncommon and slow growing. The onset of symptoms and signs is often insidious, particularly with nonfunctioning adenomas, so patients tend to present late and there is often a delay in diagnosis. A high index of suspicion is therefore essential.
Keywords assessing pituitary function; craniopharyngioma; pituitary adenoma; pituitary apoplexy; pituitary disease presentation; pituitary imaging; pituitary incidentaloma; pituitary mass differentiation
Pituitary tumours Epidemiology Pituitary tumours (Table 1) are uncommon, accounting for about 10% of intracranial neoplasms, and have an annual incidence of about 25 per million population. They are generally benign, but up to 50% show histological evidence of capsule invasion. Less than 0.2% are malignant, with local spread into the CNS. The peak incidence is at age 30e60 years; presentation is earlier in women than in men.
Background Pituitary development Epithelial tissue in the oral ectoderm, situated in the roof of the primitive buccal cavity, thickens, invaginates and becomes pinched off to form a vesicle (Rathke’s pouch) that develops into the anterior pituitary gland. The absence of mesenchyme between Rathke’s pouch and the midline ventral diencephalon allows these two structures to approximate, and the subsequent interaction leads to the development of the downwards extension of neural tissue from the brain that becomes the infundibulum (stalk) and the posterior pituitary. The signalling pathways and transcription factors involved in pituitary gland development are being characterized. Of particular importance, and currently best characterized, are the transcription factors Pit-1 and Prop-1. Pit-1 is essential for the differentiation of cells secreting growth hormone, prolactin and thyroid stimulating hormone. Prop-1 is required for the expression of Pit-1, the critical lineage-determining transcription factor. Mutations in the genes of these transcription factors lead to hypopituitarism.
Aetiology Rarely, ectopic hypothalamic-releasing hormones induce pituitary disease. For example, GH-releasing hormone (GHRH) causes pituitary somatotroph hyperplasia, GH hypersecretion and acromegaly. It seems more likely that pituitary tumours arise as a result of abnormalities in the pituitary than in the hypothalamus. Characteristically, a pituitary adenoma is not associated with surrounding hyperplasia of the rest of the gland, lesions are
Anatomy of the pituitary gland Thalamus Hypothalamic sulcus
Pituitary structure The anterior pituitary comprises five hormone-secreting cell types: somatotrophs, which synthesize, store and secrete growth hormone (GH) lactotrophs, which produce prolactin
Hypothalamic area
MEDICINE 37:8
Neurohypophysis
Alan M McGregor MA MD FRCP FMedSci is Professor of Medicine at King’s College London and Honorary Consultant with a special interest in Endocrinology at King’s College Hospital NHS Foundation Trust, London, UK. He qualified from the University of Cambridge, and trained in London, Newcastle upon Tyne and Cardiff, UK. His research interests include pituitary disease and autoimmune thyroid disease. Competing interests: none declared.
Optic chiasm Adenohypophysis
Mamillary body
Hypophysial stalk
Cleft
Posterior lobe
Anterior lobe
Figure 1
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Ó 2009 Elsevier Ltd. All rights reserved.
PITUITARY
Pituitary adenomas
a b c d
Presenting features of pituitary adenoma
Cell type
Prevalence (%)
Lactotroph cell adenoma Null cell adenomaa Somatotroph adenoma Corticotroph adenomab Plurihormonal cell adenomac Oncocytomad Gonadotroph cell adenoma Thyrotroph cell adenoma
26 17 14 15 13 6 8 1
Functioning adenoma Prolactin secreting e infertility, amenorrhoea, galactorrhoea, impotence Growth hormone secreting e acromegaly Adrenocorticotrophic hormone secreting e Cushing’s disease; commonly also silent Luteinizing hormone and/or follicle-stimulating hormone synthesizing e secretion uncommon; hypogonadism Thyroid-stimulating hormone secreting e hyperthyroidism Consequences of tumour expansion/extension Hypopituitarism e most commonly luteinizing hormone deficiency, hypogonadism Neurological e headache Suprasellar extension C Optic chiasm involved e bitemporal hemianopia C Stalk displacement, involving hypothalamus e hyperprolactinaemia C Diabetes insipidus (rare) C Hypothalamic dysfunction C Obstruction of third ventricle e hydrocephalus, headache, vomiting, altered consciousness, papilloedema
No evidence of hormone excess; negative immunocytochemistry. Can be functioning or non-functioning (silent). Particularly growth hormone and prolactin secreting. Variant of null cell with marked mitochondrial accumulation.
Table 1
usually solitary, and cure can be achieved with complete removal of the adenoma e all factors favouring a pituitary origin for the disease. Allelic X-chromosome inactivation analysis has shown that almost all pituitary adenomas are monoclonal in origin, supporting the view that the abnormality is in the pituitary and not the hypothalamus, and confirming that these tumours are true neoplasms, although characteristically benign in nature. Research continues into identifying somatic mutations leading to neoplastic transformation in anterior pituitary gland cells. The best-studied examples of this phenomenon are the activating mutations of the alpha chain of the stimulatory G protein (Gsp), which links the somatotroph cell membrane GHRH receptor to adenylate cyclase and, by its activation, induces GH secretion. This Gsp-activating mutation has been identified in up to 40% of patients with somatotroph adenomas leading to acromegaly. Genetic predisposition to pituitary tumours can occur as part of familial multiple endocrine neoplasia type 1 (see the article on multiple endocrine neoplasia in the next issue of Medicine). A variety of novel genes and mutations in them have been identified which may play a role in pituitary tumour development. These include: the pituitary tumour transforming gene (PTTG), which is over-expressed in most human pituitary adenomas a truncated form of the fibroblast growth factor 4 receptor (FGF4R) the nuclear architectural protein HMGA2, which has the ability to initiate the cell cycle in pituitary cells the aryl hydrocarbon receptor interacting protein (AIP). Identification of such genes and their mutations are also helping to characterize the pathogenic basis of families with a familial predisposition to pituitary tumours.
Lateral extension Invading cavernous sinus e cranial nerve involvement, diplopia Inferior extension C Eroding sphenoid sinus e CSF rhinorrhoea C
Incidentaloma Pituitary apoplexy Usually a large pituitary tumour Acute, haemorrhagic infarction of adenoma Increased size e infarction, bleeding, oedema Consequences C Gland destruction C Compression of surrounding structures C Obstructive hydrocephalus Presentation C Acute, severe headache C Meningism C Visual impairment C Ophthalmoplegia C Altered consciousness Differential diagnosis C C
Subarachnoid haemorrhage Meningitis
NB: Silent bleeds into an adenoma are much more common. Sheehan’s syndrome e normal pituitary gland necrosis post-partum, caused by severe blood loss/hypovolaemic shock. CSF: cerebrospinal fluid.
Table 2
Pituitary hyperplasia It is important to distinguish physiological and pathological hyperplasia of the pituitary gland from a pituitary adenoma. Prolactin cell hyperplasia, which can lead to a doubling in size of the pituitary gland, occurs physiologically during pregnancy and lactation.
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In patients with long-standing primary hypothyroidism or primary gonadal failure, hyperplasia of TSH-producing cells or LH/FSH-producing cells, respectively, may result. GH cell hyperplasia may result from ectopic production of GHRH, although this is extremely rare.
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Ó 2009 Elsevier Ltd. All rights reserved.
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Up to 10% of patients with Cushing’s disease have pituitary hyperplasia caused by ectopic production of corticotrophinreleasing factor.
Functioning and non-functioning pituitary adenomas Functioning tumours of the anterior pituitary gland lead to several well-recognized clinical syndromes (Table 2). The more common conditions (GH hypersecretion leading to acromegaly, prolactin hypersecretion leading to infertility, hypogonadism and galactorrhoea, and ACTH hypersecretion leading to Cushing’s disease) are described in other contributions. In patients with hyperprolactinaemia and a pituitary mass, it is important to note that, although this may be caused by a prolactin-secreting pituitary adenoma, it can also reflect displacement of the pituitary stalk by a mass, resulting in interference with normal hypothalamic dopamine suppression of prolactin release. Prolactin levels of more than 5000 mU/litre are most likely to be caused by a prolactin-secreting adenoma. When evaluating prolactin levels, it is important to exclude macroprolactinaemia, caused by the presence of the predominant 23 kDa prolactin monomer in the circulation, together with ‘big, big prolactin’ (a complex of this monomer with IgG). Rarely in patients with extremely high levels of prolactin, an artefactually low test result (‘hook effect’) may be reported. If this is suspected, dilution of the sample is essential. Cerebrospinal fluid (CSF) rhinorrhoea, although extremely rare in patients with untreated pituitary adenomas, occurs more commonly (<10%) with invasive macroprolactinomas. Gonadotroph cell adenomas are seen most commonly in older patients and seldom manifest as functioning tumours endocrinologically; when they do, they are associated with hypogonadism. Functioning thyrotroph cell adenomas present with hyperthyroidism with or without a goitre and are characterized by detectable and even elevated levels of TSH, in contrast to the common primary thyroid diseases causing hyperthyroidism, in which TSH is suppressed. A spectrum of cell types contribute to the development of pituitary adenomas (Table 1).
Diagnosis Pituitary tumours can present clinically in various ways (Table 2), but particularly: as a consequence of hormone overproduction (functioning adenomas), with the associated resulting clinical syndrome because of the consequences of their large size (often nonfunctioning), which may lead to hypopituitarism (Table 3) through destruction of surrounding normal pituitary tissue neurologically, when the expanding mass compresses local structures following acute, haemorrhagic infarction and expansion of a macroadenoma (pituitary apoplexy) (Table 2) by chance, when detected radiologically (‘incidentalomas’). Pituitary adenomas can be classified radiologically, according to their size, as microadenomas (<1 cm) or macroadenomas (>1 cm). Clinicians faced with a patient with a possible pituitary adenoma must address several key questions. Does the patient have a functioning or a non-functioning pituitary adenoma? How large is the lesion and does it extend outside the sella turcica? Is the lesion a pituitary adenoma or another pathology? Is hypopituitarism present as a consequence of the extent of the lesion? What are the neurological consequences of the lesion extending outside the sella turcica? How should a pituitary incidentaloma be managed?
Size and extent of pituitary adenomas Plain radiographs of the skull are non-invasive and inexpensive, but provide only limited information on the bony sella, cannot
Signs and symptoms of pituitary insufficiency Growth hormone Fatigue, loss of energy, impaired psychological well-being, increased abdominal fat mass, reduced muscle strength and exercise capacity Luteinizing hormone and follicle-stimulating hormone
Empty sella syndrome Enlarged sella, filled with CSF (‘empty’) Primary C Defective, enlarged diaphragma sella opening C Herniation of subarachnoid space into sella C Caused by raised intracranial pressure/developmental anomaly C Compression and displacement of anterior pituitary posteriorly C Most patients are middle-aged women C Usually incidental and clinically irrelevant C Secondary hyperprolactinaemia (stalk effect) can occur C Intrasellar prolapse of optic chiasm (usually asymptomatic) can occur Secondary C Post-infarction, surgery, radiotherapy of pituitary adenoma/sella mass C Fibrosis and ischaemia of prolapsed optic chiasm e visual acuity may decline
Women Oligomenorrhoea/amenorrhoea, infertility, dyspareunia, breast atrophy, flushes Men Loss of libido, impotence, infertility, flushes, regression of secondary sexual characteristics, loss of body hair, soft testicles, fine wrinkles around the mouth Thyroid-stimulating hormone Fatigue, muscle weakness, sensitivity to cold, constipation, apathy, weight gain, dry skin Adrenocorticotrophic hormone Fatigue, anorexia, weight loss, weakness, nausea, vomiting, hypoglycaemia, apathy, loss of pubic and axillary hair in women Vasopressin Polyuria, polydipsia, nocturia
Table 4
Table 3
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define soft tissue changes (e.g. to distinguish a pituitary sella mass from an empty sella, Table 4) and have no role in the management of patients with pituitary disease. CT provides excellent visualization of the bony structure of the region and is much more sensitive than MRI in detecting calcification of soft tissues, but requires intravenous contrast agents and exposes the patient to radiation. Artefacts generated from dense bone in the skull base obscure soft tissue detail, and artefacts from metallic dental materials compromise characterization of soft tissues on direct coronal imaging.
body in the eye or spinal canal or near a major blood vessel; in such situations, CT is the only alternative. Bony structures are largely unidentified, except where fatty marrow produces high signal intensity on T1-weighted images. On T1-weighted images, the normal pituitary gland is iso-intense with white matter, whereas the posterior pituitary gives a higher signal intensity. With gadolinium, the pituitary gland and stalk enhance brightly. In patients with a suspected pituitary microadenoma, MRI is required both in the coronal plain and sagittally. Usually, the tumour enhances less than normal tissue and the lesion can be further clarified using gadolinium enhancement and dynamic imaging of the gland. In patients with suspected microadenomas in whom imaging with a conventional 1.5 Tesla magnet does not detect the lesion, the improved signal-to-noise ratio and spatial resolution of a 3 Tesla system may be helpful. Similarly perfusion-weighted imaging of functioning microadenomas allows identification of their increased vascularity as compared with normal pituitary tissue. In patients with a macroadenoma, MRI allows clear definition of the margin of the tumour and involvement of the optic chiasm (Figure 2), cavernous sinus, sphenoid sinus, orbit, temporal lobe and carotid arteries, and identifies haemorrhage.
Magnetic resonance imaging of the pituitary: magnetic resonance imaging (MRI) has become the most important imaging modality in the sella region, simultaneously and effectively characterizing soft tissues, CSF spaces and blood vessels. Multiplanar images can be acquired, ionizing radiation is not required, and the contrast agent used (gadolinium) is associated with fewer adverse events than those used in computed tomography (CT). MRI cannot be used in patients with a cardiac pacemaker, metallic clips on aneurysms (newer titanium clips are not a problem), or any kind of metallic foreign
Non-pituitary pathology involving the sella Pituitary adenomas are the most common cause of sella masses, but other disorders can present in this manner (Tables 5, 6). All of these lesions can present with headaches, visual impairment and the consequences of hydrocephalus and pituitary destruction, depending on the site in which they arise, their size and the extent of involvement with local tissues. Diabetes insipidus is present more commonly than in patients with a pituitary adenoma. Careful clinical and radiological assessment have a critical role in the diagnosis of non-pituitary pathologies involving the sella turcica and the suprasellar cistern, and in distinguishing these from primary pituitary pathology. It is
Mass lesions involving the sella turcica and suprasellar cistern C C C C C C C C C
Pituitary adenoma Craniopharyngioma Meningioma Metastasis Cysts e Rathke’s cleft, dermoid, epidermoid Aneurysm Germinoma Optic glioma Inflammatory disease
Abscess e bacterial, fungal, parasitic Granulomatous disease e sarcoidosis Histiocytosis X MRI scans in the coronal a and sagittal b plains, which demonstrate a pituitary macroadenoma extending superiority to the optic chiasm in a.
Lymphocytic hypophysitis
Figure 2
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Abscess formation in the pituitary gland arises from local spread (e.g. acute sphenoid sinusitis) or as a result of septicaemia. Hypopituitarism secondary to tuberculosis is usually followed by basilar meningitis. Sarcoidosis: clinically apparent CNS involvement by sarcoidosis is uncommon and has a predilection for the base of the brain. Involvement of the pituitary stalk or the hypothalamus can occur, with the resulting clinical consequences. Langerhans’ cell histiocytosis (histiocytosis X) is a group of conditions that are non-neoplastic but vary in organ involvement and clinical course. Usually, the lesions are solitary or multifocal eosinophilic granulomata, particularly of bone. They commonly involve the CNS, and particularly the hypothalamicepituitary axis. Involvement of the anterior pituitary is uncommon, but there may be hyperprolactinaemia from stalk involvement. The most common endocrine presentation is diabetes insipidus. Bony lesions are usually detectable elsewhere in the skeleton. Lymphocytic hypophysitis is a destructive, inflammatory lesion of the anterior pituitary gland that is thought to be autoimmune in origin. It occurs almost entirely in women and most commonly during pregnancy or postpartum. It may be associated with other autoimmune conditions of the endocrine system. The anterior pituitary initially undergoes extensive lymphocytic infiltration, and the gland becomes fibrotic. Pituitary failure may result.
Craniopharyngioma C C C C C C
C
C
Arises from remnants of Rathke’s pouch Most are suprasellar in location 20% originate in sella Histologically benign tumour Adherence to local structures e difficult to treat; often recurs Adamantinous subtype Cystic tumour of childhood Often partially calcified Oily, thick cystic fluid Papillary subtype Predominantly solid tumour of adulthood Usually suprasellar origin Unlike pituitary adenoma, commonly causes diabetes insipidus
Table 6
important to remember that the primary pathology may be in the infundibulum (stalk) (Table 7). Craniopharyngiomas (Table 6) can be cystic or solid. The signal obtained on MRI depends on the cyst fluid content. Cystic adamantinous lesions tend to be hyperintense, with encasement of local vessels by the tumour. Meningiomas usually arise in the parasellar region and are intimately associated with the dura. They may be calcified and on CT are hyperdense, with or without hyperostosis of the adjacent bone. On MRI, they tend to be iso-intense with grey matter, and become hyperintense with gadolinium contrast. Aneurysms tend to be of high density on non-enhanced CT and become hyperintense following administration of intravenous contrast. On spin-echo MRI, aneurysms exhibit very low signal intensity or signal void. Magnetic resonance angiography is diagnostic. Germ cell tumours, including germinomas, are often associated with simultaneous lesions in the pineal gland, and human chorionic gonadotropin-b is detected in the serum or CSF. Onehalf of these lesions are highly malignant and metastasize readily, but they are also extremely radiosensitive.
Traumatic brain injury Historically traumatic brain injury (TBI) has not been recognized as a significant contributor to anterior pituitary dysfunction, though post traumatic onset of diabetes insipidus is well recognized. Prospective studies with longer-term follow-up often demonstrate recovery of hypopituitarism with time but in a significant number of patients with severe TBI, the abnormalities may persist, particularly GH deficiency.
Tests of pituitary function As the assays for pituitary hormones have improved, there has been slightly less reliance on dynamic tests than in the past. This particularly applies to TSH; the assay can now detect such low
Pituitary stalk lesions (‘stalk thickening’) Classification and frequency Congenital/developmental pituitary hypoplasia, septo-optic dysplasia Inflammatory/infections Lymphocytic hypophysitis, histiocytosis, sarcoidosis, TB Neoplastic Germinoma, metastases, glioma, pituicytoma, leukaemia, lymphoma Presentation Incidental finding on MRI Varying degree of hypopituitarism Hyperprolactinaemia Diabetes insipidus MRI stalk enhancement with gadolinium suggests inflammatory/infections process
33% 30% 37%
Table 7
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loss. On formal testing, they may show the classic bitemporal hemianopia, but asymmetry is characteristic. With lateral spread of adenoma tissue into the cavernous sinus, compression of the oculomotor, trochlear and abducens nerves may cause double vision. Headaches are attributed to stretching or invasion of the dura. Large tumours with marked suprasellar extension may lead to obstructive hydrocephalus. In patients with hypothalamic damage, this may precipitate diabetes insipidus (see pp. 414e415 in this issue), but it may also be associated with changes in temperature regulation, food intake and behaviour.
Laboratory findings suggesting, and tests confirming, pituitary insufficiency Growth hormone C Low insulin-like growth factor I adjusted for sex and age C Insulin-induced hypoglycaemia test (glucose <2.2 mmol/litre, 40 mg/dl), maximal stimulated growth hormone <3.5 mg/litre, 10 mU/litre (N > 10 mU/litre) Luteinizing hormone and follicle-stimulating hormone In women C Reduced oestradiol with normal or reduced basal luteinizing hormone and follicle-stimulating hormone In men C Reduced testosterone with normal or reduced basal luteinizing hormone and follicle-stimulating hormone C Normochromic, normocytic anaemia Thyroid-stimulating hormone C Reduced thyroxine or free thyroxine with normal or reduced thyroid-stimulating hormone C Elevated cholesterol
Pituitary incidentalomas Incidentalomas are defined as mass lesions, usually pituitary adenomas, identified during radiological examination of the base of the skull for other reasons. In patients with a lesion that is intrasellar, non-functioning and a microadenoma, two-yearly assessment by MRI is all that is required; therapeutic intervention is required only if the lesion increases in size. Annual MRI is sufficient in patients with non-functioning pituitary adenomas of more than 1 cm in diameter in whom hypopituitarism has been excluded and when there is no threat to the optic chiasm. In this group of patients follow-up over 5 years demonstrates that up to half will show an increase in tumour size and therefore require surgical intervention. They must therefore not be lost to follow-up. A
Adrenocorticotrophic hormone Low or reduced basal cortisol (8e9 a.m.) <100 nmol/litre, with normal or reduced adrenocorticotrophic hormone C Hypoglycaemia (glucose <2.2 mmol/litre, 40 mg/dl) C Eosinophilia C Lymphocytosis C Hyponatraemia C Insulin-induced hypoglycaemia test (glucose <2.2 mmol/litre, 40 mg/dl), maximal stimulated cortisol <550 nmol/litre, 20 mg/dl (N > 550 nmol/litre) C
FURTHER READING Asa SL. Practical pituitary pathology. Arch Pathol Lab Med 2008; 132: 1231e40. Bonneville J-F, Bonneville F, Barrali E, et al. Magnetic resonance imaging of the pituitary area: pathological aspects. In: De Werder WW, ed. Functional and morphological imaging of the endocrine system. Norwell: Kluwer, 2001. Freda PU, Post KD. Differential diagnosis of sella masses. Endocrinol Metab Clin North Am 1999; 28: 81e117. Hamilton BE, Salzman KL, Osborn AG. Anatomic and pathologic spectrum of pituitary infundibulum lesions. Amer J. Roentgenol 2007; 188: W223e32. Kerr J, Wood W, Ridgway EC. Basic science and clinical research advances in the pituitary transcription factors: Pit-1 and Prop-1. Curr Opin Endocrinol Diabetes Obes 2008; 15: 359e63. Melmed S, ed. The pituitary. 2nd edn. Oxford: Blackwell, 2002. [An exhaustive text covering the whole field.] Pituitary tumours: recommendations for service provision and guidelines for management of patients. London: Royal College of Physicians, 1997. [An excellent guide to best practice in patient care.] Scully KM, Rosenfeld MG. Pituitary development: regulatory codes in mammalian organogenesis. Science 2002; 295: 2231e5.
Vasopressin C Reduced urine osmolality C Elevated serum osmolality and sodium C Water deprivation test Table 8
levels that the TRH test is unnecessary. However, concentrations of GH and cortisol are affected by stress, and deficiencies can be proved only by failure to respond to stimulation. Both are stimulated by an episode of hypoglycaemia (<2.2 mM), so the gold-standard test is to subject the patient to insulin-induced hypoglycaemia and then to measure cortisol and GH. Tests used to determine pituitary function are listed in Table 8.
Neurological consequences of pituitary expansion The optic chiasm, optic tracts and intracranial optic nerves are vulnerable to suprasellar extension of pituitary adenoma. Initially, patients often describe nonspecific patterns of visual
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