Approach
Patients with a pituitary mass may present with clinical features of excess secretion of ≥1 pituitary hormones. Alternatively, hormonally inactive tumours may present with symptoms resulting from tumour compression of adjacent structures.[4] As a result, pituitary masses may present with a complex picture of combined hormonal excess and/or deficiencies. Hypopituitarism may result from compression of the hypothalamic-pituitary stalk or of normal pituitary tissue and may involve any or all of the endocrine axes regulated by the pituitary. In order of frequency, a compressive lesion leads to growth hormone (GH) deficiency, secondary hypogonadism, secondary hypothyroidism, and secondary adrenal failure. It may also cause diabetes insipidus.
The history and examination should, therefore, ascertain any evidence of mass compression to adjacent structures, identify the cause of the pituitary mass, and look for clinical features of pituitary hormone excess or deficiency.[35]
Features of mass effect
For all patients it is essential to look for evidence of mass effect. Headaches are common; extension into the third ventricle may cause hydrocephalus. Lateral tumour growth into the cavernous sinus may cause double vision from third, fourth, and sixth cranial nerve palsies. Facial pain and paraesthesia may occur from involvement of the V1 and V2 branches of the fifth cranial nerve. Seizures may occur from temporal lobe involvement. Recurrent sinusitis and cerebrospinal fluid rhinorrhoea may result from growth into the sphenoid sinus.
Identifying the cause of the pituitary mass
Presenting features
Hypogonadism with fatigue and low libido suggests a prolactinoma. In women of reproductive age, oligomenorrhoea, amenorrhoea, galactorrhoea, and reduced fertility may also be present. In men and postmenopausal women, symptoms are usually secondary to mass effect.[36] Erectile dysfunction may be present in men.[2][37]
Lactotroph hyperplasia, causing similar symptoms, may occur as a physiological response to pregnancy. Rarely, a follicle-stimulating hormone (FSH) adenoma may cause amenorrhoea, and a luteinising hormone (LH) adenoma may cause precocious puberty in a boy. Hypersexuality in adults is a rare manifestation.
Features of acromegaly in adults or gigantism in pre-pubertal children suggest GH excess, due to either a GH-secreting adenoma or somatotroph hyperplasia. Clinical signs and symptoms include coarsening of facial features, prominent jaw and frontal bossing, enlarged feet and hands, and macroglossia. Patients may also demonstrate skeletal complications such as nerve entrapment (carpal tunnel syndrome) or arthralgias. Patients with acromegaly have many systemic complications secondary to chronic excess GH levels and to tumoural mass effect; however, disease control has reduced the morbidity and mortality risk.[38] Patients are at increased risk of developing type 2 diabetes mellitus, which may be present in up to 25% of cases. Patients may have obstructive sleep apnoea and have an increased risk of colonic polyps and malignant transformation.[38] The Endocrine Society recommends screening for neoplasia with a colonoscopy, upon diagnosis of acromegaly.[39] GH-secreting adenomas might also co-secrete prolactin.
Cushingoid clinical stigmata (e.g., central obesity, supraclavicular and cervical fat accumulation, facial rounding, easy bruising, purple striae, proximal muscle weakness, hirsutism, acne, menstrual irregularity, and/or change in libido) suggest an adrenocorticotropic hormone (ACTH)-secreting adenoma or corticotroph hyperplasia.[9] Patients may also have metabolic alterations such as impaired glucose tolerance, diabetes mellitus, or hypertension without other clinical stigmata. Unexplained osteoporosis or osteopenia may also be present.[9]
A diffuse goitre on examination indicates thyroid-stimulating hormone (TSH) hypersecretion, due to either a TSH-secreting adenoma or thyrotroph hyperplasia after long-standing primary hypothyroidism. A diffuse goitre is observed in over 90% of patients with a TSH-secreting adenoma. There may be mild signs and symptoms of hyperthyroidism (e.g., palpitations, tremor, and heat intolerance). Other symptoms include visual-field defects, menstrual disturbances, and galactorrhoea, with or without co-secretion of prolactin.[40] About 25% of tumours secrete additional pituitary hormones, most commonly GH or prolactin.[40]
Symptoms of mass effect with secondary adrenal insufficiency may point towards the diagnosis of lymphocytic hypophysitis. Autoimmune thyroid disease and, less commonly, Addison's disease, type 1 diabetes mellitus, hypoparathyroidism, and autoimmune hepatitis may all co-exist with lymphocytic hypophysitis. Non-functional or gonadotrophin-secreting adenomas are usually clinically silent and present only with mass effect. Patients with a craniopharyngioma also commonly present with symptoms due to mass effect, rather than endocrine symptoms. Intrasellar meningiomas may mimic non-functional adenomas in their clinical presentation and may even, rarely, mimic pituitary apoplexy.[41][42]
Medical history
A previous history of a pituitary adenoma should raise suspicion of tumour recurrence. A history of previous malignancy (e.g., breast or lung cancer) may suggest metastatic disease.
Both lactotroph hyperplasia and lymphocytic hypophysitis may occur at the end of or after pregnancy. Pre-existing endocrine dysfunction (e.g., long-standing hypothyroidism, long-standing hypogonadism) is a recognised cause of pituitary hyperplasia.[13]
Rarely, somatotroph hyperplasia may occur in response to ectopic secretion of GH-releasing hormone (GHRH). This is usually associated with neuroendocrine tumours (pancreas, kidneys, adrenals, or lungs) that over-produce GHRH.
Pituitary apoplexy, abscess development, and empty sella syndrome are recognised complications of treatment of a pituitary tumour. Predisposing conditions precipitating pituitary apoplexy include a pre-existing pituitary adenoma, some drugs (e.g., anticoagulation therapy, dopamine agonist, gonadotrophin agonist), cardiac surgery, head trauma, and dynamic testing of pituitary function.[30] Pituitary apoplexy can also occur in normal pituitary tissue, during the peri- or postnatal period, as a consequence of hypovolaemic shock (Sheehan's syndrome).[29]
Empty sella syndrome occurs more commonly due to predisposing conditions such as a congenital anatomical abnormality or complications arising from previous pituitary tumours (surgery, irradiation, or tumour infarction), and regression of the pituitary (e.g., following Sheehan's syndrome or hypophysitis).[32] Most patients have no pituitary dysfunction, although a wide spectrum of pituitary deficiencies have been described, especially in those with previous pituitary tumours.
Drug therapy-induced hypophysitis is associated with a history of treatment with anti-cancer immunotherapy checkpoint inhibitors (CTLA-4 and PD-1 inhibitors). The mean time to onset is 1 month, but drug therapy-induced hypophysitis may develop as late as 19 months after initiation of therapy.[43][44]
Age
Patients with some pituitary masses have a characteristic age at presentation.
Patients with craniopharyngiomas have a bimodal age distribution (according to the histological subtype), with a primary peak between the ages of 5 and 15 years and a second smaller peak between the fifth and sixth decades.[45] Craniopharyngiomas should therefore be suspected in younger patients.
A mass presenting in the second and third decades of life may suggest a prolactinoma, and a mass presenting between the ages of 35 and 44 years is more likely to be an ACTH-secreting adenoma.
GH-secreting adenomas have a peak incidence between the fourth or fifth decades of life.[4]
Rathke cleft cysts can be seen at any age but, when symptomatic, usually present between the ages of 40 and 50 years.[46]
Sex
Many pituitary masses are more common in women than in men.
ACTH-secreting adenomas are most common (80% to 90%) in women, as are prolactinomas (female-to-male ratio of 10:1).
A Rathke cleft cyst is approximately 3 times more common in females than in males.[31]
Craniopharyngiomas and both TSH-secreting and GH-secreting adenomas occur at a similar frequency in men and women.
After the fifth decade of life, the frequency of prolactinomas is similar in men and women.[47]
Imaging
MRI
MRI is the preferred diagnostic test for most sellar masses.[48][49] Intravenous contrast medium is useful, but not essential, in the assessment of pituitary lesions.[50] MRI enables classification of pituitary adenomas by size:
Microadenomas (<10 mm)
Macroadenomas (>10 mm).
Women with a prolactinoma are more likely to have a microadenoma; men more commonly present with larger and more invasive adenomas.[36] ACTH-secreting adenomas present as a microadenoma. However, any pituitary adenoma can present as a micro- or macroadenoma.[1]
MRI also may allow discrimination between pituitary adenomas and hyperplasia, which may show diffuse pituitary enlargement.
A mixed cystic and solid mass with enhancement of the solid component and cyst wall, which may frequently show tumour calcification, indicates a craniopharyngioma.
A sellar or intrasellar mass with contrast enhancement, possibly with surrounding cerebral oedema and enhancing dural tail, is seen with a meningioma.
Germ cell tumours, lymphomas, chordomas, and Rathke cleft cysts may be sellar or intrasellar.
Chordomas demonstrate ring enhancement around the tumour. A circular sellar mass with ring enhancement is also seen with a pituitary abscess.
Thickening of the pituitary stalk in combination with an intense contrast enhancement is highly suggestive of lymphocytic hypophysitis.
Pituitary haemorrhage is diagnostic of pituitary apoplexy. An aneurysm may also be detected.
An empty sella indicates an 'empty sella syndrome'.
CT scan
Used to detect lesions of the skull base that may cause bone destruction, with possible involvement of the sella turcica. The administration of intravenous contrast medium helps assess for soft-tissue invasion.[50]
In patients with suspected craniopharyngioma or meningioma, CT may add complementary information demonstrating tumour calcification or associated bony hyperostosis.
Other imaging
In patients with a suspected cerebral aneurysm, MR or CT angiography are used to delineate the aneurysm and direct appropriate definitive management. MR angiography is particlarly useful for assessing involvement of vessels in the suprasellar region, which is important in surgical planning.[50]
Rarely, additional extracranial imaging may also be necessary. In patients with acromegaly and diffuse pituitary enlargement with no evidence of adenoma, the possibility of somatotroph hyperplasia secondary to ectopic GHRH production should be considered. Chest or abdominal CT and/or somatostatin receptor scintigraphy may show the presence of a neuroendocrine tumour (e.g., pancreas, kidneys, adrenals, or lungs). For patients with a history of malignancy (e.g., breast, lung), a chest CT (or other sites depending on the history) may be necessary to identify the primary tumour, to detect other distant metastases, or as part of the clinical staging.
Laboratory investigations
Once a pituitary mass is detected, the patient should be screened for hormone excess, depending on specific signs and symptoms, and for evidence of hypopituitarism. For patients presenting with ≥1 symptoms suggesting pituitary hormone hypersecretion, this may include:
Serum prolactin
A prolactinoma (macroadenoma) can typically be diagnosed with a serum prolactin >8696 picomol/L (>200 nanograms/mL).[51] Values between 870 picomol/L and 8696 picomol/L (20 nanograms/mL and 200 nanograms/mL) can be caused by microadenomas or by a sellar mass causing a stalk effect.
However, it should be recognised that levels may also be elevated in pregnancy, chronic kidney disease, liver disease, and severe hypothyroidism and with medication use (antidepressants, antipsychotics, opiates, cocaine, antihypertensives, gastrointestinal medications, oestrogens, and excessive alcohol intake).[52]
Cortisol and ACTH
When Cushing's disease is suspected, 24-hour urinary cortisol excretion, late-night salivary cortisol, overnight 1-mg or a 48-hour 2-mg dexamethasone suppression test, and low-dose dexamethasone suppression tests are first line tests, two of which should be abnormal to establish the diagnosis.[53][54] The 24-hour urinary cortisol excretion is generally >138 nanomol/24 hours (>50 micrograms/24 hours), and the late-night salivary cortisol is elevated (normal range 63-65 nanomol/L [2300-2400 nanograms/dL]) in these patients. Normal values vary greatly depending on the assay and clinical laboratory used.[54] An elevated urinary cortisol (triple the upper limit of normal for the assay), along with a high-normal or elevated ACTH level, confirms the diagnosis in most cases.
The low-dose dexamethasone test involves giving 1 mg of dexamethasone at 11 p.m., then measuring plasma cortisol level at 8 a.m. the following morning. Dexamethasone levels are measured simultaneously with cortisol to ensure the appropriate levels are achieved. Patients with Cushing's disease and Cushing's syndrome (adrenal cause of hypercortisolism) do not demonstrate suppression of serum cortisol (as opposed to people without Cushing's disease and Cushing's syndrome), and the 8 a.m. cortisol is >50 nanomol/L (1.8 micrograms/dL).
Cushing's disease and Cushing's syndrome are further distinguished with a high-dose dexamethasone suppression test. The patient is given 2 mg of dexamethasone at 6-hour intervals for 48 hours or as an overnight test, using a single dose of 8 mg of dexamethasone at 11 p.m. Plasma cortisol should be obtained at the start of the test and the following morning. A positive test is defined as suppression of cortisol <50% of the baseline value. A positive test suggests a pituitary source of ACTH over-secretion.
Selective venous sampling to confirm central ACTH production may be necessary in patients where no lesion is seen on MRI or the lesion is <7 mm.
Insulin-like growth factor 1 (IGF-1) and serum GH
Measurement of IGF-1 is considered the best first-line test for screening for acromegaly; random GH levels alone are not helpful. Elevated IGF-1, when associated with an elevated level of GH and a sellar mass on MRI, almost affirms the diagnosis of acromegaly.[39]
When basal GH levels are not elevated, dynamic testing for establishing the diagnosis of acromegaly is needed. The 75-g oral glucose tolerance test is the diagnostic standard; serum GH level >1 microgram/L (>1 nanogram/mL) within 2 hours is seen in patients with acromegaly.[39]
In patients with somatotroph hyperplasia secondary to ectopic GHRH production, GHRH levels are elevated, in addition to elevated IGF-1 and GH. Somatostatin receptor scintigraphy may help locate the tumour.
FSH and LH
Measurement may be of value in evaluating non-functional or glycoprotein-secreting adenomas (gonadotroph cell adenomas) and gonadotroph hyperplasia. In patients with gonadotroph hyperplasia, elevated LH and FSH levels are associated with low testosterone or estradiol. Elevated FSH, LH, and/or LH-alpha subunit may either suggest a pituitary gonadotroph adenoma or be due to primary hypogonadism.
TSH, free T4, and free T3
Normal or elevated TSH with an elevated free T4 and/or free T3 suggests a thyrotroph adenoma.
Co-existing hypopituitarism should also be assessed to identify and replace any hormone deficiency.[55] Hypopituitarism may involve any or all of the endocrine axes regulated by the pituitary. In order of frequency, it leads to GH deficiency, secondary hypogonadism, secondary hypothyroidism, and secondary adrenal failure. It may also cause diabetes insipidus. In lymphocytic hypophysitis, ACTH deficiency is the most common (and earliest) endocrine dysfunction.
Initially, baseline serum IGF-1, prolactin, TSH, free T4, 8 a.m. cortisol, ACTH, LH, FSH, testosterone (males), and estradiol (females) should be tested. A low early-morning cortisol level in the setting of an inappropriately low or normal ACTH level suggests ACTH deficiency. Low serum testosterone or estradiol levels suggest end-organ endocrine deficiency as a consequence of gonadotrophin deficiency.
Dynamic testing of pituitary hormone function, including GH provocation tests, thyrotropin-releasing hormone test, and luteinising hormone-releasing hormone (LHRH) test, as well as dynamic assessment of the hypothalamic-pituitary-adrenal axis, may rarely be needed in some situations. An ACTH stimulation test may also be performed to assess the adrenal axis. Serum cortisol concentration <497 nanomol/L (<18 micrograms/dL) at 30 minutes after 250 micrograms of ACTH suggests hypocortisolism but does not differentiate between a pituitary and an adrenal cause.
If the history suggests diabetes insipidus (excessive thirst, polyuria, weight loss, loss of appetite), paired serum and urine osmolalities and serum electrolytes should be measured.
Additional investigations to ascertain the aetiology/complications of a pituitary mass may include:
FBC, erythrocyte sedimentation rate, and C-reactive protein in any patient with a suspected pituitary abscess
Serum sodium: hyponatraemia may be present in ACTH deficiency
Serum alpha-fetoprotein and beta-hCG in any patient with suspected germ cell tumour
Autoantibody serology: in patients with suspected lymphocytic hypophysitis, autoantibodies to adrenal cortex (Addison's disease), antithyroid peroxidase (Hashimoto's thyroiditis), antinuclear antibodies, and anti-smooth muscle antibodies (autoimmune hepatitis) may support an underlying immune process
Surgical biopsy: may be necessary to establish diagnosis in the absence of specific endocrine or imaging features (e.g., lymphoma, chordoma, Rathke cleft cyst).
Visual-field examination
A clinical visual-field examination is performed in all patients as part of the initial patient assessment. Computerised visual-field testing should be performed in any patient presenting with visual-field defects or where imaging reveals a lesion close to the optic chiasm.
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