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The diagnosis of pituitary disease is generally uncomplicated. This is despite the high prevalence of occult pituitary adenomas in the general population, the widespread use of high definition imaging techniques, and the broad range of intra- and perisellar lesions that can mimic pituitary adenomas. Follow up and optimisation of pituitary hormone replacement is also relatively straightforward, but management of visual impairment, reduced fertility, coarsened facial features, arthritis, obesity, headaches, and obstructive sleep apnoea is often much more troublesome. The Pituitary Foundation (internet search term: “Pit Pat”) provides important opinion and information, and reassures patients that they are not alone.
In this brief overview, the presentation, classification, and general investigation of pituitary lesions is followed by a discussion of the diagnosis and management of specific secretory subtypes.
PRESENTATION OF PITUITARY ADENOMAS
Inappropriate pituitary hormone secretion and visual field deficits are the most characteristic presenting features of pituitary adenomas. Less specific symptoms such as headache, and subtle signs of pituitary hormone deficiency with peripheral endocrine organ hypofunction characterised by amenorrhoea, loss of libido, and lethargy, are also common. Lymphocytic hypophysitis, pituitary apoplexy, and evidence of more extensive disease such as cranial nerve palsies, temporal lobe epilepsy, hydrocephalus, and cerebrospinal fluid (CSF) rhinorrhoea are fortunately rarer. An exaggerated “physiological” trophic response to prolonged hypothyroidism presenting with visual field defects is well described but is, like pituitary carcinoma, very rare.
CLASSIFICATION OF PITUITARY ADENOMAS
Pituitary adenomas are classified by size and hormone secretory subtype. So-called “silent adenomas”, in which abnormal hormone gene activity is not accompanied by excessive hormone secretion, tend to be more aggressive than truly inactive adenomas. Erosion of the sellar walls and cavernous sinus invasion also suggest a more invasive nature, but estimation of mitotic index and subclassifications based on genetic and ultrastructural studies are research tools without significant clinical utility.
Magnetic resonance imaging (MRI) scanning of the pituitary region, involving fine cuts and saggital and coronal reconstruction, is the gold standard imaging method for pituitary disease. Some patients find the noise, confined space, and extended duration of MRI examination uncomfortable, however, and calcified lesions such as craniopharyngiomas may be more easily identified with computed tomography (CT). Gadolinium enhancement of pituitary MRI can be helpful for small microadenomas.
Progressive deterioration of visual fields is often the principle neurological criterion on which surgical management decisions are based. Humphrey computerised visual fields are useful even if there appears to be no contact between the optic pathways and pituitary mass. This is because field defects may reflect previous impingement, potential vascular shunting, or displacement of the chiasm following decompression. As dense bitemporal loss may reduce binocular field by only 25%, Esterman fields are important to objectively assess fitness to drive (internet search term: “DVLA”).
Symptoms and signs of pituitary hormone deficiency are more subtle than those seen in primary end organ failure (table 1). Syndromes of pituitary hormone excess are described below.
Oligomenorrhoea or amenorrhoea, reduced fertility, loss of libido, erectile dysfunction and in the oestrogen primed female breast, galactorrhoea, are typical.
By definition, microprolactinomas are less than 10 mm in diameter and are contained entirely within the intact sella turcica (fig 1). Microprolactinomas remain unchanged or decrease in size over time, with a small chance of complete, spontaneous resolution. Significant expansion is very rare. Circulating prolactin concentrations are often indistinguishable from those seen in other common conditions (table 2).
A prolactin value of ⩾ 5000 mU/l is highly suggestive of a macroprolactinoma (fig 2). In very large pituitary adenomas, the laboratory should be specifically asked to dilute the preoperative prolactin serum sample to disclose the “high dose hook effect”—responsible for the falsely low prolactin in the two-site chemiluminometric assay found in up to 14% of cases.
A macroprolactinoma producing relatively low concentrations of prolactin (for example, 2000–4000 IU/l) may be indistinguishable from an endocrinologically inactive adenoma reducing dopamine flow to normal lactotrophs by compressing the pituitary stalk. Dopamine analogues reduce prolactin values in both and careful follow up in the longer term is required to identify behavioural differences, such as size reduction in a macroprolactinoma and slow growth in an endocrinologically inactive adenoma. In this scenario, a degree of diagnostic uncertainty is more acceptable than potentially unnecessary surgery.
The vast majority of microprolactinomas and macroprolactinomas respond to ergot derived dopamine receptor agonists such as cabergoline or bromocriptine. For many patients cabergoline has a more satisfactory side effect profile than bromocriptine, and at doses used for pituitary disease, psychoses and clinically significant fibrotic reactions are rare. Microprolactinomas change little in size with treatment but macroprolactinomas can be expected to shrink, sometimes quite dramatically. Although not teratogenic, dopamine receptor agonists are withdrawn as soon as pregnancy is confirmed and visual fields checked at intervals to identify the small proportion of women whose macroprolactinomas enlarge significantly.
It is important that the objectives of microprolactinoma treatment are kept in mind. In a patient with galactorrhoea, reducing prolactin concentrations with dopamine analogues is clearly central, but for women in whom the problem of hyperprolactinaemia relates only to suppressed oestrogen values, sex hormone replacement may be more appropriate. No treatment at all, or specific management of osteoporotic risk with selective oestrogen receptor modulators or bisphosphonates, for example, may be a perfectly acceptable option for otherwise asymptomatic post-menopausal women. There is no link between oestrogen use and prolactinoma formation and no evidence that concurrent oestrogen use worsens prolactinoma outlook.1
Surgery is reserved for occasional patients who cannot tolerate dopamine agonists, who suffer pituitary apoplexy during treatment, or whose macroprolactinomas are otherwise non-responsive.
The diagnosis of active acromegaly is based on continuing somatic changes (table 3) and confirmed by finding two or more raised basal growth hormone (GH) values. A random growth hormone of < 1 mU/l (< 0.4 µg/l) with normal insulin-like growth factor 1 (IGF-1) essentially excludes active disease. In borderline cases the diagnosis can be established by demonstrating failure of a 75 g glucose load to suppress GH concentrations to < 2 mU/l during the subsequent two hours. An MRI of the pituitary usually discloses the adenoma.
TREATMENT FOR ACROMEGALY
Microadenomectomy or macroadenoma decompression is approached transsphenoidally in most patients. Increasingly, endoscopic surgery allows the entire surgical field to be viewed and tumour tissue that would otherwise be inaccessible with rigid instruments to be safely resected. Nevertheless, complete return of GH concentrations to normal is not often achieved.2
Specific complications of transsphenoidal surgery such as CSF leak, hypopituitarism, and some degree of nasal discomfort are for the most part predictable. Biochemically, transient diabetes insipidus is unusual after transsphenoidal surgery but mild SIADH (syndrome of inappropriate vasopressin secretion) for a week or two postoperatively is relatively common. Glucocorticoid cover for potential secondary hypoadrenocorticalism is unnecessary.
The efficacy of pituitary surgery rests entirely with the innate skill of the surgeon. This can be honed by experience and polished by continued practice but cannot be achieved through enthusiasm alone. In the opinion of the author, moral responsibility for the outcome of surgery rests with the referring physician.
The two- to fivefold reduction in pituitary adenoma relapse rate3 offered by adjuvant LINAC radiotherapy is offset by the short term inconvenience of fractionated treatment, the slow rate of reduction of excessive hormone secretion, the risk of hypopituitarism, and the small but unequivocal increase in incidence of second tumours within the radiation field (up to 2% over 20 years). The principle disincentive, however, is the widespread perception, not supported by convincing data, that pituitary radiotherapy might adversely affect cognitive function and levels of anxiety and depression. As a result adjunctive radiotherapy is increasingly reserved for tumours that extend beyond the safe operative field and are thought to pose an ongoing threat. Gamma knife radiosurgery does not appear to be associated with significantly higher cure rates or fewer complications, but may be more convenient to deliver than conventional radiation.
Parenteral long acting somatostatin analogues reduce IGF-1 concentrations to normal in up to two thirds of acromegalics, and in a minority, tumour volume diminishes. Symptoms of acromegaly such as headaches, sweating, and arthralgia decrease with treatment but the discomfort of injections and gastrointestinal side effects such as colic, diarrhoea, or constipation can be limiting.4 Somatostatin analogue induced biliary abnormalities such as sediment, sludge, and gallstones rarely become symptomatic. Particularly if used first line, the cost of this treatment modality is a major consideration when long term disease control is being considered.
Dopamine analogues are effective in reducing GH and IGF-1 in a minority of acromegalic patients. Cabergoline is more effective than bromocriptine and is said to be able to restore IGF-1 to within the normal range in a little over 35% of acromegalic patients.5
GH receptor antagonists
Pegvisomant is the first of a new class of GH receptor antagonists that work by inhibiting functional dimerisation of GH receptors. Preliminary results suggest that it may be the most effective medical treatment for acromegaly reported to date.6
Impaired glucose tolerance, hypertension, and hyperlipidaemia should be vigorously treated and great care taken to ensure that joints are suitably protected, particularly in the working population. Assistance from rheumatologists, chest physicians, and orthopaedic and maxillofacial surgeons may be required for treatment of arthritis, carpal tunnel syndrome, obstructive sleep apnoea, and prognathism.
Screening for malignancies
A consensus about cancer risk in acromegaly has yet to emerge, but data tend to support a real but relatively modest increase in colorectal cancer risk.7 Some centres screen acromegalic patients at diagnosis and offer a further colonoscopy at 55 years of age.
The lack of specificity of many of the phenotypic characteristics of Cushing’s syndrome (table 4), quantitative rather than qualitative biochemical changes, and cyclical disease makes this one of the more absorbing pituitary adenoma pathologies to diagnose and manage effectively. Prognostic markers of the efficacy of treatment, the best of which is the requirement for exogenous glucocorticoids for more than a year after surgical adenomectomy, are relatively unreliable, and the significant relapse rate after seemingly adequate treatment encourages use of the term remission rather than cure.8
Some patients develop the neuropsychiatric and physical characteristics of Cushing’s remarkably abruptly, but many seem unable to clearly identify a time before the onset of disease. Investigations seek firstly to confirm hypercortisolaemia, then to identify the source.
Establishment of hypercortisolaemia
The widely used low dose overnight dexamethasone suppression test is non-specific and insensitive. The best screening test for hypercortisolaemia currently available is the 24 hour urine-free cortisol (UFC), and the definitive test is the dexamethasone suppressed corticotrophin releasing hormone (CRH) test.9 Patients are given 8 × 0.5 mg dexamethasone tablets to take at six hourly intervals at home starting at midday and ending two days later at 6 am. Two hours after the last dose of dexamethasone, a 100 µg bolus of CRH (strictly 1 µg/kg) is given intravenously and 15 minutes later a single blood cortisol of > 38 nmol/l distinguishes hypercortisolaemia from pseudo-Cushing’s and normal subjects. The source of hypercortisolaemia is established as described (table 5).
Transsphenoidal adenomectomy, sometimes preceded in florid disease by several weeks of medical management, is the treatment of choice. Success is often accompanied by a period of dry, peeling skin and postoperative requirement for exogenous glucocorticoids. If hypercortisolaemia persists, early repeat exploration and/or radiotherapy or laparoscopic bilateral adrenalectomy may be required.
Metyrapone or ketoconazole (an inhibitor of sterol synthesis in fungi that also blocks mitochondrial P450 dependent enzyme systems) are titrated against cortisol values. Mitotane and aminoglutethimide are less widely used. In acute steroid psychoses or when a patient is unable to tolerate oral treatment, the intravenous inducing agent etomidate at 1/30th of its anaesthetic dose is dramatically effective.
THYROTROPHIN AND OTHER GLYCOPEPTIDE HORMONE SECRETING ADENOMAS
Bioactive glycopeptide hormone secretion is rare. Thyrotrophin (TSH secreting) pituitary adenomas are characterised by hyperthyroidism without TSH suppression. In many cases TSH concentrations are within the “normal” range or only minimally raised. Antithyroid treatment is inappropriate and tends to provoke further growth of these relatively aggressive lesions. Although usually sensitive to somatostatin analogues, the efficacy of medical treatment tends to wane with time.
Haemorrhage or infarction of the pituitary may be clinically benign or present catastrophically with severe headache, meningism, vomiting, reduction in visual fields, diplopia, impairment of consciousness, or death. It frequently mimics other intracranial pathologies and a high index of suspicion is required, particularly as CT identifies pituitary haemorrhage in only about half of those scanned. The normal pituitary can be affected under some circumstances, but endocrinologically inactive adenomas underlie at least half of all cases. The necessity and urgency of surgical decompression depends very much on the presence, and rate and direction of change, of visual symptoms. Many cases are managed entirely conservatively, with replacement of pituitary hormones if and when required.
Lymphocytic hypophysitis is a rare condition typically associated with pregnancy but described in both sexes and most ages. The pituitary gland is expanded by an infiltrate of lymphocytes, plasma cells, and macrophages leading in a proportion of cases to impaired pituitary function.10 The diagnosis is worth considering in the differential diagnosis of a macroadenoma presenting during pregnancy or within six months of delivery as spontaneous resolution of the mass, but not necessarily the associated hypopituitarism, may occur. Although believed to be mediated by autoimmune mechanisms, there is no evidence that immunosuppressive treatment alters the outcome of presumed or histologically confirmed disease, or that anti-pituitary antibody measurements are prognostically or diagnostically useful.
Craniopharyngiomas are calcified, cystic, suprasellar tumours arising from epithelial and squamous cell remnants of the craniopharyngeal duct, which closes in early pituitary embryogenesis to give rise to Rathke’s pouch by disconnecting Rathke’s cleft from the stomodeum (fig 3). They usually present as one or more cysts filled with oily proteinaceous material rich in cholesterol crystals, arising in the region of the pituitary stalk and projecting into the hypothalamus and expanding horizontally, apparently along the paths of least resistance.
Craniopharyngiomas have a bimodal distribution with a peak in childhood around the age of 9 years and a further peak in late middle age. Typical presenting symptoms in paediatric practice are headache, vomiting, visual disturbance, diabetes insipidus, and growth deceleration, which lead to delayed puberty, short stature, and panhypopituitarism. Owing to the proximity of these tumours to the chiasm and hypothalamus, their size before diagnosis (often exceeding 3 cm in diameter) and their tendency to recur, visual deficits, permanent diabetes insipidus, panhypopituitarism, and hypothalamic injury with obesity, somnolence, and loss of volition are relatively common. Adjunctive radiotherapy following partial resection reduces recurrence rate.
RATHKE CLEFT CYST
When the rostral invagination of the stomodeum, Rathke’s pouch, is pinched off during embryogenesis, the remaining vesicular structure often involutes completely. Remnants may persist as a cleft lined by cuboidal epithelium that can expand to form an uncalcified cystic or polycystic lesion with intra- and suprasellar components. These lesions mimic endocrinologically inactive adenomas or craniopharyngiomas but have a particularly low recurrence rate after partial excision.
FAMILIAL CANCER SYNDROME INVOLVING THE PITUITARY
There are three familial conditions associated with pituitary adenoma formation: multiple endocrine neoplasia type 1, Carney complex, and isolated familial acromegaly.1
Multiple endocrine neoplasia type 1 (MEN-1)
This is an autosomal dominant condition associated principally with tumours of the parathyroid, pancreas and, in approximately 45% of patients, the pituitary. Collagenomas, lipomas, lentiginosis, and multiple angiofibromas of the dermis are also common and MEN-1 kindreds are at increased risk of thyroid epithelioma, adrenal gland, foregut carcinoid tumours, and tumours of the central nervous system, such as spinal ependymoma.
This is a rare autosomal dominant condition characterised by myxomas of the heart, skin, and breast, spotty skin pigmentation, schwannomas, ovarian cysts, adrenal, testicular and thyroid tumours, and in 6–21% of patients, pituitary adenomas.
Isolated familial acromegaly
These individuals tend to develop acromegaly or gigantism at a relatively young age. The pattern of chromosomal loss of heterozygosity has some similarities to those found in MEN-1 and Carney complex.
A guide to diagnosis of pituitary hormone deficiency and replacement is shown in table 6.