Presentations of hypothalamic and pituitary disease
Pituitary space-occupying lesions and tumours
Pituitary tumours (Table 16.6) are the most common cause of pituitary disease. Problems may be caused by
excess hormone secretion, by local effects of a tumour, or as the result of inadequate production of
hormone by the remaining normal pituitary – hypopituitarism. The great majority of pituitary tumours are
benign pituitary adenomas.
INVESTIGATIONS
The investigation of a possible or proven tumour follows three lines.
Is there a tumour?
If there is, how big is it and what local anatomical effects is it exerting? Pituitary and hypothalamic spaceoccupying lesions, hormonally active or not, can cause symptoms by infiltration of, or pressure on:
• the visual pathways, with field defects and visual loss
• the cavernous sinus, with III, IV and VI cranial nerve lesions
• bony structures and the meninges surrounding the fossa, causing headache
• hypothalamic centres: altered appetite, obesity, thirst, somnolence/wakefulness or precocious puberty
• the ventricle, causing interruption of cerebrospinal fluid (CSF) flow leading to hydrocephalus
• rarely, the sphenoid sinus with invasion causing CSF rhinorrhoea.
Investigations
•Lateral skull X-ray. This may show enlargement of the fossa (Fig 16.8). Although an X-ray is now rarely
requested as a definitive investigation, this remains a common incidental finding and requires further
investigation.
•Visual fields. These should be plotted formally by automated computer perimetry or Goldmann perimetry
after confrontation at the bedside using a small red pin as target. Common defects are upper-temporal
quadrantanopias and bitemporal hemianopias (see p. 1014). Subtle defects may also be revealed by delay or
attenuation of visual evoked potentials (VEPs).
•MRI of the pituitary. MRI is superior to high-resolution CT scanning with reconstruction (Fig 16.9).
Is there a hormonal excess?
There are three major conditions that may be caused by tumour or hyperplasia:
• GH excess, leading to acromegaly or gigantism – these are usually acidophil adenomas, and a proportion
are due to specific G-protein mutations Gs (see p. 126)
• prolactin excess (prolactinoma or hyperprolactinaemia) – histologically, prolactinomas are chromophobe
adenomas
• Cushing’s disease and Nelson’s syndrome (excess ACTH secretion) – basophil adenomas.
Occasional tumours produce both GH and prolactin.
The clinical features of acromegaly and Cushing’s disease or hyperprolactinaemia are usually (but not
always) obvious, and are discussed below (see pages 928, 946 and 922). Hyperprolactinaemia may be
clinically ‘silent’. Tumours producing LH, FSH or TSH are very rare.
Some pituitary tumours cause no clinically apparent hormone excess and are referred to as ‘nonfunctioning’ tumours, which are common and usually chromophobe adenomas. Laboratory studies such as
immunocytochemistry show that these tumours may often produce LH and FSH or the subunit of LH,
FSH and TSH (see Table 16.5). Studies have shown that pituitary adenomas of all types are usually
monoclonal in origin.
Is there a deficiency of any hormone?
Clinical examination may give clues; thus, short stature in a child with a pituitary tumour is likely to be due
to GH deficiency. A slow, lethargic adult with pale skin is likely to be deficient in TSH and/or ACTH.
Milder deficiencies may not be obvious, and require specific testing (see Table 16.9).
Differential diagnosis of apparent pituitary adenomas additionally includes craniopharyngioma, or a
usually cystic hypothalamic tumour arising from Rathke’s pouch that often mimics an intrinsic pituitary
lesion. Although presenting at any age, it is the most common tumour in children and is often calcified.
Less common are meningiomas, gliomas, chondromas, pinealomas and carotid artery aneurysms
masquerading as tumours. Secondary deposits occasionally present as apparent pituitary tumours, often
presenting as diabetes insipidus.
TREATMENT
Treatment depends on the type and size of tumour (Table 16.7) and is discussed in more detail in the
relevant sections (acromegaly, see p. 928; prolactinoma, see p. 922). In general, therapy has three aims:
Removal/control of tumour
Surgery via the trans-sphenoidal route is usually the treatment of choice. Large tumours are occasionally
removed via the open transfrontal route. Radiotherapy is given if the tumour is incompletely removed.
Radiotherapy may be by an external three-beam technique, stereotactic or rarely via implant of yttrium
needles. It is usually employed when surgery is impracticable or incomplete as it rarely abolishes tumour
mass. The standard regimen involves a dose of about 45 Gy, given as 20–25 fractions.
Octreotide or dopamine agonists such as bromocriptine sometimes cause shrinkage of specific types of
tumour.
Reduction of excess hormone secretion
Reduction is usually obtained by surgical removal but sometimes by medical treatment (e.g. bromocriptine
or octreotide alone). Prolactinomas respond with significant tumour shrinkage to dopamine agonists (see p.
922). Acromegaly, however, responds less well (see p. 929). ACTH secretion usually cannot be controlled
by medical means.
Replacement of hormone deficiencies
Replacement of hormone deficiencies is detailed in Table 16.10.
Small tumours producing no significant symptoms, pressure or endocrine effects are observed with regular
clinical, visual field, imaging and endocrine assessments.
Lateral skull X-ray, showing double floor (arrows) and enlargement of the pituitary fossa
in a patient with acromegaly
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a) MR image of pituitary fossa, showing tumour with suprasellar extension
(b) CT scan (sagittal reconstruction), showing a pituitary tumour with suprasellar
extension (arrows show upper border)
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Hypopituitarism
PATHOPHYSIOLOGY
Deficiency of hypothalamic releasing hormones or of pituitary trophic hormones are either selective or
multiple. There are, for example, rare isolated deficiencies of LH/FSH and ACTH, some of which may be
congenital, autoimmune or idiopathic in nature.
Multiple deficiencies usually result from tumour growth or other destructive lesions. With the latter there is
generally a progressive loss of anterior pituitary function in the order shown from left to right in Fig 16.7.
GH and gonadotrophins, LH before FSH, are usually first affected. Rather than prolactin deficiency,
hyperprolactinaemia occurs relatively early because of loss of tonic inhibitory control by dopamine. TSH
and ACTH are usually last to be affected. Panhypopituitarism refers to deficiency of all anterior pituitary
hormones; it is most commonly caused by pituitary tumours, surgery or radiotherapy.
Vasopressin and oxytocin secretion will be significantly affected only if the hypothalamus is involved,
either by a hypothalamic tumour or by major suprasellar extension of a pituitary lesion.
CAUSES
Disorders causing hypopituitarism are listed in Table 16.8. Pituitary and hypothalamic tumours, and
surgical or radiotherapy treatment, are the most common.
CLINICAL FEATURES
Symptoms and signs depend upon the extent of hypothalamic and/or pituitary deficiencies, and mild
deficiencies may not lead to any complaint by the patient. Loss of libido, amenorrhoea and impotence are
symptoms of gonadotrophin and thus gonadal deficiencies, while hyperprolactinaemia may cause
galactorrhoea and hypo-gonadism. GH deficiency is relatively clinically ‘silent’ except in children, though
recent evidence suggests that it may cause markedly impaired well-being in adults. Secondary
hypothyroidism and adrenal failure lead to tiredness, slowness of thought and action, and mild hypotension. Long-standing panhypopituitarism may give the classic picture of pallor with hairlessness
(‘alabaster skin’).
Particular syndromes related to hypopituitarism are considered below.
Kallmann’s syndrome
This syndrome is isolated gonadotrophin deficiency, which leads to hypogonadism, usually associated with
anosmia (see p. 916). One sex-linked form has been shown to be due to an abnormality of a cell adhesion
molecule.
Sheehan’s syndrome
This situation, now rare, is pituitary infarction following postpartum haemorrhage.
Pituitary apoplexy
A pituitary tumour may occasionally infarct or haemorrhage into itself. This may produce severe headache
sometimes followed by acute life-threatening hypopituitarism.
The ‘empty sella’ syndrome
An ‘empty sella’ is sometimes reported on pituitary imaging. This is sometimes due to a defect in the
diaphragma and extension of the subarachnoid space (cisternal herniation) or may follow spontaneous
infarction of a tumour. All or most of the sella turcica is devoid of apparent pituitary tissue, but, despite
this, pituitary function is usually normal, the pituitary being eccentrically placed and flattened against the
floor or roof of the fossa.
INVESTIGATIONS
Each axis of the hypothalamic–pituitary system requires separate investigation. However, the presence of
normal gonadal function (ovulatory/menstruation or normal libido/ erections) suggests that multiple defects
of anterior pituitary function are unlikely.
Tests range from the simple basal levels (e.g. T 4 or free T4 for the thyroid axis), to stimulatory tests for the
pituitary, and tests of feedback for the hypothalamus (Table 16.9). The insulin tolerance test is now less
widely used, as basal 0900h cortisol levels above 500 nmol L–1, and probably even above 400 nmol L–1,
reliably indicate an adequate reserve, while levels below 100 nmol L–1 predict an inadequate response. The
Synacthen test, though an indirect measure, has been advocated as an adequate indicator of hypothalamic–
pituitary–adrenal status, but this remains controversial. Overall the assessment of adrenal reserve is best left
in the hands of a specialist endocrinologist.
TREATMENT
Steroid and thyroid hormones are essential for life. Both may be given as oral replacement drugs, aiming to
restore the patient to clinical and biochemical normality (Table 16.10). Sex hormone production may be
replaced with androgens and oestrogens for symptomatic control; if necessary, human chorionic
gonadotrophin (HCG, mainly acting as LH) and purified or biosynthetic gonadotrophins can be given if
fertility is desired. Pulsatile GnRH (luteinizing hormone releasing hormone, LHRH) therapy is sometimes
used where there is residual pituitary function, but it is expensive and time-consuming.
GH therapy should be given if necessary in the growing child under appropriate specialist supervision. In
the adult, GH therapy also produces substantial improvements in body composition, work capacity and
psychological well-being in acquired GH deficiency, together with reversal of lipid abnormalities carrying
a high cardiovascular risk. Although now licensed for such use in many countries, the long-term safety and
efficacy of GH therapy is not yet fully established, and its cost is £2500–6000 per annum. Two important
points should be noted:
• Thyroid replacement should not commence until normal glucocorticoid function has been demonstrated
or replacement steroid therapy initiated, as an adrenal ‘crisis’ may otherwise be precipitated.
• Glucocorticoid deficiency may mask impaired urine concentrating ability, diabetes insipidus only
becoming apparent after steroid replacement, the steroids being necessary for excretion of a water load.
Hypothalamic releasing hormones and the pituitary trophic hormones. See the text for
abbreviations and an explanation
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Weight, exercise and stress
Anorexia nervosa, the ‘slimming disease’ commonly affecting young females, is associated with major
functional hypopituitarism (see p. 1142). This often presents as amenorrhoea, without which the diagnosis
is extremely unlikely. Anorexia is an extreme example, but more marginal degrees of underweight are a
cause of secondary amenorrhoea and oligomenorrhoea, and are often unrecognized as a cause of
subfertility. Similar effects are seen in female athletes undergoing heavy training with menstrual
irregularity that invariably reverts to normal when training stops.
Stress, though difficult to define, also affects endocrine function, especially menstruation. Emotional
deprivation in childhood is an important cause of growth retardation and may be mediated by reduced GH
secretion.