The Hypothalamic Pituitary Axis and its Assessment
The pituitary gland is the ‘conductor of the endocrine orchestra’, controlling all peripheral glands via trophic hormones. It is approximately the size of a pea and sits in the pituitary fossa at the base of the brain (Figure 2.1). The anterior pituitary is derived embryologically from Rathke’s pouch, derived from primitive gut tissue. The posterior pituitary is derived from a down-growth of primitive brain tissue. The optic chiasm lies superior to the pituitary gland. Lateral is the cavernous sinus, which contains cranial nerves III, IV and Va and the internal carotid artery (Figure 2.1).
Hypothalamic releasing and inhibiting factors are transported along the hypophyseal portal tract to the anterior pituitary. There are five pituitary axes: GH, ACTH, gonadotrophins (FSH and LH), TSH and prolactin (Table 2.1).
GH is secreted in a pulsatile manner with peak pulses during REM sleep. GH acts on the liver to produce IGF-1, which is used as a marker of GH activity. GH exerts its action both by direct effects of GH and via IGF-1. GH causes musculoskeletal growth in children and has an important role in adults. Growth hormone releasing hormone (GHRH) stimulates GH, while somatostatin inhibits it.
ACTH has a circadian rhythm, with peak pulses early in the morning and lowest activity at midnight. ACTH stimulates cortisol release, and is itself stimulated by corticotrophin releasing hormone (CRH). Cortisol is the only hormone that inhibits ACTH.
Gonadotrophins (FSH and LH)
FSH leads to ovarian follicle development in women and spermatogenesis in men. In women, LH causes mid-cycle ovulation during the LH surge andformation of the corpus luteum. In men, LH drives testosterone secretion from testicular Leydig cells. Gonadotrophin releasing hormone (GnRH) stimulates LH and FSH release. Testosterone and oestrogen inhibit LH and FSH, while prolactin also has a direct inhibitory effect.
TSH drives thyroxine release via stimulation of TSH receptors in the thyroid gland. TRH stimulates TSH secretion and is a weak stimulator of prolactin secretion. Thyroxine directly inhibits TSH.
Prolactin causes lactation and inhibits LH and FSH. It is under predominantly negative control by dopamine and weak stimulatory control by TRH. Anything that inhibits dopamine leads to an elevation in prolactin level.
Assessment of the pituitary gland
Pituitary tumours develop as a result of compression of local structures and/or the effects of endocrine hypo- or hypersecretion. Compression of the optic chiasm classically leads to a bi-temporal hemianopia. Assessment of visual fields with a red pin is a mandatory part of the clinical examination of patients with pituitary tumours. Automated visual field assessment has superseded Goldmann perimetry as the formal way of documenting visual field defects.
Prolactin and TSH do not have major circadian rhythms so can be checked at any time of day. Both free T4 (fT4) and TSH should be checked in pituitary disease because TSH is often normal in secondary hypothyroidism. In women, LH and FSH should be measured within the first 5 days of the menstrual cycle (follicular phase). In men, LH, FSH and basal testosterone should be checked at 09.00 in the fasting state. Basal cortisol should be checked at 09.00 to exclude deficiency, although a stimulatory (Synacthen) test is usually needed to confirm this. IGF-1 is a marker of GH activity: low or low–normal levels suggesting GH deficiency; high levels suggesting GH excess.
Dynamic pituitary tests
Dynamic endocrine tests are used to assess hormones that have a pulsatile secretion or circadian rhythm. If an endocrine deficiency is suspected, a stimulation test is used; if endocrine excess is suspected, a suppression test is used (Table 2.1). All endocrine tests should be interpreted in the clinical context.
This is predominantly used to assess primary adrenal failure, but also to assess pituitary ACTH reserve. After 2 weeks of ACTH deficiency, atrophy of the adrenal cortex leads to an inadequate response to synthetic ACTH (Synacthen). This test should not be used in the acute situation, such as pituitary apoplexy, or immediately post-pituitary surgery.
Insulin tolerance test
The insulin tolerance test (ITT) is the gold standard test of ACTH and GH reserve. Insulin-induced hypoglycaemia (glucose <2.5 mmol/L) causes physiological stress, leading to a rise in ACTH and GH. A normal cortisol response to hypoglycaemia is >550 nmol/L whereas a GH value >3 µg/dL after hypoglycaemia excludes severe GH deficiency in adults. The ITT is contraindicated in patients with ischaemic heart disease and epilepsy.
Other tests of GH reserve
The ITT is the gold standard assessment of GH reserve, but is an invasive and unpleasant test to undergo. Glucagon can be used instead of the ITT, although it is a less robust test of GH reserve; nausea is a common side effect. The GHRH–arginine test has particular use in patients who have had pituitary radiotherapy. Common side effects of this are flushing, nausea and an unpleasant taste in the mouth.
Magnetic resonance imaging (MRI) is the imaging modality of choice for the pituitary gland (Figure 2.1). Dedicated pituitary views with injection of contrast highlight the difference between tumour and normal gland. Pituitary tumours >1 cm are termed macro-adenomas, while lesions <1 cm are called micro- adenomas. Computed tomography (CT) may be adequate in patients who are unable to undergo MRI. There is increasing r imaging modalities, including 11C-methionine ositron emission tomography (PET).