Hypopituitarism

Hypopituitarism is deficiency of one or more anterior and, in some cases, posterior pituitary hormones. The pattern and combination of deficiencies vary with the underlying cause and the extent of pituitary or hypothalamic involvement.

Causes:

• Pituitary or hypothalamic tumour: direct destruction of normal pituitary tissue or, importantly, the effect of subsequent surgical or radiotherapy treatment
• Traumatic brain injury
• Pituitary apoplexy (see pituitary adenoma)
• Postpartum pituitary infarction (Sheehan syndrome): historically associated with severe postpartum haemorrhage, now uncommon in resource rich settings given improved obstetric care
• Infiltrative and inflammatory conditions: neurosarcoidosis, Langerhans cell histiocytosis, and lymphocytic hypophysitis. The latter has gained contemporary relevance as an immune related adverse effect of immune checkpoint inhibitor cancer therapy
• Less commonly, genetic or congenital causes

Pathophysiology and the significance of hormone axis sequence

• Destruction or dysfunction of the anterior pituitary produces loss of one or more anterior pituitary hormone axes: growth hormone, gonadotropins, thyroid stimulating hormone, and adrenocorticotropic hormone. Causes include direct tumour infiltration, compression by an adjacent mass lesion, surgical resection, radiotherapy related atrophy, infarction, or infiltrative inflammatory disease.
• Prolactin is separate. Its control from the hypothalamus is predominantly tonic and inhibitory rather than stimulatory. It characteristically shows the opposite pattern: modest elevation rather than deficiency is the more typical finding in pituitary stalk disruption (see hyperprolactinaemia).
• A generally recognised, though not invariable, sequence of axis loss occurs with progressive pituitary damage. Growth hormone and gonadotropin deficiency typically occur earliest and most sensitively. Thyroid stimulating hormone and, adrenocorticotropic hormone deficiency generally occur later with more extensive gland destruction.
• This sequence informs the pattern of clinical presentation and the structure of hormonal screening in suspected hypopituitarism. The pattern can vary with the underlying cause.
• Posterior pituitary (arginine vasopressin) deficiency (see arginine vasopressin disorders) may coexist with anterior deficiency where the process involves the hypothalamus or pituitary stalk as well as the anterior gland. Isolated anterior deficiency without arginine vasopressin deficiency is more typical of processes confined to the anterior gland.

• The presentation reflects the combination and severity of hormone deficiencies. Onset is acute in pituitary apoplexy or significant traumatic injury. More typically it is gradual and insidious over months to years with a slowly progressive underlying process. The diagnosis is frequently substantially delayed because the symptoms are non-specific and evolve gradually.
• Adrenocorticotropic hormone deficiency (see adrenal insufficiency, secondary form) produces fatigue and weakness. Critically, it carries the risk of acute, life threatening adrenal crisis if unrecognised, particularly during intercurrent illness or other physiological stress. It is the most clinically urgent deficiency in hypopituitarism.
• Thyroid stimulating hormone deficiency produces the general features of hypothyroidism. The biochemistry differs from primary hypothyroidism: normal or inappropriately low thyroid stimulating hormone despite reduced free thyroxine, rather than elevated thyroid stimulating hormone.
• Gonadotropin deficiency in women produces amenorrhoea and features of oestrogen deficiency, including reduced bone density and, depending on the age of onset, infertility. In men it produces reduced libido, erectile dysfunction and infertility. Where onset occurs before puberty, pubertal development is delayed or absent in both sexes.
• Growth hormone deficiency in adults produces relatively subtle, non-specific features: reduced energy, altered body composition (reduced lean muscle mass with increased central adiposity), and reduced quality of life. This contrasts with the obvious growth failure of childhood onset deficiency.
• Adult growth hormone deficiency is therefore frequently the most subtle and easily overlooked component of hypopituitarism.

• Full anterior pituitary hormonal assessment is the essential diagnostic approach. It comprises:
• Morning cortisol, with formal dynamic testing such as a short synacthen test where baseline results are equivocal (see adrenal insufficiency)
• Free thyroxine, interpreted alongside thyroid stimulating hormone given the biochemical pattern of secondary hypothyroidism
• Gonadotropins together with the relevant sex hormone: testosterone in men, oestradiol in women (interpreted according to menstrual cycle timing where relevant)
• Prolactin
• Insulin like growth factor 1, as an initial screening test for growth hormone deficiency. It has limitations as a standalone measure, so formal dynamic testing, such as an insulin tolerance test or glucagon stimulation test, is generally required for definitive confirmation
• Magnetic resonance imaging of the pituitary and hypothalamus is essential to identify any underlying structural cause. It characterises the pathology and directly informs management planning.
• Assess for associated posterior pituitary (arginine vasopressin) dysfunction where the process involves the hypothalamus or pituitary stalk as well as the anterior gland. Assess clinically for polyuria and polydipsia and, where indicated, undertake formal diagnostic evaluation (see arginine vasopressin disorders).
• Where the cause is not already apparent from the clinical context (such as known prior pituitary surgery or radiotherapy), evaluate for the specific underlying pathology. Consider infiltrative or inflammatory conditions and, after recent immune checkpoint inhibitor cancer therapy, drug induced lymphocytic hypophysitis.

• Adrenocorticotropic hormone deficiency requires hydrocortisone replacement, following the principles under adrenal insufficiency. Give it as a divided daily dose regimen that mimics the physiological diurnal cortisol rhythm (a larger morning dose with smaller subsequent doses later in the day).
• Educate patients about sick day dose adjustment (increasing the dose during intercurrent illness or other physiological stress). Ensure emergency parenteral hydrocortisone is available for severe illness or inability to tolerate oral medication. Inadequate management risks life threatening adrenal crisis.
• Thyroid stimulating hormone deficiency is treated with levothyroxine replacement, following the general principles under hypothyroidism. Monitor treatment by free thyroxine level and clinical response, not thyroid stimulating hormone, which is unreliable because of the underlying pituitary dysfunction.
• Sequencing is critical. Identify and treat any coexisting, unrecognised adrenocorticotropic hormone deficiency with hydrocortisone before starting thyroid hormone replacement. Thyroid hormone increases metabolic cortisol clearance and can precipitate adrenal crisis if started first in a patient with untreated adrenal insufficiency.
• Gonadotropin deficiency is treated with sex hormone replacement: testosterone in men, and oestrogen in women, generally combined with progestogen if the uterus is intact. Individualise the formulation and route according to patient preference and clinical context.
• Standard replacement does not restore fertility. Where fertility is desired, specific gonadotropin or gonadotropin releasing hormone based treatment is required under specialist reproductive endocrinology guidance.
• Growth hormone replacement, given as a daily subcutaneous injection, is considered in adults with confirmed, biochemically significant growth hormone deficiency and relevant associated symptoms. Monitor response by insulin like growth factor 1 level and clinical assessment of symptomatic benefit. The decision is generally made with specialist endocrinology assessment, given the specific eligibility criteria and monitoring requirements.
• Arginine vasopressin deficiency, where present as part of a broader hypopituitarism syndrome, is treated with desmopressin (see arginine vasopressin disorders).
• Treat any identified underlying structural cause according to the specific diagnosis: surgery or, where appropriate, radiotherapy for a causative tumour, or specific treatment of an infiltrative or inflammatory condition. This runs alongside hormone replacement for the resulting deficiencies.
• Provide a medical alert bracelet or card documenting adrenal insufficiency and hypopituitarism, and educate patients about sick day rules and emergency management.
• Arrange regular, structured, lifelong endocrinology follow up with periodic reassessment of each affected hormone axis and monitoring of replacement adequacy. This underpins safe long term management of this complex, multi-axis condition.