Hypopituitarism
Key points
- Hypopituitarism: deficiency of one or more anterior pituitary hormones, sometimes with concurrent posterior pituitary (ADH) loss causing cranial diabetes insipidus.
- Causes: pituitary and hypothalamic tumours and their treatment, pituitary apoplexy, Sheehan syndrome, traumatic brain injury, infiltrative and infective disease, and genetic causes.
- Order of hormone loss: in gradual compressive disease, growth hormone and gonadotrophins are usually lost first, then TSH, then ACTH last - though ACTH deficiency is the most dangerous one to miss.
- Clinical features: vary by axis: fatigue and reduced muscle mass (GH), amenorrhoea and low libido (gonadotrophins), hypothyroid features without a raised TSH (TSH), and adrenal insufficiency without hyperpigmentation (ACTH).
- Diagnosis: a basal hormone panel (9 am cortisol, free T4 and TSH, LH/FSH with testosterone or oestradiol, IGF-1, prolactin), dynamic testing where results are equivocal, and MRI pituitary to find the cause.
- Management: replace hormones in the correct order - hydrocortisone always before levothyroxine - then sex hormones, then GH in selected patients, plus desmopressin if there is concurrent diabetes insipidus.
- Sick day rules: identical to primary adrenal insufficiency - every patient with ACTH deficiency needs a steroid emergency card and must know how to double their hydrocortisone dose during illness.
- Prognosis: normal life expectancy is achievable with correct multi-axis replacement, but unrecognised or mismanaged ACTH deficiency can be fatal in an adrenal crisis.
Introduction
Hypopituitarism is deficiency of one or more of the hormones produced by the anterior pituitary gland - growth hormone (GH), the gonadotrophins (LH and FSH), TSH, ACTH and prolactin.1 Panhypopituitarism describes loss of all anterior hormones. The posterior pituitary can be affected too, in which case ADH deficiency causes cranial diabetes insipidus.
The pituitary is often called the master gland because it drives the thyroid, adrenal and gonadal axes and controls growth - so its failure produces a picture that touches almost every system, usually gradually and non-specifically enough that the diagnosis is often delayed for years. It is uncommon, with an estimated prevalence of around 300 to 450 per million, but under-recognition means the true prevalence is probably higher.1
Aetiology
Almost any process that damages the pituitary gland, the pituitary stalk or the hypothalamus can cause hypopituitarism.
| Category | Causes |
|---|---|
| Tumours | Non-functioning pituitary adenoma (the commonest cause in adults), functioning adenomas, craniopharyngioma (the commonest cause in children), meningioma, Rathke cleft cyst, metastases and other parasellar tumours compressing the gland or stalk |
| Treatment of tumours | Trans-sphenoidal surgery and cranial radiotherapy - radiotherapy causes a slowly progressive, delayed hypopituitarism that can appear years later and typically affects the GH axis first |
| Vascular | Pituitary apoplexy - sudden haemorrhage or infarction into an adenoma; Sheehan syndrome - postpartum pituitary infarction after major obstetric haemorrhage |
| Trauma | Traumatic brain injury - an under-recognised cause; screening pituitary function is recommended after moderate to severe TBI |
| Infiltrative disease | Sarcoidosis, haemochromatosis (iron deposition preferentially damages gonadotrophs, causing early hypogonadism), Langerhans cell histiocytosis, and lymphocytic hypophysitis - an autoimmune inflammation, classically peripartum, that can mimic a tumour on imaging |
| Infection | Tuberculosis, syphilis, fungal infection and pituitary abscess |
| Empty sella syndrome | Primary - a congenital defect of the diaphragma sellae lets CSF flatten the gland against the sella floor, usually with normal function and found incidentally; secondary - the gland shrinks after infarction, surgery or radiotherapy |
| Genetic / congenital | Mutations in pituitary transcription factors (PROP1, POU1F1), septo-optic dysplasia, and Kallmann syndrome (isolated GnRH deficiency with anosmia) |
| Other | Immune checkpoint inhibitor hypophysitis - an increasingly common iatrogenic cause; severe critical illness |
Sheehan syndrome deserves separate mention: the pituitary enlarges physiologically during pregnancy, which makes its blood supply unusually vulnerable to the hypotension of a major postpartum haemorrhage. The classic presenting feature is failure to lactate (loss of prolactin), often with amenorrhoea afterwards; other axes fail to varying degrees and the diagnosis may not be made until years later when the patient presents with fatigue or fails to resume periods.
Clinical features
The onset is usually insidious in compressive disease, and features accumulate so gradually that patients and clinicians often attribute them to ageing or unrelated illness. Presentation can also be acute, as in apoplexy or Sheehan syndrome.
| Axis | Features |
|---|---|
| GH | Adults: fatigue, reduced muscle mass and exercise capacity, increased central adiposity, dyslipidaemia and reduced quality of life. In children: growth failure and short stature. |
| Gonadotrophins (LH/FSH) | Women: oligomenorrhoea or amenorrhoea, infertility, low libido, vaginal dryness and breast atrophy. Men: loss of libido, erectile dysfunction, infertility, reduced shaving frequency and testicular atrophy. Both: loss of axillary and pubic hair, osteoporosis. |
| TSH | Features of secondary hypothyroidism - fatigue, cold intolerance, weight gain, constipation, dry skin, bradycardia - clinically much like primary hypothyroidism, but TSH is low or inappropriately normal rather than raised |
| ACTH | Features of secondary adrenal insufficiency - fatigue, postural hypotension, nausea and hypoglycaemia (especially in children) - but without hyperpigmentation, because ACTH itself is low, and generally without hyperkalaemia, because aldosterone secretion is driven by the renin-angiotensin system rather than ACTH and is usually preserved |
| Prolactin | Deficiency causes failure of lactation (Sheehan syndrome). Note that stalk compression by a mass can instead cause a mild rise in prolactin by removing tonic dopamine inhibition - the 'stalk effect', not a true prolactinoma. |
| ADH (posterior pituitary) | Cranial diabetes insipidus - polyuria and polydipsia - if the posterior pituitary or stalk is involved |
Differential diagnosis
Because hypopituitarism produces low or low-normal target-gland hormones, the key differential for each axis is the corresponding primary organ failure, which is distinguished by the level of the pituitary trophic hormone.
| Axis | Secondary failure (hypopituitarism) | Primary failure |
|---|---|---|
| Thyroid | Low free T4, TSH low or inappropriately normal | Low free T4, TSH high (primary hypothyroidism) |
| Adrenal | Low cortisol, ACTH low or inappropriately normal, no pigmentation, aldosterone preserved | Low cortisol, ACTH high, hyperpigmentation, aldosterone also low (Addison's disease) |
| Gonadal | Low testosterone/oestradiol, LH/FSH low or inappropriately normal | Low testosterone/oestradiol, LH/FSH high (e.g. menopause, primary testicular failure) |
Other conditions that mimic parts of the picture include chronic illness of any cause, depression, anorexia nervosa or functional hypothalamic amenorrhoea (which can itself suppress gonadotrophins), and normal ageing - all reasons the diagnosis is so often delayed.
Investigations
Basal hormone panel
- 9 am serum cortisol
- Free T4 and TSH
- LH, FSH and testosterone (men) or oestradiol (women) - taken with menstrual history in women
- IGF-1 - screens for GH deficiency, though a normal level does not exclude it in adults
- Prolactin
- U&Es - hyponatraemia can occur from cortisol deficiency permitting inappropriate ADH release, or from concurrent hypothyroidism
- Paired plasma and urine osmolality if cranial diabetes insipidus is suspected
Dynamic testing
Used when basal results are equivocal, particularly to confirm ACTH or GH reserve.
- Insulin tolerance test (ITT) - the gold standard for both the GH and ACTH axes. Insulin is given to induce hypoglycaemia (blood glucose below 2.2 mmol/L), and cortisol and GH responses are measured. Contraindicated in ischaemic heart disease, epilepsy and the elderly.
- Short Synacthen test - a practical alternative for the ACTH axis, but can give a false negative in recent-onset secondary insufficiency (for example soon after pituitary surgery or apoplexy), because the adrenal glands have not yet atrophied and may still respond
- Glucagon stimulation test - used to assess GH and ACTH reserve where an ITT is contraindicated
- Do not delay treatment for testing in a patient who looks unwell - take a sample if it costs no time, then treat with hydrocortisone
Imaging
MRI pituitary with contrast to identify the cause - a tumour, stalk lesion, empty sella or infiltrative change. Formal visual field testing is essential where a mass abuts the optic chiasm, looking for the classic bitemporal hemianopia.
Management
Management addresses the underlying cause where treatable (for example surgical decompression of a compressive tumour) and replaces every deficient hormone.1 The order of replacement is not arbitrary.
| Axis | Replacement | Notes |
|---|---|---|
| ACTH | Hydrocortisone 15-25 mg daily in 2-3 divided doses, largest on waking6 | Replace first, always. Requires sick day rules and a steroid emergency card, exactly as in primary adrenal insufficiency. |
| TSH | Levothyroxine, titrated to keep free T4 in the upper half of the normal range7 | TSH cannot be used to monitor treatment - it is unreliable because the problem is pituitary, not thyroid |
| Gonadotrophins | Women: oestrogen (with a progestogen if the uterus is present) or the combined pill in younger women. Men: testosterone replacement (gel or injection), monitoring PSA and haematocrit. | Restores libido, secondary sexual characteristics and bone protection, but does not restore fertility. Fertility requires specialist pulsatile GnRH or gonadotrophin (hCG/hMG) therapy. |
| GH | Recombinant human GH (somatropin), titrated to IGF-1 and clinical response8 | Reserved for adults with biochemically confirmed severe GH deficiency and impaired quality of life; contraindicated with active malignancy |
| ADH | Desmopressin (DDAVP)9 | Only if there is concurrent cranial diabetes insipidus; titrate against thirst, urine output and sodium |
Replacement is reviewed regularly with a combination of clinical assessment and biochemistry, and patients need lifelong endocrine follow-up because pituitary axes can be lost progressively over time, particularly after radiotherapy.
Complications
- Adrenal crisis - the principal avoidable danger, especially if ACTH deficiency is unrecognised or levothyroxine is started without adequate steroid cover
- Osteoporosis - from combined gonadal and GH deficiency
- Infertility
- Increased cardiovascular risk - GH deficiency is associated with an adverse lipid profile, increased visceral fat and excess cardiovascular mortality in observational studies
- Reduced quality of life - fatigue, low mood and impaired wellbeing are common even with apparently adequate replacement
- Growth failure in children if untreated
- Complications of the underlying cause - mass effect, visual field loss, recurrence of a tumour
Red flags
Prognosis
With complete and correctly ordered hormone replacement, most patients with hypopituitarism achieve a life expectancy close to normal. Several cohort studies nonetheless show a modestly increased cardiovascular mortality, particularly in women and in patients with untreated GH deficiency, reinforcing the case for full multi-axis assessment rather than treating only the most obvious deficiency.1
The exception is unrecognised or poorly managed ACTH deficiency, where the risk is not a slow excess of cardiovascular events but a sudden, preventable death in adrenal crisis - which is why patient education, sick day rules and a steroid emergency card matter as much as the prescription itself.
Recovery of individual axes is possible in some settings - for example after conservatively managed apoplexy, or following resolution of lymphocytic hypophysitis or a reversible traumatic insult - so periodic re-testing is worthwhile rather than assuming replacement is required forever in every case. Prognosis for tumour-related causes also depends on the underlying pathology and the success of its treatment.
References
- Fleseriu M, Hashim IA, Karavitaki N et al. Hormonal Replacement in Hypopituitarism in Adults: An Endocrine Society Clinical Practice Guideline. 2016. Available here
- Rajasekaran S, Vanderpump M, Baldeweg S et al. UK guidelines for the management of pituitary apoplexy. Clinical Endocrinology. 2011. Available here
- NICE NG243. Adrenal insufficiency: identification and management. 2024. Available here
- Society for Endocrinology. Clinical practice guidance. Available here
- NHS. Pituitary tumours. Available here
- BNF. Hydrocortisone. Available here
- BNF. Levothyroxine sodium. Available here
- BNF. Somatropin. Available here
- BNF. Desmopressin acetate. Available here
This article is written for revision and education. It is not clinical guidance and must not be used to make decisions about the care of a patient. Always check current NICE guidance and local protocols.