Hypopituitarism

01OverviewDefinition, clinical context and the essential points that orientate the chapter.

The pituitary coordinates cortisol, thyroid, gonadal and growth axes while the posterior system regulates water. Symptoms are often nonspecific because fatigue, reduced concentration, altered body composition and sexual dysfunction overlap with the underlying brain disease and its treatment. A structured axis-by-axis assessment prevents the most obvious deficit from obscuring another.

Hormone values must be interpreted as pairs. Low target-gland hormone with an inappropriately non-elevated trophic hormone indicates central failure: free T4 with TSH, testosterone with LH and FSH, oestradiol and cycles with gonadotrophins, and cortisol in relation to ACTH and timing. Prolactin may rise from stalk disconnection rather than excess lactotroph tissue.

Replacement is ordered by safety and individual benefit. Cortisol comes first, thyroid next, then sex-steroid, growth hormone and fertility plans. Treatment does not repair the tumour, visual pathway or hypothalamus, so endocrine care must remain integrated with imaging, oncology, neurosurgery, neuro-ophthalmology and rehabilitation.

Key points

Hypopituitarism may follow pituitary or hypothalamic tumour, surgery, radiotherapy, apoplexy, head injury, subarachnoid haemorrhage, infiltrative disease, infection, genetic disease or immune checkpoint therapy.
Hormone loss can be isolated, sequential or complete; ACTH deficiency is the immediately dangerous component and may present with normal potassium because aldosterone remains renin-angiotensin regulated.
In central hypothyroidism, free T4 is low with TSH that is low, normal or only mildly raised; TSH cannot be used as the levothyroxine dose target.
Secure cortisol secretion or give glucocorticoid cover before thyroid replacement, because increasing thyroid hormone in an ACTH-deficient patient can precipitate adrenal crisis.
Low gonadotrophins with low sex hormone causes amenorrhoea, infertility, low libido, erectile dysfunction, hot flushes and bone loss; replacement and fertility induction have different goals and regimens.
Random growth hormone is not diagnostic because secretion is pulsatile; adults usually require appropriate dynamic testing after other pituitary deficits have been replaced.
Posterior pituitary disease causes arginine vasopressin deficiency with polyuria and thirst; desmopressin can cause fatal hyponatraemia if fluid intake and sodium are not managed.
Patients with ACTH deficiency need daily adherence, sick-day dosing, an NHS Steroid Emergency Card, emergency injection education and procedure-specific cover.

02AetiologyUnderlying causes, associations and risk factors, with why each one matters.

Sellar or hypothalamic mass

Pituitary adenoma and other sellar lesions compress normal gland, stalk or hypothalamus and can impair several hormone axes together.

Treatment-related injury

Pituitary surgery, cranial radiotherapy and cancer treatment may reduce hormone reserve immediately or progressively over years.

Vascular, inflammatory or traumatic damage

Apoplexy, head injury, hypophysitis and infiltrative disease can disrupt pituitary cells or hypothalamic signalling with variable onset.

03PathophysiologyThe causal sequence from the underlying abnormality to symptoms and harm.

1
Trophic hormone output falls
Damaged pituitary tissue releases insufficient ACTH, TSH, gonadotrophins or growth hormone for the body's target-gland needs.
2
Target hormones become deficient
Cortisol, thyroid hormone and sex-steroid production falls without the compensatory trophic-hormone rise expected in primary gland failure.
3
Several axes interact
Cortisol deficiency alters water balance, sex-steroid loss affects bone, and growth-hormone deficiency changes body composition, creating overlapping symptoms.
4
Structural disease persists
Hormone replacement corrects deficiencies but does not remove mass effect, visual compromise or evolving hypothalamic and posterior-pituitary dysfunction.

04Clinical features and red flagsSymptoms, examination findings, patterns of presentation and time-critical warnings.

ACTH deficiency

Fatigue, weight loss, anorexia, nausea, postural dizziness, hyponatraemia and hypoglycaemia can occur without hyperpigmentation, salt craving or hyperkalaemia.

Central hypothyroidism

Cold intolerance, constipation, dry skin, bradycardia and cognitive slowing accompany low free T4 despite an unconvincing TSH response.

Gonadotrophin deficiency

Amenorrhoea, anovulation, hot flushes, reduced libido, erectile dysfunction, infertility and low bone density reflect absent gonadal stimulation.

Growth hormone deficiency

Reduced exercise capacity, increased central fat, diminished lean mass, dyslipidaemia and impaired quality of life are compatible but not specific enough to diagnose the axis alone.

Prolactin change

Low prolactin can impair lactation after postpartum pituitary injury, whereas a moderate elevation may indicate stalk dysfunction and contribute to hypogonadism.

Posterior involvement

Large volumes of dilute urine, intense thirst and rising sodium suggests arginine vasopressin deficiency, especially after surgery, trauma or infiltrative stalk disease.

Red flags requiring action

Shock, recurrent vomiting, severe weakness, altered consciousness or hypoglycaemia in a patient with pituitary disease demands immediate hydrocortisone and resuscitation for possible adrenal crisis.
Sudden headache with visual or ocular-motor change requires the pituitary apoplexy pathway rather than routine hormone adjustment.
Rapid visual decline or new bitemporal field loss suggests compressive sellar progression and needs urgent MRI and specialist assessment.
Polyuria with hypernatraemia, inability to access water or impaired consciousness is a water-balance emergency requiring monitored fluid and endocrine care.
Severe hyponatraemia, confusion or seizure while taking desmopressin suggests water intoxication and needs immediate drug, fluid and sodium management.

05InvestigationsWhat to request, why it matters and how to interpret it.

Investigation order

Read from the initial assessment onwards. Tests may run in parallel in urgent care; first-line, preferred, confirmatory, definitive and gold-standard labels appear only when the chapter explicitly states them.

01
Eight to nine am cortisolFirst step
Why
Screen the ACTH-cortisol axis before elective replacement or dynamic testing.
Interpretation and limitations
Use NICE modern-immunoassay thresholds and local laboratory advice; acute illness and exogenous steroid change interpretation, while crisis treatment must never wait for the result.
02
Dynamic cortisol testing
Why
Clarify adrenal reserve when basal results remain uncertain and the patient is stable.
Interpretation and limitations
A Synacthen or insulin-tolerance approach is selected by endocrinology; recent pituitary injury may yield a misleading preserved adrenal response before cortical atrophy develops.
03
Free T4 and TSH
Why
Diagnose and monitor central thyroid hormone deficiency.
Interpretation and limitations
Low free T4 with inappropriately low, normal or mildly elevated TSH supports central disease; replacement is titrated to free T4 and symptoms, not TSH normalisation.
04
LH FSH and sex hormones
Why
Assess central hypogonadism and guide replacement or fertility referral.
Interpretation and limitations
Interpret testosterone in a properly timed sample and oestradiol within menstrual, menopausal or treatment context; low target hormone without expected gonadotrophin elevation is central.
05
IGF-1 and GH stimulation
Why
Evaluate suspected adult growth hormone deficiency after more urgent axes are stable.
Interpretation and limitations
Normal IGF-1 does not exclude deficiency in a high-risk pituitary patient; insulin, glucagon or macimorelin testing uses test, BMI and assay-specific criteria.
06
Pituitary MRI and formal visual fields
Why
Identify a structural cause, treatment consequence and optic involvement.
Interpretation and limitations
Imaging and perimetry are urgent for visual progression, while surveillance timing depends on tumour type, residual tissue and prior surgery or radiotherapy.
07
Paired serum and urine osmolality
Why
Investigate polyuria and suspected arginine vasopressin deficiency safely.
Interpretation and limitations
Hypotonic urine despite rising plasma osmolality supports impaired AVP action; glucose, calcium, potassium, renal function and intake must be assessed before specialised testing.

06Differential diagnosisRealistic alternatives and the features that help distinguish them.

Primary target-gland failure

Low target hormone with a clearly raised trophic hormone supports thyroid, adrenal or gonadal failure outside the pituitary.

Non-thyroidal illness

Severe acute illness can transiently lower several hormone measurements without permanent pituitary failure; timing and recovery testing matter.

Medicine-induced suppression

Glucocorticoids, opioids and dopamine-active medicines can suppress selected axes or alter prolactin, sometimes reversibly when supported by the history and examination.

Depression or chronic fatigue

Fatigue, low libido and poor concentration overlap, but paired axis abnormalities and structural context support endocrine deficiency.

07ManagementImmediate care, first-line treatment, alternatives and escalation.

01MAPAxis-by-axis assessmentFirst stepPituitary disease or treatment creates symptoms compatible with partial or complete hormone loss.

1Identify urgent cortisol, visual, neurological and sodium threats before arranging non-urgent dynamic investigations.
2Measure paired target and trophic hormones, document exogenous steroids and hormone therapies, and obtain dedicated pituitary imaging where cause is unknown.
3Classify each axis as intact, deficient, uncertain or confounded rather than applying a single diagnosis of panhypopituitarism.
4DefinitiveAgree replacement sequence, definitive tumour treatment and a timed reassessment plan through the pituitary multidisciplinary service.

02REPLACESafe hormone sequenceMultiple anterior pituitary deficits require treatment.

1Establish glucocorticoid replacement or demonstrate cortisol sufficiency before levothyroxine or major physiological stress.
2Titrate levothyroxine with free T4 and clinical response, leaving adequate time after dose changes for steady-state review.
3Discuss sex-steroid replacement from symptoms, age, bone, cardiovascular, cancer and fertility considerations using the relevant specialist guidance.
4Consider somatropin only after other axes and tumour status are stable and the patient meets current NICE eligibility.

03ILLNESSACTH-deficient sick-day careFever, trauma, surgery, severe psychological stress or gastrointestinal illness increases cortisol requirement.

1Use the current adult oral sick-day regimen when the patient remains stable and can absorb medicine.
2If vomiting repeats, inject emergency hydrocortisone and attend hospital by ambulance rather than relying on further tablets.
3Treat the precipitating illness and monitor pressure, glucose, sodium and renal function, using parenteral replacement in severe disease.
4Return to routine dosing only after recovery and document any crisis to improve future prevention and kit readiness.

04WATERPolyuria in pituitary diseaseUrine output rises substantially with thirst, low urine concentration or changing serum sodium.

1Measure fluid input, urine output, capillary glucose, sodium, plasma and urine osmolality and review diuretics before attributing symptoms to AVP deficiency.
2EscalationEnsure free access to water when thirst is intact and escalate urgently for hypernatraemia, impaired consciousness or inability to drink.
3Start desmopressin only through a monitored diagnosis and route-specific plan, observing whether dilute polyuria returns before repeat dosing.
4Educate about planned aquaresis, fluid intake and hyponatraemia symptoms, especially after discharge or dose formulation changes.

Key medicines and prescribing safety5 treatments · regimens, roles and cautions

Replace cortisol in secondary adrenal insufficiency and permit safe thyroid, surgical and illness management.

Hydrocortisone

NICE first-choice replacement is 15 to 25 mg orally each day in two to three divided doses, with the larger dose earlier.

Provide sick-day and emergency injection measures; monitor weight, blood pressure, glucose and bone, and remember that fludrocortisone is not routinely required centrally.

Replace thyroid hormone in central hypothyroidism despite an unreliable TSH signal.

Levothyroxine

Begin after cortisol safety is established and titrate an individual once-daily dose to free T4, symptoms, age and cardiovascular status.

Do not reduce solely because TSH becomes suppressed; check adherence, interactions and free T4 timing, and avoid precipitating untreated adrenal failure.

Treat hypogonadal symptoms and support sexual function, muscle and bone when fertility induction is not the immediate aim.

Sex-steroid replacement

Use a guideline-appropriate testosterone or oestrogen-progestogen regimen individualised to sex, uterus status, age, contraindications and reproductive goals.

Review thrombotic, cancer, haematocrit, prostate, bleeding and pregnancy considerations; routine replacement does not induce fertility and needs specialist monitoring.

Improve selected quality-of-life, body-composition and metabolic outcomes in adults meeting NICE eligibility.

Somatropin

Start a low specialist subcutaneous dose only after confirmed severe deficiency and titrate to age-adjusted IGF-1, response and adverse effects.

Avoid active malignancy and acute critical illness; monitor oedema, arthralgia, carpal tunnel, glucose, thyroid and cortisol requirements as replacement unmasks or alters other axes.

Replace arginine vasopressin action and reduce excessive free-water loss in confirmed central deficiency.

Desmopressin

Use the endocrinologist-selected oral, sublingual, nasal or parenteral regimen, allowing a planned period of breakthrough dilute urine between doses when appropriate.

Fluid overconsumption causes dilutional hyponatraemia and seizure; acute illness, low intake and formulation switches require sodium review and explicit sick-day instructions.

08ComplicationsImportant consequences, why they occur and why they matter clinically.

Adrenal crisis

Unrecognised ACTH deficiency can cause hypotension, hypoglycaemia and hyponatraemia during illness, surgery or vomiting, and may progress to shock.

Visual loss

An enlarging sellar mass can compress the optic chiasm or cavernous sinus, causing field loss, diplopia and irreversible impairment.

Osteoporosis and infertility

Prolonged gonadotrophin and sex-steroid deficiency reduces bone strength and disrupts ovulation or spermatogenesis, with consequences for fracture risk and fertility.

Unsafe replacement sequence

Starting thyroid hormone before protecting a deficient cortisol axis can increase metabolic demand and precipitate acute adrenal decompensation.

09Monitoring and follow-upTreatment response, safety checks and longer-term review.

At least annually, review every axis, replacement adherence, crisis or hospital episodes, blood pressure, weight, glucose, lipids, bone and psychological function.
Use free T4 for central thyroid monitoring and avoid ordering TSH alone on primary-care repeat panels that may falsely suggest over-treatment.
Reassess cortisol after pituitary surgery, apoplexy or tumour response only with a valid specialist protocol; never withdraw cover from a random result obtained on hydrocortisone.
Monitor sex-steroid therapy with the agent-specific blood count, prostate, bleeding, breast, thrombotic and bone safeguards.
For desmopressin, review thirst, urine breakthrough and sodium, especially after hospital admission when missed or duplicated doses can be dangerous.
Repeat MRI and fields according to the cause, and investigate new headache, vision or cranial nerve symptoms outside the scheduled interval.

10Special situationsVariants, exceptions and circumstances that change the usual approach.

Axes fail on different clocks

Growth and gonadal function may decline before TSH and ACTH, while radiotherapy can create new deficits years after apparently successful tumour treatment.

Central thyroid needs free hormone

A suppressed TSH on levothyroxine is expected when pituitary signalling is defective and cannot by itself diagnose excessive replacement.

Mineralocorticoid is preserved

The adrenal zona glomerulosa responds chiefly to renin and potassium, explaining why central ACTH failure usually lacks salt craving, hyperkalaemia and fludrocortisone need.

Fertility uses different hormones

Testosterone or routine oestrogen protects symptoms and bone but suppresses or bypasses gametogenesis; gonadotrophin or pulsatile therapy requires a fertility service.

Cortisol can mask diabetes insipidus

Free-water clearance improves after glucocorticoid starts, sometimes revealing brisk polyuria that was not apparent during adrenal deficiency.

11Common pitfallsFrequent interpretation and management errors.

01
Do not interpret a normal TSH as normal thyroid status in a patient whose pituitary cannot mount an appropriate response.
02
Do not start or increase levothyroxine until the ACTH-cortisol axis has been made safe.
03
Do not prescribe fludrocortisone routinely for secondary adrenal insufficiency when aldosterone regulation remains intact.
04
Do not diagnose adult GH deficiency from fatigue, low IGF-1 or a random GH result without the appropriate specialist context and test.
05
Do not administer repeated desmopressin to a patient with falling sodium and no breakthrough urine; water intoxication may be developing.
06
Do not assume pituitary deficits are static after surgery or radiotherapy; recovery, recurrence and delayed new hormone loss all occur.