EndocrinologyTier 2Disease (DEADMAN)

Hypothalamic–pituitary axis disorders - hypopituitarism

Description

Deficiency of >=1 anterior pituitary hormone; panhypopituitarism = all
Hypothalamic vs pituitary origin matters: hypothalamic disease loses dopamine inhibition -> prolactin rises, whereas pituitary destruction lowers it

Order of loss - "Go Look For The Adenoma"

GH -> LH/FSH -> TSH -> ACTH (prolactin variable, last)
- GH and gonadotrophins go first; ACTH is lost last and signals near-complete loss of reserve
- Posterior pituitary (ADH) usually spared in pituitary adenoma - cranial DI points to hypothalamus, stalk, infiltration or surgery

Clinical picture by axis

Axis	Adult
GH	Central adiposity, dec muscle and BMD, fatigue, dec QoL
LH/FSH	Amenorrhoea, dec libido, ED, infertility, loss of body hair, osteoporosis
TSH	Fatigue, cold intolerance, weight gain. Low fT4 with low/normal TSH
ACTH	Fatigue, weight loss, hyponatraemia, hypoglycaemia, postural drop. No hyperpigmentation, no hyperkalaemia - aldosterone intact
ADH	Polyuria, polydipsia, hypernatraemia

Prevalence ~30-45/100,000; incidence ~4/100,000/yr
Pituitary adenoma + its treatment accounts for the majority in adults
Hypopituitarism after moderate-severe TBI in 15-90% of series - hugely under-recognised, often transient, retest at 3-6 and 12 months
Congenital forms present in infancy or early childhood

Acquired

Tumour - non-functioning (chromophobe) adenoma commonest; craniopharyngioma, Rathke cleft cyst, meningioma, germinoma, chordoma/chondroma
Metastasis - breast, lung, colon, prostate (classically involves posterior lobe -> DI, unlike adenoma)
Iatrogenic - trans-sphenoidal surgery, cranial radiotherapy (progressive over 5-10y - lifelong follow-up)
Vascular
- Pituitary apoplexy - haemorrhage/infarction into an adenoma. Thunderclap headache, ophthalmoplegia, visual loss, acute ACTH deficiency
- Sheehan syndrome - postpartum haemorrhage -> infarction of a hyperplastic gland. Failure of lactation, then amenorrhoea
Infiltrative/inflammatory - sarcoidosis, TB, Langerhans cell histiocytosis, IgG4-related hypophysitis, granulomatosis with polyangiitis
Lymphocytic hypophysitis - late pregnancy/postpartum, F>M; thickened stalk with symmetrical enlargement on MRI; ACTH lost early and disproportionately
Checkpoint-inhibitor hypophysitis - CTLA-4 > PD-1; ACTH and TSH loss usually permanent
Iron deposition - haemochromatosis, transfusion-dependent thalassaemia (gonadotrophins first)
Trauma; empty sella; apoplexy of Rathke cyst

Congenital / genetic

PROP1 - commonest genetic cause of combined pituitary hormone deficiency
- Expressed late in pituitary development -> pituitary-limited, no midline defects; GH deficiency typically evident around age 6, not neonatally
- Progressive - ACTH loss may appear in adulthood
POU1F1 (PIT1) - GH, prolactin, TSH; HESX1 - septo-optic dysplasia (de Morsier)
Midline defects predicting pituitary hypoplasia: holoprosencephaly, cleft lip/palate, solitary central incisor
Isolated GH deficiency - GHRH-receptor or GH1 mutation; X-linked form with hypogammaglobulinaemia
GH insensitivity is a different problem - defect distal to GH
- Laron syndrome (GH-receptor mutation), IGF-1 or IGF-1-receptor defects
- *GH normal or high, IGF-1 low* - the discriminating pair

Examination

Pale, finely wrinkled skin; loss of axillary/pubic and body hair; gynaecomastia; small testes
Bitemporal hemianopia, optic atrophy; CN III, IV, VI and V1 palsies from cavernous sinus invasion
Hypophysectomy or craniotomy scar

Baseline biochemistry - paired pituitary and target hormone

09:00 cortisol + ACTH, fT4 + TSH, LH/FSH + testosterone/oestradiol, IGF-1, prolactin
A "normal" TSH with a low fT4 is central hypothyroidism - never interpret TSH alone here
Paired serum/urine osmolality if polyuric

Dynamic testing

ACTH axis: 09:00 cortisol <100 nmol/L = deficient, >400 nmol/L = intact; between -> short Synacthen (may be falsely normal in the first 4-6 weeks after pituitary injury - use insulin tolerance test or glucagon test)
GH: insulin tolerance test is the reference (contraindicated in IHD, epilepsy); glucagon test as alternative
- >=3 other pituitary hormone deficiencies + low IGF-1 -> no stimulation test needed
Copeptin-stimulated testing for cranial DI

Imaging

Replacement - the sequence is examinable

1. Glucocorticoid ALWAYS first - hydrocortisone 15-25 mg/day in 2-3 divided doses, largest on waking
- *Starting thyroxine before glucocorticoid accelerates cortisol clearance and precipitates adrenal crisis*
- Sick-day rules, double dosing, parenteral hydrocortisone at home, medical alert identification
- Monitor clinically - there is no useful biochemical marker; ACTH and cortisol levels do not guide dose
2. Thyroxine - titrate to fT4 in the upper half of the reference range. TSH is useless for monitoring
3. Sex steroids - testosterone (men); oestrogen +/- progestogen (women, until ~51y)
- Fertility requires gonadotrophins (hCG +/- FSH) or pulsatile GnRH, not sex steroid
4. Growth hormone last - titrate to IGF-1 mid-normal for age, start low in older patients
Desmopressin for cranial DI (only once glucocorticoid is replaced - cortisol deficiency masks DI)

GH replacement - specific issues

Can unmask occult hypoadrenalism or hypothyroidism (inc cortisol -> cortisone conversion via 11beta-HSD1, inc T4 -> T3)
Side effects: arthralgia, myalgia, fluid retention, paraesthesia, carpal tunnel, OSA, hypertension, hyperglycaemia
Childhood-onset GHD: excess second neoplasm risk
Monitoring: IGF-1 at 6 weeks then after each dose change; weight/BP/waist and metabolic profile 6-monthly; thyroid and adrenal axis; DEXA every 18 months; MRI for residual tumour; QoL

Acute

Pituitary apoplexy: immediate hydrocortisone 100 mg IV, fluids, urgent MRI, neurosurgical review
- Surgery for visual loss or deteriorating consciousness; conservative if isolated ophthalmoplegia

Pituitary adenoma - MEN1, AIP (familial isolated pituitary adenoma), Carney complex
Haemochromatosis and transfusion iron overload
IgG4-related disease elsewhere - retroperitoneal fibrosis, pancreatitis, sialadenitis
Checkpoint inhibitor therapy - hypophysitis, thyroiditis, adrenalitis, T1DM
Empty sella - obesity, idiopathic intracranial hypertension, multiparity
TBI and subarachnoid haemorrhage
Prader-Willi - isolated ACTH deficiency, GH deficiency, hypogonadism

Sequential loss: GH and gonadotrophins first, TSH with more extensive damage, ACTH last
- ACTH deficiency implies near-total loss of reserve
Radiotherapy-induced deficiency accrues over 5-15y - lifelong annual pituitary function testing
Post-TBI and post-apoplexy deficits may recover - retest at 3-6 and 12 months before committing to lifelong replacement
Lymphocytic hypophysitis may remit spontaneously
Excess mortality ~2x, driven by cardiovascular and cerebrovascular disease
- Over-replacement of glucocorticoid is a major and modifiable contributor - use the lowest effective dose
Adrenal crisis is the main preventable cause of death - recurrent education is the intervention that works

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