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endo.hypopituitarism.core.v1PRODUCTION
endo.hypopituitarism.core.v1

Hypopituitarism

endocrinologychronicsubacuteadult
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Care setting:

Encounter flow

12/12 authored

Canonical 12-phase frame with authored status for this dossier.

Current phase

Frame

Detailed

Recognize anterior ± posterior pituitary hormone deficiency: peripheral hormone low WITH inappropriately low/normal trophic hormone, in a patient with a pituitary/hypothalamic insult; combined anterior+posterior deficiency points to stalk/hypothalamic disease (Fleseriu JCEM 2016 ES)

Inputs
4
Actions
0
Advance rule
Set
Advance when

central deficiency pattern recognized and pituitary substrate plausible (Fleseriu JCEM 2016 ES)

Patient inputs (14)

Dedicated sellar MRI defines tumor/parasellar mass, stalk thickening (hypophysitis/infiltrative), empty sella, apoplexy and mass effect on optic chiasm (Fleseriu JCEM 2016 ES)

GH replacement decision and sex-steroid targets are age-dependent; growth-axis irrelevant in older adults (Fleseriu JCEM 2016 ES)

Gonadotropin-axis assessment and sex-steroid replacement differ by sex; pregnancy intent drives fertility-induction referral (Fleseriu JCEM 2016 ES)

Surgery/RT/apoplexy/Sheehan/TBI-SAH/infiltrative/genetic etiology drives screening tempo and reversibility (Fleseriu JCEM 2016 ES; Husebye Lancet 2021)

Immune-checkpoint inhibitors (anti-CTLA-4/PD-1/PD-L1), opioids and high-dose glucocorticoids cause acquired central hormone suppression / hypophysitis (Husebye Lancet 2021)

0800 cortisol is the screening anchor for the ACTH axis; interpret by CENTRAL rules (paired with ACTH), never by primary-AI cutoffs alone (Fleseriu JCEM 2016 ES)

Inappropriately low/normal ACTH with low cortisol defines SECONDARY adrenal insufficiency and separates this engine from primary adrenal failure (Fleseriu JCEM 2016 ES)

Central hypothyroidism is diagnosed by LOW free T4 with low/normal TSH — TSH alone must NOT be used (Fleseriu JCEM 2016 ES; Persani JCEM 2018)

TSH is inappropriately low/normal in central hypothyroidism; it is read only paired with free T4, never as a standalone screen (Persani JCEM 2018)

Hyponatremia signals secondary AI, central hypothyroidism, or SIADH; hypernatremia + polyuria signals central DI (posterior axis) (Fleseriu JCEM 2016 ES)

Hypotension flags secondary adrenal insufficiency / impending adrenal crisis — the life-threatening axis (Fleseriu JCEM 2016 ES; Husebye Lancet 2021)

Bitemporal visual-field loss or new severe headache flags chiasmal compression / apoplexy needing urgent neurosurgery + ophthalmology (Fleseriu JCEM 2016 ES)

IGF-1 screens the GH axis; low IGF-1 with multiple deficiencies supports GHD without provocative testing in some contexts (Yuen JCEM 2019 AACE/ACE GH)

Mild hyperprolactinemia (stalk effect/disconnection) vs low prolactin (gland destruction, Sheehan) localizes the lesion (Fleseriu JCEM 2016 ES)

* = hard-required. Engine cannot meaningfully run until these are filled.

Severity triggers (6)

6 need judgement
  • informationallife_threateningsecondary_adrenal_crisis — ES 2016
    Secondary adrenal insufficiency decompensation: hypotension ± hypoglycemia ± hyponatremia in pituitary-failure substrate (Fleseriu JCEM 2016 ES; Husebye Lancet 2021)
    Trigger could not be auto-evaluated — needs clinician judgement.
  • informationallife_threateningmass_effect_visual_compromise — ES 2016
    Sellar/parasellar mass with bitemporal field loss or acute apoplexy (thunderclap headache + ophthalmoplegia) (Fleseriu JCEM 2016 ES)
    Trigger could not be auto-evaluated — needs clinician judgement.
  • informationalseverecentral_hypothyroid_with_acth_deficiency — ES 2016
    Concurrent central hypothyroidism AND ACTH-axis deficiency — levothyroxine started before glucocorticoid risks adrenal crisis (Fleseriu JCEM 2016 ES; Persani JCEM 2018)
    Trigger could not be auto-evaluated — needs clinician judgement.
  • informationalseveresevere_symptomatic_hyponatremia — ES 2016
    Sodium <125 with neurologic symptoms (secondary AI, central hypothyroidism, or SIADH from pituitary disease) (Fleseriu JCEM 2016 ES)
    Trigger could not be auto-evaluated — needs clinician judgement.
  • informationalseverecheckpoint_inhibitor_hypophysitis — Husebye 2021
    New central hormone deficiency (often hypocortisolism ± central hypothyroidism) in a patient on anti-CTLA-4 / PD-1 / PD-L1 therapy (Husebye Lancet 2021)
    Trigger could not be auto-evaluated — needs clinician judgement.
  • informationalseverecentral_DI_in_unconscious_or_NPO — ES 2016
    Central diabetes insipidus with impaired thirst access (unconscious / NPO / post-op) — rapid hypernatremic dehydration (Fleseriu JCEM 2016 ES)
    Trigger could not be auto-evaluated — needs clinician judgement.

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Recommended regimen

Hypopituitarism replacement — glucocorticoid FIRST → levothyroxine → sex steroid → GH → desmopressin for central DI (Fleseriu JCEM 2016 ES)
axis: hypopituitarism_replacement_sequencestep 1 - Step 1 — Glucocorticoid replacement FIRST (cardinal safety rule) (Fleseriu JCEM 2016 ES)
Selected step "Step 1 — Glucocorticoid replacement FIRST (cardinal safety rule) (Fleseriu JCEM 2016 ES)" — ACTH-axis deficiency confirmed or strongly suspected; ALWAYS before levothyroxine; empiric/stress dose if adrenal-crisis pattern (Fleseriu JCEM 2016 ES; Husebye Lancet 2021)
  • hydrocortisone
    first line
    glucocorticoid_short_acting
    15–20 mg/day PO in 2–3 divided doses with the largest dose on waking (e.g., 10 mg AM + 5 mg early-PM ± 2.5 mg late-PM) • PO • BID-TID
    triggers: secondary_adrenal_insufficiency_confirmed, before_levothyroxine, central_hypothyroid_plus_acth_axis
    Fleseriu JCEM 2016 ES — replaces cortisol mimicking diurnal rhythm; MUST be established before levothyroxine because thyroid hormone accelerates cortisol clearance and precipitates adrenal crisis; no reliable biomarker — titrate to clinical response avoiding over-replacement
    rxcui 5492
  • prednisone
    second line
    glucocorticoid_intermediate_acting
    3–5 mg PO once daily (on waking) • PO • once daily
    triggers: adherence_concern_once_daily_preferred, hydrocortisone_unavailable
    Fleseriu JCEM 2016 ES — once-daily alternative when adherence favors single dosing; less physiologic than divided hydrocortisone
    rxcui 8640
  • hydrocortisone (parenteral stress dose)
    rescue
    glucocorticoid_short_acting
    100 mg IV/IM bolus then 50 mg IV q6h or 200 mg/24h infusion • IV • q6h or continuous
    triggers: adrenal_crisis_pattern, major_intercurrent_stress, unable_to_take_PO
    Fleseriu JCEM 2016 ES; Husebye Lancet 2021 — secondary AI decompensation is the life-threatening axis; do NOT delay for cortisol/ACTH result; route to adrenal-crisis pathway
    rxcui 5492

outpatient playbook — drug actions (5)

  1. 1. hydrocortisone
    15–20 mg/day PO divided (largest AM dose) • PO • BID-TID
    trigger: ACTH-axis deficiency confirmed — FIRST, before levothyroxine (Fleseriu JCEM 2016 ES)
    Glucocorticoid cornerstone; precedes thyroid hormone (Fleseriu JCEM 2016 ES)
  2. 2. levothyroxine
    1.0–1.6 mcg/kg/day PO titrated to free T4 • PO • once daily
    trigger: Central hypothyroidism AND glucocorticoid already established (Persani JCEM 2018)
    Titrate by free T4, never TSH (Persani JCEM 2018)
  3. 3. sex steroid (testosterone or estradiol+progestin)
    Sex-appropriate physiologic replacement • transdermal/IM/PO • per agent
    trigger: Gonadotropin deficiency, no contraindication (Fleseriu JCEM 2016 ES)
    Bone/sexual health; fertility pathway substitutes if pregnancy desired (Fleseriu JCEM 2016 ES)
  4. 4. somatropin
    0.2–0.4 mg SC daily titrated to IGF-1 • SC • once daily
    trigger: Adult GHD confirmed, symptomatic, no active malignancy (Yuen JCEM 2019 AACE/ACE GH)
    Last axis; recheck adrenal/thyroid after start (Yuen JCEM 2019 AACE/ACE GH)
  5. 5. desmopressin
    0.05–0.1 mg PO BID lowest effective • PO/intranasal • BID
    trigger: Confirmed central DI, secondary AI already replaced (Fleseriu JCEM 2016 ES)
    Under-dose deliberately; monitor sodium (Fleseriu JCEM 2016 ES)

Auto-drafted A&P note

outpatient

Subjective

- Possible entry pathways: Pituitary / parasellar mass or stalk lesion on MRI (Fleseriu JCEM 2016 ES); Low peripheral hormone with inappropriately low/normal trophic hormone (low cortisol + low/normal ACTH, low FT4 + low/normal TSH) (Fleseriu JCEM 2016 ES); Fatigue, hypotension, amenorrhea/low libido, cold intolerance, polyuria after pituitary insult (Fleseriu JCEM 2016 ES).

Objective

- No vitals, labs, or imaging entered for this encounter.

Assessment

**Hypopituitarism** (endo.hypopituitarism.core.v1).
Phenotype framing: Phenotype etiology: tumor/parasellar mass + mass effect, surgical/RT-induced, apoplexy, Sheehan, lymphocytic / checkpoint-inhibitor hypophysitis, infiltrative (sarcoid/hemochromatosis/LCH/IgG4), TBI/SAH, empty sella, genetic, infection; distinguish secondary AI from primary AI, central from primary hypothyroidism, and central DI from SIADH/primary polydipsia (Fleseriu JCEM 2016 ES; Husebye Lancet 2021)
Scope: Recognize anterior ± posterior pituitary hormone deficiency: peripheral hormone low WITH inappropriately low/normal trophic hormone, in a patient with a pituitary/hypothalamic insult; combined anterior+posterior deficiency points to stalk/hypothalamic disease (Fleseriu JCEM 2016 ES)

No severity triggers fired against current inputs.

Plan

Regimen axis: **Hypopituitarism replacement — glucocorticoid FIRST → levothyroxine → sex steroid → GH → desmopressin for central DI (Fleseriu JCEM 2016 ES)** — step "Step 1 — Glucocorticoid replacement FIRST (cardinal safety rule) (Fleseriu JCEM 2016 ES)".
1. hydrocortisone 15–20 mg/day PO in 2–3 divided doses with the largest dose on waking (e.g., 10 mg AM + 5 mg early-PM ± 2.5 mg late-PM) PO BID-TID (glucocorticoid_short_acting, first line) — Fleseriu JCEM 2016 ES — replaces cortisol mimicking diurnal rhythm; MUST be established before levothyroxine because thyroid hormone accelerates cortisol clearance and precipitates adrenal crisis; no reliable biomarker — titrate to clinical response avoiding over-replacement
2. prednisone 3–5 mg PO once daily (on waking) PO once daily (glucocorticoid_intermediate_acting, second line) — Fleseriu JCEM 2016 ES — once-daily alternative when adherence favors single dosing; less physiologic than divided hydrocortisone
3. hydrocortisone (parenteral stress dose) 100 mg IV/IM bolus then 50 mg IV q6h or 200 mg/24h infusion IV q6h or continuous (glucocorticoid_short_acting, rescue) — Fleseriu JCEM 2016 ES; Husebye Lancet 2021 — secondary AI decompensation is the life-threatening axis; do NOT delay for cortisol/ACTH result; route to adrenal-crisis pathway

Setting playbook (outpatient) — Confirm axis-by-axis deficiency by central rules, sequence replacement (glucocorticoid FIRST), educate on sick-day rules, image the sella (Fleseriu JCEM 2016 ES)
4. hydrocortisone 15–20 mg/day PO divided (largest AM dose) PO BID-TID — ACTH-axis deficiency confirmed — FIRST, before levothyroxine (Fleseriu JCEM 2016 ES) (Glucocorticoid cornerstone; precedes thyroid hormone (Fleseriu JCEM 2016 ES))
5. levothyroxine 1.0–1.6 mcg/kg/day PO titrated to free T4 PO once daily — Central hypothyroidism AND glucocorticoid already established (Persani JCEM 2018) (Titrate by free T4, never TSH (Persani JCEM 2018))
6. sex steroid (testosterone or estradiol+progestin) Sex-appropriate physiologic replacement transdermal/IM/PO per agent — Gonadotropin deficiency, no contraindication (Fleseriu JCEM 2016 ES) (Bone/sexual health; fertility pathway substitutes if pregnancy desired (Fleseriu JCEM 2016 ES))
7. somatropin 0.2–0.4 mg SC daily titrated to IGF-1 SC once daily — Adult GHD confirmed, symptomatic, no active malignancy (Yuen JCEM 2019 AACE/ACE GH) (Last axis; recheck adrenal/thyroid after start (Yuen JCEM 2019 AACE/ACE GH))
8. desmopressin 0.05–0.1 mg PO BID lowest effective PO/intranasal BID — Confirmed central DI, secondary AI already replaced (Fleseriu JCEM 2016 ES) (Under-dose deliberately; monitor sodium (Fleseriu JCEM 2016 ES))

Non-pharmacologic actions:
- Sick-day rules training: double/triple oral GC for illness; IM 100 mg + ED for vomiting/trauma (Fleseriu JCEM 2016 ES; Husebye Lancet 2021)
- Emergency IM hydrocortisone kit + steroid card + MedicAlert (Husebye Lancet 2021)
- Dedicated sellar MRI + visual-field testing if mass (Fleseriu JCEM 2016 ES)
- Neurosurgery referral for compressive lesion; reproductive endocrinology if fertility desired (Fleseriu JCEM 2016 ES)

AVOID / contraindication checks:
- Never_start_levothyroxine_before_glucocorticoid (Fleseriu JCEM 2016 ES)
- Do_not_under_replace_glucocorticoid_during_intercurrent_stress (Fleseriu JCEM 2016 ES; Husebye Lancet 2021)
- Do_not_delay_stress_dose_hydrocortisone_for_diagnostic_cortisol (Fleseriu JCEM 2016 ES)
- Do_not_titrate_levothyroxine_by_TSH_in_central_hypothyroidism (Persani JCEM 2018)
- Replace_glucocorticoid_before_desmopressin_cortisol_deficiency_masks_DI (Fleseriu JCEM 2016 ES)
- Avoid_GH_with_active_malignancy_and_recheck_adrenal_thyroid_axes_after_GH_start (Yuen JCEM 2019 AACE/ACE GH)
- Routine_fludrocortisone_not_indicated_in_secondary_AI (Fleseriu JCEM 2016 ES)

Monitoring

Regimen monitoring:
- glucocorticoid by clinical response — no biomarker; avoid over-replacement (Fleseriu JCEM 2016 ES)
- free T4 (NOT TSH) at 6-8 weeks then with dose change (Persani JCEM 2018)
- testosterone trough / estradiol + symptoms at 3-6 months (Fleseriu JCEM 2016 ES)
- IGF-1 age-adjusted for GH titration q1-2 months during titration (Yuen JCEM 2019 AACE/ACE GH)
- sodium + serum/urine osmolality for desmopressin — avoid hyponatremia (Fleseriu JCEM 2016 ES)
- recheck adrenal + thyroid axes after starting GH (Yuen JCEM 2019 AACE/ACE GH)
- surveillance MRI for residual tumor and delayed post-RT hypopituitarism (Fleseriu JCEM 2016 ES)

Setting (outpatient) monitoring:
- Glucocorticoid by clinical response — avoid over-replacement (Fleseriu JCEM 2016 ES)
- Free T4 (NOT TSH) at 6-8 weeks (Persani JCEM 2018)
- Testosterone/estradiol + symptoms at 3-6 months (Fleseriu JCEM 2016 ES)
- IGF-1 for GH; sodium/osmolality for desmopressin (Yuen JCEM 2019 AACE/ACE GH; Fleseriu JCEM 2016 ES)

Follow-up plan: Lifelong endocrine follow-up; stress-dosing / sick-day-rules education, emergency IM hydrocortisone kit, steroid card + MedicAlert; serial MRI for residual tumor; re-screen axes after RT (delayed hypopituitarism years later); fertility-induction referral if pregnancy desired (Fleseriu JCEM 2016 ES; Husebye Lancet 2021)
- Close-out criterion: sick-day rules taught; emergency kit + steroid card issued; surveillance MRI and axis re-screening scheduled (Fleseriu JCEM 2016 ES)

Monitoring phase: Glucocorticoid by clinical response (no reliable biomarker — avoid over-replacement); levothyroxine by free T4 (NOT TSH) at 6–8 weeks; testosterone/estradiol and symptoms; IGF-1 for GH titration; sodium and osmolality for desmopressin (avoid hyponatremia from over-treatment of DI) (Fleseriu JCEM 2016 ES; Persani JCEM 2018; Yuen JCEM 2019 AACE/ACE GH)

Disposition

Current setting: outpatient — Confirm axis-by-axis deficiency by central rules, sequence replacement (glucocorticoid FIRST), educate on sick-day rules, image the sella (Fleseriu JCEM 2016 ES)

Disposition criteria:
- Continue outpatient titration if hemodynamically stable, no mass effect, tolerating replacement (Fleseriu JCEM 2016 ES)
- Refer/admit for adrenal crisis, apoplexy with visual loss, or checkpoint-inhibitor hypophysitis with hypocortisolism (Husebye Lancet 2021)

Escalation triggers (move to higher acuity):
- Hypotension/hypoglycemia/hyponatremia → adrenal-crisis pathway + admit (Fleseriu JCEM 2016 ES)
- New visual-field loss or thunderclap headache → urgent MRI + neurosurgery (apoplexy) (Fleseriu JCEM 2016 ES)
- Severe symptomatic hyponatremia → admit + cautious correction (Fleseriu JCEM 2016 ES)

Earlier-Return Triggers

Return-precaution thresholds (watch for):
- [LIFE_THREATENING] Secondary adrenal insufficiency decompensation: hypotension ± hypoglycemia ± hyponatremia in pituitary-failure substrate (Fleseriu JCEM 2016 ES; Husebye Lancet 2021)
- [LIFE_THREATENING] Sellar/parasellar mass with bitemporal field loss or acute apoplexy (thunderclap headache + ophthalmoplegia) (Fleseriu JCEM 2016 ES)
- [SEVERE] Concurrent central hypothyroidism AND ACTH-axis deficiency — levothyroxine started before glucocorticoid risks adrenal crisis (Fleseriu JCEM 2016 ES; Persani JCEM 2018)

Citations

- 2016 Endocrine Society Hormonal Replacement in Hypopituitarism in Adults (Fleseriu JCEM 2016); 2021-2025 updates incl checkpoint-inhibitor hypophysitis (Husebye Lancet 2021); 2018 ETA central hypothyroidism (Persani); 2019 AACE/ACE adult GH deficiency (Yuen) [PMID:27736313](https://pubmed.ncbi.nlm.nih.gov/27736313/)
- Cited evidence (PMID 33484633) [PMID:33484633](https://pubmed.ncbi.nlm.nih.gov/33484633/)
- Cited evidence (PMID 30374425) [PMID:30374425](https://pubmed.ncbi.nlm.nih.gov/30374425/)
- Cited evidence (PMID 31760824) [PMID:31760824](https://pubmed.ncbi.nlm.nih.gov/31760824/)
- Cited evidence (PMID 27041067) [PMID:27041067](https://pubmed.ncbi.nlm.nih.gov/27041067/)

Last reconciled with current guidelines: 2026-05-22.
References
  • 2016 Endocrine Society Hormonal Replacement in Hypopituitarism in Adults (Fleseriu JCEM 2016); 2021-2025 updates incl checkpoint-inhibitor hypophysitis (Husebye Lancet 2021); 2018 ETA central hypothyroidism (Persani); 2019 AACE/ACE adult GH deficiency (Yuen) — PMID:27736313
  • Cited evidence (PMID 33484633) — PMID:33484633
  • Cited evidence (PMID 30374425) — PMID:30374425
  • Cited evidence (PMID 31760824) — PMID:31760824
  • Cited evidence (PMID 27041067) — PMID:27041067