Lesson
HPA Axis and Levels of Failure
Adrenal insufficiency is a cortisol-deficiency syndrome whose clinical pattern depends on whether failure begins in the adrenal cortex, pituitary, hypothalamus, or exogenous glucocorticoid feedback loop.
- Primary adrenal insufficiency
- Secondary and tertiary failure
- ACTH
- RAAS
- Aldosterone preservation
Low cortisol, high ACTH, and possible aldosterone loss
Low cortisol and low or inappropriately normal ACTH
Reduced CRH and ACTH with preserved RAAS
Map primary failure
Primary adrenal insufficiency damages the adrenal cortex. Cortisol falls, feedback raises ACTH, and aldosterone deficiency may produce high renin, salt craving, postural hypotension, hyponatremia, and hyperkalemia.
Map central failure
Pituitary or hypothalamic disease lowers ACTH drive. Cortisol falls, but the renin-angiotensin-aldosterone system usually preserves mineralocorticoid secretion, so hyperkalemia and severe salt wasting are less characteristic.
Map exogenous suppression
Exogenous glucocorticoids suppress CRH and ACTH. After sufficient exposure, the adrenal cortex may not generate the cortisol required for illness, surgery, or abrupt withdrawal even when aldosterone remains intact.
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Lesson
Primary Adrenal Insufficiency and Addison Disease
Addison disease is chronic primary adrenal insufficiency, most often autoimmune in many settings, while infection, hemorrhage, infiltration, metastases, and genetic disorders form important alternative pathways.
- Autoimmune adrenalitis
- 21-hydroxylase antibodies
- Polyglandular autoimmunity
- Hemorrhage and infection
- Hyperpigmentation
Reduce glucocorticoid and mineralocorticoid reserve
Feedback loss can produce hyperpigmentation
High renin, low aldosterone, and hyperkalemia can emerge
Recognize autoimmune disease
Autoimmune adrenalitis can be supported by 21-hydroxylase antibodies and may coexist with autoimmune thyroid disease, type 1 diabetes, celiac disease, vitiligo, or gonadal failure. Use periodic screening for associated autoimmunity, often annually, as well as symptom-driven evaluation; do not wait for symptoms alone.
Read the phenotype
Fatigue, weight loss, nausea, abdominal symptoms, postural dizziness, salt craving, hyponatremia, and hyperkalemia may develop gradually. High POMC-derived ACTH can darken scars, pressure areas, palmar creases, and oral mucosa.
Respect destructive causes
Tuberculosis and other infections, bilateral hemorrhage or infarction, metastatic disease, infiltrative disorders, adrenal surgery, and selected genetic conditions can remove cortical reserve. Abrupt pain, sepsis, anticoagulation, or shock raises concern for acute bilateral injury.
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Lesson
Central and Glucocorticoid-Induced Adrenal Insufficiency
Pituitary and hypothalamic disease can reduce ACTH, but the most common preventable central pathway is sustained exogenous glucocorticoid exposure followed by withdrawal or inadequate stress coverage.
- Pituitary disease
- Chronic glucocorticoids
- Multiple routes
- CYP3A4 interactions
- Current risk thresholds
Risk generally rises beyond physiologic exposure for three to four weeks
Multiple formulations can produce systemic suppression
Reduced metabolism can reveal Cushing features and HPA suppression
Identify structural central disease
Pituitary tumors, surgery, radiation, infarction, trauma, and hypothalamic disorders can reduce ACTH. Other pituitary hormone deficits may provide the clue. Evaluate adrenal function before starting levothyroxine for central hypothyroidism; if timely evaluation is not feasible, the hypopituitarism guideline advises empiric glucocorticoid coverage until definitive assessment.
Use current exposure thresholds
Risk from oral therapy is generally expected when exposure lasts at least three to four weeks and exceeds a physiologic daily equivalent, roughly hydrocortisone 15 to 25 mg or prednisone 4 to 6 mg. Short courses under three to four weeks usually do not require tapering solely for HPA protection.
Count every route and interaction
High-dose inhaled or topical therapy, repeated intra-articular injections, multiple formulations, long-acting agents, nighttime dosing, and CYP3A4 inhibition can raise suppression risk. Exogenous Cushing features are practical evidence that adrenal recovery cannot be assumed.
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Lesson
Clinical Recognition and Biochemical Patterns
Symptoms are often nonspecific, but the combination of hemodynamics, electrolytes, glucose, pigmentation, ACTH, renin, and aldosterone can reveal both severity and level of failure.
- Hypotension
- Hyponatremia and hyperkalemia
- Hypoglycemia
- ACTH
- Renin and aldosterone
Weakness, nausea, hypotension, and hypoglycemia can appear
The direction locates confirmed cortisol deficiency
Mineralocorticoid loss separates primary from most central disease
Recognize cortisol deficiency
Fatigue, anorexia, weight loss, nausea, vomiting, abdominal pain, myalgia, weakness, hypotension, fever, confusion, and hypoglycemia can reflect cortisol deficiency. None is diagnostic alone, so pattern and context matter.
Use mineralocorticoid clues
Hyperkalemia, salt craving, volume depletion, high renin, and low or inappropriately normal aldosterone support primary disease. Hyponatremia can occur in either primary or central disease because cortisol deficiency increases vasopressin and impairs free-water clearance.
Preserve diagnostic value
When feasible, obtain cortisol and ACTH before hydrocortisone, plus renin and aldosterone when primary disease is suspected. A diagnostic sample is useful only if collecting it does not delay treatment of hypotension or crisis.
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Lesson
Morning Cortisol and Corticotropin Testing
Diagnostic testing must answer a specific question: establish cortisol deficiency, classify the level, or demonstrate recovery after glucocorticoid-induced suppression.
- Morning cortisol
- 250 microgram corticotropin
- Assay context
- Recovery thresholds
- Testing limits
Interpret through timing, binding, assay, and recent exposure
Measure adrenal response when the patient is stable
After a supervised taper: >10 micrograms/dL supports recovery; 5-10 needs follow-up
Start with timed physiology
Morning cortisol is most informative near the expected circadian peak and before the day's replacement dose. Acute illness, sleep schedule, estrogen, low binding proteins, assay method, and recent glucocorticoids can change interpretation.
Test adrenal reserve
For stable suspected primary disease in adults, the standard 250 microgram corticotropin test measures cortisol response to synthetic ACTH. The stimulated cutoff is assay dependent, and recent-onset central disease can retain an apparently normal adrenal response before atrophy develops.
Separate central diagnosis from recovery
For suspected central insufficiency, the hypopituitarism guideline uses an 8-9 AM cortisol: below 3 micrograms/dL supports deficiency, above 15 makes it unlikely, and intermediate results require stimulation testing. These diagnostic guides differ from recovery thresholds after a steroid taper. Assay, sleep schedule and recent steroid exposure still matter; random cortisol is not a routine diagnostic substitute.
Measure glucocorticoid recovery
For recovery testing after tapering to physiologic dosing, use a clinician-planned 8-9 AM sample at least 24 hours after the last glucocorticoid dose; dexamethasone requires separate planning. A morning cortisol above 10 micrograms per deciliter supports recovery, 5 to 10 is indeterminate and should be repeated after weeks to months, and below 5 supports continued replacement with later reassessment. Dynamic testing is not routine during every taper.
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Lesson
Physiologic Glucocorticoid Replacement
Replacement aims to provide enough cortisol action for daily physiology without recreating chronic glucocorticoid excess.
- Hydrocortisone 15 to 25 mg
- Morning-weighted dosing
- Prednisolone alternative
- Clinical titration
- Under- and over-replacement
Approximate the normal morning peak
Support function while limiting evening exposure
Separate under-replacement from over-replacement and timing problems
Use physiologic ranges
Adults with primary adrenal insufficiency commonly use hydrocortisone 15 to 25 mg per day in two or three doses, with the largest dose on waking. Cortisone acetate 20 to 35 mg is another option where available.
Select an alternative carefully
Prednisolone 3 to 5 mg daily can simplify dosing when adherence is difficult. Dexamethasone is generally avoided for routine replacement because high potency and long action make physiologic titration and recovery assessment difficult.
Monitor the person
Routine replacement is titrated clinically rather than to serum cortisol targets. Fatigue, weight loss, nausea, and postural symptoms can suggest under-replacement, while weight gain, insomnia, bruising, hypertension, hyperglycemia, and osteoporosis can suggest excess.
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Lesson
Mineralocorticoid Replacement
Fludrocortisone replaces aldosterone action in primary adrenal insufficiency, while central and glucocorticoid-induced disease usually preserve the RAAS and do not need it.
- Fludrocortisone
- Renin
- Postural blood pressure
- Electrolytes
- Salt and heat
Adults with aldosterone deficiency may start at 50-100 micrograms daily
Use the whole volume and electrolyte pattern
Balance craving and postural symptoms against edema and hypertension
Start for aldosterone deficiency
Adults with confirmed primary adrenal insufficiency often begin fludrocortisone near 50 to 100 micrograms daily. Dose needs vary with climate, sweating, salt intake, pregnancy, kidney function, and residual adrenal activity.
Monitor replacement
Adequate replacement reduces salt craving and postural symptoms and supports appropriate electrolytes and renin in clinical context; renin near the upper reference range can be compatible with adequate replacement. Hypertension, edema, hypokalemia, or suppressed renin suggests excessive mineralocorticoid effect.
Do not default to salt restriction
Confirmed aldosterone deficiency generally requires adequate salt intake. Reassess fludrocortisone when hypertension develops; persistent hypertension can require antihypertensive treatment while necessary replacement continues.
Separate treatment layers
Fludrocortisone does not replace physiologic cortisol and should not be routine in secondary, tertiary, or glucocorticoid-induced adrenal insufficiency. Hydrocortisone has some mineralocorticoid activity, but routine doses may not fully replace aldosterone in primary disease.
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Lesson
Formulations and Safe Administration
Replacement succeeds only when the prescribed product, measured dose, administration route, and emergency technique deliver the intended hydrocortisone exposure.
- Hydrocortisone tablets
- Granules and liquid
- Dose measurement
- Emergency injection
- Route transition
Match tablets, granules, liquid, or injection to the clinical need
Verify concentration and use a calibrated device
Rehearse the exact kit and confirm technique before crisis
Choose an oral product deliberately
Tablets support flexible divided dosing for many adults. Pediatric granules and compounded or marketed liquid formulations may support smaller doses or swallowing needs, but concentrations, measuring devices, storage, and preparation instructions are product specific and are not interchangeable by volume.
Prevent measurement errors
Write the dose in milligrams and confirm the concentration whenever a liquid is used. Use the supplied oral syringe or an appropriate calibrated device rather than household spoons. Granules should be administered according to their labeling, and caregivers should demonstrate the complete technique.
Administer Alkindi Sprinkle correctly
Open the capsule; do not swallow its shell or crush or chew the granules. Give the granules directly, from a spoon, or on a small spoonful of cool soft food, and swallow within five minutes. Follow with fluid, but do not mix the granules into liquid or administer through nasogastric or gastric tubes. Contact the care team if the full dose is not retained. Switching oral formulations requires close monitoring for under-replacement even when the initial total daily milligram dose is unchanged.
Prepare the emergency route
Emergency hydrocortisone sodium succinate may require activation or reconstitution before IV or IM administration. Training should use the exact device dispensed, cover expiration and storage checks, and end with a return demonstration by the patient and a close contact.
Distinguish the injection presentations
A Solu-Cortef plain vial needs a separate compatible diluent; an Act-O-Vial contains its diluent in another compartment. For the 100 mg Act-O-Vial, the mixed volume is 2 mL (50 mg/mL). Activate the compartments, gently mix to dissolve, expose and disinfect the stopper, then withdraw the prescribed dose with the trained aseptic technique. Check the actual strength and instructions; this concentration must not be assumed for other presentations. Reconstitution is not an extra conversion from salt weight to hydrocortisone dose.
Transition after stabilization
Parenteral stress dosing continues while oral absorption or hemodynamics remain unreliable. Once the trigger is controlled and the patient is stable and absorbing medication, the regimen can step down toward oral stress dosing and then physiologic replacement under the treating team's direction.
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Lesson
Sick-Day Rules and Emergency Preparedness
Most preventable adrenal crises begin with an ordinary stressor, delayed dose escalation, failed oral absorption, or an emergency kit that no one knows how to use.
- Oral stress dosing
- Emergency injection
- Steroid card
- Vomiting
- Procedure planning
Use the personalized higher dose when stable and absorbing
Parenteral hydrocortisone replaces failed oral coverage
A rehearsed response shortens time to treatment
Scale by stress and absorption
Minor fever or illness can often be managed with the prescribed higher oral dose when the patient is stable and absorbing medication. Major illness, anesthesia, trauma, hemodynamic instability, vomiting, or severe diarrhea requires parenteral coverage.
Make the written oral plan concrete
For established primary insufficiency, the guideline gives fever examples of doubling hydrocortisone above 38°C or tripling it above 39°C until recovery, often two to three days, with tolerated electrolyte-containing fluids. Use the individualized plan; worsening illness or unreliable absorption requires escalation rather than repeated oral dosing.
Act when tablets fail
If medication cannot be retained, emergency hydrocortisone should be injected and urgent medical care obtained. Repeated oral dosing during persistent vomiting is not a substitute for parenteral treatment.
Build a reliable system
Patients need medical identification, a current steroid emergency card, an unexpired injection kit, written sick-day instructions, and trained family or caregivers. Procedure teams should receive the diagnosis and stress-dose plan in advance.
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Lesson
Adrenal Crisis Recognition and Immediate Treatment
Adrenal crisis is a clinical emergency defined by inadequate cortisol action during physiologic stress, often with hypotension or shock and rapidly progressive systemic illness.
- Hydrocortisone 100 mg
- Isotonic saline
- 200 mg over 24 hours
- Hypoglycemia
- No treatment delay
Give IV or IM immediately
Restore intravascular volume and correct hypoglycemia
Use infusion or 50 mg every six hours while treating the trigger
Recognize the emergency
Hypotension, volume depletion, vomiting, abdominal pain, fever, weakness, confusion, hypoglycemia, and electrolyte abnormalities can occur. Primary disease may be more hemodynamically severe because aldosterone is also deficient.
Treat immediately
For adults, give hydrocortisone 100 mg IV or IM immediately and begin rapid 0.9 percent saline. Continue hydrocortisone 200 mg over 24 hours by infusion or 50 mg IV or IM every six hours, while treating hypoglycemia and the precipitating illness.
Individualize fluid resuscitation
The adult guideline starts with about one liter of isotonic saline during the first hour, then adjusts further fluid to circulation, urine output, electrolytes and comorbidity. Reassess frequently for fluid overload and treat hypoglycemia. A fixed adult fluid volume is not a pediatric instruction.
Use pediatric dosing for children
Do not apply the fixed adult regimen to a small child. The primary-insufficiency guideline specifies initial hydrocortisone 50 mg/m², followed by 50-100 mg/m² over 24 hours. Use an age/body-size-specific pediatric emergency protocol and fluid plan.
Do not wait
Cortisol and ACTH may be drawn first only when that causes no delay. The short-term risk of empiric hydrocortisone is small compared with the risk of untreated crisis. Once stable, taper stress dosing toward oral replacement under specialist guidance.
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Lesson
Special Populations and Long-Term Follow-Up
Replacement changes with pregnancy, labor, surgery, childhood, heat exposure, shift schedules, intercurrent disease, and the cause of adrenal failure.
- Pregnancy
- Labor
- Procedures
- Autoimmune surveillance
- Post-crisis review
Plan stress coverage before demand rises
Look for both deficiency and chronic excess
Correct the failed instruction, supply, recognition, or communication step
Plan pregnancy and delivery
Hydrocortisone is preferred in pregnancy because placental enzymes limit fetal exposure. Reassess each trimester, often increase replacement in later pregnancy, monitor clinically, and provide parenteral stress dosing during labor. Routine dexamethasone replacement is avoided.
Follow the cause and consequences
Primary autoimmune disease warrants attention to associated autoimmune conditions. Long-term care reviews weight, blood pressure, glucose, bone health, quality of life, adherence, dosing times, fludrocortisone effect, and whether current replacement remains physiologic.
Learn from every crisis
After stabilization, identify the trigger and the system failure: no dose escalation, absent kit, expired drug, untrained caregiver, delayed recognition, or inadequate procedure planning. Repair that point before discharge and communicate the plan across care settings.
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Module practice
Check the connections.
Each attempt draws 10 questions from the complete 35 question bank.
Each attempt draws a fresh set and rearranges the answer choices.
References
Current clinical foundation.
Core source material was synthesized with the following contemporary guidance. Verify local policy and current guidance before applying clinical information.
- Primary Adrenal Insufficiency: Full Guideline and Stress-Dosing Table
- Alkindi Sprinkle Prescribing Information (April 2026)
- Endocrine Society primary adrenal insufficiency guideline
- 2024 ESE and Endocrine Society glucocorticoid-induced adrenal insufficiency guideline
- Endocrine Society hypopituitarism hormone replacement guideline
- Society for Endocrinology adrenal crisis guidance
- NIH Endotext adrenal insufficiency
- DailyMed Solu-Cortef prescribing information
- Current Cortef prescribing information
- Current Solu-Cortef prescribing information
- Current fludrocortisone prescribing information