- 01Adrenal failure vs a switched-off signal
A low cortisol alone cannot tell Addison's disease from pituitary or steroid-related insufficiency; the paired ACTH can, because it runs high only when the adrenal gland itself has failed. Only that adrenal kind loses aldosterone and darkens the skin, so only it usually needs fludrocortisone.
Addison's disease is lifelong failure of the adrenal glands to make enough of two hormones, cortisol and aldosterone. About 1 to 2 in 10,000 people in Western countries have it, and the number has been rising 2. The early signs are vague enough that many people see several doctors before anyone checks their adrenal glands, and some are only diagnosed in hospital during an adrenal crisis 2. Once it is found, tablets replace the missing hormones, and with good treatment many people go on to work, travel, exercise and have children.
What are the first signs of Addison's disease?
Addison's disease usually builds over months or years, because symptoms tend to appear only once about 90% of the adrenal cortex has been destroyed 2. Until then the remaining tissue keeps up. The symptoms fall into three groups, and the group tells you which missing hormone is behind each one.
From missing cortisol
- Tiredness and weakness that rest does not fix (see fatigue for the commoner causes)
- Poor appetite and weight loss
- Nausea, vomiting and stomach pain
- Low mood and poor concentration
- Low blood sugar, mainly in children
- In women, loss of underarm and pubic hair and lower sex drive, because the adrenals are their main source of androgens (male-type hormones that women also make in small amounts)
From missing aldosterone
- Dizziness or light-headedness on standing, from low blood pressure
- Craving salt, sometimes eating it straight or drinking pickle juice
- Muscle cramps
From high ACTH
The body makes ACTH alongside a second hormone that darkens skin, so when ACTH runs high, the skin darkens too 2. After months of high ACTH, skin darkens most in creases of the palms, knuckles, elbows, scars and gums, and a tan lasts longer than it should. This darkening happens only in primary adrenal insufficiency; when the pituitary is the problem, ACTH is low and skin stays pale.
What causes Addison's disease?
In the US and Europe, about 80 to 90% of Addison's disease is autoimmune: the immune system attacks the adrenal cortex 1. Antibodies against 21-hydroxylase, an enzyme the cortex needs to make cortisol, are found in most people with the autoimmune form, and the Endocrine Society guideline advises testing for them to confirm the cause 1. Our guide to autoimmune antibody tests explains how antibody results read.
| Cause | Who it tends to affect | Clue on the tests |
|---|---|---|
| Autoimmune adrenalitis | Most cases in high-income countries; more often women | 21-hydroxylase antibodies positive; often thyroid antibodies too |
| Tuberculosis | People from or living in areas where TB is common | Antibodies negative; adrenals may be enlarged or calcified on a scan |
| Other infections (HIV, fungal) | People with weakened immunity | Antibodies negative; infection markers |
| Bleeding into the adrenals | Severe sepsis, blood thinners, antiphospholipid syndrome | Sudden crisis; bleeding seen on a scan |
| Medicines | Ketoconazole and etomidate block cortisol production; immune checkpoint inhibitors used in cancer care can inflame the adrenals, though they more often affect the pituitary | Timing matches the medicine |
| Cancer spread to both adrenals | People with lung, breast or other cancers | Adrenal masses on a scan |
| Genetic forms | Adrenoleukodystrophy in boys and young men; congenital adrenal hyperplasia from birth | Very long chain fatty acids raised; 17-hydroxyprogesterone raised |
About half of people with autoimmune Addison's disease have, or go on to develop, a second autoimmune condition, most often autoimmune thyroid disease and then type 1 diabetes, a cluster called autoimmune polyendocrine syndrome type 2 6. Celiac disease, vitiligo and pernicious anemia also show up more often. If you have Addison's disease, it is reasonable to ask whether your doctor checks for Hashimoto's disease, hypothyroidism, diabetes, celiac disease (a tTG-IgA blood test) and B12 deficiency from time to time. A positive thyroid antibody is not a verdict on its own; as our Hashimoto's page puts it, "A positive TPO antibody test says the immune system is attacking the thyroid. It does not say the thyroid has failed."
Primary, secondary or from steroids: which kind is it?
Adrenal insufficiency means too little cortisol, and the fault can sit in one of two places. Addison's disease is the primary form, where the adrenal gland itself fails. Secondary adrenal insufficiency starts in the pituitary, which stops sending ACTH. The most common kind overall comes from steroid medicines such as prednisone: months of steroid tablets, injections or high-dose inhalers switch off the body's own ACTH, and stopping them suddenly leaves too little cortisol 2. Steroid-related insufficiency behaves like the secondary form.
Renin is a signal from the kidneys that rises when the body is short of salt and fluid; aldosterone is the hormone that answers it. In Addison's disease the adrenal gland cannot answer, so renin climbs while aldosterone stays low.
| Primary (Addison's disease) | Secondary (pituitary) | After stopping steroids | |
|---|---|---|---|
| Where the fault is | Adrenal cortex | Pituitary gland | Pituitary switched off by the medicine |
| ACTH | High | Low or normal | Low or normal |
| Aldosterone and renin | Aldosterone low, renin high | Usually normal | Usually normal |
| Potassium | Can be high | Normal | Normal |
| Skin | Darker | Pale or unchanged | Unchanged |
| Needs aldosterone replacement | Yes, usually | No | No |
The split matters for treatment. Only the primary form loses aldosterone, so only Addison's disease usually needs fludrocortisone on top of hydrocortisone. Steroid-related suppression often recovers over months as the medicine is tapered under a doctor's care.
The blood tests and what the numbers mean
The first test is a morning cortisol, drawn between about 7 and 9 a.m. when cortisol normally peaks. A very low morning cortisol makes adrenal insufficiency likely, a clearly high one makes it unlikely, and the large middle band needs a stimulation test to decide. Our page on low morning cortisol covers the other reasons a cortisol reads low.
Where an example morning cortisol of 4 µg/dL fallsµg/dL
- 1Ask for a paired morning testA cortisol drawn at 7 to 9 a.m. with an ACTH from the same sample.
- 2Ask for the stimulation test and a referralIf cortisol is very low or ACTH is high, ask for an ACTH stimulation test and an endocrinology referral within days, not months.
- 3Don't start new steroids before the blood draw, if you are wellSteroid tablets taken before the test distort the result, so only start them before blood is drawn if a doctor advises it. Never stop a steroid you are already prescribed without your doctor's advice.
- 4Go to emergency care if you are vomiting, fainting or confusedTreatment comes first and the tests can wait.
A cortisol result needs its ACTH beside it. As our ACTH page puts it, "ACTH is the signal and cortisol is the output. On its own an ACTH number says little; beside a cortisol drawn the same morning it shows whether a cortisol problem starts in the adrenal gland or in the pituitary above it." A high ACTH says the adrenal gland is the problem; a low or normal ACTH points to the pituitary or to steroid medicines.
The confirming test is the ACTH stimulation test (also called the cosyntropin or Synacthen test): a dose of synthetic ACTH is injected and cortisol is measured 30 and 60 minutes later. The Endocrine Society guideline names it the standard test:
We recommend a short corticotropin test (250 μg) as the "gold standard" diagnostic tool to establish the diagnosis.Bornstein SR et al., Endocrine Society clinical practice guideline, J Clin Endocrinol Metab 2016 1
In that guideline, a peak cortisol below 18 µg/dL (500 nmol/L) confirms adrenal insufficiency 1. Newer, more specific cortisol assays (the lab's testing method) read lower than older ones, and a 2021 study put the matching cut-off at about 14 to 15 µg/dL for those assays 4. That leaves a band where the answer depends on the lab, so ask which assay yours uses.
Where an example peak cortisol of 16 µg/dL falls after an ACTH stimulation testµg/dL
| Test | Typical pattern in Addison's disease | Why |
|---|---|---|
| Morning cortisol | Low | The adrenal cortex cannot make enough |
| ACTH | High, often very high | The pituitary pushes harder on a failing gland |
| Sodium | Low in about 70 to 80% | Aldosterone loss lets sodium leak into urine |
| Potassium | High in about 30 to 40% | Aldosterone normally clears potassium |
| Renin | High | The kidneys sense low salt and fluid |
| Aldosterone | Low | The gland cannot answer renin |
| DHEA sulfate | Low | Adrenal androgens are lost too |
| Eosinophils | Sometimes raised | Cortisol normally holds them down |
| Glucose | Sometimes low | Cortisol helps keep blood sugar up |
The core Addison's disease tests
Sodium and potassium are the results most often spotted first, on a routine metabolic panel (our electrolytes guide explains each line). Our pages on low sodium, high potassium and high eosinophils (a type of white blood cell) cover the many other causes of each. A lone high potassium also needs care in reading: as our electrolytes guide puts it, "A high potassium on a routine draw is often caused by the sample, so a careful repeat is the usual first step."
Tests that fill in the picture
A few things skew these results. Tell the lab about any steroid tablets, inhalers, creams or injections, since they lower cortisol and ACTH. Estrogen, including the combined pill, raises the protein that carries cortisol, so total cortisol reads higher than the true free level. High-dose biotin can upset some hormone assays, and a sample that clotted or sat too long can falsely raise potassium. Our guide on preparing for a blood test covers timing and fasting.
Adrenal crisis: the emergency to know
Adrenal crisis is a sudden, life-threatening shortage of cortisol. It is triggered by vomiting or diarrhea (tablets do not get absorbed), infections, injury, surgery or missed doses, and in undiagnosed people it is sometimes the first sign of Addison's disease. Crises still happen in people who have been taught how to prevent them 3.
In hospital, adrenal crisis is treated with an immediate 100 mg hydrocortisone injection followed by intravenous fluids 1. That is why people with Addison's disease carry an emergency injection kit, a steroid emergency card and a medical ID.
Treatment: replacing what the adrenals no longer make
Addison's disease is treated by replacing both missing hormones for life, with the dose set and adjusted by a doctor 1. Hydrocortisone replaces cortisol, usually 15 to 25 mg a day split into two or three doses, with the largest on waking to mimic the natural morning peak; prednisolone is an alternative for some people. Fludrocortisone replaces aldosterone, usually 50 to 100 micrograms a day 1. Some women with low energy or libido despite good replacement are offered a trial of DHEA 1.
Replacement is judged by how you feel, your weight and blood pressure, and blood tests for sodium, potassium and renin, the kidney signal that rises when the body is short of salt 1. Repeat cortisol levels are not used to set the hydrocortisone dose, since they swing with each tablet. Salt does not usually need to be restricted, and some people are advised to take a little extra in hot weather or with heavy sweating; ask your care team what suits you.
- 1Learn the sick-day rulesYour doctor or endocrine nurse explains how to raise the tablet dose during a fever or illness, commonly doubling or tripling it 1, and when to switch to the injection instead.
- 2Use the injection when you cannot keep tablets downVomiting or diarrhea means the tablets may not be absorbed. Standard sick-day guidance, which your care team will go through with you, is to use the emergency injection and seek emergency care.
- 3Carry proofA steroid emergency card and medical ID tell paramedics and hospital staff what you need.
- 4Plan ahead for proceduresSurgery, colonoscopy preparation, dental work under sedation and labor need extra steroid cover, agreed with your team in advance.
Living with Addison's disease
With good replacement, many people with Addison's disease live full, active lives. President John F. Kennedy had Addison's disease, treated with steroid replacement, and his records suggest it was part of autoimmune polyendocrine syndrome type 2 7. Some extra risk remains: a Swedish population study found a death rate more than twice that of the general population (a risk ratio of about 2.2 in men and 2.9 in women), mainly from heart disease, cancer and infections 5. That study used older treatment practice, and the clearest way to cut the risk is to prevent crises and treat them fast. Pregnancy is possible and needs an endocrinologist involved, because hormone needs shift in the third trimester and during labor 1. Long or intense exercise sometimes needs a small extra dose, agreed with your doctor.
Is Addison's disease the same as "adrenal fatigue"?
No. Addison's disease is measurable adrenal failure: low cortisol, high ACTH and a failed stimulation test. "Adrenal fatigue" is a label used online for tiredness supposedly caused by worn-out adrenals; it is not a recognized diagnosis, and tests in tired people do not show it. If you are exhausted and your cortisol and ACTH are normal, the cause is usually elsewhere: sleep, iron, thyroid, mood or chronic fatigue syndrome. Our fatigue guide walks through the common causes and the tests that find them.
Citations
- Bornstein SR et al. Diagnosis and treatment of primary adrenal insufficiency: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2016;101(2):364-389
- Husebye ES, Pearce SH, Krone NP, Kampe O. Adrenal insufficiency. Lancet. 2021;397:613-629
- Hahner S et al. High incidence of adrenal crisis in educated patients with chronic adrenal insufficiency: a prospective study. J Clin Endocrinol Metab. 2015;100(2):407-416
- Javorsky BR et al. New cutoffs for the biochemical diagnosis of adrenal insufficiency after ACTH stimulation using specific cortisol assays. J Endocr Soc. 2021;5(4):bvab022
- Bergthorsdottir R et al. Premature mortality in patients with Addison's disease: a population-based study. J Clin Endocrinol Metab. 2006;91(12):4849-4853
- Husebye ES, Anderson MS, Kampe O. Autoimmune polyendocrine syndromes. N Engl J Med. 2018;378:1132-1141
- Mandel LR. Endocrine and autoimmune aspects of the health history of John F. Kennedy. Ann Intern Med. 2009;151(5):350-354
Educational context only, not medical advice or a diagnosis. Always discuss your results with a clinician.
