The adrenal cortex is the outer layer of each adrenal gland — the small triangular cap sitting on top of each kidney. It is a separate organ, both embryologically and functionally, from the inner medulla. The cortex is organized into three concentric zones, each making a different class of steroid hormone: glomerulosa for aldosterone, fasciculata for cortisol, reticularis for DHEA and other weak androgens.
At a glance
What it does
Three outputs for three different jobs. Aldosterone from the zona glomerulosa regulates sodium, potassium, and blood pressure by acting on the distal nephron in the kidney — retain sodium and water, excrete potassium. Cortisol from the zona fasciculata is the main glucocorticoid — raises blood glucose, mobilizes fuel, dampens inflammation, supports blood pressure, permits a stress response, and runs a strong circadian rhythm. DHEA and DHEA-S from the zona reticularis are weak androgens that also serve as precursors for peripheral conversion to testosterone and estradiol in both sexes.
The three zones are under different control. Aldosterone is primarily driven by the renin-angiotensin system and serum potassium, not ACTH. Cortisol and DHEA are ACTH-driven. A cortex can fail selectively — isolated aldosterone deficiency exists, and isolated cortisol deficiency is the picture in iatrogenic HPA suppression.
How it works
All cortical hormones are synthesized from cholesterol through a set of cytochrome P450 and hydroxysteroid dehydrogenase enzymes. The pathway diverges by zone because each zone expresses different enzymes — the zona glomerulosa has aldosterone synthase (CYP11B2) and cannot make cortisol; the zona fasciculata has 11-beta-hydroxylase (CYP11B1) and makes cortisol but not aldosterone. This specialization is why congenital adrenal hyperplasia has different clinical pictures depending on which enzyme is deficient.
ACTH from the anterior pituitary binds the melanocortin-2 receptor on fasciculata and reticularis cells, increases cAMP, and drives cholesterol uptake and the rate-limiting step (cholesterol desmolase). Cortisol then feeds back to suppress CRH and ACTH. Aldosterone's main driver is angiotensin II — when kidneys sense low perfusion, they release renin, which cleaves angiotensinogen to angiotensin I, which ACE converts to angiotensin II, which stimulates the zona glomerulosa.
When it goes wrong
Primary adrenal insufficiency (Addison's disease) is usually autoimmune destruction of the cortex in developed countries — both cortisol and aldosterone tank. Symptoms: fatigue, weight loss, nausea, salt craving, low blood pressure, hyperpigmentation (because ACTH is high and its precursor POMC also produces MSH). Addisonian crisis — triggered by infection, surgery, or other stress in an unsuspected case — presents as hypotensive shock and is a medical emergency treated with IV hydrocortisone and saline.
Secondary adrenal insufficiency is far more common in clinical practice and usually iatrogenic — chronic exogenous steroid use suppresses the HPA axis; when steroids are stopped too fast, the atrophied cortex cannot produce enough cortisol. Aldosterone is preserved because it does not depend on ACTH. Anyone on systemic steroids for more than a few weeks should understand this.
Cushing's syndrome is the opposite — chronic cortisol excess. Most cases are iatrogenic from prescribed steroids. Endogenous Cushing's is usually pituitary ACTH-secreting adenoma (Cushing's disease), less often an adrenal adenoma or ectopic ACTH from a tumor. Presentation: central obesity, moon face, buffalo hump, thin skin and purple striae, easy bruising, hypertension, glucose intolerance, bone loss, proximal muscle weakness, mood disturbance.
Primary hyperaldosteronism (Conn's syndrome) is under-diagnosed hypertension from an aldosterone-secreting adenoma or bilateral hyperplasia. Look for hypertension with unexplained hypokalemia, or resistant hypertension despite three drugs. Screening is the aldosterone-to-renin ratio, which is a worthwhile test in patients with tough-to-control blood pressure.
Adrenal incidentalomas — nodules found on imaging done for other reasons — are common with aging. Most are non-functional and benign, but they need biochemical screening for Cushing's, pheochromocytoma (medullary), and hyperaldosteronism.
"Adrenal fatigue" is not a real diagnosis. The idea that chronic stress depletes the adrenals into a subclinical failure state has never been demonstrated with proper testing — most people diagnosed with it in the wellness industry have normal cortisol on careful evaluation. Actual adrenal insufficiency requires cortisol deficiency on ACTH stimulation testing or 8 a.m. cortisol, not saliva panel pattern-matching.
Interactions
Chronic stress, severe illness, and sleep loss all activate the HPA axis and raise cortisol output short-term. Chronic elevation drives visceral fat, insulin resistance, bone loss, and mood changes. Ketoconazole, metyrapone, osilodrostat, and mifepristone are pharmacological tools for Cushing's, each blocking a different step.
Licorice (glycyrrhizin) inhibits 11-beta-HSD2 in the kidney, which normally protects the mineralocorticoid receptor from being hit by cortisol. Inhibiting it causes a syndrome that looks exactly like hyperaldosteronism — hypertension and hypokalemia — from chronic high-dose licorice. Real, not rare, not obvious unless you think to ask.
Honest take
If you feel tired and stressed, the answer is almost never an adrenal supplement. Sleep, food, exercise, and reducing actual stressors are unglamorous but they work. If you are on chronic prednisone, know your taper plan and carry emergency hydrocortisone for sick days — iatrogenic adrenal crisis is one of the genuine medical emergencies you can prevent with five minutes of patient education. If your blood pressure is resistant to three drugs, get the aldosterone-to-renin ratio checked; primary hyperaldosteronism is real and under-diagnosed in a way that "adrenal fatigue" is not.
Sources
- Bornstein et al., Journal of Clinical Endocrinology and Metabolism — Endocrine Society guideline on primary adrenal insufficiency.
- Nieman et al., JCEM — Endocrine Society guideline on Cushing's syndrome diagnosis.
- Funder et al., JCEM — Endocrine Society guideline on primary aldosteronism.