What Causes Low Cortisol?

What Cortisol Actually Does in Your Body

Cortisol is a glucocorticoid hormone produced by the zona fasciculata of the adrenal cortex, and it touches nearly every organ system. It mobilizes glucose from liver glycogen stores, modulates immune cell trafficking, maintains vascular tone, and permits the action of catecholamines on blood vessels during stress.

The hypothalamic-pituitary-adrenal (HPA) axis governs its release. Corticotropin-releasing hormone (CRH) from the hypothalamus stimulates adrenocorticotropic hormone (ACTH) from the anterior pituitary, which then drives cortisol secretion from the adrenals [1]. Cortisol feeds back on both the hypothalamus and pituitary to limit further CRH and ACTH release. This negative feedback loop is central to understanding every cause of low cortisol. When the loop is disrupted at any level (hypothalamus, pituitary, or adrenal gland), cortisol production drops.

Cortisol follows a diurnal rhythm, peaking between 6:00 and 8:00 AM and reaching its nadir around midnight [2]. This rhythm is why timing matters when testing. A random afternoon cortisol value of 7 mcg/dL may be physiologically normal, while the same value at 8 AM is concerning. The hormone also surges during acute illness, surgery, or trauma, a response essential for survival. Without that surge, patients risk hemodynamic collapse, a scenario called adrenal crisis.

Primary Adrenal Insufficiency: When the Glands Themselves Fail

Primary adrenal insufficiency (Addison disease) results from destruction or dysfunction of the adrenal cortex itself. The hallmark is simultaneous deficiency of cortisol, aldosterone, and adrenal androgens.

Autoimmune adrenalitis accounts for 80 to 90% of primary cases in industrialized countries [3]. Autoantibodies target 21-hydroxylase, a key enzyme in cortisol synthesis. About 50% of patients with autoimmune Addison disease have at least one additional autoimmune disorder (type 1 diabetes, autoimmune thyroiditis, or vitiligo), forming autoimmune polyendocrine syndromes (APS) types 1, 2, and 4 [4].

Infectious causes remain significant worldwide. Tuberculosis was historically the leading cause and still accounts for a substantial proportion of cases in endemic regions [3]. CMV adrenalitis occurs in immunocompromised patients, particularly those with advanced HIV where the CD4 count drops below 50 cells/mcL.

Other primary causes include:

• Bilateral adrenal hemorrhage (associated with anticoagulant therapy, sepsis, or antiphospholipid syndrome)
• Metastatic infiltration (lung, breast, melanoma, and lymphoma are the most frequent primary sites)
• Congenital adrenal hyperplasia, particularly 21-hydroxylase deficiency, the most common inborn error of adrenal steroidogenesis with an incidence of roughly 1 in 15,000 births [5]
• Adrenoleukodystrophy, an X-linked disorder that should be considered in any young male presenting with primary adrenal insufficiency
• Bilateral adrenalectomy (surgical)

Because the adrenal glands are destroyed in primary insufficiency, ACTH levels are elevated (often above 100 pg/mL), and patients frequently develop hyperpigmentation from excess ACTH-driven melanocyte stimulation. This skin darkening, especially in palmar creases, buccal mucosa, and scars, is a clinical clue that distinguishes primary from secondary forms.

Secondary and Tertiary Adrenal Insufficiency: The Pituitary and Hypothalamic Causes

Secondary adrenal insufficiency arises from insufficient ACTH secretion by the pituitary. Tertiary insufficiency results from inadequate CRH from the hypothalamus. In practice, the two are often grouped together because they share the same clinical profile: low cortisol with low or inappropriately normal ACTH, preserved aldosterone production (aldosterone is primarily regulated by the renin-angiotensin system, not ACTH), and no hyperpigmentation.

Exogenous glucocorticoid use is the most common cause overall. Prednisone, dexamethasone, inhaled fluticasone at high doses, intra-articular triamcinolone injections, and even potent topical steroids can suppress the HPA axis [6]. The risk increases with dose and duration, but suppression has been documented after as little as two weeks of supraphysiologic dosing. An estimated 1 to 2% of the general population in Western countries takes chronic oral glucocorticoids [7], making iatrogenic adrenal insufficiency far more prevalent than Addison disease.

Pituitary and hypothalamic structural lesions are the next most frequent group:

• Pituitary adenomas (particularly large nonfunctioning macroadenomas compressing corticotroph cells)
• Craniopharyngiomas and other sellar/parasellar tumors
• Pituitary surgery or radiation (ACTH deficiency may emerge months to years after treatment)
• Sheehan syndrome (postpartum pituitary necrosis from severe hemorrhage)
• Lymphocytic hypophysitis, an autoimmune condition that has gained new visibility because immune checkpoint inhibitors (ipilimumab, nivolumab, pembrolizumab) induce hypophysitis in 5 to 17% of patients receiving combination regimens [8]
• Traumatic brain injury and subarachnoid hemorrhage, which can damage the pituitary stalk or gland

Checkpoint-inhibitor-induced hypophysitis deserves special attention given the expanding use of immunotherapy in oncology. The Endocrine Society's 2024 clinical practice guideline on endocrine side effects of immune checkpoint inhibitors recommends baseline morning cortisol before starting therapy and a low threshold for ACTH stimulation testing if symptoms develop [8]. ACTH deficiency from this cause is typically permanent, while thyroid and gonadal axes may recover.

The "Adrenal Fatigue" Question

The term "adrenal fatigue" is widely used in wellness and functional medicine communities to describe chronic fatigue, brain fog, salt cravings, and poor stress tolerance attributed to suboptimal (but not frankly deficient) cortisol output. The Endocrine Society issued a position statement in 2016 concluding that "adrenal fatigue" is not a recognized medical diagnosis and that no scientific evidence supports the concept that chronic stress causes the adrenal glands to "burn out" or produce inadequate cortisol [9].

A systematic review by Cadegiani and Kater (2016) evaluated 58 studies that assessed adrenal function in patients labeled with "adrenal fatigue." The review found no consistent pattern of cortisol abnormality that differentiated these patients from healthy controls [10]. Some patients had slightly lower salivary cortisol at certain time points, but the heterogeneity of methods and lack of validated diagnostic criteria made the findings uninterpretable.

This does not mean the symptoms are imaginary. Fatigue, poor sleep, and cognitive difficulty are real and may point toward thyroid dysfunction, sleep disorders, depression, iron deficiency, or other identifiable conditions. The concern is that the "adrenal fatigue" label may delay the diagnosis of treatable disease or lead to unmonitored use of over-the-counter adrenal supplements, some of which contain undisclosed glucocorticoids that could paradoxically worsen HPA suppression.

Patients experiencing persistent fatigue should receive a structured workup rather than an empiric diagnosis. A morning cortisol, TSH, CBC, ferritin, and metabolic panel represent a reasonable first pass.

How Cortisol Is Tested: Morning Levels, ACTH Stimulation, and Beyond

Morning serum cortisol is the appropriate screening test. Blood should be drawn between 7:00 and 9:00 AM. A value <3 mcg/dL (83 nmol/L) has high specificity for adrenal insufficiency; a value ≥15 mcg/dL (414 nmol/L) effectively rules it out [11]. Values between 3 and 15 mcg/dL occupy a gray zone requiring dynamic testing.

The 250 mcg cosyntropin stimulation test is the standard confirmatory test. Synthetic ACTH (cosyntropin) is administered intravenously or intramuscularly, and serum cortisol is measured at baseline and 30 or 60 minutes. A peak cortisol ≥18 mcg/dL (500 nmol/L) is traditionally considered a normal response [11]. The test performs well for primary adrenal insufficiency. For recent-onset secondary insufficiency (e.g., weeks after pituitary surgery), adrenal glands may not yet be atrophied and can still respond to exogenous ACTH, producing a false-negative result. In this scenario, the insulin tolerance test (ITT) or a low-dose (1 mcg) cosyntropin test may be more sensitive, although neither is universally adopted [12].

Simultaneous ACTH measurement helps localize the problem. In primary insufficiency, ACTH is elevated (often >100 pg/mL). In secondary or tertiary insufficiency, ACTH is low or inappropriately normal despite low cortisol.

Salivary cortisol testing has clinical utility in two specific scenarios: late-night salivary cortisol for screening high cortisol states (Cushing syndrome) and four-point salivary cortisol profiles in research settings. It is not validated as a stand-alone diagnostic for adrenal insufficiency by the Endocrine Society.

A note on testing for Cushing syndrome, since many patients researching cortisol disorders want to understand both ends of the spectrum: the recommended screening tests are late-night salivary cortisol (two measurements), 24-hour urinary free cortisol, and the 1 mg overnight dexamethasone suppression test [13]. At least two positive screening tests should be present before pursuing confirmatory evaluation with an endocrinologist.

Symptoms of Low Cortisol and When They Become Dangerous

Low cortisol symptoms develop gradually and are nonspecific, which is why the average time from symptom onset to diagnosis of Addison disease has historically been 2 to 5 years.

Common symptoms include: persistent fatigue that worsens with activity, orthostatic hypotension, unintentional weight loss, nausea and abdominal pain, salt craving (reflecting aldosterone deficiency in primary cases), and mood disturbance including depression and irritability [3].

Adrenal crisis is the acute, life-threatening expression of cortisol deficiency. It typically occurs when a patient with undiagnosed or undertreated adrenal insufficiency encounters a physiologic stressor (infection, surgery, trauma, or abrupt glucocorticoid withdrawal). Presentation includes severe hypotension, hyponatremia, hyperkalemia (in primary cases), hypoglycemia, and altered consciousness. A European registry study reported an adrenal crisis incidence of approximately 6, 8 episodes per 100 patient-years, with a mortality rate of 0.5 per 100 patient-years [14].

Every patient with confirmed adrenal insufficiency should carry a medical alert identification and an emergency injection kit containing 100 mg hydrocortisone for intramuscular administration, with clear "sick day" dosing rules: double the oral hydrocortisone dose during febrile illness and administer parenteral hydrocortisone if vomiting prevents oral intake [15].

Treatment: Replacing What the Body Cannot Make

Physiologic glucocorticoid replacement is the cornerstone. The Endocrine Society's 2016 guideline for primary adrenal insufficiency recommends hydrocortisone 15 to 25 mg daily in two or three divided doses, with the largest dose given upon waking to mimic the normal diurnal rhythm [15]. Some clinicians prefer modified-release hydrocortisone (Plenadren), which provides a more physiologic cortisol curve in a single morning tablet. A randomized crossover trial (N=64) showed that modified-release hydrocortisone reduced body weight and improved metabolic parameters compared to conventional thrice-daily dosing [16].

For primary adrenal insufficiency, fludrocortisone 0.05 to 0.2 mg daily replaces aldosterone. Dose adequacy is monitored through blood pressure, serum potassium, and plasma renin activity. Secondary adrenal insufficiency does not require mineralocorticoid replacement because the renin-angiotensin-aldosterone axis remains intact.

DHEA supplementation (25 to 50 mg daily) has been studied for quality of life and mood in women with adrenal insufficiency. A Cochrane review found limited evidence of benefit, primarily in subjective well-being and sexual function, but noted that the evidence quality was low [17]. It is not universally recommended but may be considered on a case-by-case basis.

Glucocorticoid dose adjustment during illness, surgery, or significant physical stress is mandatory. For major surgery, stress-dose coverage typically involves hydrocortisone 100 mg IV at induction followed by 50 mg every 8 hours, tapering over 1 to 3 days as the patient recovers [15].

Recovering From HPA Axis Suppression After Steroid Use

For patients whose adrenal insufficiency is iatrogenic (from exogenous glucocorticoid use), the question is whether and when the HPA axis will recover. Recovery is variable: some patients regain normal function within weeks of steroid discontinuation, while others remain suppressed for 6 to 12 months or longer [6].

The general approach involves a slow taper of the exogenous glucocorticoid to a physiologic equivalent dose (approximately 5 mg prednisone or 20 mg hydrocortisone daily), followed by switching to morning-only hydrocortisone and serial morning cortisol or ACTH stimulation testing every 4 to 6 weeks. Once the morning cortisol consistently exceeds 10 mcg/dL and the cosyntropin-stimulated cortisol exceeds 18 mcg/dL, replacement can be stopped, though stress-dose coverage during illness should continue for an additional 6 to 12 months in some cases.

A practical caution: patients should never abruptly stop glucocorticoids they have taken for more than 2 to 3 weeks at supraphysiologic doses. Abrupt withdrawal risks adrenal crisis.