Adrenals

The Adrenal (Suprarenal) System: A Comprehensive Reference

Overview and Definition

The adrenal glands are paired endocrine organs that play a vital role in maintaining homeostasis by regulating blood pressure, metabolism, electrolyte balance, and the body's response to stress. The adrenal glands, also called the suprarenal glands, are a significant part of the endocrine system. These glands play a vital role in the body's fight-or-flight response, generating stress hormones that activate physiological adaptations necessary to counteract changes in the external environment. The adrenal glands also secrete several essential hormones that significantly regulate the body's immune system, metabolism, and salt and water balance.

The adrenal gland was first described by Eustachius in 1563, and its importance was later recognized by the work of Thomas Addison in 1855 and Brown-Séquard in 1856.

Anatomy and Structure

Gross Anatomy

The paired adrenal glands are triangular-shaped organs that measure approximately 5 cm by 2 cm, are located on the superior aspect of each kidney, and weigh 4 to 5 grams each. The adrenals are golden-yellow retroperitoneal organs, lying just superior to the kidneys (suprarenal glands) bilaterally at the level of T11–12.

The venous drainage from the adrenal glands is dependent on the side of the gland. The left adrenal gland is anatomically further away from the inferior vena cava; therefore, the left adrenal vein drains into the left renal vein. The right adrenal vein is much closer to the inferior vena cava and drains directly into this large vessel.

Structural Divisions: Cortex and Medulla

Each gland comprises the adrenal cortex, which produces steroid hormones, and the adrenal medulla, responsible for catecholamine synthesis. These two compartments have distinct embryological origins, separate regulatory mechanisms, and produce chemically distinct hormone families.

The Adrenal Cortex

The adrenal cortex takes part in steroidogenesis, producing glucocorticoids, mineralocorticoids, and androgen precursors. It has three distinct functional and histological zones: the zona glomerulosa (outermost layer), the zona fasciculata (middle layer), and the zona reticularis (innermost layer). Each layer produces steroid hormones from the precursor cholesterol.

• Zona Glomerulosa (outermost): The outer zona glomerulosa is the site of mineralocorticoid production (e.g., aldosterone), mainly regulated by angiotensin II, potassium, and ACTH. In addition, dopamine, atrial natriuretic peptide (ANP), and other neuropeptides modulate adrenal zona glomerulosa function. Zona glomerulosa cells are scattered and produce and secrete aldosterone.
• Zona Fasciculata (middle): The central zona fasciculata is responsible mainly for glucocorticoid synthesis and is regulated by ACTH. In addition, several cytokines (IL-1, IL-6, TNF), neuropeptides, and catecholamines influence the biosynthesis of glucocorticoids. The zona fasciculata contains large cells replete with lipids — the "clear cells" — which synthesize and release cortisol.
• Zona Reticularis (innermost): The inner zona reticularis is the site of adrenal androgen (predominantly dehydroepiandrosterone [DHEA], DHEA sulfate [DHEA-S], and Δ4-androstenedione) secretion, as well as some glucocorticoid production (cortisol and corticosterone). The zona reticularis consists of cells containing lipofuscin granules, termed "compact" cells, that are responsible for adrenal androgen biosynthesis and secretion.

Adrenocortical cells are arranged in a cord-like manner, extending from the adrenal capsule to the medulla, and are embedded within a widespread capillary network. These cells are rich in mitochondria and smooth endoplasmic reticulum, which form an extended network of anastomosing tubules.

The Adrenal Medulla

The adrenal medulla contains chromaffin cells, which are responsible for the biosynthesis and secretion of the catecholamines epinephrine and norepinephrine. The hormones produced by the adrenal medulla are called catecholamines. They act as hormones and as chemical messengers in the nervous system (called neurotransmitters). They manage the body's response to stress.

High cortisol concentrations reaching the adrenal medulla stimulate the synthesis of phenylethanolamine-N-methyltransferase, which catalyzes the conversion of norepinephrine to epinephrine. Thus, the structural relationship between the cortex and medulla and its blood supply has additional functional implications within the medulla.

Physiological Functions

The Hypothalamic–Pituitary–Adrenal (HPA) Axis

Cortisol production is regulated by the hypothalamic–pituitary–adrenal (HPA) axis. The corticotropin-releasing hormone (CRH) from the hypothalamus stimulates adrenocorticotropic hormone (ACTH) release from the anterior pituitary, which subsequently drives cortisol synthesis from cholesterol via several enzymatic steps in the zona fasciculata of the adrenal cortex. Serum cortisol then inhibits the production of both CRH and ACTH (negative feedback loop), allowing the system to self-regulate and maintain appropriate cortisol levels.

Glucocorticoids: Cortisol

The major secretions of the adrenal cortex are cortisol (the main member of the glucocorticoid family in humans), aldosterone (a mineralocorticoid), and the "weak" androgens androstenedione and dehydroepiandrosterone (DHEA). In the long-term stress response, the hormone cortisol is involved in catabolism of glycogen stores, proteins, and triglycerides, glucose and ketone synthesis, and downregulation of the immune system.

Mineralocorticoids: Aldosterone

Aldosterone is a mineralocorticoid hormone that plays a central role in regulating blood pressure and the levels of sodium and potassium (electrolytes) in the blood. This means aldosterone helps regulate blood pH (how acidic or basic it is) by controlling the levels of electrolytes in the blood.

The two primary regulators of aldosterone are (1) the renin–angiotensin–aldosterone system (RAAS) and (2) potassium levels. The kidney releases renin in response to decreased renal perfusion sensed by the juxtaglomerular apparatus. Renin converts angiotensinogen to angiotensin I (AT-I), which is then converted to angiotensin II (AT-II) via angiotensin-converting enzyme (ACE) in the lung. AT-II stimulates aldosterone synthesis in the zona glomerulosa by activating aldosterone synthase.

Adrenal Androgens: DHEA and Androstenedione

The adrenal androgens, primarily DHEA, require peripheral conversion to active sex steroids in the gonads and peripheral tissue. Circulating DHEA-sulfate is the best measure of adrenal androgen excess. Some DHEA is also converted to androstenedione. These hormones are weak male hormones, meaning they do not have much direct biologic impact. They are converted into female hormones (estrogens) in the ovaries and into male hormones (androgens) in the testes.

Catecholamines: Epinephrine and Norepinephrine

The short-term stress response involves the hormones epinephrine and norepinephrine, which work to increase the oxygen supply to organs important for extreme muscular action such as the brain, lungs, and muscles. Epinephrine (adrenaline) is released during times of short-term stress such as sudden shock or fear. It increases heart rate, blood pressure, and blood sugar level. Norepinephrine (noradrenaline) constricts blood vessels. Like epinephrine, it also increases heart rate, blood pressure, and blood sugar level.

The adrenal medulla also produces the protein chromogranin A, which is stored and secreted with epinephrine and norepinephrine.

Stress Response and General Adaptation

The body responds in different ways to short-term stress and long-term stress following a pattern known as the general adaptation syndrome (GAS). Stage one of GAS is called the alarm reaction. This is short-term stress — the fight-or-flight response — mediated by the hormones epinephrine and norepinephrine from the adrenal medulla. Their function is to prepare the body for extreme physical exertion. Once this stress is relieved, the body quickly returns to normal.

Assessment of Adrenal Health

Serum and Salivary Cortisol Testing

Cortisol levels can be measured in blood, saliva, and urine. Recommended initial screening tests include late-night salivary cortisol (two samples on separate days), 24-hour urinary free cortisol (two collections), or the overnight 1-mg dexamethasone suppression test (DST). At least two abnormal results are generally required to establish endogenous hypercortisolism, and testing should be repeated if results are equivocal or suggest cyclic disease.

The ACTH (Cosyntropin) Stimulation Test

The cosyntropin stimulation test is a dynamic endocrine test used to evaluate adrenal cortical function and assess the integrity of the hypothalamic–pituitary–adrenal (HPA) axis. Cosyntropin is a synthetic analog of adrenocorticotropic hormone (ACTH) that stimulates the adrenal cortex to produce cortisol. By measuring serum cortisol levels before and after cosyntropin administration, clinicians can determine whether the adrenal glands respond appropriately to ACTH stimulation.

In primary adrenal insufficiency, destruction or dysfunction of the adrenal cortex prevents an appropriate cortisol response to ACTH stimulation, regardless of the dose administered. Under these conditions, the cosyntropin stimulation test functions as the diagnostic gold standard because endogenous ACTH secretion is already maximally elevated and exogenous cosyntropin fails to elicit a significant increase in cortisol secretion.

Adrenal insufficiency is diagnosed if the peak cortisol level is below 500 nmol/L (18 µg/dL); however, this cutoff is assay-dependent, and every laboratory should provide a specific threshold value.

24-Hour Urinary Free Cortisol

This test is done to check for increased or decreased cortisol production. Cortisol is a glucocorticoid (steroid) hormone released from the adrenal gland in response to adrenocorticotropic hormone (ACTH). Normal range is less than 45 mcg/24 hours (124 nmol/24 hours) for women and less than 60 mcg/24 hours (165 nmol/24 hours) for men, though normal value ranges may vary slightly among different laboratories.

DHEA-S Measurement

DHEA-S is the most abundant hormone in the body and serves as a precursor to testosterone and estrogen. Levels naturally decline with age, making this test useful for assessing adrenal function and hormonal aging.

Imaging

Imaging tests such as an MRI or CT scan allow providers to see the adrenal glands and check for a possible tumor. Sometimes adrenal nodules show up on an imaging scan (CT scan or MRI) done for an unrelated medical condition. This is a relatively common finding occurring in as many as 10% of all abdominal imaging studies and is known as an asymptomatic or incidental adrenal nodule. Fortunately, most incidental adrenal nodules do not cause health problems. However, the adrenal nodule requires evaluation for possible excess hormone production or suspicion of cancer.

Conditions and Disorders Associated with the Adrenal System

Adrenal Insufficiency (Addison's Disease)

Addison's disease occurs when the adrenal glands do not produce enough hormones due to either the adrenal cortex not producing enough cortisol and aldosterone, or when both adrenal glands have been surgically removed. The most common form of primary adrenal insufficiency (PAI) in adults from high-income countries is autoimmune adrenalitis, while in children it is congenital adrenal hyperplasia (CAH). Patients with primary adrenal insufficiency causing low levels of aldosterone may experience low blood pressure, increased potassium levels, and lethargy.

Cushing's Syndrome and Cushing's Disease

Cushing syndrome is a rare disease that results from having too much cortisol hormone in the body. In some cases, Cushing syndrome develops from long-term or overuse of steroid medications (medicines that act like cortisol in the body). In other cases, the body itself produces too much cortisol. Cushing's disease refers specifically to pituitary tumors that cause Cushing's syndrome. Another common cause of Cushing syndrome is excessive and prolonged consumption of external steroids, such as prednisone or dexamethasone, which are prescribed to treat many autoimmune or inflammatory diseases.

Primary Hyperaldosteronism (Conn's Syndrome)

Primary aldosteronism (PA) is the most common cause of secondary hypertension and affects an estimated 5–10% of all patients with hypertension. Hyperaldosteronism results from overproduction of aldosterone from one or both adrenal glands. This is characterized by an increase in blood pressure that often requires many medications to control. Some people can develop low potassium levels in the blood, which can cause muscle aches, weakness, and spasms. When the cause is adrenal oversecretion, the disease is called Conn syndrome.

Pheochromocytoma

Pheochromocytoma is a tumor that results in excess production of adrenaline or noradrenaline by the adrenal medulla, and this often happens in bursts. If you have this condition, your glands make too much epinephrine and norepinephrine, which can raise your blood pressure or make your heart race.

Congenital Adrenal Hyperplasia (CAH)

Congenital adrenal hyperplasia (CAH) is a group of inherited disorders in which the adrenal glands don't make enough cortisol. The most common type is 21-hydroxylase deficiency (also called CAH1). In the United States, newborn babies receive a blood test to check for CAH. People born with CAH may not have symptoms until childhood or later in life.

Adrenocortical Carcinoma

Adrenocortical carcinoma is a rare adrenal gland disorder that occurs when cancer forms in the adrenal gland's outer layer. Cancerous adrenal tumors are often found years after they start growing, at which point the cancer may have spread to other organs.

Adrenal Incidentalomas

If tumors or hyperplasia arise from the adrenal gland, any of these hormones can be produced in excess and give rise to disorders such as pheochromocytoma, primary aldosteronism, and Cushing syndrome. Some conditions are common (e.g., adrenal incidentalomas) while others are rare (e.g., adrenal medullary hyperplasia).

The "Adrenal Fatigue" Controversy

"Adrenal fatigue" is a term invented in 1998 by chiropractor James Wilson and applied to a collection of mostly non-specific symptoms. A systematic review published in BMC Endocrine Disorders concluded that there is no substantiation that "adrenal fatigue" is an actual medical condition. Therefore, adrenal fatigue remains a myth. The Endocrine Society and other mainstream medical organizations do not acknowledge adrenal fatigue as a valid diagnosis, saying its symptoms overlap with many other conditions such as depression, sleep apnea, and hypothyroidism. Unlike recognized adrenal disorders like Addison's disease (underactive adrenal glands) or Cushing's syndrome (excess cortisol production), adrenal fatigue has no defined clinical markers.

Lifestyle Factors Supporting Normal Adrenal Function

Several lifestyle changes have solid evidence behind them for normalizing cortisol regulation. Physical activity is one of the most reliable tools. Regular moderate exercise helps calibrate the body's stress response, improving both the peak and recovery of cortisol throughout the day. Sleep quality matters as much as sleep quantity: cortisol follows a natural daily rhythm that depends heavily on consistent sleep-wake timing. Disrupted or insufficient sleep throws that rhythm off, which can perpetuate fatigue regardless of how many hours are spent in bed.

Nutrients Studied in Relation to Adrenal Function

Several micronutrients are present in high concentrations in adrenal tissue or serve as biochemical cofactors in adrenal steroidogenesis. The evidence for each varies considerably; the following sections distinguish between the known biochemical role of these nutrients and clinical evidence in humans.

Vitamin C (Ascorbic Acid)

Biochemical role and human evidence: A study was designed to determine whether paracrine secretion of vitamin C from the adrenal glands occurs. During diagnostic evaluation of 26 patients with hyperaldosteronism, adrenocorticotrophic hormone was administered intravenously and vitamin C and cortisol were measured in adrenal and peripheral veins. Adrenal vein vitamin C concentrations increased in all cases, reaching a peak of 176 ± 71 µmol/L at 1–4 min, whereas the corresponding peripheral vein vitamin C concentrations were 35 ± 15 µmol/L. Adrenocorticotrophic hormone stimulation increases adrenal vein — but not peripheral vein — vitamin C concentrations. This small human study (n=26) provides direct evidence of ACTH-responsive vitamin C secretion from the adrenal gland. Evidence is preliminary and mechanism-focused; large controlled trials of vitamin C supplementation specifically on adrenal output in healthy humans are lacking.

Studies suggest that vitamin C stores are rapidly depleted from the adrenal glands during periods of physiological stress, highlighting a continuous need for replenishment to maintain adrenal resilience. This finding comes primarily from observational and mechanistic data; robust interventional trials in humans are limited.

Pantothenic Acid (Vitamin B5)

Biochemical role: Pantothenic acid is a precursor for the production of acetyl coenzyme A (acetyl-CoA), a compound that is essential for the production of steroid hormones. Therefore, the adrenal glands require pantothenic acid to produce several adrenal hormones. Vitamin B5 (pantothenic acid) is particularly critical — it is a key component of coenzyme A, which drives steroidogenesis (the process of producing hormones from cholesterol).

Evidence status: The biochemical necessity of pantothenic acid in steroid hormone synthesis is well-established. A study found that pantothenic acid supplementation stimulates the ability of adrenal cells in male rats to secrete corticosterone (a glucocorticoid involved in regulation of energy, immune reactions, and stress responses) and progesterone. Human clinical trial evidence specifically examining pantothenic acid supplementation and adrenal cortisol output is very limited; available data are primarily from animal studies or mechanistic in-vitro work.

Magnesium

Biochemical role and evidence: Magnesium participates in over 300 enzymatic reactions in the body, including those governing energy production, nervous system function, and stress modulation. Magnesium is a mineral frequently depleted by chronic stress. It helps regulate the HPA axis by decreasing the release of corticotropin-releasing hormone (CRH), exerting an inhibitory effect on the stress response. Magnesium also promotes muscle relaxation and supports sleep quality, both critical for recovery from chronic fatigue. Evidence in humans for direct adrenal effects is largely mechanistic and observational. Studies showing HPA axis modulation by magnesium are preliminary, and dedicated interventional trials targeting adrenal-specific endpoints are sparse.

Herbs and Botanical Ingredients Studied in Relation to Adrenal Function

Ashwagandha (Withania somnifera)

Traditional use: Withania somnifera, also known as "Ashwagandha" in Sanskrit and as "Indian ginseng" in Ayurveda, is a very popular medicinal plant of the Solanaceae family. It has been used in traditional medicine for more than 2,500 years. It is described in the Indian Ayurvedic medicine system and referred to as an important herb in the traditional Unani and Chinese medicinal systems. This Ayurvedic herb has been used to treat a variety of diseases such as arthritis, anxiety, insomnia, tuberculosis, asthma, and fibromyalgia.

Proposed mechanisms: Ashwagandha's bioactive compounds, such as withanolides, sitoindosides, and alkaloids, modulate the hypothalamic–pituitary–adrenal (HPA) axis, inhibit NF-κB, induce Nrf2 activation, and affect GABAergic signaling, collectively contributing to its anti-inflammatory, antioxidant, and anxiolytic actions.

Scientific evidence — clinical trials: In a 60-day, randomized, double-blind, placebo-controlled study, the stress-relieving and pharmacological activity of an ashwagandha extract was investigated in stressed, healthy adults. Sixty adults were randomly allocated to take either a placebo or 240 mg of a standardized ashwagandha extract (Shoden) once daily. Outcomes were measured using the Hamilton Anxiety Rating Scale (HAM-A), Depression, Anxiety, and Stress Scale-21 (DASS-21), and hormonal changes in cortisol, DHEA-S, and testosterone. Ashwagandha supplementation was associated with a statistically significant reduction in the HAM-A (P = .040) and with greater reductions in morning cortisol (P < .001) and DHEA-S (P = .004) compared with the placebo.

A 2025 systematic review and meta-analysis published in BJPsych Open included 15 randomized controlled trials with a combined sample size of 873 patients. The meta-analysis found a significant effect in reducing both stress (Perceived Stress Scale: µ = −4.88, 95% CI: −7.84 to −1.91, p = 0.0013) and cortisol levels (µ = −2.3626, 95% CI: −3.2622 to −1.4629, p < 0.0001) at 8 weeks of treatment.

Evidence limitations: These findings suggest that ashwagandha's stress-relieving effects may occur via its moderating effect on the hypothalamic–pituitary–adrenal axis. However, further investigation utilizing larger sample sizes, diverse clinical and cultural populations, and varying treatment dosages are needed to substantiate these findings. Reviews emphasize methodological shortcomings, including heterogeneity in extract preparation, small sample sizes, variability in endpoints, and possible funding-related biases. Overall evidence strength: moderate, with consistent directional effects across small-to-medium RCTs, but limited by short trial durations (most ≤8 weeks).

Rhodiola rosea (Golden Root, Arctic Root)

Traditional use: Rhodiola rosea L. has a long history of use in traditional medicine to stimulate the nervous system, treat stress-induced fatigue and depression, enhance physical performance and work productivity, and treat gastrointestinal ailments and impotence. Rhodiola is used as traditional medicine in many countries and regions for the treatment of altitude sickness and hypoxia, the promotion of longevity, and for resistance to stress and fatigue as an adaptogen. The Inuit people of northern Canada have traditionally used preparations of R. rosea for both mental and physical rejuvenation, and the Sami of northern Sweden use the plant to promote physical endurance.

Proposed mechanisms: Rhodiola rosea extracts act as an adaptogen to provide nonspecific resistance to physical, chemical, and biological stresses. The stress-protective effects of Rhodiola rosea extracts have been shown to be engaged with the HPA axis and several key mediators of stress responses, such as heat shock proteins, stress-activated c-JUN N-terminal protein kinase 1 (JNK1), cortisol, nitric oxide, and beta-endorphin.

Scientific evidence: Rhodiola rosea possesses ergogenic and adaptogenic properties, improving cognitive and physical performance in conditions that challenge physiological homeostasis. Clinical evidence has been reviewed for its use in exercise performance, mood disorders, fatigue, and stress conditions. A significant number of publications on the clinical efficacy of various R. rosea preparations can be found in the literature. Clinical trials are generally small and of short duration. Evidence strength: preliminary-to-moderate; studies are encouraging but larger, well-controlled trials are needed.

Eleuthero (Eleutherococcus senticosus, Siberian Ginseng)

Traditional use: Eleutherococcus senticosus (Araliaceae) has been known as a traditional medicine for twenty centuries. Various preparations of E. senticosus root are available as an adaptogen to reduce fatigue and stress, decrease blood glucose levels, and stimulate the immune system.

Regulatory status and evidence: The European Medicines Agency approved E. senticosus root for the treatment of symptoms of asthenia, such as fatigue and weakness. Available reviews compile the phytochemistry of the root as well as quality assessment of plant material and commercial products, with reports on biological activities including relief of symptoms of asthenia and an immunomodulating effect. The clinical evidence of E. senticosus preparations for the treatment of symptoms of asthenia as an adaptogen has been critically reviewed. The pharmacological effect of E. senticosus is connected with various constituents, among which caffeoylquinic acids, a phenylpropanoid-syringin (eleutheroside B), and syringaresinol derivatives prevail. Evidence strength: limited; the EMA approval is for the symptomatic indication of asthenia (traditional use basis), not a pharmacological claim on adrenal function per se.

Licorice Root (Glycyrrhiza glabra)

Traditional use: Used for centuries in traditional medicinal practices, licorice root, or Glycyrrhiza glabra, contains compounds like glycyrrhizin that have been studied for their potential to influence cortisol levels and adrenal function. Traditional Chinese medicine has long recognized this plant's value as a "guide drug" that enhances other herbs' effects.

Mechanism of action on cortisol metabolism: Cortisol is decomposed by type 2 11β-hydroxysteroid dehydrogenase (11β-HSD2) in renal tubule cell cytoplasm into cortisone, which has a lower affinity for the mineralocorticoid receptor. Inhibition of 11β-HSD2 by glycyrrhizin (GL) metabolites — rather than direct binding of GL or its metabolites to mineralocorticoid receptors — is the primary mechanism. With GL metabolites in the 11β-HSD2-expressing cells, inhibition of 11β-HSD2 results in a higher concentration of cortisol that binds to and stimulates the mineralocorticoid receptor.

Scientific evidence: After consuming liquorice-containing confectionary for one week, cortisol and cortisone levels in volunteers reflected expected inhibition of 11β-hydroxysteroid dehydrogenase type 2 by glycyrrhetinic acid. Salivary aldosterone was decreased, but deoxycorticosterone, dehydroepiandrosterone, and testosterone were increased. A rat study showed that oral administration of a water freeze-dried extract of Glycyrrhiza glabra at doses of 100, 250, and 500 mg/kg induced dose-dependent and mostly significant decreases in the concentration of cortisol, ACTH, aldosterone, and potassium, with concomitant dose-dependent increases in the concentrations of renin and sodium, suggesting a strong and dose-dependent suppression of the adrenal–pituitary axis.

Safety and evidence limitations: The 11β-HSD2 inhibition mechanism is pharmacologically well-characterized, but this same mechanism also carries a well-documented risk. Licorice contains glycyrrhizin (GL), a glycoside of glycyrrhetinic acid. Licorice has long been known to exert a corticosteroid-like action, and GL and GA are considered to cause pseudoaldosteronism (PsA). Long-term or high-dose licorice consumption carries documented risks of hypertension and hypokalemia. The available human evidence consists predominantly of mechanistic pharmacokinetic studies and short-term volunteer studies; large controlled trials on adrenal clinical outcomes are absent. Evidence strength: well-characterized mechanism, but clinical utility versus risk profile requires careful individualized assessment.

Summary of Evidence Strength

• Ashwagandha (Withania somnifera): Moderate evidence from multiple RCTs and a published meta-analysis showing reductions in cortisol and stress measures; limited by small sample sizes, short durations, and extract heterogeneity.
• Vitamin C: Strong mechanistic and observational evidence for high adrenal concentrations and ACTH-responsive secretion; human interventional trial evidence for adrenal-specific outcomes is limited.
• Pantothenic Acid (B5): Essential biochemical role in steroidogenesis is well established; clinical trial evidence in humans is insufficient to support supplementation claims beyond correcting deficiency.
• Magnesium: Broad physiological importance in HPA axis modulation, supported by mechanistic data; direct interventional evidence for adrenal endpoints in humans is sparse.
• Rhodiola rosea: Preliminary-to-moderate evidence from small clinical trials for stress and fatigue outcomes; direct adrenal biomarker data are limited.
• Eleuthero (E. senticosus): EMA traditional-use recognition for asthenia; limited high-quality RCT evidence specifically for adrenal function.
• Licorice root (Glycyrrhiza glabra): Well-characterized pharmacological mechanism (11β-HSD2 inhibition); clinical utility is offset by pseudoaldosteronism risk; short-term mechanistic human studies only.

References

• Megha R, Wehrle CJ, Kashyap S, Leslie SW. Anatomy, Abdomen and Pelvis: Adrenal Glands (Suprarenal Glands). StatPearls. NCBI Bookshelf.
• Adrenal Anatomy and Physiology. PubMed (2025).
• Dutt M, Wehrle CJ, Jialal I. Physiology, Adrenal Gland. StatPearls. NCBI Bookshelf.
• Willenberg HS, Bornstein SR. Adrenal Cortex: Embryonic Development, Anatomy, Histology and Physiology. Endotext. NCBI Bookshelf.
• The Adrenal Gland. Endocrinology. NCBI Bookshelf (NIH).
• Adrenal Hormones. Endocrine Society.
• Overview of the Adrenal Glands. Merck Manual Consumer Version.
• What are some types of adrenal gland disorders? NICHD — Eunice Kennedy Shriver National Institute of Child Health and Human Development.
• Adrenal Gland Disorders. MedlinePlus (NIH National Library of Medicine).
• Adrenal Glands. Johns Hopkins Medicine.
• Adrenocorticotropic Hormone (Cosyntropin) Stimulation Test. StatPearls. NCBI Bookshelf (Updated February 2026).
• The Reliability of Salivary Cortisol Compared to Serum Cortisol for Diagnosing Adrenal Insufficiency with the Gold Standard ACTH Stimulation Test in Children. PMC.
• Specialty Grand Challenge in Adrenal Endocrinology. Frontiers in Endocrinology. PMC.
• Cadegiani FA, Kater CE. Adrenal fatigue does not exist: a systematic review. BMC Endocrine Disorders. PMC.
• Is adrenal fatigue "real"? Harvard Health Blog.
• Padayatty SJ, et al. Human adrenal glands secrete vitamin C in response to adrenocorticotrophic hormone. PubMed.
• Lopresti AL, Smith SJ, Malvi H, Kodgule R. An investigation into the stress-relieving and pharmacological actions of an ashwagandha extract: A randomized, double-blind, placebo-controlled study. Medicine (Baltimore). PMC.
• Effects of Withania somnifera on Cortisol Levels in Stressed Human Subjects: A Systematic Review. PMC.
• Effects of Ashwagandha Supplements on Cortisol, Stress, and Anxiety Levels in Adults: A Systematic Review and Meta-Analysis. BJPsych Open. Cambridge Core.
• Ashwagandha as an Adaptogenic Herb: A Comprehensive Review of Immunological and Neurological Effects. PMC.
• Stojcheva EI, Quintela JC. The Effectiveness of Rhodiola rosea L. Preparations in Alleviating Various Aspects of Life-Stress Symptoms and Stress-Induced Conditions. Molecules. PMC.
• Lucius K. Rhodiola rosea: Clinical Evidence for Adaptogenic and Ergogenic Effects. Integrative Cancer Therapies. 2024.
• Rhodiola rosea L.: an herb with anti-stress, anti-aging, and immunostimulating properties for cancer chemoprevention. PMC.
• Eleutherococcus root: a comprehensive review of its phytochemistry and pharmacological potential in the context of its adaptogenic effect. PMC.
• The Effect of Glycyrrhetinic Acid on Pharmacokinetics of Cortisone and Its Metabolite Cortisol in Rats. PMC.
• Clinical Risk Factors of Licorice-Induced Pseudoaldosteronism Based on Glycyrrhizin-Metabolite Concentrations: A Narrative Review. PMC.
• Liquorice and glycyrrhetinic acid increase DHEA and deoxycorticosterone levels in vivo and in vitro by inhibiting adrenal SULT2A1 activity. PubMed.
• Liquorice (Glycyrrhiza glabra) and the adrenal-kidney-pituitary axis in rats. PubMed.