Fact-checked by Grok 2 weeks ago

Adrenal cortex

The adrenal cortex is the outer region of the adrenal glands, small triangular endocrine organs located atop each in the of the upper abdomen. It synthesizes and secretes a variety of hormones derived from , which are essential for regulating , and , immune function, and the body's response to . Structurally, the adrenal cortex is organized into three concentric zones, each with specialized cellular arrangements and hormone-producing capabilities. The outermost consists of clustered cells that primarily produce mineralocorticoids, such as aldosterone, which promote sodium reabsorption and potassium excretion in the kidneys to maintain and . The middle , composed of cells arranged in straight columns, secretes glucocorticoids like , which elevate blood glucose levels through , suppress and immune activity, and support cardiovascular function during . Innermost is the zona reticularis, featuring a network of cells that generate weak androgens, including dehydroepiandrosterone (DHEA) and , which serve as precursors for sex hormones and contribute to , , and secondary sexual characteristics, particularly in females where the adrenals are a major source of androgens. Hormone production in the adrenal cortex is tightly regulated by external signals to ensure physiological homeostasis. Glucocorticoids and androgens are primarily controlled by adrenocorticotropic hormone (ACTH) from the anterior pituitary, which is released in response to corticotropin-releasing hormone (CRH) from the hypothalamus as part of the hypothalamic-pituitary-adrenal (HPA) axis, enabling rapid adaptation to stressors. In contrast, mineralocorticoids like aldosterone are mainly stimulated by the renin-angiotensin-aldosterone system (RAAS), activated by low blood pressure or sodium levels, with angiotensin II binding to receptors on zona glomerulosa cells to trigger secretion. Dysfunctions in the adrenal cortex, such as in Addison's disease (insufficient hormone production) or Cushing's syndrome (excess glucocorticoids), can lead to significant health issues, underscoring its critical role in endocrine physiology.

Anatomy

Location and gross structure

The adrenal cortex constitutes the outer layer of the , forming 80–90% of its total mass. The are paired structures situated in the at the superior poles of the kidneys, embedded within the perirenal fascia. Each adult gland measures approximately 5 cm in height, 3 cm in width, and 1 cm in thickness, weighing 4–6 grams. They exhibit a generally pyramidal shape, with the right gland appearing triangular and positioned adjacent to the , while the left is semilunar and lies medial to the , superior to the splenic vessels, and near the tail of the . The anterior surface of each gland is partially covered by , and the posterior surface is invested by . The arterial supply to the adrenal glands derives from three sources: the superior suprarenal arteries branching from the , the middle suprarenal arteries from the , and the inferior suprarenal arteries from the renal arteries. These vessels form an extensive subcapsular arterial that delivers primarily to the through sinusoidal capillaries, supporting its endocrine functions. The adrenal receives the majority of this arterial inflow, estimated at around 90% of the total glandular supply. Venous primarily occurs via a single central emerging from the hilum; the right central drains directly into the , whereas the left drains into the left . Accessory anterior veins may contribute in some cases. Lymphatic vessels within the adrenal capsule drain to the lumbar lymph nodes, including the para-aortic and paracaval chains. Innervation of the arises from preganglionic sympathetic fibers of the greater, lesser, and least (originating from –T9 spinal segments), which primarily target the medulla but also influence cortical vascular tone.

Histological layers

The adrenal cortex consists of three distinct histological zones arranged in concentric layers from the outer capsule inward: the , , and zona reticularis. These zones exhibit unique cellular arrangements, compositions, and staining properties under standard hematoxylin and (H&E) preparations, reflecting their specialized functions. The cortex as a whole is supported by a delicate framework that originates from the fibrous capsule and extends throughout the glandular , providing structural support while allowing for vascular and sinusoidal networks. The outermost comprises approximately 15% of the cortical volume and features small cells arranged in rounded or arched clusters resembling glomeruli, with relatively scant and minimal droplets. These cells appear dark-staining due to their basophilic nuclei and lack of extensive . The middle accounts for about 78% of the and is characterized by large, polygonal spongiocytes organized into straight radial cords or fascicles, typically one to two cells wide, separated by prominent sinusoidal capillaries. These -rich cells contain abundant vacuoles from extracted during tissue processing, resulting in pale, frothy under H&E ; ultrastructurally, they possess extensive and numerous mitochondria adapted for steroidogenesis. The innermost zona reticularis makes up roughly 7% of the cortical volume and consists of smaller, densely packed cells with or slightly basophilic cytoplasm arranged in irregular, anastomosing cords that blend into the . These cells contain less lipid than those in the fasciculata and accumulate pigments, giving a compact appearance. While humans exhibit these three well-defined zones, species variations exist; for instance, lack a distinct zona reticularis, with their inner cortex more resembling an undifferentiated transition between fasciculata and medulla.

Development

Embryonic origin

The adrenal cortex derives from the of the urogenital ridge approximately 28–30 days post-conception (corresponding to the sixth week of ), where it forms the adrenocortical as a ventral outgrowth adjacent to the developing . This primordium initially arises from the adrenogonadal , a common shared with the gonads, which separates into distinct adrenal and gonadal components by around the eighth week. The steroidogenic factor-1 (SF-1, also known as NR5A1) plays a critical role in initiating and regulating this primordium formation, driving the expression of genes necessary for adrenal specification and steroidogenic capacity; loss-of-function mutations in NR5A1 result in adrenal congenita, characterized by underdeveloped adrenal glands. Early in development, by the seventh to eighth week of gestation, the adrenal cortex differentiates into two primary zones: a large inner fetal zone and a thin outer definite zone. The fetal zone, comprising the majority of the cortical mass, expands rapidly during the second trimester and accounts for about 80% of the gland's volume at birth, functioning primarily to synthesize dehydroepiandrosterone (DHEA) via enzymes such as , which serves as a key precursor for production in the to support fetal and maternal . This zone is transient, undergoing postnatal regression through mechanisms including , thereby allowing the definitive zone to expand. The definitive zone, emerging concurrently with the fetal zone around week 8, begins to differentiate into the by approximately week 12, marking the onset of adult-like zonal organization, while the neural crest-derived invades the central region later in , around the second . By the end of , the adrenal cortex achieves basic zonation with the fetal zone dominant and the outer layers establishing mineralocorticoid-producing capabilities, though complete functional maturation of the zones, including and synthesis, extends into early childhood.

Postnatal growth and renewal

Following birth, the adrenal cortex undergoes continuous renewal to maintain its zonal structure and function, primarily through the centripetal migration model first proposed by Gottschau in 1883. In this model, undifferentiated stem and progenitor cells reside in the subcapsular periphery, where they proliferate and differentiate into steroidogenic cells of the (zG). These cells then migrate centripetally inward, progressing through the (zF) and zona reticularis (zR), before undergoing and being shed into the . This inward flow ensures zonal , with cells adopting zone-specific identities—such as aldosterone production in zG or synthesis in zF—during their migration. Key populations driving this process include GLI1+ mesenchymal cells in the adrenal capsule, which act as multipotent capable of generating steroidogenic SF1+ cells across all zones, and SHH+ cells in the subcapsular zG, which secrete Sonic to signal the capsule and promote . GLI1+ cells contribute significantly to cortical expansion during regeneration, such as after enucleation, while SHH+ progenitors initiate the lineage by differentiating into CYP11B2+ zG cells before further migration and conversion to CYP11B1+ zF cells via Wnt repression and activation. This migration is supported by interactions like RSPO3/LGR4 signaling from the capsule, reinforcing its role as a niche for progenitor . The renewal rate is rapid, with the entire adrenal cortex replaced approximately every 100-200 days, though rates vary by zone and sex— turnover occurs in about 42 days in females versus 126 days in males, driven by higher peripheral in females. This process is balanced by active of progenitors at the cortex periphery, as evidenced by bromodeoxyuridine incorporation primarily in subcapsular cells, and in the inner zF and zR zones, where cells lose steroidogenic capacity and are eliminated to prevent overaccumulation. In humans, similar dynamics are inferred from fetal studies showing peripheral and inner , supporting centripetal remodeling postnatally. Hormonal regulation plays a critical role, with adrenocorticotropic hormone (ACTH) from the pituitary stimulating proliferation and cortical expansion through cAMP/PKA-independent pathways, enhancing VEGF production and vascular support for growth. In contrast, aging disrupts this balance, leading to progressive zonal —particularly in the zR—with reduced cell size, altered , and increased due to immune infiltration and , ultimately diminishing output while sparing zones to a lesser extent. Recent advances in single-cell sequencing have illuminated postnatal zonal , revealing dynamic conversions (e.g., zG to zF cells) and confirming the capsule as a niche enriched in DLK1/PREF1+ that sustain renewal via Wnt and signaling. A 2023 study on human adrenal transcriptomes identified HOPX as a subcapsular marker decreasing with age, alongside ligand-receptor pairs like / that coordinate mesenchymal-cortical interactions for replenishment, highlighting sexually dimorphic in zone maintenance. Disruptions in renewal contribute to disorders like (LCAH), caused by mutations in the gene encoding the , which impairs transport into mitochondria and halts steroidogenesis in all zones. This leads to lipid-laden cortical enlargement followed by and failed progenitor differentiation, as StAR-deficient cells accumulate toxic lipids, undergo , and disrupt the centripetal flow essential for postnatal maintenance.

Physiology

Hormone biosynthesis

The biosynthesis of hormones in the adrenal cortex begins with , primarily derived from circulating (LDL) particles taken up via by adrenocortical cells. (HDL) also contributes , but LDL is the predominant source. The rate-limiting step in this process is the transport of free from the outer to the , facilitated by the (StAR). Once inside the mitochondria, undergoes side-chain cleavage catalyzed by the enzyme CYP11A1 (also known as P450scc), converting it to through three sequential monooxygenase reactions that cleave the C20–C22 bond. This initial conversion requires NADPH and molecular oxygen as cofactors. Pregnenolone, the common precursor for all steroid hormones, then exits the mitochondria and enters the smooth endoplasmic reticulum, where it is isomerized and oxidized to progesterone by 3β-hydroxysteroid dehydrogenase (3β-HSD, specifically type 2 isoform HSD3B2 in the adrenal cortex). From progesterone, the pathway branches based on zonal enzyme expression: in the zona fasciculata and reticularis, CYP17A1 (17α-hydroxylase/17,20-lyase) performs 17α-hydroxylation to yield 17α-hydroxyprogesterone, a key intermediate for glucocorticoid and androgen synthesis. In contrast, the zona glomerulosa lacks CYP17A1 activity, restricting its output to mineralocorticoids via the Δ4 pathway from progesterone. The utilizes (21-hydroxylase) to hydroxylate , leading to the production of , while the zona reticularis primarily produces DHEA through the lyase activity of on 17α-hydroxypregnenolone, without significant involvement of CYP21A2. These zonal differences in enzyme distribution—such as the absence of in glomerulosa and presence of in inner zones—determine the specific hormones synthesized in each layer. All -mediated steps in adrenal steroidogenesis, including those catalyzed by , , and CYP21A2, are NADPH-dependent and rely on to shuttle electrons from NADPH to the P450 enzymes. The complete pathway from to a final adrenal typically involves approximately seven enzymatic reactions, highlighting the multi-step nature of steroid production.

Regulation of hormone production

The regulation of hormone production in the adrenal cortex is primarily governed by the hypothalamic-pituitary-adrenal (HPA) axis for glucocorticoids and androgens, and the renin-angiotensin-aldosterone system (RAAS) for mineralocorticoids. Corticotropin-releasing hormone (CRH) is secreted by neurons in the paraventricular nucleus of the hypothalamus in response to circadian rhythms or stressors, stimulating the anterior pituitary to release adrenocorticotropic hormone (ACTH). ACTH binds to melanocortin-2 receptors (MC2R) on cells in the zona fasciculata and zona reticularis, activating adenylate cyclase to increase cyclic AMP (cAMP) levels, which promotes the synthesis and secretion of cortisol and adrenal androgens. ACTH release occurs in a pulsatile manner, with ultradian oscillations every 60-90 minutes that maintain the diurnal rhythm of secretion, peaking in the early morning (around 6-8 AM) and reaching a at . This circadian pattern is orchestrated by the and entrained by light-dark cycles, ensuring anticipatory readiness for daily stressors. Acute or further activates the axis through neural inputs to the , amplifying CRH and ACTH pulses to elevate levels for metabolic and immune responses. For production, the RAAS provides the primary regulatory signal independent of the axis. Low renal or sympathetic prompts juxtaglomerular cells in the to secrete renin, which cleaves circulating angiotensinogen to I; () then converts this to II. II binds to angiotensin type 1 (AT1) receptors on cells, triggering , intracellular calcium mobilization, and upregulation of aldosterone synthase (CYP11B2) to drive aldosterone biosynthesis. Negative feedback mechanisms maintain in both systems. Circulating exerts inhibitory effects on the (long-loop feedback via glucocorticoid receptors) and (short-loop feedback), suppressing CRH and ACTH release to prevent overproduction. Aldosterone secretion is similarly restrained by (ANP), which is released from cardiac atria in response to volume expansion and directly inhibits activity by reducing and blocking angiotensin II and effects; additionally, levels provide ionic feedback, with stimulating and inhibiting aldosterone release. At the molecular level, ACTH signaling converges on genetic regulation through the . Upon ACTH binding to MC2R, elevated activates , which phosphorylates CREB; phosphorylated CREB then binds to cAMP-responsive elements in the promoters of key steroidogenic genes, including the and , enhancing their transcription to initiate cholesterol transport and steroid biosynthesis in the adrenal cortex.

Hormones

Mineralocorticoids

Mineralocorticoids are a class of hormones produced by the adrenal cortex that primarily regulate and in the body. The principal mineralocorticoid is aldosterone, which accounts for nearly all mineralocorticoid activity. Aldosterone is synthesized exclusively in the , the outermost layer of the adrenal cortex, where it is produced through a series of enzymatic reactions culminating in the conversion of to aldosterone by the enzyme aldosterone synthase (CYP11B2). This final step is unique to the zona glomerulosa and distinguishes mineralocorticoid biosynthesis from that of glucocorticoids, although early precursor pathways are shared. Chemically, aldosterone is a C21 characterized by an group at the C18 position, which is essential for its biological potency. This structure enables aldosterone to bind with high affinity to the (MR), a predominantly expressed in the principal cells of the kidney's and collecting duct. Upon binding, the aldosterone-MR complex translocates to the nucleus, where it modulates to enhance the activity of epithelial sodium channels (ENaC) and Na+/K+-ATPase pumps on the basolateral membrane. Aldosterone's daily production rate in humans typically ranges from 50 to 100 μg, varying with factors such as dietary salt intake. The primary physiological role of aldosterone is to promote sodium (Na+) reabsorption and (K+) and hydrogen (H+) excretion in the kidneys, thereby maintaining volume, , and . This action occurs mainly in the cortical collecting duct, where increased Na+ retention leads to osmotic reabsorption, expanding volume and supporting cardiovascular stability during conditions like or salt depletion. Beyond the kidneys, aldosterone exerts similar effects on sodium and in extrarenal sites, including the sweat glands, salivary glands, and colon, contributing to overall mineral balance. Secretion of aldosterone is tightly regulated by the renin-angiotensin-aldosterone system (RAAS), where angiotensin II stimulates its release from cells, and by elevated levels (), which directly depolarize these cells to promote synthesis. Aldosterone is essential for balance; its deficiency impairs sodium conservation, resulting in salt-wasting crises characterized by , , and .

Glucocorticoids

Glucocorticoids are a class of hormones primarily produced in the of the adrenal cortex, with (also known as ) serving as the predominant in humans. synthesis occurs through a series of enzymatic reactions starting from , culminating in the conversion of to by the CYP11B1 (11β-hydroxylase). This is stimulated by (ACTH) from the . Chemically, cortisol is a C21 characterized by an 11β-hydroxy group, as well as 17α- and 21-dihydroxy groups, along with oxo groups at positions 3 and 20. In circulation, approximately 80-90% of is bound to corticosteroid-binding globulin (CBG), with 10-15% bound to and the remainder free and biologically active. Daily production of in adults typically ranges from 10 to 20 mg, with as a key precursor and as an inactive metabolite formed via . Cortisol exerts diverse metabolic effects, including promotion of by inducing the expression of (PEPCK), an essential for glucose synthesis from non-carbohydrate precursors. It also facilitates in peripheral tissues to provide for gluconeogenesis and stimulates through activation of hormone-sensitive , releasing free fatty acids as an energy source. In terms of immune function, cortisol suppresses by inhibiting the transcription factor , thereby reducing the production of pro-inflammatory cytokines. As a key component of the stress response, cortisol mobilizes energy reserves during acute stress, enhancing overall physiological adaptation. Additionally, cortisol provides a permissive effect, enabling catecholamines such as norepinephrine to exert their full vasoactive influence on vascular tone.

Adrenal androgens

The adrenal androgens, primarily dehydroepiandrosterone (DHEA) and , are synthesized in the zona reticularis of the adrenal cortex through the 17,20-lyase activity of the cytochrome P450 enzyme , which acts on 17-hydroxypregnenolone as a key step in the Δ5 pathway. This process branches from the shared pathway but favors production in the reticularis due to low expression of (3β-HSD), which limits conversion to glucocorticoids. These C19 steroids function as weak androgens and are major precursors for peripheral hormone synthesis. DHEA, the most abundant adrenal androgen, is rapidly sulfated primarily in the liver and kidneys to form (DHEA-S), which circulates at high concentrations (up to 10-20 μM in adults) and serves as a stable reservoir due to its longer half-life compared to unsulfated DHEA. Both DHEA and are converted in peripheral tissues—such as , adipose, and gonads—into potent androgens like testosterone via enzymes including and 17β-hydroxysteroid dehydrogenase, or into estrogens through . This peripheral amplifies their biological impact beyond direct adrenal secretion. In adult women, adrenal androgens contribute approximately 5-10% to the total circulating pool, with a greater relative importance during reproductive years when ovarian production predominates but adrenal sources provide a steady baseline. They play a central role in pubertal , a process initiating around ages 6-8 characterized by a 10- to 100-fold rise in DHEA and DHEA-S levels, which drives the maturation of secondary such as pubic and axillary hair growth, development, and . Beyond , these androgens support skin activity, muscle maintenance, and emerging evidence points to neuroprotective effects, including modulation of neuronal excitability and potential protection against cognitive decline. Daily adrenal production of DHEA averages 2-10 mg in adults, with females exhibiting higher output due to greater zona reticularis activity, though levels vary widely by age and health status. peaks in the third of life and then progressively declines—a phenomenon termed adrenopause—with DHEA levels dropping by about 2% per year after age 30, reaching 10-20% of peak values by the eighth . This age-related diminution contributes to reduced tone in aging individuals. Deficiency in 3β-HSD, an enzyme that converts Δ5 steroids like DHEA to Δ4 forms such as , blocks the pathway to more potent androgens, resulting in accumulation of weak precursors and impaired androgenic effects, as seen in variants. This enzymatic limitation is physiologically relevant in the zona reticularis, where low 3β-HSD expression favors DHEA output over stronger androgens.

Clinical significance

Disorders of hormone excess

Disorders of the adrenal cortex characterized by excess primarily involve overproduction of , , or , leading to distinct clinical syndromes. These conditions arise from autonomous by adrenal tumors or , disrupting normal feedback mechanisms and causing metabolic, cardiovascular, and virilizing effects. Cushing syndrome results from chronic excess of glucocorticoids, most commonly , due to adrenal causes such as benign adenomas or carcinomas that autonomously produce , independent of (ACTH) stimulation. Other etiologies include pituitary adenomas secreting excess ACTH (Cushing disease, accounting for about 70% of endogenous cases) or ectopic ACTH production from non-pituitary tumors like small cell lung carcinoma. Symptoms manifest as central obesity with fat redistribution to the face (moon facies), upper back (), and abdomen; from 's activity; due to impaired glucose tolerance; and from reduced bone formation and increased resorption. Additional features include easy bruising, proximal , and wide purple striae on the skin. The annual incidence of Cushing syndrome is approximately 2.4 to 5 cases per million population, with endogenous forms affecting adults aged 30-50 years and a three-fold predominance in women. Genetic associations include (MEN1), where inactivating mutations in the MEN1 gene lead to pituitary adenomas causing ACTH excess in up to 10% of affected individuals, or rarely adrenal tumors. Primary aldosteronism, also known as Conn syndrome, stems from excess production, typically aldosterone, by the due to unilateral (in 30-50% of cases) or bilateral . Less commonly, aldosterone-secreting adrenal carcinomas contribute. This leads to sodium retention, volume expansion, and suppression of renin, resulting in resistant to standard therapy and from wasting in the kidneys. Manifestations include , cramps, fatigue, , , and arrhythmias from . Diagnosis relies on an elevated plasma (>30 ng/dL per ng/mL/h), confirmed by failure of aldosterone suppression during saline loading or other provocative tests. It accounts for 5-10% of all cases and up to 20% of resistant , with higher in women. Adrenal virilism arises from overproduction of androgens by tumors in the zona reticularis, such as adrenocortical adenomas or , causing predominantly in females. These tumors secrete excess dehydroepiandrosterone (DHEA) and , bypassing normal regulation. Symptoms in women include (excess facial and body hair), deepening voice, , menstrual irregularities or amenorrhea, , and male-pattern baldness; and may also occur due to suppressed ovarian function. In severe cases from malignant tumors, rapid progression with or weight loss signals . Diagnosis involves elevated serum levels and to localize the adrenal mass. Recent advances in have identified somatic mutations in the KCNJ5 gene, encoding a in cells, as drivers in up to 40% of aldosterone-producing adenomas; these mutations, first described in 2011, cause channel dysfunction leading to membrane , calcium influx, and autonomous aldosterone synthesis. Such discoveries, expanded in the through genomic sequencing of adenomas, enable targeted genetic screening to guide surgical decisions and improve outcomes in mutation-positive cases, which often present at younger ages with more severe .

Disorders of hormone deficiency

Disorders of hormone deficiency in the adrenal cortex primarily manifest as , where inadequate production of () and/or () leads to metabolic disruptions, electrolyte imbalances, and potentially life-threatening crises. Primary , also known as , arises from direct damage to the adrenal cortex, resulting in low levels of both and . In developed countries, autoimmune destruction accounts for approximately 80% of cases, while infections such as or other pathogens contribute to the remainder, particularly in endemic regions. Symptoms include profound , , due to elevated (ACTH), from deficiency, and acute characterized by and if untreated. Congenital adrenal hyperplasia (CAH) represents a major genetic form of primary adrenal insufficiency, caused by inherited enzyme defects that impair steroid hormone biosynthesis in the adrenal cortex. The most common variant, 21-hydroxylase deficiency due to mutations in the CYP21A2 gene, accounts for about 95% of CAH cases and disrupts the conversion of precursors to cortisol and aldosterone. This leads to two main classic forms: salt-wasting CAH, affecting around 75% of cases with severe aldosterone deficiency causing dehydration and electrolyte crises in infancy; and simple virilizing CAH, where androgen excess predominates without significant salt loss, often presenting with ambiguous genitalia in genetic females and precocious puberty in both sexes. Recent advancements include CRISPR-based models, such as humanized mouse strains with specific CYP21A2 mutations, which have facilitated studies of disease mechanisms and potential gene therapies in the 2020s; however, a phase 1/2 gene therapy candidate (BBP-631) was discontinued in 2024. In December 2024, the FDA approved crinecerfont (CRENESSITY), the first therapy specifically for CAH, which targets the corticotropin-releasing factor receptor to reduce androgen excess and potentially lower required glucocorticoid doses. Secondary adrenal insufficiency stems from dysfunction, leading to deficient ACTH production and consequent shortfall, while synthesis remains largely intact due to its regulation by the renin-angiotensin system. Common causes include pituitary tumors, autoimmune , or surgical interventions affecting the gland. Unlike primary forms, patients typically lack because ACTH levels are low, and aldosterone-related symptoms like are absent or mild. , , and may occur, but adrenal crises are less severe without involvement. The prevalence of Addison's disease is estimated at 1 in 10,000 individuals worldwide, while CAH affects approximately 1 in 15,000 newborns. Treatment for both primary and secondary deficiencies focuses on hormone replacement: hydrocortisone for cortisol (typically 15-25 mg/day in divided doses) and fludrocortisone (0.05-0.2 mg/day) for aldosterone in primary cases, with dose adjustments during stress to prevent crises. In secondary insufficiency, only glucocorticoid replacement is usually required, alongside addressing the underlying pituitary pathology. Lifelong management improves outcomes, though challenges persist in mimicking physiologic hormone rhythms.

Tumors and other pathologies

Adrenal adenomas are the most common benign tumors of the adrenal cortex, frequently discovered as incidentalomas on imaging studies, with a of up to 4% in abdominal scans. These tumors can be non-functional, meaning they do not secrete excess hormones, or functional, leading to conditions such as from overproduction or from aldosterone excess. Non-functional adenomas, which constitute the majority—approximately 80% of incidentalomas—are typically lipid-rich and benign, though a subset may develop subclinical hypercortisolism over time. Adrenocortical carcinoma (ACC) represents a rare and aggressive malignant arising from the adrenal cortex, with an annual incidence of 0.7 to 2 cases per million population. Often presenting with symptoms attributable to hormone excess, such as or , ACC has a poor prognosis, with 5-year overall survival rates ranging from 20% to 50%, influenced by stage at diagnosis and resectability. Germline or somatic TP53 mutations are frequently implicated, particularly in pediatric cases where they occur in 50-80% of instances, associating with Li-Fraumeni syndrome. Non-neoplastic pathologies of the adrenal cortex include hemorrhage and . Bilateral adrenal hemorrhage, notably in Waterhouse-Friderichsen syndrome, arises during severe —often from meningococcal infection—leading to acute and high mortality rates approaching 60% despite supportive care. , characterized by bilateral enlargement, commonly results from chronic ACTH excess, as seen in pituitary-dependent , where sustained stimulation drives adrenocortical proliferation. Diagnosis of adrenal cortical tumors relies primarily on imaging modalities such as and MRI, which distinguish adenomas (typically <4 cm, homogeneous, lipid-rich) from (larger, heterogeneous, invasive). is rarely performed due to risks of seeding and hemorrhage, reserved for cases where metastasis origin is unclear. Genetic testing for TP53 and other mutations aids in confirming hereditary predispositions, particularly in young patients or those with family history. Recent advances in management highlight as the cornerstone , an adrenolytic agent that inhibits steroidogenesis and induces tumor cell necrosis, often combined with like , , and for advanced disease. Multi-omics analyses, including transcriptomic profiling, have unveiled tumor heterogeneity and potential therapeutic targets such as and inhibitors, with ongoing trials exploring combinations like and to improve outcomes in metastatic settings.

References

  1. [1]
    Physiology, Adrenal Gland - StatPearls - NCBI Bookshelf
    The adrenal gland is made up of the cortex and medulla. The cortex produces steroid hormones including glucocorticoids, mineralocorticoids, and adrenal ...
  2. [2]
    Adrenal glands: MedlinePlus Medical Encyclopedia
    May 20, 2024 · The outer part of the gland is called the cortex. It produces steroid hormones such as cortisol, aldosterone, and hormones that can be changed ...
  3. [3]
    Adrenal Gland - SEER Training Modules - National Cancer Institute
    Glucocorticoids are secreted by the middle region of the adrenal cortex. The principal glucocorticoid is cortisol, which increases blood glucose levels. The ...
  4. [4]
    Adrenal Hormones - EdTech Books
    The cortex secretes a variety of steroid hormones, including cortisol, aldosterone and androgens. The medulla produces primarily epinephrine (80%) and ...
  5. [5]
    Serotonin and the serotonin transporter in the adrenal gland - PMC
    The adrenal cortex. The cortex, which accounts for 80–90% of the adrenal gland, is of mesodermal origin and in humans contains three concentric ...
  6. [6]
    Anatomy, Abdomen and Pelvis: Adrenal Glands (Suprarenal Glands)
    The left adrenal gland sits medially to the spleen, superior to the splenic artery and vein, lateral to the abdominal aorta, and anterior to the diaphragm.Structure and Function · Blood Supply and Lymphatics · Surgical Considerations
  7. [7]
    Adrenal glands, normal, gross - Endocrine Pathology
    Here are normal adrenal glands. Each adult adrenal gland weighs from 4 to 6 grams.
  8. [8]
    Anatomy Tables - Viscera of the Abdomen
    adrenal gland, endocrine gland located superomedial to the kidney; right adrenal gland is somewhat triangular in shape, left is semilunar in shape, adrenal ...Missing: vascular | Show results with:vascular
  9. [9]
    https://teachmeanatomy.info/abdomen/viscera/adrenal-glands/
  10. [10]
    Endocrine System - Duke Histology
    The zona glomerulosa [example] is found outermost in the cortex and consists of cells arranged in rounded or arched clusters although in the human adrenal gland ...
  11. [11]
    Histologic:Chapter 14 - Pathology Education Instructional Resource
    The zona glomerulosa is the outer zone immediately beneath the capsule. It accounts for 15% of the total cortical volume. The zona fasciculata occupies the ...
  12. [12]
    Adrenal Cortex: Embryonic Development, Anatomy, Histology and ...
    Jun 12, 2023 · Adrenal cortex hormones bind onto specific steroid receptors that belong to the nuclear receptor superfamily of transcription factors, and play ...
  13. [13]
    Functional Zonation of the Adult Mammalian Adrenal Cortex - PMC
    The standard model of adrenocortical zonation holds that the three main zones, glomerulosa, fasciculata, and reticularis each have a distinct function, ...
  14. [14]
    Regulation of stem and progenitor cells in the adrenal cortex - PMC
    Adrenal development. The fetal adrenal cortex is derived from the adrenogonadal primordium (AGP), which originates from the coelomic epithelium and underlying ...
  15. [15]
    Developmental Links between the Fetal and Adult Zones of the ... - NIH
    The nuclear receptor Ad4BP/SF-1 is essential for development of the adrenal cortex and the gonads, which derive from a common adrenogonadal primordium.
  16. [16]
    Development of Adrenal Cortical Zonation and Expression of Key ...
    During human fetal development, a specialized zone of the adrenal cortex, known as the fetal zone, comprises about 80% of the mass of the adrenal and ...Missing: embryonic | Show results with:embryonic
  17. [17]
    Embryonic Development and Adult Regeneration of the Adrenal Gland
    DEVELOPMENT OF THE ADRENAL GLAND. The developmental program of the adrenal gland begins in the embryo and continues in the fetus and postnatal infant (Fig. 1).
  18. [18]
    Development and function of the fetal adrenal - PMC - NIH
    The adrenal cortex undergoes multiple structural and functional rearrangements to satisfy the systemic needs for steroids during fetal life, ...
  19. [19]
    Regulation of the adrenocortical stem cell niche - NIH
    The adrenal cortex produces different corticosteroid hormones necessary for human life. The organ is subdivided into discrete histological and functional ...
  20. [20]
    [PDF] Adrenocortical zonation, renewal, and remodeling
    Mar 5, 2015 · In one long- standing model of adrenal zonation, the cell migration model, stem/progenitor cells in the periphery of the adrenal cortex.
  21. [21]
    Regulation of Zonation and Homeostasis in the Adrenal Cortex - NIH
    The centripetal migration model implies that mature aldosterone-producing zG cells have the ability to convert into zF cells as they cross the zonal boundary.
  22. [22]
    Shh signaling regulates adrenocortical development and identifies ...
    We have explored adrenal Shh activity and found that Shh is expressed in relatively undifferentiated steroidogenic cells, which signal to the overlying capsule.
  23. [23]
    Sonic Hedgehog and WNT Signaling Promote Adrenal Gland ...
    During adrenal organogenesis, Gli1+ cells give rise to cortical Sf1+ cells, including Shh+ progenitor cells located in the outermost zG (12, 16, 47).
  24. [24]
    Adrenocortical Zonation, Renewal, and Remodeling - Frontiers
    Mar 4, 2015 · In the adult adrenal gland, most cell proliferation occurs near the periphery of the cortex, as shown by bromodeoxyuridine and [3H]thymidine ...
  25. [25]
    Proliferation and Apoptosis in the Human Adrenal Cortex during the ...
    Thus, we propose that cell growth of the human fetal adrenal cortex is a dynamic process in which cells proliferate in the periphery, migrate centripetally, ...
  26. [26]
    ACTH Action on the Adrenals - Endotext - NCBI Bookshelf
    Jun 13, 2020 · Thus, among other things, ACTH stimulates the intra-adrenal production of vascular endothelial growth factor (VEGF) and the vaso-relaxant epoxy ...INTRODUCTION · EFFECTS OF ACTH ON... · MELANOCORTIN 2 (MC2...
  27. [27]
    Adrenocorticotrophic hormone is a potent regulator of gene ... - NIH
    ACTH subsequently induces adrenal cortex expansion and corticosteroid production (mainly cortisol in humans).
  28. [28]
    Age-related Changes in the Adrenal Cortex: Insights and Implications
    With increasing age, features such as reduced adrenal cortex size, altered zonation, and increased myeloid immune cell infiltration substantially alter the ...
  29. [29]
    Human Adrenal Cortex Development: Single-Cell Analysis
    Here, we combined single-cell and bulk RNA sequencing, spatial transcriptomics, IHC, and micro-focus computed tomography to investigate key aspects of adrenal ...
  30. [30]
    The Pathophysiology and Genetics of Congenital Lipoid Adrenal ...
    Dec 19, 1996 · Congenital lipoid adrenal hyperplasia results in severe impairment of steroid biosynthesis in the adrenal glands and gonads that is manifested both in utero ...
  31. [31]
    Adrenal cortex development and related disorders leading to ...
    May 1, 2021 · During adrenarche, increased circulating androgens result in stereotypical systemic effects including growth of pubic and axillary hair and ...
  32. [32]
    Classic and current concepts in adrenal steroidogenesis: a reappraisal
    In this paper, we review classic and current concepts of adrenal steroidogenesis, plus control mechanisms of steroid pathways, distribution of unique enzymes ..
  33. [33]
    Adrenal Steroidogenesis and Congenital Adrenal Hyperplasia - PMC
    The syntheses of mineralocorticoids, glucocorticoids and adrenal androgens occur in separate adrenal cortical zones, each expressing specific enzymes.
  34. [34]
    Physiology, Adrenocorticotropic Hormone (ACTH) - StatPearls - NCBI
    CRH is released from the hypothalamus. CRH stimulates the anterior pituitary to release ACTH. ACTH acts on the adrenal cortex to release cortisol and androgens.Missing: RAAS | Show results with:RAAS
  35. [35]
    Regulation of the hypothalamic-pituitary-adrenocortical stress ...
    At the adrenal cortex, ACTH acts on melanocortin 2 receptors ... Regulation of the synthesis of steroidogenic enzymes in adrenal cortical cells by ACTH.Missing: RAAS | Show results with:RAAS
  36. [36]
    Renin–angiotensin system: Basic and clinical aspects—A general ...
    The renin–angiotensin system (RAS) is one of the most complex hormonal regulatory systems, involving several organs that interact to regulate multiple body ...
  37. [37]
    Aldosterone Deficiency and Resistance - Endotext - NCBI Bookshelf
    Nov 24, 2020 · Atrial natriuretic peptide (ANP) directly inhibits aldosterone secretion and blocks the stimulatory effects of angiotensin II, potassium and ...
  38. [38]
    Impact of ACTH Signaling on Transcriptional Regulation of ... - NIH
    Mar 29, 2016 · This review provides a general view of the transcriptional control exerted by the ACTH/cAMP system on the expression of genes encoding for steroidogenic ...
  39. [39]
    The Biology of Normal Zona Glomerulosa and Aldosterone ... - NIH
    The fundamental enzyme for aldosterone synthesis is aldosterone synthase, or the CYP11B2 enzyme. Its expression identifies cells that synthesize aldosterone ...
  40. [40]
    Physiology, Aldosterone - StatPearls - NCBI Bookshelf - NIH
    Aldosterone causes sodium to be absorbed and potassium to be excreted into the lumen by principal cells. In alpha intercalated cells, located in the late distal ...
  41. [41]
    [PDF] Chapter 1 Steroid Chemistry and Steroid Hormone Action
    The 18-aldehyde is critical for mineralocorticoid activity; the sole difference between corticosterone and aldosterone is the 18- aldehyde, but aldosterone has ...
  42. [42]
    Adrenal Incidentaloma - PMC - PubMed Central - NIH
    The daily production rate of aldosterone varies between 80 and 200 μg/day (104), depending on daily salt intake. Aldosterone functions as the ligand for the ...
  43. [43]
    Extrarenal Effects of Aldosterone on Potassium Homeostasis - PMC
    In addition to effects on the kidney, aldosterone modulates K+ and Na+ transport in salivary fluid, sweat, airway epithelia, and colonic fluid.Missing: pressure | Show results with:pressure
  44. [44]
    Endocrine and Hypertensive Disorders of Potassium Regulation
    The second major regulator of aldosterone secretion is AngII, which acting through the angiotensin II, type 1 (AT1) receptor, stimulates aldosterone secretion.
  45. [45]
    Mineralocorticoid Deficiency and Treatment in Congenital Adrenal ...
    Aldosterone deficiency results in excessive sodium and insufficient potassium excretion in the urine which results in hyperkalemia, hyponatremia, hypovolemia, ...
  46. [46]
    Physiology, Glucocorticoids - StatPearls - NCBI Bookshelf
    Jul 17, 2023 · Cortisol upregulates or activates or induces enzymes involved in gluconeogenesis and glycogenolysis. It antagonizes the actions of insulin and ...Missing: lipolysis | Show results with:lipolysis
  47. [47]
    Cortisol | C21H30O5 | CID 5754 - PubChem - NIH
    Cortisol is a 17alpha-hydroxy-C21-steroid that is pregn-4-ene substituted by oxo groups at positions 3 and 20 and hydroxy groups at positions 11, 17 and 21.Missing: 17α, | Show results with:17α,
  48. [48]
    Cortisol Binding Globulin: More Than Just a Carrier? - PubMed Central
    Under normal, nonstressed conditions, 80–90% of circulating cortisol is bound to CBG, 10–15% is bound to albumin, and the remaining 5–10% circulate as free and ...
  49. [49]
    Corticosteroids and Endothelial Dysfunction - PMC - NIH
    Cortisol also has a permissive effect in enhancing vasoactive actions of catecholamines through glucocorticoid receptors, and has been suggested to have ...Missing: permissiveness | Show results with:permissiveness
  50. [50]
    Steroidogenic Cytochrome P450 17A1 Structure and Function - PMC
    This lyase reaction leaves a ketone at C17, forming the androgen dehydroepiandrosterone or androstenedione. As the catalytic efficiency of 17OH-progesterone ...
  51. [51]
    Adrenal androgens and androgen precursors: definition, synthesis ...
    The adrenal glands synthesize an assortment of C 19 steroids, of which DHEA and DHEAS have been have been the major focus and biomarkers of adrenal androgen ...
  52. [52]
    Adrenal Androgens and Aging - Endotext - NCBI Bookshelf - NIH
    Jan 18, 2023 · In females of reproductive age, the adrenal contribution to total androgen production is more important; during the follicular phase, the ...
  53. [53]
    Normal and Premature Adrenarche - PMC - PubMed Central - NIH
    Adrenarche is the maturational increase in adrenal androgen production that normally begins in early childhood. It results from changes in the secretory ...
  54. [54]
    Congenital Adrenal Hyperplasia - StatPearls - NCBI Bookshelf - NIH
    Jan 27, 2025 · Defects in 3β-HSD-2 (HSD3B2/1p13.1) impair the conversion of pregnenolone, 17-hydroxypregnenolone, and dehydroepiandrosterone (DHEA) to ...
  55. [55]
    Implications for the Mechanism of Adrenarche - Nature
    Mar 1, 1999 · We have shown a decrease of the expression 3βHSD type II gene as a function of age in prepubertal and early pubertal normal human adrenal tissue.
  56. [56]
    Cushing's Syndrome - NIDDK
    Cushing's syndrome occurs when your body makes too much of the hormone cortisol. Learn about symptoms, causes, diagnosis, and treatment of Cushing's ...
  57. [57]
    Conn Syndrome - StatPearls - NCBI Bookshelf - NIH
    Primary hyperaldosteronism is the most common cause of secondary hypertension and occurs in about 6% to 20% of adult hypertensive individuals and is higher in ...Continuing Education Activity · Epidemiology · Evaluation · Treatment / Management
  58. [58]
    Cushing's Syndrome and Cushing Disease | Endocrine Society
    Jan 24, 2022 · Too much ACTH in the body causes the adrenal glands to produce cortisol in high levels. Cushing disease can also occur with diffuse growth ...
  59. [59]
    Cushing syndrome - Symptoms and causes - Mayo Clinic
    Jun 7, 2023 · High levels of the hormone cortisol in your body cause this endocrine disorder. Learn about symptoms, causes and treatment.
  60. [60]
    Expressions of Cushing's syndrome in multiple endocrine neoplasia ...
    Jun 20, 2023 · Pituitary tumors are present in about 40% of MEN1 patients, and up to 10% of such tumors secrete ACTH that can result in Cushing's disease.
  61. [61]
    Primary Aldosteronism (Conn's Syndrome): What It Is
    Primary aldosteronism (Conn's syndrome) occurs when your adrenal glands make too much aldosterone, resulting in higher blood pressure and lower potassium ...
  62. [62]
    Primary Aldosteronism | Johns Hopkins Medicine
    Primary aldosteronism, also called Conn's syndrome, is a disorder in which your adrenal glands make too much of a hormone called aldosterone. Aldosterone helps ...
  63. [63]
    Adrenal Virilism - Endocrine and Metabolic Disorders - Merck Manuals
    Adrenal virilism is a syndrome in which excessive adrenal androgens cause virilization. Diagnosis is clinical and confirmed by elevated androgen levels.
  64. [64]
    Virilization: What It Is, Causes, Symptoms & Treatment
    In adult males, excess adrenal hormones might suppress testicular function and lead to infertility.
  65. [65]
    Virilization - Hormonal and Metabolic Disorders - MSD Manuals
    Symptoms of Virilization​​ In women, the uterus shrinks, the clitoris enlarges, the breasts become smaller, and normal menstruation stops. In men, the excess ...
  66. [66]
    Somatic and inherited mutations in primary aldosteronism in
    Over the past few years, somatic mutations in KCNJ5, CACNA1D, ATP1A1 and ATP2B3 have been proven to be associated with APA development, representing more than ...Somatic mutations in APA · Prevalence and clinical... · Familial forms of PA and...
  67. [67]
    https://www.ahajournals.org/doi/10.1161/HYPERTENSIONAHA.120.15679
  68. [68]
    Addison Disease - StatPearls - NCBI Bookshelf - NIH
    Primary adrenal insufficiency is termed Addison disease when an autoimmune process causes the condition and is a rare but potentially life-threatening ...
  69. [69]
    Models of Congenital Adrenal Hyperplasia for Gene Therapies Testing
    The present review focuses on modern models for inherited adrenal gland insufficiency and their detailed characterization.
  70. [70]
    Symptoms & Causes of Adrenal Insufficiency & Addison's Disease
    Early treatment can help avoid an adrenal crisis. ... Anything that affects the pituitary's ability to make ACTH can cause secondary adrenal insufficiency.
  71. [71]
    Guidelines for the management of the incidentally discovered ...
    The prevalence of adrenal incidentalomas (AI) has been reported as high as 8% in autopsy series and 4% in radiologic series. ... As improved imaging techniques ...Missing: incidence | Show results with:incidence
  72. [72]
    Adrenal Adenoma - StatPearls - NCBI Bookshelf - NIH
    Adrenal incidentalomas without excessive hormone production have a risk of becoming hormonally active, estimated at 17%, 29%, and 47% within 1, 2, or 5 years, ...Continuing Education Activity · Introduction · Epidemiology · Evaluation
  73. [73]
    Do Non-Functional Adrenal Adenomas Affect Metabolic Profile and ...
    Jul 11, 2023 · Nearly 80% of adrenal lesions are benign, hormonally inactive adenomas (non-functional adrenal incidentalomas, NFAI). The most common endocrine ...
  74. [74]
    Adrenocortical carcinoma: Diagnosis, prognostic classification and ...
    Adrenocortical carcinoma (ACC) is a rare cancer with an estimated incidence of 0.7 to 2.0 cases per 1 million population per year in the United States.
  75. [75]
    Predictors of Survival in Adrenocortical Carcinoma: An Analysis ...
    The prognosis of ACC is generally poor, with a median overall survival (OS) of 3.21 years and a 5-year survival rate of 15% to 44%.Abstract · Methods · Results · Discussion
  76. [76]
    Prevalence and Functional Consequence of TP53 Mutations in ...
    Jan 12, 2015 · We have demonstrated that half of children with ACC carry germline TP53 mutations and that the likelihood of mutation is highest in the first ...
  77. [77]
    Adrenal Hemorrhage - StatPearls - NCBI Bookshelf - NIH
    Waterhouse Friderichsen syndrome has a mortality approaching 60% despite adequate medical management with fluids, antibiotics, and glucocorticoids.
  78. [78]
    Effects of Chronic ACTH Excess on Human Adrenal Cortex - PMC
    Mar 8, 2017 · In ACTH-dependent Cushing's syndrome, chronic ACTH excess leads to bilateral adrenal hyperplasia: both adrenals are enlarged, their weight ...
  79. [79]
    Adrenal Lesions: A Review of Imaging - PMC - PubMed Central
    Sep 8, 2022 · The average width of the adrenal glands is between 6 and 8 mm, with a slightly greater width of the left adrenal gland [41].Missing: cortex | Show results with:cortex
  80. [80]
    Adrenal Incidentaloma - Endotext - NCBI Bookshelf - NIH
    May 28, 2024 · ... adrenal cortex, the medulla, or being of extra-adrenal origin (Table ... In general, the vast majority (80-90%) of AIs are benign ...
  81. [81]
    Prevalence of Germline TP53 Mutations in a Prospective Series of ...
    It is estimated that 50–80% of children diagnosed with ACC have a germline TP53 mutation (8). In certain pediatric ACC populations, the risk of TP53 mutations ...
  82. [82]
    A Review on Mitotane: A Target Therapy in Adrenocortical Carcinoma
    Mitotane is the only reimbursed drug currently approved for adrenocortical carcinoma (ACC), a rare and aggressive malignancy.
  83. [83]
    Multi-omics-based molecular classification of adrenocortical ...
    Oct 2, 2025 · Abstract. Adrenal cortical carcinoma (ACC) is a rare and highly aggressive malignant tumor with dismal outcomes.