The adrenal cortex produces three main types ofsteroid hormones:mineralocorticoids,glucocorticoids, andandrogens. Mineralocorticoids (such asaldosterone) produced in the zona glomerulosa help in the regulation of blood pressure andelectrolyte balance. The glucocorticoidscortisol andcortisone are synthesized in the zona fasciculata; their functions include the regulation ofmetabolism andimmune system suppression. The innermost layer of the cortex, the zona reticularis, produces androgens that are converted to fully functional sex hormones in thegonads and other target organs.[4] The production of steroid hormones is calledsteroidogenesis, and involves a number of reactions and processes that take place in cortical cells.[5] The medulla produces thecatecholamines, which function to produce arapid response throughout the body instress situations.[4]
Adrenal glands, anterior (left) and posterior (right) surface
The adrenal glands are located on both sides of the body in theretroperitoneum, above and slightlymedial to thekidneys. In humans, the right adrenal gland is pyramidal in shape, whereas the left is semilunar or crescent shaped and somewhat larger.[8] The adrenal glands measure approximately 5 cm in length, 3 cm in width, and up to 1 cm in thickness.[9] Their combined weight in an adult human ranges from 7 to 10 grams.[10] The glands are yellowish in colour.[8]
Each adrenal gland has two distinct parts, each with a unique function, the outeradrenal cortex and the innermedulla, both of which produce hormones.[12]
Section of human adrenal glandunder the microscope, showing its different layers. From the surface to the center: zona glomerulosa, zona fasciculata, zona reticularis, medulla. In the medulla, the central adrenomedullary vein is visible.
Theadrenal cortex is the outer region and also the largest part of an adrenal gland. It has three layers, or zones: zona glomerulosa, zona fasciculata and zona reticularis. Each zone is responsible for producing specific hormones. Whenviewed under a microscope, each layer has a distinct appearance and each has a different function.[13] The adrenal cortex produceshormones, namelyaldosterone,cortisol andandrogens.[14]
The outermost zone of the adrenal cortex is thezona glomerulosa, which lies immediately beneath the gland's fibrous capsule. Cells in this layer form oval groups that are separated bythin strands of connective tissue from the fibrous capsule and carry widecapillaries.[15]
Thezona fasciculata is situated between the zona glomerulosa and the zona reticularis. Cells in this layer are responsible for producingglucocorticoids such ascortisol.[19] It is the largest of the three layers, accounting for nearly 80% of the volume of the cortex.[3] In the zona fasciculata, cells are arranged in columns that are radially oriented towards the medulla. Cells contain numerous lipid droplets, abundantmitochondria and a complexsmooth endoplasmic reticulum.[15]
The innermost cortical layer, thezona reticularis, lies directly adjacent to the medulla and producesandrogens, mainlydehydroepiandrosterone (DHEA),DHEA sulfate (DHEA-S), andandrostenedione (the precursor totestosterone) in humans.[19] Its small cells form irregular cords and clusters that are separated by capillaries and connective tissue. The cells contain small quantities of cytoplasm and lipid droplets, and sometimes display brownlipofuscin pigment.[15]
Theadrenal medulla is at the center of each adrenal gland, and is surrounded by the adrenal cortex. Thechromaffin cells of the medulla are the body's main source of thecatecholamines, such as adrenaline and noradrenaline, released by the medulla. Approximately 20% noradrenaline (norepinephrine) and 80% adrenaline (epinephrine) are secreted here.[19]
The adrenal glands have one of the greatest blood supply rates per gram of tissue of any organ: up to 60small arteries may enter each gland.[21] Three arteries usually supply each adrenal gland:[8]
These blood vessels supply a network of small arteries within the capsule of the adrenal glands. Thin strands of the capsule enter the glands, carrying blood to them.[8]
The central adrenomedullary vein, in the adrenal medulla, is an unusual type of blood vessel. Its structure is different from the other veins in that thesmooth muscle in itstunica media (the middle layer of the vessel) is arranged in conspicuous, longitudinally oriented bundles.[3]
The adrenal glands may not develop at all, or may be fused in the midline behind theaorta.[12] These are associated with othercongenital abnormalities, such as failure of the kidneys to develop, or fused kidneys.[12] The gland may develop with a partial or complete absence of the cortex, or may develop in an unusual location.[12]
Different hormones are produced in different zones of the cortex and medulla of the gland. Light microscopy at magnification × 204.[22]
The adrenal gland secretes a number of different hormones which are metabolised byenzymes either within the gland or in other parts of the body. These hormones are involved in a number of essential biological functions.[23]
The adrenal gland producesaldosterone, amineralocorticoid, which is important in the regulation of salt ("mineral") balance andblood volume. In the kidneys, aldosterone acts on thedistal convoluted tubules and thecollecting ducts by increasing the reabsorption ofsodium and the excretion of both potassium and hydrogen ions.[18] Aldosterone is responsible for the reabsorption of about 2% of filteredglomerular filtrate.[27] Sodium retention is also a response of the distal colon and sweat glands to aldosterone receptor stimulation.Angiotensin II and extracellularpotassium are the two main regulators of aldosterone production.[19] The amount of sodium present in the body affects the extracellular volume, which in turn influencesblood pressure. Therefore, the effects of aldosterone in sodium retention are important for the regulation of blood pressure.[28]
Glucocorticoids
Cortisol is the mainglucocorticoid in humans. In species that do not create cortisol, this role is played bycorticosterone instead. Glucocorticoids have many effects onmetabolism. As their name suggests, they increase the circulating level ofglucose. This is the result of an increase in the mobilization ofamino acids from protein and the stimulation ofsynthesis of glucose from these amino acids in the liver. In addition, they increase the levels offree fatty acids, which cells can use as an alternative to glucose to obtain energy. Glucocorticoids also have effects unrelated to the regulation of blood sugar levels, including the suppression of the immune system and a potentanti-inflammatory effect. Cortisol reduces the capacity ofosteoblasts to produce new bone tissue and decreases the absorption of calcium in thegastrointestinal tract.[28]
The adrenal gland secretes a basal level of cortisol but can also produce bursts of the hormone in response toadrenocorticotropic hormone (ACTH) from theanterior pituitary. Cortisol is not evenly released during the day – its concentrations in the blood are highest in the early morning and lowest in the evening as a result of thecircadian rhythm of ACTH secretion.[28]Cortisone is an inactive product of the action of the enzyme11β-HSD on cortisol. The reaction catalyzed by 11β-HSD is reversible, which means that it can turn administered cortisone into cortisol, the biologically active hormone.[28]
Formation
Steroidogenesis in the adrenal glands – different steps occur in different layers of the gland
Allcorticosteroid hormones sharecholesterol as a common precursor. Therefore, the first step insteroidogenesis is cholesterol uptake or synthesis. Cells that produce steroid hormones can acquire cholesterol through two paths. The main source is through dietary cholesterol transported via the blood ascholesterol esters withinlow density lipoproteins (LDL). LDL enters the cells throughreceptor-mediated endocytosis. The other source of cholesterol is synthesis in the cell'sendoplasmic reticulum. Synthesis can compensate when LDL levels are abnormally low.[4] In thelysosome, cholesterol esters are converted to free cholesterol, which is then used for steroidogenesis or stored in the cell.[29]
The initial part of conversion of cholesterol into steroid hormones involves a number of enzymes of thecytochrome P450 family that are located in the inner membrane ofmitochondria. Transport of cholesterol from the outer to the inner membrane is facilitated bysteroidogenic acute regulatory protein and is the rate-limiting step of steroid synthesis.[29]
The layers of the adrenal gland differ by function, with each layer having distinct enzymes that produce different hormones from a common precursor.[4] The first enzymatic step in the production of all steroid hormones is cleavage of the cholesterol side chain, a reaction that formspregnenolone as a product and is catalyzed by the enzymeP450scc, also known ascholesterol desmolase. After the production of pregnenolone, specific enzymes of each cortical layer further modify it. Enzymes involved in this process include both mitochondrial andmicrosomal P450s andhydroxysteroid dehydrogenases. Usually a number of intermediate steps in which pregnenolone is modified several times are required to form the functional hormones.[5] Enzymes that catalyze reactions in these metabolic pathways are involved in a number of endocrine diseases. For example, the most common form ofcongenital adrenal hyperplasia develops as a result of deficiency of21-hydroxylase, an enzyme involved in an intermediate step of cortisol production.[30]
Glucocorticoids are under the regulatory influence of thehypothalamic–pituitary–adrenal axis (HPA) axis. Glucocorticoid synthesis is stimulated byadrenocorticotropic hormone (ACTH), a hormone released into the bloodstream by theanterior pituitary. In turn, production of ACTH is stimulated by the presence ofcorticotropin-releasing hormone (CRH), which is released by neurons of thehypothalamus. ACTH acts on the adrenal cells first by increasing the levels of StAR within the cells, and then of all steroidogenic P450 enzymes. The HPA axis is an example of a negativefeedback system, in which cortisol itself acts as a direct inhibitor of both CRH and ACTH synthesis. The HPA axis also interacts with the immune system through increased secretion of ACTH at the presence of certain molecules of theinflammatory response.[4]
Mineralocorticoid secretion is regulated mainly by therenin–angiotensin–aldosterone system (RAAS), the concentration ofpotassium, and to a lesser extent the concentration of ACTH.[4] Sensors of blood pressure in thejuxtaglomerular apparatus of the kidneys release the enzymerenin into the blood, which starts a cascade of reactions that lead to formation ofangiotensin II.Angiotensin receptors in cells of the zona glomerulosa recognize the substance, and upon binding they stimulate the release ofaldosterone.[31]
Cells inzona reticularis of the adrenal glands produce male sex hormones, orandrogens, the most important of which isDHEA. In general, these hormones do not have an overall effect in the male body, and are converted to more potent androgens such astestosterone andDHT or toestrogens (female sex hormones) in thegonads, acting in this way as ametabolic intermediate.[32]
Also calledepinephrine andnorepinephrine,adrenaline andnoradrenaline, respectively, arecatecholamines – water-solublecompounds that have a structure made of acatechol group and anamine group.[33] The adrenal glands are responsible for most of the adrenaline that circulates in the body, but only for a small amount of circulating noradrenaline.[23] These hormones are released by the adrenal medulla, which contains a dense network of blood vessels. Adrenaline and noradrenaline act by binding toadrenoreceptors throughout the body, with effects that include an increase in blood pressure and heart rate.[33] Actions of adrenaline and noradrenaline are responsible for thefight or flight response, characterised by a quickening of breathing and heart rate, an increase in blood pressure, and constriction of blood vessels in many parts of the body.[33]
Catecholamines are produced in chromaffin cells in the medulla of the adrenal gland, fromtyrosine, a non-essential amino acid derived from food or produced fromphenylalanine in the liver.[33] The enzymetyrosine hydroxylase converts tyrosine toL-DOPA in the first step of catecholamine synthesis. L-DOPA is then converted todopamine before it can be turned into noradrenaline. In thecytosol, noradrenaline is converted to epinephrine by the enzymephenylethanolamine N-methyltransferase (PNMT) and stored in granules. Glucocorticoids produced in the adrenal cortex stimulate the synthesis of catecholamines by increasing the levels of tyrosine hydroxylase and PNMT.[4][13]
The human genome includes approximately 20,000 protein coding genes and 70% of these genes are expressed in the normal adult adrenal glands.[35][36] Only some 250 genes are more specifically expressed in the adrenal glands compared to other organs and tissues. The adrenal-gland-specific genes with the highest level of expression include members of thecytochrome P450 superfamily of enzymes. Corresponding proteins are expressed in the different compartments of the adrenal gland, such asCYP11A1,HSD3B2 andFDX1 involved insteroid hormone synthesis and expressed in cortical cell layers, andPNMT andDBH involved innoradrenaline andadrenaline synthesis and expressed in the medulla.[37]
The adrenal glands in a newborn baby are much larger as a proportion of the body size than in an adult.[38] For example, at age three months the glands are four times the size of the kidneys. The size of the glands decreases relatively after birth, mainly because of shrinkage of the cortex. The cortex, which almost completely disappears by age 1, develops again from age 4–5. The glands weigh about1 gram at birth[12] and develop to an adult weight of about4 grams each.[28] In a fetus the glands are first detectable after the sixth week of development.[12]
Adrenal cortex tissue is derived from theintermediate mesoderm. It first appears 33 days afterfertilisation, showssteroid hormone production capabilities by the eighth week and undergoes rapid growth during the first trimester of pregnancy. The fetal adrenal cortex is different from its adult counterpart, as it is composed of two distinct zones: the inner "fetal" zone, which carries most of the hormone-producing activity, and the outer "definitive" zone, which is in aproliferative phase. The fetal zone produces large amounts of adrenalandrogens (male sex hormones) that are used by theplacenta forestrogen biosynthesis.[39] Cortical development of the adrenal gland is regulated mostly byACTH, a hormone produced by thepituitary gland that stimulatescortisol synthesis.[40] During midgestation, the fetal zone occupies most of the cortical volume and produces 100–200 mg/day ofDHEA-S, anandrogen and precursor of both androgens andestrogens (female sex hormones).[41] Adrenal hormones, especiallyglucocorticoids such as cortisol, are essential for prenatal development of organs, particularly for the maturation of thelungs. The adrenal gland decreases in size after birth because of the rapid disappearance of the fetal zone, with a corresponding decrease in androgen secretion.[39]
During early childhood androgen synthesis and secretion remain low, but several years before puberty (from 6–8 years of age) changes occur in both anatomical and functional aspects of cortical androgen production that lead to increased secretion of the steroidsDHEA andDHEA-S. These changes are part of a process calledadrenarche, which has only been described in humans and some other primates. Adrenarche is independent ofACTH orgonadotropins and correlates with a progressive thickening of thezona reticularis layer of the cortex. Functionally, adrenarche provides a source of androgens for the development of axillary and pubic hair before the beginning of puberty.[42][43]
The adrenal medulla is derived fromneural crest cells, which come from theectoderm layer of theembryo. These cellsmigrate from their initial position and aggregate in the vicinity of thedorsal aorta, a primitive blood vessel, which activates the differentiation of these cells through the release of proteins known asBMPs. These cells then undergo a second migration from the dorsal aorta to form the adrenal medulla and other organs of thesympathetic nervous system.[44] Cells of the adrenal medulla are calledchromaffin cells because they contain granules that stain withchromium salts, a characteristic not present in all sympathetic organs.Glucocorticoids produced in the adrenal cortex were once thought to be responsible for the differentiation of chromaffin cells. More recent research suggests thatBMP-4 secreted in adrenal tissue is the main responsible for this, and that glucocorticoids only play a role in the subsequent development of the cells.[45]
The normal function of the adrenal gland may be impaired by conditions such as infections, tumors, genetic disorders andautoimmune diseases, or as aside effect of medical therapy. These disorders affect the gland either directly (as with infections or autoimmune diseases) or as a result of the dysregulation of hormone production (as in some types ofCushing's syndrome) leading to an excess or insufficiency of adrenal hormones and the related symptoms.
Cushing's syndrome is the manifestation of glucocorticoid excess. It can be the result of a prolonged treatment with glucocorticoids or be caused by an underlying disease which produces alterations in theHPA axis or the production of cortisol. Causes can be further classified intoACTH-dependent or ACTH-independent. The most common cause ofendogenous Cushing's syndrome is apituitary adenoma which causes an excessive production of ACTH. The disease produces a wide variety of signs and symptoms which include obesity, diabetes, increased blood pressure, excessive body hair (hirsutism),osteoporosis, depression, and most distinctively,stretch marks in the skin, caused by its progressive thinning.[4][6]
When the zona glomerulosa produces excessaldosterone, the result isprimary aldosteronism. Causes for this condition are bilateralhyperplasia (excessive tissue growth) of the glands, or aldosterone-producingadenomas (a condition calledConn's syndrome). Primary aldosteronism produces hypertension andelectrolyte imbalance, increasingpotassium depletion sodium retention.[6]
Adrenal insufficiency (the deficiency ofglucocorticoids) occurs in about 5 in 10,000 in the general population.[6] Diseases classified asprimary adrenal insufficiency (includingAddison's disease and genetic causes) directly affect the adrenal cortex. If a problem that affects thehypothalamic–pituitary–adrenal axis arises outside the gland, it is asecondary adrenal insufficiency.[46]
Addison's disease refers to primary hypoadrenalism, which is a deficiency in glucocorticoid and mineralocorticoid production by the adrenal gland. In the Western world, Addison's disease is most commonly anautoimmune condition, in which the body producesantibodies against cells of the adrenal cortex. Worldwide, the disease is more frequently caused by infection, especially fromtuberculosis. A distinctive feature of Addison's disease ishyperpigmentation of the skin, which presents with other nonspecific symptoms such as fatigue.[4]
A complication seen in untreated Addison's disease and other types of primary adrenal insufficiency is theadrenal crisis, amedical emergency in which low glucocorticoid and mineralocorticoid levels result inhypovolemic shock and symptoms such as vomiting and fever. An adrenal crisis can progressively lead tostupor andcoma.[4] The management of adrenal crises includes the application ofhydrocortisone injections.[47]
In secondary adrenal insufficiency, a dysfunction of thehypothalamic–pituitary–adrenal axis leads to decreased stimulation of the adrenal cortex. Apart from suppression of the axis by glucocorticoid therapy, the most common cause of secondary adrenal insufficiency are tumors that affect the production ofadrenocorticotropic hormone (ACTH) by thepituitary gland.[6] This type of adrenal insufficiency usually does not affect the production ofmineralocorticoids, which are under regulation of therenin–angiotensin system instead.[4]
Congenital adrenal hyperplasia is a family ofcongenital diseases in whichmutations of enzymes that produce steroid hormones result in aglucocorticoid deficiency and malfunction of the negative feedback loop of theHPA axis. In the HPA axis, cortisol (a glucocorticoid) inhibits the release ofCRH andACTH, hormones that in turn stimulate corticosteroid synthesis. As cortisol cannot be synthesized, these hormones are released in high quantities and stimulate production of other adrenal steroids instead. The most common form of congenital adrenal hyperplasia is due to21-hydroxylase deficiency. 21-hydroxylase is necessary for production of both mineralocorticoids and glucocorticoids, but notandrogens. Therefore, ACTH stimulation of the adrenal cortex induces the release of excessive amounts ofadrenal androgens, which can lead to the development of ambiguousgenitalia andsecondary sex characteristics.[30]
Pheochromocytomas are tumors of the adrenal medulla that arise fromchromaffin cells. They can produce a variety of nonspecific symptoms, which include headaches, sweating, anxiety andpalpitations. Common signs includehypertension andtachycardia. Surgery, especially adrenallaparoscopy, is the most common treatment for small pheochromocytomas.[50]
Bartolomeo Eustachi, an Italian anatomist, is credited with the first description of the adrenal glands in 1563–4.[51][52][53] However, these publications were part of thepapal library and did not receive public attention, which was first received withCaspar Bartholin the Elder's illustrations in 1611.[52]
The adrenal glands are named for their location relative to the kidneys. The term "adrenal" comes fromLatinad, "near", andren, "kidney".[54] Similarly, "suprarenal", as termed byJean Riolan the Younger in 1629, is derived from theLatinsupra, "above", andren, "kidney", as well. The suprarenal nature of the glands was not truly accepted until the 19th century, as anatomists clarified the ductless nature of the glands and their likely secretory role – prior to this, there was some debate as to whether the glands were indeed suprarenal or part of the kidney.[52]
One of the most recognized works on the adrenal glands came in 1855 with the publication ofOn the Constitutional and Local Effects of Disease of the Suprarenal Capsule, by the English physicianThomas Addison. In his monography, Addison described what the French physicianGeorge Trousseau would later nameAddison's disease, an eponym still used today for a condition ofadrenal insufficiency and its related clinical manifestations.[55] In 1894, English physiologistsGeorge Oliver andEdward Schafer studied the action of adrenal extracts and observed theirpressor effects. In the following decades several physicians experimented with extracts from the adrenal cortex to treat Addison's disease.[51]Edward Calvin Kendall,Philip Hench andTadeusz Reichstein were then awarded the 1950Nobel Prize in Physiology or Medicine for their discoveries on the structure and effects of the adrenal hormones.[56]
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