Adrenal gland

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Adrenal Gland
Illu endocrine system New.png
Illu adrenal gland.jpg
Adrenal gland
Details
Latin Glandula suprarenalis
Precursor Mesoderm and neural crest
System Endocrine system
Superior, middle and inferior suprarenal arteries
Suprarenal veins
Celiac and renal plexus
Lumbar lymph nodes
Identifiers
Gray's p.1278
MeSH A06.407.071
Dorlands
/Elsevier
Adrenal gland
TA A11.5.00.001
FMA 9604
Anatomical terminology

The adrenal glands (also known as suprarenal glands) are endocrine glands that produce a wide variety of hormones.[1] They are found on the top of the kidneys and consist of a number of different layers that directly influence the structure and function of the glands. Each gland has an outer cortex made of steroid-producing cells surrounding a core of medulla, formed by chromaffin cells in direct relationship with the sympathetic nervous system. The adrenal cortex is divided into three zones according to their functions and microscopic appearance.[2]

The adrenal cortex produces a class of steroid hormones, the corticosteroids, which are classified according to their effects. Mineralocorticoids, produced in the zona glomerulosa, help in the regulation of blood pressure and electrolyte balance. Glucocorticoids such as cortisol, are synthesized in the zona fasciculata and their functions include regulation of glycogen and lipid metabolism and immune system suppression. The innermost layer of the cortex produces androgens (steroid hormones) that are converted to fully functional sex hormones in the gonads and other target organs.[3] The production of steroid hormones is named steroidogenesis, and involves a number of reactions and processes that take place in cortical cells.[4] The medulla produces the catecholamines epinephrine and norepinephrine, which function to provoke a quick response on diverse organs in stress situations.[3]

Regulation of synthesis and secretion of adrenal hormones is equally varied. Mineralocorticoid production is mainly under influence of the renin–angiotensin–aldosterone system, in which specialized cells of the kidneys monitor blood volume and start a cascade of reactions that leads to the stimulation of aldosterone synthesis in the zona glomerulosa. Cortisol and androgen synthesis are under control of the hypothalamic-pituitary-adrenal (HPA) axis in a classic example of a negative feedback loop, in which the hypothalamus and pituitary gland release stimulating hormones whenever cortisol levels are low. In contrast, release of medullary catecholamines is regulated by direct innervation from the sympathetic nervous system.[3]

There are a number of endocrine diseases and disorders that can affect the normal functioning of the adrenal gland. Overproduction of corticosteroid hormones leads to Cushing's syndrome, whereas insufficiency is commonly associated with Addison's disease. Congenital adrenal hyperplasia is a genetic disease produced by a disregulation of endocrine control mechanisms.[3][5] A variety of tumors can arise from adrenal tissue, and are commonly found in medical imaging when searching for other diseases.[6]

Structure[edit]

The adrenal glands are located bilaterally in the retroperitoneum superior and slightly medial to the kidneys. In humans, the right adrenal gland is pyramidal in shape, whereas the left adrenal gland is semilunar in shape;[7] in non-humans, they are quadrilateral in shape. The combined weight of the adrenal glands in an adult human ranges from 7 to 10 grams.[8]

Histology section of human adrenal gland, showing the different layers that compose it. From the surface to the center: zona glomerulosa, zona fasciculata, zona reticularis, medulla. In the medulla, the central adrenomedullary vein is visible.

The adrenal glands are surrounded by an adipose capsule and are enclosed within the renal fascia, a fibrous structure that also surrounds the kidney. A weak septum of connective tissue separates the glands from the kidneys and facilitates surgical removal of the kidneys without damage to the glands. The adrenal glands are in close relationship with the diaphragm, and are attached to the crura of the diaphragm by means of the renal fascia.[9]

Each adrenal gland has two anatomically and functionally distinct parts, the outer adrenal cortex and the inner medulla, both of which produce hormones. The cortex mainly produces aldosterone, cortisol and androgens, while the medulla produces adrenaline and noradrenaline.

Cortex[edit]

Main article: Adrenal cortex

The adrenal cortex is devoted to production of corticosteroid and androgen hormones. Specific cortical cells produce particular hormones including aldosterone, cortisol, and androgens such as androstenedione. Under normal unstressed conditions, the human adrenal glands produce the equivalent of 35–40 mg of cortisone acetate per day.[10]

The adrenal cortex comprises three zones, or layers. This anatomic zonation can be appreciated at the microscopic level, where each zone can be recognized and distinguished from one another based on structural and anatomic characteristics.[11] The adrenal cortex exhibits functional zonation as well: by virtue of the characteristic enzymes present in each zone, the zones produce and secrete distinct hormones.[11]

Zona glomerulosa[edit]

Sections of human adrenal glands immunostained for neuronal cell adhesion molecule (NCAM). Staining for NCAM was restricted to the zona glomerulosa (zg) and the adrenal medulla (m).[12]

The outermost layer of the adrenal cortex, the zona glomerulosa, lies immediately under the fibrous capsule of the gland. Cells in this layer form ovoid groups, separated by trabeculae of connective tissue that are continuous with the fibrous capsule of the gland and carry wide capillaries.[13] This layer is the main site for production of aldosterone, a mineralocorticoid, by the action of the enzyme aldosterone synthase.[14][15] Aldosterone is a hormone largely responsible for the long-term regulation of blood pressure.[16]

The expression of neuron-specific proteins in the zona glomerulosa cells of human adrenocortical tissues has been predicted and reported by several authors[12][17][18] and it was suggested that the expression of proteins like the neuronal cell adhesion molecule (NCAM) in the cells of the zona glomerulosa reflects the regenerative feature of these cells, which would lose NCAM immunoreactivity after moving to the zona fasciculata.[12][19] However, together with other data on neuroendocrine properties of zona glomerulosa cells, NCAM expression may reflect a neuroendocrine differentiation of these cells.[12] Voltage-dependent calcium channels have been detected in the zona glomerulosa of the human adrenal, which suggests that calcium-channel blockers may directly influence the adrenocortical biosynthesis of aldosterone in vivo.[20]

Zona fasciculata[edit]

Situated between the glomerulosa and reticularis, the zona fasciculata is responsible for producing mainly glucocorticoids such as cortisol.[21] It is the widest of the three layers as it composes nearly 80% of the cortical volume.[2] The cells, arranged in columns radially oriented towards the medulla, have numerous lipid droplets responsible of the pale staining nature of the cytoplasm. Abundant mitochondria and a complex smooth endoplasmic reticulum are also present in the cells of this layer.[13]

Zona reticularis[edit]

The innermost cortical layer, the zona reticularis, lies directly next to the medulla. It produces androgens, mainly dehydroepiandrosterone (DHEA), DHEA sulfate (DHEA-S), and androstenedione (the precursor to testosterone) in humans.[21] Its small cells form irregular cords and clusters, separated by capillaries and connective tissue. The cells contain relatively small quantities of cytoplasm and lipid droplets, and sometimes display brown lipofuscin pigment.[13]

Medulla[edit]

Main article: Adrenal medulla

The adrenal medulla is the core of the adrenal gland, and is surrounded by the adrenal cortex. The chromaffin cells of the medulla (named for their characteristic brown staining with chromic acid salts) are the body's main source of the circulating catecholamines adrenaline and noradrenaline, released by the medulla. Approximately 20% noradrenaline (norepinephrine) and 80% adrenaline (epinephrine) are secreted.[21]

To carry out its part of this response, the adrenal medulla receives input from the sympathetic nervous system through preganglionic fibers originating in the thoracic spinal cord from T5–T11.[22] Because it is innervated by preganglionic nerve fibers, the adrenal medulla can be considered as a specialized sympathetic ganglion.[22] Unlike other sympathetic ganglia, however, the adrenal medulla lacks distinct synapses and releases its secretions directly into the blood.

Blood supply[edit]

Although variations of the blood supply to the adrenal glands (and indeed the kidneys themselves) are common, there are usually three arteries that supply each adrenal gland:

Venous drainage of the adrenal glands is achieved via the suprarenal veins:

The central adrenomedullary vein is a particular type of blood vessel in the adrenal medulla. Its structure is different from the other veins in that the smooth muscle in its tunica media (the middle layer of the vessel) is arranged in conspicuous, longitudinally oriented bundles.[2]

The suprarenal vein exits the adrenal gland through a depression on its anterior surface known as the hilum. Note that the arteries supplying the suprarenal gland do not pass through the hilum.[23] The suprarenal veins may form anastomoses with the inferior phrenic veins. Since the right supra-renal vein is short and drains directly into the inferior vena cava it is likely to injure the latter during removal of right adrenal for various reasons.

The adrenal glands (alongside the thyroid gland) have one of the greatest blood supply per gram of tissue of any organ. Up to 60 arterioles may enter each adrenal gland.[24] This may be one of the reasons that lung cancer commonly metastasizes to the adrenals.

Function[edit]

The adrenal gland secretes a number of different hormones which are metabolised by enzymes either within the gland or in other parts of the body. These hormones are involved in a number of different pathways.[25]

Corticosteroid production[edit]

Steroidogenesis in the adrenal glands

All corticosteroid hormones share cholesterol as a common precursor. In consequence, the first step in steroidogenesis is cholesterol uptake or synthesis. Cells that produce steroid hormones provide themselves with cholesterol in various ways. Their main source is dietary cholesterol transported in the blood as LDL, which enters the cells through receptor-mediated endocytosis, although endogenous synthesis in the endoplasmic reticulum is sufficient when LDL levels are abnormally low as represented in people with abetalipoproteinemia (a genetic disorder of intestinal lipid absorption).[3] In lysosomes, cholesterol is separated from the proteic component of LDL and then stored within cell membranes or bound with proteins.[26]

The initial part of conversion of cholesterol into steroid hormones involves a number of enzymes of the cytochrome P450 family that are located in the inner membrane of mitochondria. Transport of cholesterol from the outer to the inner membrane is facilitated by steroidogenic acute regulatory protein (StAR) and is the rate-limiting step of steroid synthesis.[26] The functional zonation of the adrenal cortex is determined by the presence of distinct enzymes in each particular layer, explaining how the different layers produce unique hormones from a common precursor.[3]

The first enzymatic step in the production of all steroid hormones is cleavage of the cholesterol side chain, a reaction that forms pregnenolone as a product and is catalyzed by the enzyme P450scc, also known as cholesterol desmolase. After the production of pregnenolone, specific enzymes of each cortical layer further modify it. Enzymes involved in this process include both mitochondrial and cytoplasmic P450s and hydroxysteroid dehydrogenases (HSDs). Usually a number of intermediate steps in which pregnenolone is modified several times are required to form the functional hormones.[4] Enzymes that catalyze reactions in these metabolic pathways are involved in a number of endocrine diseases. For example, the most common form of congenital adrenal hyperplasia develops as a result of deficiency of 21-hydroxylase, an enzyme involved in an intermediate step of cortisol production.[27]

Regulation of corticosteroid production[edit]

Negative feedback in the HPA axis

Glucocorticoids are under the regulatory influence of the hypothalamus-pituitary-adrenal (HPA) axis. Glucocorticoid synthesis is stimulated by adrenocorticotropic hormone (ACTH), a hormone of the anterior pituitary. In turn, production of ACTH is stimulated by the presence of corticotropin-releasing hormone (CRH), which is released by neurons of the hypothalamus. 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 negative feedback 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 the inflammatory response.[3]

Mineralocorticoid secretion is regulated mainly by the renin–angiotensin–aldosterone system (RAAS), the concentration of potassium, and ACTH to a lesser extent.[3] Sensors of blood pressure in the juxtaglomerular apparatus of the kidneys release the enzyme renin into the blood, which starts a cascade of reactions that lead to formation of angiotensin II. Angiotensin receptors in cells of the zona glomerulosa recognize the substance, and upon binding they stimulate the release of aldosterone.[28]

Catecholamine production[edit]

Epinephrine and norepinephrine are catecholamines, water-soluble substances that have a structure made of a catechol group and an amino group. The adrenal glands are responsible for the majority of circulating epinephrine (adrenaline) in the body, but only for a small amount of circulating norepinephrine (noradrenaline).[25] These hormones are released in the adrenal medulla, which is richly vascular. Epinephrine and norepinephrine act at adrenoreceptors throughout the body, with effects that include increase of blood pressure and heart rate.[25]

Catecholamines are produced in chromaffin cells (the main type of cells in the adrenal medulla) from tyrosine, a non-essential amino acid derived from food or produced from phenylalanine in the liver. The enzyme tyrosine hydroxylase converts tyrosine to L-DOPA in the first step of catecholamine synthesis. L-DOPA is then converted to dopamine before it can be turned into norepinephrine. In the cytosol, norepinephrine is converted to epinephrine by the enzyme phenylethanolamine 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.[3][11]

The adrenal medulla is innervated by splanchnic nerves of the sympathetic nervous system, which signal the release of catecholamines from the storage granules by stimulating the opening of calcium channels in the cell membrane.[29]

Effects of adrenal hormones[edit]

Mineralocorticoids[edit]

Main article: Aldosterone

Aldosterone is the main mineralocorticoid produced. Its effects are on the distal convoluted tubule and collecting duct of the kidney where it causes increased reabsorption of sodium and increased excretion of both potassium (by principal cells) and hydrogen ions (by intercalated cells of the collecting duct).[16] Sodium retention is also a response of the distal colon, and sweat glands to aldosterone receptor stimulation. Although sustained production of aldosterone requires persistent calcium (Ca2+) entry through low-voltage activated Ca2+ channels, isolated zona glomerulosa cells are considered nonexcitable, with recorded membrane voltages that are too hyperpolarized to permit Ca2+ channels entry.[30] However, mouse zona glomerulosa cells within adrenal slices spontaneously generate membrane potential oscillations of low periodicity; this innate electrical excitability of zona glomerulosa cells provides a platform for the production of a recurrent Ca2+ channels signal that can be controlled by angiotensin II and extracellular potassium, the two major regulators of aldosterone production.[30] Angiotensin II originates from plasmatic angiotensin I after the conversion of angiotensinogen by renin produced by the juxtaglomerular cells of the kidney.[21]

Glucocorticoids[edit]

Main article: Cortisol

Cortisol is the main glucocorticoid produced under normal conditions and its actions include mobilization of fats, proteins, and carbohydrates, but it does not increase under starvation conditions.[21] Additionally, cortisol enhances the activity of other hormones including glucagon and catecholamines. The zona fasciculata secretes a basal level of cortisol but can also produce bursts of the hormone in response to adrenocorticotropic hormone (ACTH) from the anterior pituitary.

Adrenal androgens[edit]

Main article: Androgen

Cells in zona reticularis of the adrenal glands produce male sex hormones, or androgens, the most important of which is DHEA. In general, these hormones do not have an overall effect in the male body, and are converted to more potent androgens such as testosterone and DHT or to estrogens (female sex hormones) in the gonads, acting in this way as a metabolic intermediate.[31]

Epinephrine and norepinephrine[edit]

Main articles: Epinephrine and Norepinephrine

Epinephrine and norepinephrine are catecholamines that act at adrenergic receptors throughout the body, with effects including constriction of small arteries, dilation of veins, and an increase in the heartrate.[25] Adrenergic receptors are G protein-coupled receptors. This means that they interact with G proteins, a family of enzymes that start a chain of reactions leading to the formation of intracellular second messengers. There are many classes of adrenergic receptors, and the specific response in the cell upon binding of either epinephrine or norepinephrine depends on the mechanism of action of those receptors. For example, when epinephrine or norepinephrine bind to β-adrenergic receptors, the level of cAMP (a second messenger) rises inside the cell, but if they bind to α2-adrenergic receptors in other tissues, the level of cAMP lowers.[32]

Development[edit]

The adrenal glands are composed of two heterogenous types of tissue: in the center there is the adrenal medulla, which produces and releases mostly adrenaline to the blood in stress situations as part of the sympathetic nervous system. Surrounding the medulla is the cortex, which produces a wide variety of steroid hormones. These tissues come from different embryological precursors and have distinct prenatal developments.

Cortex[edit]

Adrenal cortex tissue is derived from the intermediate mesoderm. It first appears 33 days after fertilisation, shows steroidogenic (steroid 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 a proliferative phase. The fetal zone produces large amounts of adrenal androgens (male sex hormones) that are used by the placenta for estrogen biosynthesis.[33] Cortical development of the adrenal gland is regulated mostly by ACTH, a hormone produced by the pituitary gland that stimulates cortisol synthesis.[34] During midgestation, the fetal zone occupies most of the cortical volume and produces 100–200 mg/day of DHEA-S, an androgen and precursor of both androgens and estrogens (female sex hormones).[35] Adrenal hormones, especially glucocorticoids such as cortisol are considered essential for prenatal development of organs, particularly for the maturation of the fetal lungs. The adrenal gland decreases in size after birth because of the rapid disappearance of the fetal zone, with a decrease in androgen secretion.[33]

Adrenarche[edit]

Main article: Adrenarche

During 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 DHEA and DHEA-S. These changes are part of a process called adrenarche, which has only been described in humans and some other primates. Adrenarche is independent of ACTH or gonadotropins and correlates with a progressive thickening of the zona 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.[36][37]

Medulla[edit]

The adrenal medulla is derived from a type of cell known as neural crest cells, which come from the ectoderm layer of the embryo. These cells migrate from their initial position and aggregate in the vicinity of the dorsal aorta, a primitive blood vessel, which activates the differentiation of these cells through the release of proteins known as BMPs. These cells then undergo a second migration step away from the dorsal aorta to form the adrenal medulla, along other organs of the sympathetic nervous system.[38] Cells of the adrenal medulla are also called chromaffin cells because they contain granules that stain with chromium salts, a characteristic not present in all sympathetic organs. Glucocorticoid production by the adrenal cortex was thought to be responsible for this differentiation, but now the available data suggest that BMP-4 secreted in the adrenal tissue is the primary responsible for the differentiation, and that glucocorticoids have a role in the posterior development of the cells.[39]

Clinical significance[edit]

Corticosteroid overproduction[edit]

Cushing's syndrome[edit]

Main article: Cushing's syndrome

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 the HPA axis or the production of cortisol. Causes can be further classified into ACTH-dependent or ACTH-independent. The most common cause of endogenous Cushing's syndrome are ACTH-producing pituitary adenomas. 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, striae in the skin, caused by its progressive thinning.[5][3]

Primary aldosteronism[edit]

Main article: Primary aldosteronism

When the zona glomerulosa produces excess aldosterone, the result is primary aldosteronism. Causes for this condition are bilateral hyperplasia of the glands and aldosterone-producing adenomas, which is called Conn's syndrome. Primary aldosteronism produces hypertension and electrolyte imbalance, increasing potassium depletion and sodium retention.[5]

Adrenal insufficiency[edit]

Addison's disease[edit]

Main article: Addison's disease
Characteristic skin hyperpigmentation in Addison's disease

Addison's disease refers to primary hypoadrenalism, which is a deficiency in glucocorticoid production. In the Western world, Addison's disease is more commonly autoimmune, where the body produces antibodies against cells of the adrenal cortex. Worldwide, the disease is more frequently caused by infection, especially from tuberculosis. A distinctive feature of Addison's disease is hyperpigmentation of the skin, which presents with other nonspecific symptoms, such as fatigue. An adrenal crisis is a medical emergency in which low glucocorticoid and mineralocorticoid levels result in hypovolemic shock and an array of nonspecific symptoms such as vomiting and fever. An adrenal crisis can progressively derive in stupor and coma.[3]

Secondary and tertiary adrenal insufficiency[edit]

Secondary adrenal insufficiency occurs when a part of the body is affected by a condition that impairs the production of hormones in the adrenal cortex. The most common cause of secondary adrenal insufficiency is a pituitary adenoma, which may affect the ability of the pituitary gland to produce adrenocorticotropic hormone (ACTH).[40] This hormone is vital in the event of physiological stress, as it stimulates the adrenal glands into action: if absent, this action will not occur and an Addisonian crisis may follow unless an emergency hydrocortisone injection is given.[41]

Tertiary adrenal insufficiency results from a deficiency in the production of CRH (produced by the hypothalamus).

Congenital adrenal hyperplasia[edit]

Congenital adrenal hyperplasia is a congenital disease in which mutations of enzymes that produce steroid hormones result in a glucocorticoid deficiency and malfunction of the negative feedback loop of the HPA axis. In the HPA axis, cortisol (a glucocorticoid) inhibits the release of CRH and ACTH, hormones that in turn stimulate corticosteroid synthesis. As cortisol cannot be synthesized, these hormones are released in high quantities and stimulate production of other corticosteroids instead. The most common form of congenital adrenal hyperplasia is due to 21-hydroxylase deficiency. 21-hydroxylase is necessary for production of both mineralocorticoids and glucocorticoids, but not androgens. Therefore, ACTH stimulation of the adrenal cortex induces the release of excessive amounts of adrenal androgens, which can lead to the development of ambiguous genitalia and secondary sex characteristics.[27]

Adrenal tumors[edit]

Adrenal tumors are commonly found as incidentalomas, unexpected asymptomatic tumors found during medical imaging. They are seen in around 3.4% of CT scans,[6] and in most cases they are benign adenomas.[42] Adrenal carcinomas are very rare, with an incidence of 1 case per million per year.[3]

Pheochromocytomas are tumors of the adrenal medulla that arise from chromaffin cells. They can produce a variety of nonspecific symptoms, which include headaches, sweating, anxiety and palpitations. Common signs include hypertension and tachycardia. Surgery, especially adrenal laparoscopy, is the most common treatment for small pheochromocytomas.[43]

History[edit]

Bartolomeo Eustachi, an Italian anatomist, is credited with the first description of the adrenal glands in 1564.[44] One of the most recognized works on the adrenal glands came in 1855 with the publication of On the Constitutional and Local Effects of Disease of the Suprarenal Capsule, by the English physician Thomas Addison. In his monography, Addison described what the French physician George Trousseau would later name Addison's disease, an eponym still used today for a condition of adrenal insufficiency and its related clinical manifestations.[45] In 1894, English physiologists George Oliver and Edward Schafer studied the action of adrenal extracts and observed their pressor effects. In the following decades several physicians experimented with extracts form the adrenal cortex to treat Addison's disease.[44] Edward Calvin Kendall, Philip Hench and Tadeusz Reichstein were then awarded the 1950 Nobel Prize in Physiology or Medicine for the isolation of cortisone from the adrenal cortex.[46]

Etymology[edit]

The adrenal glands are named for their location relative to the kidneys. The term "adrenal" comes from ad- (Latin, "near") and renes (Latin, "kidney").[47] Similarly, "suprarenal" is derived from supra- (Latin, "above") and renes.

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