system through increased secretion of acth at the presence of certain molecules of the inflammatory response. mineralocorticoid secretion is regulated mainly by the renin–angiotensin–aldosterone system (raas), the concentration of potassium, and to a lesser extent the concentration of acth. 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. androgens 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. catecholamines primarily referred to in the united states as epinephrine and norepinephrine, adrenaline and noradrenaline are catecholamines, water-soluble compounds that have a structure made of a catechol group and an amine group. the adrenal glands are responsible for most of the adrenaline that circulates in the body, but only for a small amount of circulating noradrenaline. these hormones are released by the adrenal medulla, which contains a dense network of blood vessels. adrenaline and noradrenaline act by interacting with adrenoreceptors throughout the body, with effects that include an increase in blood pressure and heart rate. actions of adrenaline and noradrenaline are responsible for the fight 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. formation catecholamines are produced in chromaffin cells in the medulla of the adrenal gland, 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 noradrenaline. in the cytosol, noradrenaline 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. catecholamine release is stimulated by the activation of the sympathetic nervous system. splanchnic nerves of the sympathetic nervous system innervate the medulla of the adrenal gland. when activated, it evokes the release of catecholamines from the storage granules by stimulating the opening of calcium channels in the cell membrane. gene and protein expression further information: bioinformatics § gene and protein expression the human genome includes approximately 20,000 protein coding genes and 70% of these genes are expressed in the normal adult adrenal glands. 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 the cytochrome p450 superfamily of enzymes. corresponding proteins are expressed in the different compartments of the adrenal gland, such as cyp11a1, hsd3b2 and fdx1 involved in steroid hormone synthesis and expressed in cortical cell layers, and pnmt and dbh involved in noradrenaline and adrenaline synthesis and expressed in the medulla. development the adrenal glands are composed of two heterogenous types of tissue. in the center is the adrenal medulla, which produces adrenaline and noradrenaline and releases them into the bloodstream, as part of the sympathetic nervous system. surrounding the medulla is the cortex, which produces a variety of steroid hormones. these tissues come from different embryological precursors and have distinct prenatal development paths. the cortex of the adrenal gland is derived from mesoderm, whereas the medulla is derived from the neural crest, which is of ectodermal origin. the adrenal glands in a newborn baby are much larger as a proportion of the body size than in an adult. 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 about 1 g at birth and develop to an adult weight of about 4 grams each. in a fetus the glands are first detectable after the sixth week of development. cortex adrenal cortex tissue is derived from the intermediate mesoderm. it first appears 33 days after fertilisation, shows 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. cortical development of the adrenal gland is regulated mostly by acth, a hormone produced by the pituitary gland that stimulates cortisol synthesis. 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). adrenal hormones, especially glucocorticoids such as cortisol, are essential for prenatal development of organs, particularly for the maturation of the lungs. the adrenal gland decreases in size after birth because of the rapid disappearance of the fetal zone, with a corresponding decrease in androgen secretion. adrenarche main article: adrenarche 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 steroids 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. medulla the adrenal medulla is derived from 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 from the dorsal aorta to form the adrenal medulla and other organs of the sympathetic nervous system. cells of the adrenal medulla are called chromaffin cells because they contain granules that stain with chromium 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 that bmp-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. clinical significance main article: adrenal gland disorder the normal function of the adrenal gland may be impaired by conditions such as infections, tumors, genetic disorders and autoimmune diseases, or as a side 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 of cushing's syndrome) leading to an excess or insufficiency of adrenal hormones and the related symptoms. 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 is a pituitary 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. primary aldosteronism when the zona glomerulosa produces excess aldosterone, the result is primary aldosteronism. causes for this condition are bilateral hyperplasia (excessive tissue growth) of the glands, or aldosterone-producing adenomas (a condition called conn's syndrome). primary aldosteronism produces hypertension and electrolyte imbalance, increasing potassium depletion sodium retention. adrenal insufficiency adrenal insufficiency (the deficiency of glucocorticoids) occurs in about 5 in 10,000 in the general population. diseases classified as primary adrenal insufficiency (including addison's disease and genetic causes) directly affect the adrenal cortex. if a problem that affects the hypothalamic-pituitary-adrenal axis arises outside the gland, it is a secondary adrenal insufficiency. addison's disease characteristic skin hyperpigmentation in addison's disease 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 an autoimmune condition, in which 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. a complication seen in untreated addison's disease and other types of primary adrenal insufficiency is the adrenal crisis, a medical emergency in which low glucocorticoid and mineralocorticoid levels result in hypovolemic shock and symptoms such as vomiting and fever. an adrenal crisis can progressively lead to stupor and coma. the management of adrenal crises includes the application of hydrocortisone injections. secondary adrenal insufficiency in secondary adrenal insufficiency, a dysfunction of the hypothalamic-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 of adrenocorticotropic hormone (acth) by the pituitary gland. this type of adrenal insufficiency usually does not affect the production of mineralocorticoids, which are under regulation of the renin–angiotensin system instead. congenital adrenal hyperplasia 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 adrenal steroids 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. adrenal tumors incidences and prognoses of adrenal tumors. main article: adrenal tumor adrenal tumors are commonly found as incidentalomas, unexpected asymptomatic tumors found during medical imaging. they are seen in around 3.4% of ct scans, and in most cases they are benign adenomas. adrenal carcinomas are very rare, with an incidence of 1 case per million per year. 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. history bartolomeo eustachi, an italian anatomist, is credited with the first description of the adrenal glands in 1563–4. however, these publications were part of the papal library and did not receive public attention, which was first received with caspar bartholin the elder's illustrations in 1611. the adrenal glands are named for their location relative to the kidneys. the term "adrenal" comes from latin ad, "near", and ren, "kidney". similarly, "suprarenal", as termed by jean riolan the younger in 1629, is derived from the latin supra, "above", and ren, "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