Adrenal Gland

In mammals, the adrenal glands (also known as suprarenal glands) are the triangular-shaped endocrine glands that sit on top of the kidneys. They are chiefly responsible for releasing hormones in conjunction with stress through the synthesis of corticosteroids and catecholamines, including cortisol and adrenaline (epinephrine), respectively. Anatomy and function Anatomically, the adrenal glands are located in the retroperitoneum situated atop the kidneys, one on each side. They are surrounded by an adipose capsule and renal fascia.

In humans, the adrenal glands are found at the level of the 12th thoracic vertebra. Each adrenal gland is separated into two distinct structures, the adrenal cortex and medulla, both of which produce hormones. The cortex mainly produces cortisol, aldosterone, and androgens, while the medulla chiefly produces epinephrine and norepinephrine. Cortex The adrenal cortex is devoted to the synthesis of corticosteroid hormones from cholesterol. Some cells belong to the hypothalamic-pituitary-adrenal axis and are the source of cortisol and corticosterone synthesis.

Under normal unstressed conditions, the human adrenal glands produce the equivalent of 35–40 mg of cortisone acetate per day. [1] Other cortical cells produce androgens such as testosterone, while some regulate water and electrolyte concentrations by secreting aldosterone. In contrast to the direct innervation of the medulla, the cortex is regulated by neuroendocrine hormones secreted by the pituitary gland and hypothalamus, as well as by the renin-angiotensin system. 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. [2] 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. [2] Zona glomerulosa The outermost layer, the zona glomerulosa is the main site for production of mineralocorticoids, mainly aldosterone, which is largely responsible for the long-term regulation of blood pressure. Zona fasciculata

Situated between the glomerulosa and reticularis, the zona fasciculata is responsible for producing glucocorticoids, chiefly cortisol in humans. 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. Zona reticularis The inner most cortical layer, the zona reticularis produces androgens, mainly dehydroepiandrosterone (DHEA) and DHEA sulfate (DHEA-S) in humans. 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 (epinephrine) and noradrenaline (norepinephrine). Derived from the amino acid tyrosine, these water-soluble hormones are major hormones underlying the fight-or-flight response. 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. 3] Because it is innervated by preganglionic nerve fibers, the adrenal medulla can be considered as a specialized sympathetic ganglion. [3] Unlike other sympathetic ganglia, however, the adrenal medulla lacks distinct synapses and releases its secretions directly into the blood. Cortisol also promotes epinephrine synthesis in the medulla. Produced in the cortex, cortisol reaches the adrenal medulla and at high levels, the hormone can promote the upregulation of phenylethanolamine N-methyltransferase (PNMT), thereby increasing epinephrine synthesis and secretion. [2] Blood supply

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: * The superior suprarenal artery is provided by the inferior phrenic artery * The middle suprarenal artery is provided by the abdominal aorta * The inferior suprarenal artery is provided by the renal artery Venous drainage of the adrenal glands is achieved via the suprarenal veins: * The right suprarenal vein drains into the inferior vena cava * The left suprarenal vein drains into the left renal vein or the left inferior phrenic vein.

The suprarenal veins may form anastomoses with the inferior phrenic veins. The adrenal glands and the thyroid gland are the organs that have the greatest blood supply per gram of tissue. Up to 60 arterioles may enter each adrenal gland. [4] Terminology The adrenal glands are named for their location relative to the kidneys. The term “adrenal” comes from ad- (Latin, “near”) and renes (Latin, “kidney”). Similarly, “suprarenal” is derived from supra- (Latin, “above”) and renes. Colloquially, they are referred to as “kidney hats”.

Adrenal cortex Situated along the perimeter of the adrenal gland, the adrenal cortex mediates the stress response through the production of mineralocorticoids and glucocorticoids, including aldosterone and cortisol respectively. It is also a secondary site of androgen synthesis. Contents * 1 Layers * 2 Hormone synthesis * 3 Production * 3. 1 Mineralocorticoids * 3. 2 Glucocorticoids * 3. 3 Androgens * 4 Pathology * 5 See also * 6 References * 7 External links| Layers Layer| Name| Primary product|

Most superficial cortical layer| zona glomerulosa| mineralocorticoids (eg, aldosterone)| Middle cortical layer| zona fasciculata| glucocorticoids (eg, cortisol)| Deepest cortical layer| zona reticularis| weak androgens (eg, dehydroepiandrosterone)| * Notably, the reticularis in all animals is not always easily distinguishable and dedicated to androgen synthesis. In rodents, for instance, the reticularis also generates corticosteroids (specifically corticosterone, not cortisol). The two layers are collectively referred to as the fasciculo-reticularis.

Female rodents also exhibit another cortical layer called the “X zone” whose function is not yet clear. Zona glomerulosaThe zona glomerulosa of the adrenal gland is the most superficial layer of the adrenal cortex, lying directly beneath the adrenal gland’s capsule. Its cells are ovoid in shape and are arranged in clusters or arches (glomus is Latin for “ball”). In response to increased potassium levels, renin or decreased blood flow to the kidneys, cells of the zona glomerulosa produce and secrete the mineralocorticoid aldosterone into the blood as part of the renin-angiotensin system.

Aldosterone regulates the body’s concentration of electrolytes, primarily sodium and potassium, by acting on the distal convoluted tubule of kidney nephrons to: * increase sodium reabsorption * increase potassium excretion * increase water reabsorption through osmosisThe enzyme aldosterone synthase acts in this location. Zona fasciculataThe zona fasciculata constitutes the middle zone of the adrenal cortex, sitting directly beneath the zona glomerulosa. Constituent cells are organized into bundles or “fascicles”.

The zona fasciculata chiefly produces glucocorticoids (mainly cortisol in the human), which regulates the metabolism of glucose, especially in times of stress (e. g. , part of the fight-or-flight response). This tissue also generates a small amount of weak androgens (e. g. , dehydroepiandrosterone). In certain animals such as rodents, the lack of 17alpha-hydroxylase results in the synthesis of corticosterone instead of cortisol. Steroid-producing adrenal tumours and hyperplasias of the zona fasciculata result in excess cortisol production and are the cause for adrenal Cushing’s syndrome.

The genetic disorder McCune-Albright syndrome can also present Cushing’s syndrome in affected patients. | Zona reticularisThe zona reticularis is the innermost layer of the adrenal cortex, lying deep to the zona fasciculata and superficial to the adrenal medulla. The cells are arranged cords that project in different directions giving a net-like appearance (L. reticulum – net)[1]. Cells in the zona reticularis produce precursor androgens including dehydroepiandrosterone (DHEA) and androstenedione from cholesterol[2]. DHEA is further converted to DHEA-sulfate via a sulfotransferase, SULT2A1[3].

These precursors are not further converted in the adrenal cortex as the cells lack 3? -hydroxysteroid dehydrogenase. Instead, they are released into the blood stream and taken up in the testis and ovaries to produce testosterone and the estrogens respectively. In humans the reticularis layer does contain 17 alpha-hydroxylase which hydroxylates pregnenolone which is then converted to cortisol by a mixed function oxidase. In rodents too, the lack of 17alpha-hydroxylase results in the synthesis of corticosterone instead of cortisol as in the human. | Hormone synthesis

All adrenocortical hormones are synthesized from cholesterol. Cholesterol is transported into the Adrenal gland. The steps up to this point occur in many steroid-producing tissues. Subsequent steps to generate aldosterone and cortisol, however, primarily occur in the adrenal cortex: * Progesterone ; (hydroxylation at C21) ; 11-Deoxycorticosterone ; (two further hydroxylations at C11 and C18) ; Aldosterone * Progesterone ; (hydroxylation at C17) ; 17-alpha-hydroxyprogesterone ; (hydroxylation at C21) ; 11-Deoxycortisol ; (hydroxylation at C11) ; Cortisol Production

The adrenal cortex produces a number of different corticosteroid hormones. Mineralocorticoids They are produced in the zona glomerulosa. The primary mineralocorticoid is aldosterone. Its secretion is regulated by the oligopeptide angiotensin II (angiotensin II is regulated by angiotensin I, which in turn is regulated by renin). Aldosterone is secreted in response to high extracellular potassium levels, low extracellular sodium levels, and low fluid levels and blood volume. Aldosterone affects metabolism in different ways: * It increases urinary excretion of potassium ions It increases interstitial levels of sodium ions * It increases water retention and blood volume Glucocorticoids They are produced in the zona fasciculata. The primary glucocorticoid released by the adrenal gland in the human is cortisol and corticosterone in many other animals. Its secretion is regulated by the hormone ACTH from the anterior pituitary. Upon binding to its target, cortisol enhances metabolism in several ways: * It stimulates the release of amino acids from the body * It stimulates lipolysis, the breakdown of fat It stimulates gluconeogenesis, the production of glucose from newly-released amino acids and lipids * It increases blood glucose levels in response to stress, by inhibiting glucose uptake into muscle and fat cells * It strengthens cardiac muscle contractions * It increases water retention * It has anti-inflammatory and anti-allergic effects Androgens They are produced in the zona reticularis. The most important androgens include: * Testosterone: a hormone with a wide variety of effects, ranging from enhancing muscle mass and stimulation of cell growth to the development of the secondary sex characteristics. Dihydrotestosterone (DHT): a metabolite of testosterone, and a more potent androgen than testosterone in that it binds more strongly to androgen receptors. * Androstenedione (Andro): an androgenic steroid produced by the testes, adrenal cortex, and ovaries. While androstenediones are converted metabolically to testosterone and other androgens, they are also the parent structure of estrone. * Dehydroepiandrosterone (DHEA): It is the primary precursor of natural estrogens. DHEA is also called dehydroisoandrosterone or dehydroandrosterone.

The reticularis also produces DHEA-sulfate due to the actions of a sulfotransferase, SULT2A1. Mineralocorticoid Mineralocorticoids are a class of steroid hormones characterised by their similarity to aldosterone and their influence on salt and water balances. Physiology The name mineralocorticoid derives from early observations that these hormones were involved in the retention of sodium, a mineral. The primary endogenous mineralocorticoid is aldosterone, although a number of other endogenous hormones (including progesterone and deoxycorticosterone) have mineralocorticoid function.

Aldosterone acts on the kidneys to provide active reabsorption of sodium and an associated passive reabsorption of water, as well as the active secretion of potassium in the principal cells of the cortical collecting tubule and active secretion of protons via proton ATPases in the lumenal membrane of the intercalated cells of the collecting tubule. This in turn results in an increase of blood pressure and blood volume. Aldosterone is produced in the cortex of the adrenal gland and its secretion is mediated principally by angiotensin II but also by adrenocorticotrophic hormone (ACTH) and local potassium levels.

Mode of action The effects of mineralocorticoids are mediated by slow genomic mechanisms through nuclear receptors as well as by fast nongenomic mechanisms through membrane-associated receptors and signaling cascades. Genomic mechanisms Mineralocorticoids bind to the cytosolic mineralocorticoid receptor. This type of receptor gets activated upon ligand binding. After a hormone binds to the corresponding receptor, the newly formed receptor-ligand complex test itself into the cell nucleus, where it binds to many hormone response elements (HRE) in the promoter region of the target genes in the DNA.

The opposite mechanism is called transrepression. The hormone receptor without ligand binding interacts with heat shock proteins and prevents the transcription of targeted genes. Aldosterone and cortisol (a glucosteroid) have similar affinity for the mineralocorticoid receptor; however, glucocorticoids circulate at roughly 100 times the level of mineralocorticoids. An enzyme exists in mineralocorticoid target tissues to prevent overstimulation by glucocorticoids. This enzyme, 11-beta hydroxysteroid dehydrogenase type II (Protein:HSD11B2), catalyzes the deactivation of glucocorticoids to 11-dehydro metabolites.

Licorice is known to be an inhibitor of this enzyme and chronic consumption can result in a condition known as pseudohyperaldosteronism. 18 hydroxy 11 deoxycorticosterone (also designated 18OH-DOC) is a steroid hormone probably used to conserve sodium and stimulate hydrogen ion (or acid) excretion. 18OH-DOC lowers urine pH but has no affect on potassium excretion. [1] This would seem to indicate that 18OH-DOC’s primary purpose is to stimulate hydrogen ion or ammonium excretion. Under low sodium intake 18 OH DOC is increased in serum. 2] There is a marked increase in serum 18OH DOC after injection of insulin[3] and this may be due to the hypokalemic (low serum potassium) tendency after a rise in insulin[4] which in turn would make the serum more acidic. Since 18OH-DOC lowers urine pH (increases acidity) but has no affect on potassium excretion, this would seem to indicate that 18OH-DOC’s primary purpose is to stimulate hydrogen ion or ammonium excretion. Its use by the body to conserve potassium would be indirect by virtue of hydrogen ion’s interference with potassium excretion. 5] This interference is further indicated because injecting sodium bicarbonate or even hyperventilating (breathing rapidly beyond need) can triple potassium excretion. [6] The daily rhythm for potassium and hydrogen ion excretion show a rather close inverse relationship,[7] which gives additional circumstantial support to the supposition that they compete at a common site. 18OH-DOC is strongly dependent on the potassium cell or plasma content, because in potassium deficient rats markedly less 18OH-DOC is converted to 18OH-corticosterone and less yet if sodium is deficient. 8] ACTH (a peptide hormone) has a large affect on 18OH DOC, causing 18OH DOC to go down to zero when ACTH does. [9] This could be for the primary purpose of keeping serum immune enzymes and cell fluids at a high pH (alkaline) during internal infection, but not doing so during the intestinal infection of diarrhea, during which disease the resulting dehydration forces ACTH to decline. [10] It probably is important normally to keep the vacuoles where pathogens are digested at a high pH because if the pH or alkalinity is not high enough, the pathogens inside the immune cells are not digested [11] and thus released intact.

So when an intestinal disease is not calling for ACTH to decline, the indirect potassium conserving attribute of 18OH-DOC by virtue of stimulating acid excretion would be valuable, as would increased acid excretion during internal disease. 18OH DOC may act primarily by blocking aldosterone’s effect on potassium, and must have aldosterone to assist it with sodium. Nichols, et al. , have been able to show that injection of 18OH-DOC, which raised blood levels of this hormone ten times, were more retentive of sodium than a similar amount of aldosterone. So there must be a synergism involved.

At the same time, the ratio of sodium to potassium excretion declined very little for 18OH-DOC, while for aldosterone, the ratio fell to as little as 1/3 that of control men. [12] This implies a considerable sparing of potassium by 18OH-DOC. Urine potassium excretion is not altered by 18OH-DOC injection. [12] Angiotensin II has very little effect on 18OH-DOC and is ambiguous (nor does serum potassium above 4. 8 mEq/liter (187 mg)). [13] This last is not surprising since 18OH-DOC should not be used by the body at high serum potassium. Under low sodium intake, 18OH-DOC rises in the serum. 2] ACTH causes a marked increase in 18OH-DOC,[14] probably by a generalized affect on the zona fasciculata of the adrenal cortex where 18OH-DOC is synthesized. So when it is necessary for sodium to be unloaded during the dehydration induced decline of ACTH [10] during diarrhea in order to preserve osmotic pressure, the resulting 18OH-DOC decline would assist in this. 18OH-DOC is deeply involved in one of the three forms (at least) of hypertension (high blood pressure). [15] Pathophysiology Hyperaldosteronism (the syndrome caused by elevated aldosterone) generally results from adrenal cancers.

The two main resulting problems: 1. Hypertension and edema due to excessive Na+ and water retention. 2. Accelerated excretion of potassium ions (K+). With extreme K+ loss there is muscle weakness and eventually paralysis. Underproduction, or hypoaldosteronism, leads to the salt-wasting state associated with Addison’s disease, although classical congenital adrenal hyperplasia and other disease states may also cause this situation. Pharmacology An example of a synthetic mineralocorticoid is fludrocortisone (Florinef). Important mineralocorticoid inhibitors are spironolactone and eplerenone. Glucocorticoid

Glucocorticoids (GC) are a class of steroid hormones that bind to the glucocorticoid receptor (GR), which is present in almost every vertebrate animal cell. The name glucocorticoid (glucose + cortex + steroid) derives from their role in the regulation of the metabolism of glucose, their synthesis in the adrenal cortex, and their steroidal structure (see structure to the right). GCs are part of the feedback mechanism in the immune system that turns immune activity (inflammation) down. They are therefore used in medicine to treat diseases that are caused by an overactive immune system, such as allergies, asthma, autoimmune diseases and sepsis.

GCs have many diverse (pleiotropic) effects, including potentially harmful side effects. [1] They also interfere with some of the abnormal mechanisms in cancer cells, so they are used in high doses to treat cancer. GCs cause their effects by binding to the glucocorticoid receptor (GR). The activated GR complex in turn up-regulates the expression of anti-inflammatory proteins in the nucleus (a process known as transactivation) and represses the expression of pro-inflammatory proteins in the cytosol by preventing the translocation of other transcription factors from the cytosol into the nucleus (transrepression). 1] Glucocorticoids are distinguished from mineralocorticoids and sex steroids by their specific receptors, target cells, and effects. In technical terms, corticosteroid refers to both glucocorticoids and mineralocorticoids (as both are mimics of hormones produced by the adrenal cortex), but is often used as a synonym for glucocorticoid. Cortisol (or hydrocortisone) is the most important human glucocorticoid. It is essential for life, and it regulates or supports a variety of important cardiovascular, metabolic, immunologic, and homeostatic functions.

Glucocorticoid receptors are found in the cells of almost all vertebrate tissues. Various synthetic glucocorticoids are available; these are used either as replacement therapy in glucocorticoid deficiency or to suppress the immune system. Effects Glucocorticoid effects may be broadly classified into two major categories: immunological and metabolic. In addition, glucocorticoids play important roles in fetal development. Immune

As discussed in more detail below, glucocorticoids through interaction with the glucocorticoid receptor: * up-regulate the expression of anti-inflammatory proteins * down-regulate the expression of pro-inflammatory proteins Glucocorticoids are also shown to play a role in the development and homeostasis of T lymphocytes. This has been shown in the transgenic mice with either increased or decreased sensitivity of T cell lineage to glucocorticoids. [2] Metabolic The name “glucocorticoid” derives from early observations that these hormones were involved in glucose metabolism.

In the fasted state, cortisol stimulates several processes that collectively serve to increase and maintain normal concentrations of glucose in blood. Metabolic effects: * Stimulation of gluconeogenesis, particularly in the liver: This pathway results in the synthesis of glucose from non-hexose substrates such as amino acids and glycerol from triglyceride breakdown, and is particularly important in carnivores and certain herbivores. Enhancing the expression of enzymes involved in gluconeogenesis is probably the best-known metabolic function of glucocorticoids. Mobilization of amino acids from extrahepatic tissues: These serve as substrates for gluconeogenesis. * Inhibition of glucose uptake in muscle and adipose tissue: A mechanism to conserve glucose. * Stimulation of fat breakdown in adipose tissue: The fatty acids released by lipolysis are used for production of energy in tissues like muscle, and the released glycerol provide another substrate for gluconeogenesis. Excessive glucocorticoid levels resulting from administration as a drug or hyperadrenocorticism have effects on many systems.

Some examples include inhibition of bone formation, suppression of calcium absorption (both of which can lead to osteoporosis), delayed wound healing, muscle weakness, and increased risk of infection. These observations suggest a multitude of less-dramatic physiologic roles for glucocorticoids. [2] Developmental Glucocorticoids have multiple effects on fetal development. An important example is their role in promoting maturation of the lung and production of the surfactant necessary for extrauterine lung function.

Mice with homozygous disruptions in the corticotropin-releasing hormone gene (see below) die at birth due to pulmonary immaturity. In addition, they are necessary for normal brain development, by initiating terminal maturation, remodelling axons and dendrites, and affecting cell survival. [3] Arousal and cognition Glucocorticoids act on the hippocampus, amygdala, and frontal lobes. Along with adrenaline these enhance the formation of flashbulb memories of events associated with strong emotions both positive and negative.

This has been confirmed in studies whereby blockade of either glucocorticoids or noradrenaline activity impaired the recall of emotionally relevant information. Additional sources have shown that subjects whose fear learning was accompanied by high cortisol levels had better consolidation of this memory (this effect was more important in men). They have also been shown to have a significant impact on vigilance and cognitive performance. This appears to follow the Yerkes-Dodson Curve as studies have shown that circulating levels of glucocorticoids vs. emory performance follows an upside down U pattern, much like the Yerkes-Dodson curve. For example, long term potentiation (the process of forming long term memories) is optimal when glucocorticoid levels are mildly elevated whereas significant decreases of LTP are observed after adrenalectomy (low GC state) or after exogenous glucocorticoid administration (high GC state). It has also been shown that elevated levels of glucocorticoids enhanced memory for emotionally arousing events but lead more often than not to poor memory for material unrelated to the source of stress/emotional arousal. 4] Mechanism of action Transactivation Glucocorticoids bind to the cytosolic glucocorticoid receptor (GR). This type of receptor is activated by ligand binding. After a hormone binds to the corresponding receptor, the newly-formed receptor-ligand complex translocates itself into the cell nucleus, where it binds to glucocorticoid response elements (GRE) in the promoter region of the target genes resulting in the regulation of gene expression. This process is commonly referred to as transactivation. 5] The proteins encoded by these upregulated genes have a wide range of effects including for example:[5] * anti-inflammatory – lipocortin I and p11/calpactin binding protein * increased gluconeogenesis – glucose-6-phosphatase and tyrosine aminotransferase Transrepression The opposite mechanism is called transrepression. The activated hormone receptor interacts with specific transcription factors (such as AP-1 and NF-? B) and prevents the transcription of targeted genes.

Glucocorticoids are able to prevent the transcription of pro-inflammatory genes, including interleukins IL-1B, IL-4, IL-5, and IL-8, chemokines, cytokines, GM-CSF, and TNFA genes. [5] Dissociation The ordinary glucocorticoids do not distinguish among transactivation and transrepression and influence both the “wanted” immune and “unwanted” genes regulating the metabolic and cardiovascular functions. Intensive research is aimed at discovering selectively acting glucocorticoids that will be able to repress only the immune system. 6][7] Genetically modified mice which express a modified GR which is incapable of DNA binding are still responsive to the antiinflammatory effects of glucocorticoids while the stimulation of gluconeogenesis by glucocorticoids is blocked. [8] This result strongly suggests that most of the desirable antiinflammatory effects are due to transrepression while the undesirable metabolic effects arise from transactivation, a hypothesis also underlying the development of selective glucocorticoid receptor agonists.

Non-genomic Glucocorticoids have been shown to exert a number of rapid actions that are independent of the regulations of gene transcription. Binding of corticosteroids to the glucocorticoid receptor (GR) stimulates phosphatidylinositol 3-kinase and protein kinase AKT, leading to endothelial nitric oxide synthase (eNOS) activation and nitric oxide dependent vasorelaxation. [9] Membrane associated GR has been shown to mediate lymphocytolysis. 10][11][12] Finally some glucocorticoids have been shown to rapidly inhibit the release of the inflammatory prostaglandin PGE2 and this effect is blocked by the glucocorticoid receptor antagonist RU-486 and this effect is not affected by protein synthesis inhibitors. This data together suggests a non-genomic mechanism of action. [13] Pharmacology A variety of synthetic glucocorticoids, some far more potent than cortisol, have been created for therapeutic use.

They differ in the pharmacokinetics (absorption factor, half-life, volume of distribution, clearance) and in pharmacodynamics (for example the capacity of mineralocorticoid activity: retention of sodium (Na+) and water; see also: renal physiology). Because they permeate the intestines easily, they are primarily administered per os (by mouth), but also by other methods, such as topically on skin. More than 90 percent of them bind different plasma proteins, however with a different binding specificity.

Endogenous glucocorticoids and some synthetic corticoids have high affinity to the protein transcortin (also called CBG, corticosteroid-binding globulin), whereas all of them bind albumin. In the liver, they quickly metabolise by conjugation with a sulfate or glucuronic acid, and are secreted in the urine. Glucocorticoid potency, duration of effect, and overlapping mineralocorticoid potency varies. Cortisol (hydrocortisone) is the standard of comparison for glucocorticoid potency. Hydrocortisone is the name used for pharmaceutical preparations of cortisol.

Data refer to oral dosing, except when mentioned. Oral potency may be less than parenteral potency because significant amounts (up to 50% in some cases) may not be absorbed from the intestine. Fludrocortisone, DOCA (Deoxycorticosterone acetate), and aldosterone are, by definition, not considered glucocorticoids, although they may have minor glucocorticoid potency, and are included in this table to provide perspective on mineralocorticoid potency. Comparative steroid potencies [14] [15]|

Name| Glucocorticoid potency| Mineralocorticoid potency| Duration of action (t1/2 in hours)| Hydrocortisone (Cortisol)| 1| 1| 8| Cortisone acetate| 0. 8| 0. 8| oral 8, intramuscular 18+| Prednisone| 3. 5-5| 0. 8| 16-36| Prednisolone| 4| 0. 8| 16-36| Methylprednisolone| 5-7. 5| 0. 5| 18-40| Dexamethasone| 25-80| 0| 36-54| Betamethasone| 25-30| 0| 36-54| Triamcinolone| 5| 0| 12-36| Beclometasone| 8 puffs 4 times a day equals 14 mg oral prednisone once a day| -| -| Fludrocortisone acetate| 15| 200| 24| Deoxycorticosterone acetate (DOCA)| 0| 20| -| Aldosterone| 0. | 200-1000| -| Therapeutic use Glucocorticoids may be used in low doses in adrenal insufficiency. In much higher doses, oral or inhaled glucocorticoids are used to suppress various allergic, inflammatory, and autoimmune disorders. Inhaled glucocorticoids are the second-line treatment for Asthma. They are also administered as posttransplantory immunosuppressants to prevent the acute transplant rejection and the graft-versus-host disease. Nevertheless, they do not prevent an infection and also inhibit later reparative processes. Physiological replacement

Any glucocorticoid can be given in a dose that provides approximately the same glucocorticoid effects as normal cortisol production; this is referred to as physiologic, replacement, or maintenance dosing. This is approximately 6-12 mg/m? /day (m? refers to body surface area (BSA), and is a measure of body size; an average man is 1. 7 m? ). Immunosuppression Glucocorticoids suppress the cell-mediated immunity. They act by inhibiting genes that code for the cytokines IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-8 and IFN-? , the most important of which is IL-2.

Smaller cytokine production reduces the T cell proliferation. [16] Glucocorticoids do, however, not only reduce T cell proliferation, but also lead to another well known effect called glucocorticoid induced apoptosis. The effect is more prominent in immature T cells that still reside in the thymus, but also affect peripheral T cells. The exact mechanism underlying this glucocorticoid sensitivity still remains to be elucidated. [citation needed] Glucocorticoids also suppress the humoral immunity, causing B cells to express smaller amounts of IL-2 and of IL-2 receptors.

This diminishes both B cell clone expansion and antibody synthesis. The diminished amounts of IL-2 also causes fewer T lymphocyte cells to be activated. Since glucocorticoid is a steroid, it regulates transcription factors; another factor it down-regulates is the expression of Fc receptors on macrophages, so there is a decreased phagocytosis of opsonised cells. [citation needed] Anti-inflammatory Glucocorticoids are potent anti-inflammatories, regardless of the inflammation’s cause. Glucocorticoids’ primary anti-inflammatory mechanism is lipocortin-1 (annexin-1) synthesis.

Lipocortin-1 both suppresses phospholipase A2, thereby blocking eicosanoid production, and inhibits various leukocyte inflammatory events (epithelial adhesion, emigration, chemotaxis, phagocytosis, respiratory burst, etc… ). In other words, Glucocorticoids not only suppress immune response, but also inhibit the two main products of inflammation, prostaglandins and leukotrienes. In addition, glucocorticoids also suppress cyclooxygenase (both COX-1 and COX-2) expression much like NSAIDs, potentiating the anti-inflammatory effect.

Glucocorticoids marketed as anti-inflammatories are often topical formulations, such as nasal sprays for rhinitis or inhalers for asthma. These preparations have the advantage of only affecting the targeted area, thereby reducing side effects or potential interactions. In this case, the main compounds used are beclometasone, budesonide, fluticasone, mometasone and ciclesonide. In rhinitis, sprays are used. For asthma, glucocorticoids are administered as inhalants with a metered-dose or dry powder inhaler. [17] Hyperaldosteronism

Glucocorticoids can be used in the management of familial hyperaldosteronism type 1. They are not effective however, for use in the type 2 condition. Resistance Resistance to the therapeutic uses of glucocorticoids can present difficulty; for instance, 25% of cases of severe asthma may be unresponsive to steroids. This may be the result of genetic predisposition, ongoing exposure to the cause of the inflammation (such as allergens), immunological phenomena that bypass glucocorticoids, and pharmacokinetic disturbances (incomplete absorption or accelerated excretion or metabolism). 16] Side-effects Glucocorticoid drugs currently being used act nonselectively, so in the long run they may impair many healthy anabolic processes. To prevent this, much research has been focused recently on the elaboration of selectively-acting glucocorticoid drugs. These are the side-effects that could be prevented: * immunosuppression * hyperglycemia due to increased gluconeogenesis, insulin resistance, and impaired glucose tolerance (“steroid diabetes”); caution in those with diabetes mellitus * increased skin fragility, easy bruising negative calcium balance due to reduced intestinal calcium absorption[18] * Steroid-induced osteoporosis: reduced bone density (osteoporosis, osteonecrosis, higher fracture risk, slower fracture repair) * weight gain due to increased visceral and truncal fat deposition (central obesity) and appetite stimulation * adrenal insufficiency (if used for long time and stopped suddenly without a taper) * muscle breakdown (proteolysis), weakness; reduced muscle mass and repair * expansion of malar fat pads and dilation of small blood vessels in skin * anovulation, irregularity of menstrual periods growth failure, pubertal delay * increased plasma amino acids, increased urea formation; negative nitrogen balance * excitatory effect on central nervous system (euphoria, psychosis) * glaucoma due to increased cranial pressure * cataracts In high doses, hydrocortisone (cortisol) and those glucocorticoids with appreciable mineralocorticoid potency can exert a mineralocorticoid effect as well, although in physiologic doses this is prevented by rapid degradation of cortisol by 11? -hydroxysteroid dehydrogenase isoenzyme 2 (11? -HSD2) in mineralocorticoid target tissues.

Mineralocorticoid effects can include salt and water retention, extracellular fluid volume expansion, hypertension, potassium depletion, and metabolic alkalosis. The combination of clinical problems produced by prolonged, excess glucocorticoids, whether synthetic or endogenous, is termed Cushing’s syndrome. Withdrawal In addition to the effects listed above, use of high-dose steroids for more than a week begins to produce suppression of the patient’s adrenal glands because the exogenous glucocorticoids suppress hypothalamic corticotropin-releasing hormone (CRH) and pituitary adrenocorticotropic hormone (ACTH).

With prolonged suppression, the adrenal glands atrophy (physically shrink), and can take months to recover full function after discontinuation of the exogenous glucocorticoid. During this recovery time, the patient is vulnerable to adrenal insufficiency during times of stress, such as illness. While there is wide individual variation in suppressive dose and time for adrenal recovery, clinical guidelines have been devised to estimate potential adrenal suppression and recovery, to reduce risk to the patient.

The following is one example, but many variations exist or may be appropriate in individual circumstances. [citation needed] * If a patient has been receiving daily high doses for 5 days or less, they can be abruptly stopped (or reduced to physiologic replacement if patient is adrenal-deficient). Full adrenal recovery can be assumed to occur by a week afterward. * If high doses were used for 6-10 days, reduce to replacement dose immediately and taper over 4 more days. Adrenal recovery can be assumed to occur within 2-4 weeks of completion of steroids. If high doses were used for 11-30 days, cut immediately to twice replacement, and then by 25% every 4 days. Stop entirely when dose is less than half of replacement. Full adrenal recovery should occur within 1-3 months of completion of withdrawal. * If high doses were used more than 30 days, cut dose immediately to twice replacement, and reduce by 25% each week until replacement is reached. * Then change to oral hydrocortisone or cortisone as a single morning dose, and gradually decrease by 2.  mg each week. When a. m. dose is less than replacement, the return of normal basal adrenal function may be documented by checking 0800 cortisol levels prior to the morning dose; stop drugs when 0800 cortisol is 10 ? g/dl. It is difficult to predict the time to full adrenal recovery after prolonged suppressive exogenous steroids; some people may take nearly a year. * Flare-up of the underlying condition for which steroids are given may require a more gradual taper than outlined above. Androgen

Androgen, also called androgenic hormones or testoids, is the generic term for any natural or synthetic compound, usually a steroid hormone, that stimulates or controls the development and maintenance of male characteristics in vertebrates by binding to androgen receptors. This includes the activity of the accessory male sex organs and development of male secondary sex characteristics. Androgens were first discovered in 1936. Androgens are also the original anabolic steroids and the precursor of all estrogens, the female sex hormones.

The primary and most well-known androgen is testosterone. Androgen ablation can be used as an effective therapy in prostate cancer. Types A subset of androgens, adrenal androgens, includes any of the 19-carbon steroids synthesized by the adrenal cortex, the outer portion of the adrenal gland (zonula reticularis—innermost region of the adrenal cortex), that function as weak steroids or steroid precursors, including dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEA-S), and androstenedione. Besides testosterone, other androgens include: Dehydroepiandrosterone (DHEA): a steroid hormone produced in the adrenal cortex from cholesterol. It is the primary precursor of natural estrogens. DHEA is also called dehydroisoandrosterone or dehydroandrosterone. * Androstenedione (Andro): an androgenic steroid produced by the testes, adrenal cortex, and ovaries. While androstenediones are converted metabolically to testosterone and other androgens, they are also the parent structure of estrone. Use of androstenedione as an athletic or body building supplement has been banned by the International Olympic Committee as well as other sporting organizations. Androstenediol: the steroid metabolite that is thought to act as the main regulator of gonadotropin secretion. * Androsterone: a chemical by-product created during the breakdown of androgens, or derived from progesterone, that also exerts minor masculinising effects, but with one-seventh the intensity of testosterone. It is found in approximately equal amounts in the plasma and urine of both males and females. * Dihydrotestosterone (DHT): a metabolite of testosterone, and a more potent androgen than testosterone in that it binds more strongly to androgen receptors. It is produced in the adrenal cortex.

Androgen functions Development of the male Testes formation During mammalian development, the gonads are at first capable of becoming either ovaries or testes. [1] In humans, starting at about week 4 the gonadal rudiments are present within the intermediate mesoderm adjacent to the developing kidneys. At about week 6, epithelial sex cords develop within the forming testes and incorporate the germ cells as they migrate into the gonads. In males, certain Y chromosome genes, particularly SRY, control development of the male phenotype, including conversion of the early bipotential gonad into testes.

In males, the sex cords fully invade the developing gonads. Androgen production The mesoderm-derived epithelial cells of the sex cords in developing testes become the Sertoli cells which will function to support sperm cell formation. A minor population of non-epithelial cells appear between the tubules by week 8 of human fetal development. These are Leydig cells. Soon after they differentiate, Leydig cells begin to produce androgens. Androgen effects The androgens function as paracrine hormones required by the Sertoli cells in order to support sperm production.

They are also required for masculinization of the developing male fetus (including penis and scrotum formation). Under the influence of androgens, remnants of the mesonephron, the Wolffian ducts, develop into the epididymis, vas deferens and seminal vesicles. This action of androgens is supported by a hormone from Sertoli cells,MIH (Mullerian Inhibitory Hormone), which prevents the embryonic Mullerian ducts from developing into fallopian tubes and other female reproductive tract tissues in male embryos. MIH and androgens cooperate to allow for the normal movement of testes into the scrotum. Early regulation

Before the production of the pituitary hormone LH by the embryo starting at about weeks 11–12, human chorionic gonadotrophin (hCG) promotes the differentiation of Leydig cells and their production of androgens. Androgen action in target tissues often involves conversion of testosterone to 5? -dihydrotestosterone (DHT). Spermatogenesis During puberty, androgen, LH and FSH production increase and the sex cords hollow out, forming the seminiferous tubules, and the germ cells start to differentiate into sperm. Throughout adulthood, androgens and FSH cooperatively act on Sertoli cells in the testes to support sperm production. 2] Exogenous androgen supplements can be used as a male contraceptive. Elevated androgen levels caused by use of androgen supplements can inhibit production of LH and block production of endogenous androgens by Leydig cells. Without the locally high levels of androgens in testes due to androgen production by Leydig cells, the seminiferous tubules can degenerate resulting in infertility. For this reason, many transdermal androgen patches are applied to the scrotum. Inhibition of fat deposition Males typically have less adipose tissue than females.

Recent results indicate that androgens inhibit the ability of some fat cells to store lipids by blocking a signal transduction pathway that normally supports adipocyte function. [3] Also, androgens, but not estrogens, increase beta adrenergic receptors while decreasing alpha adrenergic receptors- which results in increased levels of epinephrine/ norepinephrine due to lack of alpha-2 receptor negative feedback and decreased fat accumulation due to epinephrine/ norepinephrine then acting on lipolysis-inducing beta receptors. Muscle mass Males typically have more skeletal muscle mass than females.

Androgens promote the enlargement of skeletal muscle cells and probably act in a coordinated manner to function by acting on several cell types in skeletal muscle tissue. [4] One type of cell that conveys hormone signals to generating muscle is the myoblast. Higher androgen levels lead to increased expression of androgen receptor. Fusion of myoblasts generates myotubes, in a process that is linked to androgen receptor levels. [5] Brain Circulating levels of androgens can influence human behavior because some neurons are sensitive to steroid hormones. Androgen levels have been implicated in the regulation of human aggression[6] and libido.

Indeed, androgens are capable of altering the structure of the brain in several species, including mice, rats, and primates, producing sex differences. [7] Although, their potential for conversion makes identifying which alterations in neuroanatomy stem from androgens or estrogens slightly difficult, numerous reports have outlined that androgens alone are capable of altering the structure of the brain. [8] Insensitivity to androgen in humans Reduced ability of a XY karyotype fetus to respond to androgens can result in one of several conditions, including infertility and several forms of intersex conditions.

Pathology * Adrenal insufficiency (e. g. due to Addison’s disease) * Cushing’s syndrome * Conn’s syndrome Adrenal insufficiency Adrenal insufficiency is a condition in which the adrenal glands, located above the kidneys, do not produce adequate amounts of steroid hormones (chemicals produced by the body that regulate organ function), primarily cortisol, but may also include impaired aldosterone production (a mineralcorticoid) which regulates sodium, potassium and water retention. [1][2] Craving for salt or salty foods due to the urinary losses of sodium is common. [3] Addison’s disease is the worst degree of adrenal nsufficiency, which if not treated, results in severe abdominal pains, diarrhea, vomiting, profound muscle weakness and fatigue, depression, extremely low blood pressure, weight loss, kidney failure, changes in mood and personality and shock may occur (adrenal crisis). [4] An adrenal crisis often occurs if the body is subjected to stress, such as an accident, injury, surgery, or severe infection; death may quickly follow. [4] Adrenal insufficiency can also occur when the hypothalamus or the pituitary gland, both located at the base of the skull, doesn’t make adequate amounts of the hormones that assist in regulating adrenal function. 1][5][6] This is called secondary adrenal insufficiency and is caused by lack of production of ACTH in the pituitary or lack of CRH in the hypothalamus. [7] Types There are two major types of adrenal insufficiency. * Primary adrenal insufficiency is due to impairment of the adrenal glands. * The most common subtype is called idiopathic or unknown cause of adrenal insufficiency. * Some are due to an autoimmune disease called Addison’s disease or autoimmune adrenalitis. * Other cases are due to congenital adrenal hyperplasia or an adenoma (tumor) of the adrenal gland. Secondary adrenal insufficiency is caused by impairment of the pituitary gland or hypothalamus. [8] These can be due to a form of cancer: a pituitary microadenoma, or a hypothalamic tumor; Sheehan’s syndrome, which is associated with impairment of only the pituitary gland; or a past head injury. Causes * Autoimmune (may be part of Type 2 autoimmune polyglandular syndrome, which can include type I Diabetes Mellitus), hyperthyroidism, autoimmune thyroid disease (also known as autoimmune thyroiditis, Hashimoto’s thyroiditis and Hashimoto’s disease)[9].

Hypogonadism and pernicious anemia may also present with this syndrome. * Adrenoleukodystrophy[10] * Discontinuing corticosteroid therapy without tapering the dosage (severe adrenal suppression with ACTH suppression) * Illness or any other forms of stress (this is termed critical illness–related corticosteroid insufficiency) * kidney injury * environmental * genetics * Head injury * Radiation * Surgery * infections (eg, miliary tuberculosis affecting the adrenal glands, meningitis, histoplasmosis) * congenital hypopituitarism * congential hypoadrenalism chronic opioid use[11][12] Symptoms The person may show symptoms of hypoglycemia, dehydration, weight loss and disorientation. They may experience weakness, tiredness, dizziness, low blood pressure that falls further when standing (orthostatic hypotension), muscle aches, nausea, vomiting, and diarrhea. These problems may develop gradually and insidiously. Addison’s can present with tanning of the skin which may be patchy or even all over the body. In some cases a person with normally light skin may be mistaken for another race with darker pigmentation.

Characteristic sites of tanning are skin creases (e. g. of the hands) and the inside of the cheek (buccal mucosa). Goitre and vitiligo may also be present. [4] Diagnosis If the person is in adrenal crisis, the ACTH stimulation test may be given. If not in crisis, cortisol, ACTH, aldosterone, renin, potassium and sodium are tested from a blood sample before the decision is made if the ACTH stimulation test needs to be performed. X-rays or CT of the adrenals may also be done. 1] The best test for adrenal insufficiency of autoimmune origin, representing more than 90% of all cases in a Western population, is measurement of 21-hydroxylase autoantibodies. [13] Treatment * Adrenal crisis * Intravenous fluids[4] * Intravenous steroid (Solu-Cortef or Solumedrol), later hydrocortisone, prednisone or methylpredisolone tablets[4] * Rest * Cortisol deficiency (primary and secondary) * Adrenal cortical extract (usually in the form of a supplement, non prescription in the United States) * Hydrocortisone (Cortef) (between 20 and 35 mg)[4] Prednisone (Deltasone) (7 1/2 mg) * Prednisolone (Delta-Cortef) (7 1/2 mg) * Methylprednisolone (Medrol) (6 mg) * Dexamethasone (Decadron) (1/4 mg, some doctors[who? ] prescribe 1/2 to 1 mg, but those doses tend to cause side effects resembling Cushing’s disease[citation needed]) * Mineralcorticoid deficiency (low aldosterone) * Fludrocortisone (Florinef) (To balance sodium, potassium and increase water retention)[4] Simple diagnostic chart Source of pathology| CRH| ACTH| DHEA| DHEA-S| cortisol| aldosterone| renin| Na| K| Causes5| ‘hypothalamus ‘tertiary)1| low| low| low| low| low3| low| low| low| low| tumor of the hypothalamus (adenoma), antibodies, environment, head injury| pituitary (secondary)| high2| low| low| low| low3| low| low| low| low| tumor of the pituitary (adenoma), antibodies, environment, head injury, ‘surgical removal6, Sheehan’s syndrome| adrenal glands (primary)7| high| high| high| high| low4| low| high| low| high| tumor of the adrenal (adenoma), stress, antibodies, environment, Addison’s, injury, surgical removal, miliary tuberculosis of the adrenal| | Automatically includes diagnosis of secondary (hypopituitarism)| 2| Only if CRH production in the hypothalamus is intact| 3| Value doubles or more in stimulation| 4| Value less than doubles in stimulation| 5| Most common, doesn’t include all possible causes| 6| Usually because of very large tumor (macroadenoma)| 7| Includes Addison’s disease| Cushing’s syndrome From Wikipedia, the free encyclopedia Jump to: navigation, search Cushing’s syndrome (also called hyperadrenocorticism or hypercorticism) is a hormone (endocrine) disorder caused by high levels of cortisol (hypercortisolism) in the blood.

This can be caused by taking glucocorticoid drugs, or by tumors that produce cortisol or adrenocorticotropic hormone (ACTH). [1] Cushing’s disease refers to one specific cause, a tumor (adenoma) in the pituitary gland that produces large amounts of ACTH, which in turn elevates cortisol. It can usually be cured by surgery. It was described by Harvey Cushing in 1932. [2][3] Cushing’s syndrome is not confined to humans and is also a relatively common condition in domestic dogs and horses. Classification and etiology There are several possible causes of Cushing’s syndrome. Exogenous vs. ndogenous Hormones that come from outside the body are called exogenous; hormones that come from within the body are called endogenous. The most common is exogenous administration of glucocorticoids prescribed by a health care practitioner to treat other diseases (called iatrogenic Cushing’s syndrome). This can be an effect of steroid treatment of a variety of disorders such as asthma and rheumatoid arthritis, or in immunosuppression after an organ transplant. Administration of synthetic ACTH is also possible, but ACTH is less often prescribed due to cost and lesser utility.

Endogenous Cushing’s syndrome results from some derangement of the body’s own system of secreting cortisol. Normally, ACTH is released from the pituitary gland when necessary to stimulate the release of cortisol from the adrenal glands. * In pituitary Cushing’s, a benign pituitary adenoma secretes ACTH. This is also known as Cushing’s disease and is responsible for 65% of endogenous Cushing’s syndrome. * In adrenal Cushing’s, excess cortisol is produced by adrenal gland tumors, hyperplastic adrenal glands, or adrenal glands with nodular adrenal hyperplasia. Finally, tumors outside the normal pituitary-adrenal system can produce ACTH that affects the adrenal glands. This final etiology is called ectopic or paraneoplastic Cushing’s syndrome and is seen in diseases like small cell lung cancer. Signs and symptoms In humans Symptoms include rapid weight gain, particularly of the trunk and face with sparing of the limbs (central obesity). A common sign is the growth of fat pads along the collar bone and on the back of the neck (buffalo hump) and a round face often referred to as a “moon face”.

Other symptoms include hyperhidrosis (excess sweating), telangiectasia (dilation of capillaries), thinning of the skin (which causes easy bruising and dryness, particularly the hands) and other mucous membranes, purple or red striae (the weight gain in Cushing’s syndrome stretches the skin, which is thin and weakened, causing it to hemorrhage) on the trunk, buttocks, arms, legs or breasts, proximal muscle weakness (hips, shoulders), and hirsutism (facial male-pattern hair growth), baldness and/or cause hair to become extremely dry and brittle. In rare cases, Cushing’s can cause hypercalcemia, which can lead to skin necrosis.

The excess cortisol may also affect other endocrine systems and cause, for example, insomnia, inhibited aromatase, reduced libido, impotence, amenorrhoea/oligomenorrhea and infertility due to elevations in androgens. Patients frequently suffer various psychological disturbances, ranging from euphoria to psychosis. Depression and anxiety are also common. [4] Other striking and distressing skin changes that may appear in Cushing’s syndrome include facial acne, susceptibility to superficial dermatophyte and malassezia infections, and the characteristic purplish, atrophic striae on the abdomen. 5]:500 Other signs include polyuria (and accompanying polydipsia), persistent hypertension (due to cortisol’s enhancement of epinephrine’s vasoconstrictive effect) and insulin resistance (especially common in ectopic ACTH production), leading to hyperglycemia (high blood sugar) which can lead to diabetes mellitus. Untreated Cushing’s syndrome can lead to heart disease and increased mortality. Cushing’s syndrome due to excess ACTH may also result in hyperpigmentation, such as acanthosis nigricans in the axilla.

This is due to Melanocyte-Stimulating Hormone production as a byproduct of ACTH synthesis from Pro-opiomelanocortin (POMC). Cortisol can also exhibit mineralcorticoid activity in high concentrations, worsening the hypertension and leading to hypokalemia (common in ectopic ACTH secretion). Furthermore, gastrointestinal disturbances, opportunistic infections and impaired wound healing (cortisol is a stress hormone, so it depresses the immune and inflammatory responses). Osteoporosis is also an issue in Cushing’s syndrome since, as mentioned before, cortisol evokes a stress-like response.

Consequently, the body’s maintenance of bone (and other tissues) becomes secondary to maintenance of the false stress response. Additionally, Cushing’s may cause sore and aching joints, particularly in the hip, shoulders, and lower back. Diagnosis When Cushing’s syndrome is suspected, either a dexamethasone suppression test (administration of dexamethasone and frequent determination of cortisol and ACTH level), or a 24-hour urinary measurement for cortisol offer equal detection rates. 6] Dexamethasone is a glucocorticoid and simulates the effects of cortisol, including negative feedback on the pituitary gland. When dexamethasone is administered and a blood sample is tested, high cortisol would be indicative of Cushing’s syndrome because there is an ectopic source of cortisol or ACTH (eg: adrenal adenoma) that is not inhibited by the dexamethasone. A novel approach, recently cleared by the US FDA, is sampling cortisol in saliva over 24 hours, which may be equally sensitive, as late night levels of salivary cortisol are high in Cushingoid patients.

Other pituitary hormone levels may need to be ascertained. Performing a physical examination to determine any visual field defect may be necessary if a pituitary lesion is suspected, which may compress the optic chiasm causing typical bitemporal hemianopia. When any of these tests are positive, CT scanning of the adrenal gland and MRI of the pituitary gland are performed to detect the presence of any adrenal or pituitary adenomas or incidentalomas (the incidental discovery of harmless lesions). Scintigraphy of the adrenal gland with iodocholesterol scan is occasionally necessary.

Very rarely, determining the cortisol levels in various veins in the body by venous catheterization, working towards the pituitary (petrosal sinus sampling) is necessary. Pathophysiology The hypothalamus is in the brain and the pituitary gland sits just below it. The paraventricular nucleus (PVN) of the hypothalamus releases corticotropin-releasing hormone (CRH), which stimulates the pituitary gland to release adrenocorticotropin (ACTH). ACTH travels via the blood to the adrenal gland, where it stimulates the release of cortisol.

Cortisol is secreted by the cortex of the adrenal gland from a region called the zona fasciculata in response to ACTH. Elevated levels of cortisol exert negative feedback on the pituitary, which decreases the amount of ACTH released from the pituitary gland. Strictly, Cushing’s syndrome refers to excess cortisol of any etiology. One of the causes of Cushing’s syndrome is a cortisol secreting adenoma in the cortex of the adrenal gland. The adenoma causes cortisol levels in the blood to be very high, and negative feedback on the pituitary from the high cortisol levels causes ACTH levels to be very low.

Cushing’s disease refers only to hypercortisolism secondary to excess production of ACTH from a corticotrophic pituitary adenoma. This causes the blood ACTH levels to be elevated along with cortisol from the adrenal gland. The ACTH levels remain high because a tumor causes the pituitary to be unresponsive to negative feedback from high cortisol levels. Cushing’s Syndrome was also the first autoimmune disease identified in humans. [7] Treatment Most Cushing’s syndrome cases are caused by steroid medications (iatrogenic).

Consequently, most patients are effectively treated by carefully tapering off (and eventually stopping) the medication that causes the symptoms. If an adrenal adenoma is identified it may be removed by surgery. An ACTH-secreting corticotrophic pituitary adenoma should be removed after diagnosis. Regardless of the adenoma’s location, most patients will require steroid replacement postoperatively at least in the interim as long-term suppression of pituitary ACTH and normal adrenal tissue does not recover immediately. Clearly, if both adrenals are removed, replacement with hydrocortisone or prednisolone is imperative.

In those patients not suitable for or unwilling to undergo surgery, several drugs have been found to inhibit cortisol synthesis (e. g. ketoconazole, metyrapone) but they are of limited efficacy. Removal of the adrenals in the absence of a known tumor is occasionally performed to eliminate the production of excess cortisol. In some occasions, this removes negative feedback from a previously occult pituitary adenoma, which starts growing rapidly and produces extreme levels of ACTH, leading to hyperpigmentation. This clinical situation is known as Nelson’s syndrome. 8] Epidemiology Iatrogenic Cushing’s syndrome (caused by treatment with corticosteroids) is the most common form of Cushing’s syndrome. The incidence of pituitary tumors may be relatively high, as much as one in five people,[9] but only a minute fraction are active and produce excessive hormones. Adults with the disease may also have symptoms of extreme weight gain, excess hair growth in women, high blood pressure, and skin problems. In addition, they may show: * muscle and bone weakness * moodiness, irritability, or depression * sleep disturbances * high blood sugar menstrual disorders in women and decreased fertility in men * baldness * hypercholesterolemia Primary aldosteronism Primary aldosteronism, also known as primary hyperaldosteronism, is characterized by the overproduction of the mineralocorticoid hormone aldosterone by the adrenal glands. [1] Aldosterone causes increase in sodium and water retention and potassium excretion in the kidneys, leading to arterial hypertension (high blood pressure). An increase in the production of mineralocorticoid from the adrenal gland is evident. It is the most common cause of secondary hypertension [2].

Primary hyperaldosteronism has many causes, including adrenal hyperplasia and adrenal carcinoma. [3] When it occurs due to a solitary aldosterone-secreting adrenal adenoma (a type of benign tumor), it is known as Conn’s syndrome. [4] In practice, however, the two terms are often used interchangeably, regardless of the underlying physiology. Causes The syndrome is due to: * bilateral idiopathic adrenal hyperplasia 70 % * unilateral idiopathic adrenal hyperplasia 20 % * aldosterone-secreting adrenal adenoma (benign tumor, ;lt; 5%) * rare forms, including disorders of the renin-angiotensin system Signs, symptoms and findings

Aldosterone enhances exchange of sodium for potassium in the kidney so increased aldosteronism will lead to hypernatremia and hypokalemia. Once the potassium has been significantly reduced by aldosterone, a sodium/hydrogen pump in the nephron becomes more active leading to increased excretion of hydrogen ions and further exacerbating the hypernatremia. The hydrogen ions that are exchanged for sodium are generated by carbonic anhydrase in the renal tubule epithelium causing increased production of bicarbonate. The increased bicarbonate and the excreted hydrogen combine to generate a metabolic alkalosis.

The high pH of the blood makes calcium less available to the tissues and causes symptoms of hypocalcemia (low calcium levels). The sodium retention leads to plasma volume expansion and elevated blood pressure. The increased blood pressure will lead to increased glomerular filtration rate and cause a decrease in renin release from the peritubular capillary epithelium in the kidney. If there is a primary hyperaldosteronism the decreased renin (and subsequent decreased angiotensin II) will not lead to a decrease in aldosterone levels (a very helpful clinical tool in diagnosis of primary hyperaldosteronism).

Aside from high blood pressure manifestations of muscle cramps (due to hyperexcitability of neurons secondary to hypocalcemia), muscle weakness (due to hypoexcitability of skeletal muscles secondary to hypokalemia), and headaches (due to hypokalemia or high blood pressure) may be seen. Secondary hyperaldosteronism is often related to decreased cardiac output which is associated with elevated renin levels. Diagnosis Measuring aldosterone alone is not considered adequate to diagnose primary hyperaldosteronism. Rather, both renin and aldosterone are measured, and the ratio is diagnostic. 5][6] Usually, renin levels are suppressed, leading to a very low renin-aldosterone ratio (;lt;0. 0005). This test is confounded by antihypertensive drugs, which have to be stopped up to 6 weeks. If plasma levels of renin and aldosterone suggest hyperaldosteronism, CT scanning can confirm the presence of an adrenal adenoma. If the clinical presentation primarily involves hypertension and elevated levels of catecholamines, CT or MRI scanning can confirm a tumor on the adrenal medulla, typically a pheochromocytoma. Hyperaldosteronism can be mimicked by Liddle syndrome, and by ingestion of licorice and other foods containing glycyrrhizin.

In one case report, hypertension and quadriparesis resulted from intoxication with a non-alcoholic pastis (an anise-flavored aperitif containing glycyrrhizinic acid). [7] Therapy The treatment for hyperaldosteronism depends on the underlying cause. In patients with a single benign tumor (adenoma), surgical removal (adrenalectomy) is curative. This is usually performed laparoscopically, through several very small incisions. For patients with hyperplasia of both glands, successful treatment is often achieved with spironolactone or eplerenone, drugs that block the effect of aldosterone.

In males, one common side effect of spironolactone drug therapy sometimes seen is gynecomastia. Gynecomastia usually does not occur with eplerenone drug therapy. In the absence of proper treatment, individuals with hyperaldosteronism often suffer from poorly controlled high blood pressure, which may be associated with increased rates of stroke, heart disease, and kidney failure. With appropriate treatment, the prognosis is excellent. [8] Eponym Conn’s syndrome is named after Jerome W. Conn (1907–1994), the American endocrinologist who first described the condition at the University of Michigan in 1955. [1]