Theadrennal Glands, Their Parts, and What Each Partsecretes

Over Secretion of Growth Hormone - Giantism (Gigantism): is a condition characterized by excessive growth and height above average, caused by over-production of growth hormone. It is a rare disorder resulting from increased levels of growth hormone before the fusion of the growth plate which usually occurs at some point after puberty. Characteristics include: 1- Their height is 8-9 feet(1 foot=30.5m); they are more than 2.5m tall. 2- Their extremities have normal proportions compared to their height. 3- The giants have hyperglycemia (GH increases glucose level in blood), 10% develops diabetes mellitus. Extra Note: Since Giantism causes hyperglycemia, the beta cells of the islets of Langerhans in the pancreas become hyperactive and thus they become prone to degeneration. Beta cells produce insulin, and diabetes is due to the pancreas not producing enough insulin, therefore, by the degeneration of beta cells, not enough insulin will be produced and diabetes mellites may develop. - If patients with Giantism remain without treatment, they will develop panhypopituitarism; that is because gigantism is usually caused by a tumor of the pituitary gland that grows until the gland is destroyed. - Gigantism should not be confused with Acromegaly, the adult form of the disorder, characterized by enlargement specifically in the extremities and face. Since Acromegaly occurs after puberty, i.e. after the fusion of the growth plate, it doesn’t cause excessive height. Characteristics include: 1- Enlargment marked in the small bones of the hands, feet, and in the membranous bones, including the cranium, nose, forehead, supraorbital ridge, the lower jaw bones, and portions of the vertebrae. 2- Many soft tissues or organs like the liver, tongue, and especially the kidneys become greatly enlarged.  Gigantism occurs when the growth hormone over-secretion occurs before puberty (adolescence), while in Acromegaly, over-secreion occurs after puberty. 2 Adrenal Glands - There are two adrenal glands (suprarenal glands), left and right. They lie in the superior pole of the two kidneys, their total weight is 6-10g. The blood supply of these glands comes directly from the aorta, which indicates the importance of these gland. - The adrenal glands have the greatest blood supply rates per gram of tissue compared to all other organs. If we remove both adrenal glands, the person does not survive, but one gland alone is sufficient. - The adrenal gland is composed of two major parts, these parts differ in their embryology, histology, and physiology: 1- The Adrenal medulla (20%): it the central part of the gland and is functionally related to the sympathetic nervous system. It secretes the hormones epinephrine and norepinephrine (catecholamines) in response to sympathetic stimulation. 2- The Adrenal cortex (80%): secretes an entirely different group of hormones called corticosteroids, these hormones are synthesised form steroid cholestrol. ‘our main topic’ - The adrenal cortex is composed of 3 zones, and each zone produces specific hormones: 1- Glomerulosa (12%): It produces several hormones collectively known as mineralocorticoids. The most potent hormone of these is aldosterone. From their name, these hormones only function on the metabolism of minerals. 2- Fasciculata (65%): This zone produces a group of hormones called glucocorticoids which function on glucose metabolism. The most potent glucocorticoid is cortisol. This zone also produces a small amount of androgens and estrogens. 3- Reticularis (23%): It mainly produces androgens and estrogens, but it also produces small amounts of cortisol. - The zona reticularis does not differentiate fully until the age of 6-8yrs. In the adult gland, the cells of the glomerulosa migrate down through the zona fasciculata to the zona Reticularis, changing their secretory pattern, shape, and function as they migrate. The functional significance of this migration is not yet clear. 3 Note 1: Mineralcorticoids (aldosteron ) secretion from zona glomerulosa is controlled by angiotensin II and potassium, while glucocrticoids (cortisol) secretion froma zona fasciculata and adrenal androgens secretion from zona reticularis are contolled by ACTH. Note 2: Notice that zona fasciculata which secrets cortisol account 65% of the adrenal cortex while zona glomerulosa which secretes aldosteron accounts for only 12%, for this reason cortisol secretion rate is much higher than aldosteron secretion rate. - The adrenal cortex hormones are essential for life because they: 1- Control Na+, k+ and H2O metabolism. 2- Control carbohydrate, fat and protein metabolism and mobilization for energy. 3- Participates in responses of stresses of various kinds. The Synthesis of the Adrenal Cortical Hormones - All the adrenal cortical hormones are steroids and are synthesized from cholesterol. They are synthesized in many steps; many enzymes are needed and then secreted by the cortex of the adrenal gland. Note: Steroid hormones are Adrenocortical hormones, sex hormones in both females and males and vitamin D. - The adrenal cortex produces steroids that regulates: 1- Na+ and k+ balance (Mineralocorticoids). 2- Glucose balance (glucocorticoids). 3- Small amounts of sex steroid hormones. 4 - Sometimes there is a problem in the last step of cortisol production which leads to increase in the level of corticosterone. - When the adrenal cortex hormones are produced, they are not stored in the gland, rather they are released immediately and this means that in any need of new hormones, i.e. new synthesis of these hormones is required because there are no hormones stored in the adrenal cortex. Cortisol - Cortisol is a steroid hormone, in the glucocorticoid class of hormones. It is produced mainly by the zona fasciculata of the adrenal cortex within the adrenal gland. - Being a steroid allows the Cortisol to act on all the systems of the body. The main Functions of cortisol are: 1- Production of glucose from noncarbohydrate sources. 2- Facilitates fat mobilization. 3- Increases the response of blood vessels to catecholamines. 4- Modulates CNS function. - The most important function of cortisol is that it facilitates the production of glucose from non-carbohydrate sources. This makes cortisol essential for life for humans and animals especially during fasting; it has a role in the defence against hypoglycaemia; meaning that humans and animals cannot fast in case of cortisol deficiency.  Hypoglycemia occurs because of the deficincy of cortisol, hypoglycemia is a kind of stress (danger). - Cortisol has a permisive interaction with glucagon in the process of glycogenolysis (the presence of one hormone is required in order for another hormone to exert its full effects), i.e. Cortisol facilitates the action of glucagon in glycogenolysis, this is similar to the permissive relation between adrenaline and thyroxin on the fat cell ‘recall sheet 2 page 5’. - Cortisol binds very well to the aldosteron receptors to produce mineralcorticoid activity. But there is an enzyme in the kidney that inactivates cortisol. In this case cortisol does not function effectively as mineralcorticoid. 5 - Cortisol is important even during fetal life. It is essential for the normal development of the fetus; it is involved in the production of surfactant from type II cells of the alveoli of the lung -a lack of which leads to the respiratory distress syndrome in newborn infants. - Cortisol is considered as a magical drug since it works on all body systems and is used in many diseases; from skin to cardiovascular diseases. However, it sometimes does not function in some people. If it finds the receptor it functions, if not it doesn't function. - People who have cortisol as drug they look obese because it retains minerals and increases apetite. - There are natural as well as synthetic glucocorticoids: 1- Cortisol: natural, very potent accounting for about 95% of all glucocorticoid activity. 2- Corticosterone: natural, provides about 4 per cent of total glucocorticoid activity but much less potent than cortisol. Any problem in the last step of the synthesis of cortisol causes increased levels of corticosterone. 3- Cortisone: synthetic, almost as potent as cortisol. 4- Methyl prednisone: synthetic, five times as potent as cortisol. 5- Dexamethasone: synthetic, 30 times as potent as cortisol. Adrenocorticotropic Hormone (ACTH) in Regulating Cortisol - Adrenocorticotropic hormone ACTH, an anterior pituitary hormone that stimulates the growth of the adrenal cortex and the synthesis and secretion of all its hormones. It’s main effects are increased production and release of cortisol by the cortex of the adrenal gland and it’s growth. - ACTH stimulates desmolase enzyme that converts cholesterol to pregnenolone thus increasing the synthesis of cortisol. Foetus ACTH synthesis and secretion begins just before the development of the adrenal cortex. - ACTH has extra-adrenal actions like: lipolysis and MSH-like action. 6 The hypothalamus-pituitary-adrenal axis (HPA axis): - HPA axis is a complex set of direct influences and feedback interactions among three components: the hypothalamus, the pituitary gland, and the adrenal glands. It has a major role in regulation cortisol secretion. Corticotropin releasing hormone (CRH) from the hypothalamus controls the secretion of ACTH. ACTH, from the anterior pituitary gland, stimulates cortisol secretion from the adrenal gland. - CRH and ADH are the main stimuli for ACTH secretion. ACTH secretion responds most strikingly to stressful stimuli of all types, a response that is critical for survival:  Pain stimuli caused by physical stress or tissue damage are transmitted first upward through the brain stem and eventually to the median eminence of the hypothalamus and then carried to the anterior pituitary gland where it induces ACTH secretion. The main effect of ACTH on the adrenocortical cells is to activate adenylyl cyclase in the cell membrane. This induces the formation of cAMP, which activates intracellular enzymes that causes the formation of adrenocortical hormones. One of the most important intracellular enzymes to be activated is the desmolase, which causes the conversion of cholesterol to pregnenolone raising the serum level of cortisol. This conversion is the rate-limiting step for all the adrenocortical hormones synthesis. Cortisol produced in the adrenal cortex will negatively feedback to inhibit both the hypothalamus and the pituitary gland if the pain persists, causing cortisol serum levels to fall below normal. 7 Rhythm of ACTH and cortisol throughout the day (Diurnal Rhythm): - Recall that the main target hormone of ACTH is cortisol, thus when ACTH level changes, cortisol level changes as well. - Cortisol is relatively high in the morning but low in the afternoon and early evening. - ACTH and cortisol are also related to the circadian rhythm (sleep-wake cycle) in many organisms, as well as having a pulsatile type of secretion. Mineralocorticoids - Mineralocorticoids are a class of corticosteroids, which in turn are a class of steroid hormones. Mineralocorticoids are produced by the adrenal cortex of the adrenal gland. The primary mineralocorticoid is aldosterone. - As for all adrenocortical hormones, mineralocorticoids are synthesized from cholesterol ‘page 4’. - Mineralocorticoids influence salt and water balances, they have gained this name because they affect the electrolytes (minerals) of the extracellular fluids (ECF), especially sodium and potassium. - Important mineralocorticoids, including the synthetic ones, are: 123456- Aldosterone: very potent; accounts for about 90% of all mineralocorticoid activity. Deoxycorticosterone: 1/30 as potent as aldosterone, but very small quantities are secreted. Corticosterone: slight mineralocorticoid activity. 9-α-Fluorocortisol: synthetic; slightly more potent than aldosterone. Cortisol: very slight mineralocortiocoid activity, but a large quantitiy is secreted. Cortisone: slight mineralocorticoid activity. - Aldosterone, which is the principle mineralocorticoid and the most potent, is synthesized by a thin layer of cells in Zona glomerulosa of the adrenal cortex, these cells are the only ones in the adrenal gland capable of secreting significant amounts of aldosterone because they contain the enzyme aldosterone synthase, which is necessary for synthesis of aldosterone. - ECF concentrations of angiotensin II and potassium, both of which stimulate aldosterone secretion, are the most potent regulators of aldosterone secretion, other two factors are: 1- Increased sodium ion concentration in the ECF slightly decrease aldosterone secretion. 2- ACTH from the anterior pituitary is necessary for aldosterone secretion but has little effect in controlling the rate of secretion in most physiological conditions. 8 - Functions of the mineralocorticoids (aldosterone): to maintain normal body fluid volume, blood volume and blood pressure mainly by controlling the concentration of sodium and potassium in the body. Any decrease in blood volume and pressure induces the renin-angiotensin system. The Renin–Angiotensin System (RAS): 1- RAS is a hormone system that regulates blood pressure and fluid balance. When renal blood flow is reduced, juxtaglomerular cells in the kidneys convert the precursor – prorenin, already present in the blood, into renin and secrete it directly into the circulation. 2- Plasma renin then carries out the conversion of angiotensinogen, released by the liver, into Angiotensin I. Angiotensin I is subsequently converted to angiotensin II by the angiotensinconverting enzyme (ACE) found in the lungs. 3- Angiotensin II is a potent vasoconstrictive peptide that causes blood vessels to narrow, resulting in increased blood pressure. Angiotensin II also stimulates the secretion of the hormone aldosterone from the adrenal cortex. 4- Aldosterone causes the renal tubules to increase the reabsorption of sodium and water into the blood, while at the same time causing the excretion of potassium’ in order to maintain electrolyte balance. This increases the volume of ECF in the body, which also increases blood pressure. Decrease in blood volume or pressure. Water and salt retention → Volume increases 9 Now to discuss the role of Aldosterone and Angiotensin II in details: Aldosterone mechanism of action ‘understand’: - Aldosterone is an important regulator of sodium reabsorption and secretion of potassium and hydrogen ions by the renal tubules. A major renal tubular site of aldosterone action is on the principal cells of the cortical collecting ducts of the kidney. 1- Aldosternone is lipid soluble, thus it diffuses readily to the interior of the renal tubular epithelial cells. 2- In the cytoplasm of the tubular cells, aldosterone combines with a highly specific cytoplasmic mineralocorticoid receptor (MR) protein. 3- The aldosterone-MR complex diffuses into the nucleus, inducing one or more specific portions of the DNA to form one or more types of mRNA related to the process of sodium and potassium transport. 4- The mRNA diffuses back into the cytoplasm causing protein formation, the proteins formed are a mixture of one or more enzymes and membrane transport proteins that, all acting together, are required for sodium, potassium and hydrogen transport through cell membranes. - The most important produced enzyme is sodium-potassium adenosine triphosphates associated with the pump for Na and K exchange at the basolateral membranes of the renal tubular cells. - Additional important produced protein are sodium channel proteins, inserted to the luminal membrane of the same tubular cells allowing rapid diffusion of sodium ions from the lumen into the cells, sodium is then pumped by the Na+/K+ pump into the interstitial fluid then into the blood. Angiotensin II mechanism of action: - Angiotensin acts by increasing reabsorption of NaCl, H2O, and increasing the secretion of H+. By regulating these factors, angiotensin maintains normal blood pressure and ECF volume when they decrease. The three main effects of Angiotensin are: 1- Angiotensin II stimulates aldosterone secretion which in turn increases sodium reabsorption as discussed before. 10 2- It constricts the efferent arterioles, which has two effects on peritubular capillary dynamics that increase sodium and water reabsorption: Indirect Effect: a- Efferent arteriolar constriction reduces peritubular capillary hydrostatic pressure, which increases net tubular reabsorption, especially from the proximal tubules. b- Efferent arteriole constriction reduced renal blood flow, thus increasing the concentration of proteins and the colloid osmotic pressure in the peritubular capillaries; this increases the reabsorptive force at the peritubular capillaries and raises tubular reabsorption of sodium and water. Direct Effect: c- Angiotensin II directly stimulates sodium reabsorption by stimulating the sodiumpotassium ATPase pump on the tubular epithelial cell basolateral membrane of the proximal tubules, the loops of Henle, the distal tubules, and the collecting tubules. d- It also stimulates sodium-hydrogen exchange in the luminal membrane, especially in the proximal tubule. 3- Angiotensin II stimulates sodium-bicarbonate co-transport in the basolateral membrane. - Controlling blood pressure and blood volume is mainly stimulated by angiotensin which control aldosterone. Aldosterone does not only function on renal tubules; it also functions on salivary gland, intestine and sweating gland. - There are 3 types of angiotensin, angiotensin III is similar to angiotensin II in potency, but it is released in smaller amounts. - We inhibit the synthesis of angiotensin II by using angiotensin II converting enzyme inhibitors, this will we inhibit the formation of angiotensin II from angiotensin I, thus angiotensin I concentration will increase. These inhibitors are usually safe drugs, but they don’t work on every individual so we have to depend on other drugs that may have some side effects. 11 Comparison Between Cortisol and Aldosterone Graphs Explanation: c) Secretion rate: Here, the rate of secretion was compared and it was found that cortisol is secreted in a much higher rate than aldosterone. d) Glucocorticoid contribution, means how much both (cortisol and aldosterone) contribute to the amount of glucocorticoids, Cortisol was found to have a higher contribution, i.e. the amount of cortisol that works as a glucocorticoid is higher than the amount of aldosterone that works as a glucocorticoid. Relative Potency µmol/day b) Mineralocorticoid activity, means which one is more potent as a mineralocorticoid, which is aldosterone. Aldosterone Relative contribution a) Glucocorticoid activity, shows which one is more potent as a glucocorticoid, which is cortisol. Cortisol e) Mineralocorticoids contribution, means how much both (cortisol and aldosterone) contribute to the amount of mineralocorticoids. Aldosteron was found to be a higher contributor.  The contribution of cortisol in mineralocorticoid activity is relatively much more than the contribution of aldosterone in glucocorticoid activity; that is because it is secreted in much higher rate (more than 200 folds) so its levels will always be much greater than aldosterone’s levels. Graphs interpretation: a) Glucocorticoid activity → Even aldosterone (a mineralocorticoid) plays a role in glucose metabolism. b) Mineralocorticoid activity → In addition to aldosterone, cortisol (a glucocorticoid) plays a role in the metabolism of minerals. c) Secretion rate → The secretion rate of cortisol is higher, as mentioned in note 2, page 4. d) Glucocorticoid contribution → Cortisol has the main role, while aldosterone has some contribution. 12 e) Mineralocorticoid contribution → Cortisol contributes in mineralocorticoid activity, however, its relative contribution is much more than that of aldosterone to glucocorticoids; because it has a higher secretion rate (according to c), the amount of cortisol secreted is more than the amounts of aldosterone. Note that in “contribution” we take the secretion rate into consideration, not only the potency like in “activity”. Stimulation: - Angiotensin II and potassium stimulate aldosterone secretion, while cortisol is stimulated through ACTH. Steroid Hormones in the blood stream: - 90% of cortisol is bound to Corticosteroid-binding protein, while 6% binds with albumin. Therefore, free cortisol is the physiologically active form of the hormone and its normal percentage is ≈ 4%. - As for Aldosterone, about 40% are in the free form (functional), the other 60% combines with plasma proteins; where 20% are bound to cortisol-binding globulin (CBG), also called transcortin, and the other 40% is bound to serum albumin. Note: The high degree of binding (94%) of cortisol slows the rate of elimination thus it has a long half-life. Unlike aldosterone where relatively low degrees of binding (60%) has a short half-life. In this sheet we discussed the adrennal glands, their parts (medulla and cortex), and what each part secretes. The doctor focused on hormones produced by the adrenal cortex, discussing their mechanism of action and regulators; the mineralocorticoids (Aldosterone) and the glucocorticoids (Cortisol). In addition to these hormones, small amounts of sex hormones are secreted, especially androgens and estrogens which will be discussed further in the next sheet. 13