mechanisms yielding this effect on progesterone differ among species. in the sheep, where progesterone sufficient for maintaining pregnancy is produced by the placenta after about day 70 of gestation, the prepartum fetal cortisol surge induces placental enzymatic conversion of progesterone to estrogen. (the elevated level of estrogen stimulates prostaglandin secretion and oxytocin receptor development.) exposure of fetuses to cortisol during gestation can have a variety of developmental outcomes, including alterations in prenatal and postnatal growth patterns. in marmosets, a species of new world primates, pregnant females have varying levels of cortisol during gestation, both within and between females. infants born to mothers with high gestational cortisol during the first trimester of pregnancy had lower rates of growth in body mass indices than infants born to mothers with low gestational cortisol (about 20% lower). however, postnatal growth rates in these high-cortisol infants were more rapid than low-cortisol infants later in postnatal periods, and complete catch-up in growth had occurred by 540 days of age. these results suggest that gestational exposure to cortisol in fetuses has important potential fetal programming effects on both pre and postnatal growth in primates. synthesis and release cortisol is produced in the human body by the adrenal gland in the zona fasciculata, the second of three layers comprising the adrenal cortex. the cortex forms the outer "bark" of each adrenal gland, situated atop the kidneys. the release of cortisol is controlled by the hypothalamus, a part of the brain. the secretion of corticotropin-releasing hormone by the hypothalamus triggers cells in the neighboring anterior pituitary to secrete another hormone, the adrenocorticotropic hormone (acth), into the vascular system, through which blood carries it to the adrenal cortex. acth stimulates the synthesis of cortisol and other glucocorticoids, mineralocorticoid aldosterone, and dehydroepiandrosterone. testing of individuals normal values indicated in the following tables pertain to humans (normal levels vary among species). measured cortisol levels, and therefore reference ranges, depend on the sample type, analytical method used, and factors such as age and sex. test results should, therefore, always be interpreted using the reference range from the laboratory that produced the result. an individual's cortisol levels can be detected in blood, serum, urine, and saliva, and sweat. reference ranges for blood plasma content of free cortisol timelower limitupper limitunit 09:00 am140700nmol/l 525μg/dl midnight80350nmol/l 2.913μg/dl using the molecular weight of 362.460 g/mole, the conversion factor from µg/dl to nmol/l is approximately 27.6; thus, 10 µg/dl is about 276 nmol/l. reference ranges for urinalysis of free cortisol (urinary free cortisol or ufc) lower limitupper limitunit 28 or 30280 or 490nmol/24h 10 or 11100 or 176µg/24 h cortisol follows a circadian rhythm, and to accurately measure cortisol levels is best to test four times per day through saliva. an individual may have normal total cortisol but have a lower than normal level during a certain period of the day and a higher than normal level during a different period. therefore, some scholars question the clinical utility of cortisol measurement. cortisol is lipophilic, and is transported bound to transcortin (also known as corticosteroid-binding globulin) and albumin, while only a small part of the total serum cortisol is unbound and has biological activity. this binding to the corticosteroid-binding globulin is accomplished through hydrophobic interactions in which cortisol binds in a 1:1 ratio. serum cortisol assays measures total cortisol, and its results may be misleading for patients with altered serum protein concentrations. the salivary cortisol test avoids this problem because only free cortisol can pass through the salivary barrier. transcortin particles are too large to pass through this barrier. automated immunoassays lack specificity and show significant cross-reactivity due to interactions with structural analogs of cortisol, and show differences between assays. liquid chromatography-tandem mass spectrometry (lc-ms/ms) can improve specificity and sensitivity. disorders of cortisol production some medical disorders are related to abnormal cortisol production, such as: primary hypercortisolism (cushing's syndrome): excessive levels of cortisol secondary hypercortisolism (pituitary tumor resulting in cushing's disease, pseudo-cushing's syndrome) primary hypocortisolism (addison's disease, nelson's syndrome): insufficient levels of cortisol secondary hypocortisolism (pituitary tumor, sheehan's syndrome) regulation the primary control of cortisol is the pituitary gland peptide, acth, which probably controls cortisol by controlling the movement of calcium into the cortisol-secreting target cells. acth is in turn controlled by the hypothalamic peptide corticotropin-releasing hormone (crh), which is under nervous control. crh acts synergistically with arginine vasopressin, angiotensin ii, and epinephrine. (in swine, which do not produce arginine vasopressin, lysine vasopressin acts synergistically with crh.) when activated macrophages start to secrete il-1, which synergistically with crh increases acth, t-cells also secrete glucosteroid response modifying factor (grmf), as well as il-1; both increase the amount of cortisol required to inhibit almost all the immune cells. immune cells then assume their own regulation, but at a higher cortisol setpoint. the increase in cortisol in diarrheic calves is minimal over healthy calves, however, and falls over time. the cells do not lose all their fight-or-flight override because of interleukin-1's synergism with crh. cortisol even has a negative feedback effect on interleukin-1—especially useful to treat diseases that force the hypothalamus to secrete too much crh, such as those caused by endotoxic bacteria. the suppressor immune cells are not affected by grmf, so the immune cells' effective setpoint may be even higher than the setpoint for physiological processes. grmf affects primarily the liver (rather than the kidneys) for some physiological processes. high-potassium media (which stimulates aldosterone secretion in vitro) also stimulate cortisol secretion from the fasciculata zone of canine adrenals — unlike corticosterone, upon which potassium has no effect. potassium loading also increases acth and cortisol in humans. this is probably the reason why potassium deficiency causes cortisol to decline (as mentioned) and causes a decrease in conversion of 11-deoxycortisol to cortisol. this may also have a role in rheumatoid-arthritis pain; cell potassium is always low in ra. ascorbic acid presence, particularly in high doses has also been shown to mediate response to psychological stress and speed the decrease of the levels of circulating cortisol in the body post-stress. this can be evidenced through a decrease in systolic and diastolic blood pressures and decreased salivary cortisol levels after treatment with ascorbic acid. factors increasing cortisol levels viral infections increase cortisol levels through activation of the hpa axis by cytokines. intense (high vo2 max) or prolonged aerobic exercise transiently increases cortisol levels to increase gluconeogenesis and maintain blood glucose; however, cortisol declines to normal levels after eating (i.e., restoring a neutral energy balance) severe trauma or stressful events can elevate cortisol levels in the blood for prolonged periods. low-carbohydrate diets cause a short-term increase in resting cortisol (~3 weeks), and increase the cortisol response to aerobic exercise in the short- and long-term. increase in the concentration of ghrelin, the hunger stimulating hormone, increases levels of cortisol. biochemistry biosynthesis steroidogenesis, showing cortisol at right. cortisol is synthesized from cholesterol. synthesis takes place in the zona fasciculata of the adrenal cortex. (the name cortisol is derived from cortex.) while the adrenal cortex also produces aldosterone (in the zona glomerulosa) and some sex hormones (in the zona reticularis), cortisol is its main secretion in humans and several other species. (however, in cattle, corticosterone levels may approach or exceed cortisol levels.). the medulla of the adrenal gland lies under the cortex, mainly secreting the catecholamines adrenaline (epinephrine) and noradrenaline (norepinephrine) under sympathetic stimulation. the synthesis of cortisol in the adrenal gland is stimulated by the anterior lobe of the pituitary gland with acth; acth production is, in turn, stimulated by crh, which is released by the hypothalamus. acth increases the concentration of cholesterol in the inner mitochondrial membrane, via regulation of the steroidogenic acute regulatory protein. it also stimulates the main rate-limiting step in cortisol synthesis, in which cholesterol is converted to pregnenolone and catalyzed by cytochrome p450scc (side-chain cleavage enzyme). 11beta-hydroxysteroid dehydrogenases cortisol is metabolized reversibly to cortisone by the 11-beta hydroxysteroid dehydrogenase system (11-beta hsd), which consists of two enzymes: 11-beta hsd1 and 11-beta hsd2. the metabolism of cortisol to cortisone involves oxidation of the hydroxyl group at the 11-beta position. 11-beta hsd1 uses the cofactor nadph to convert biologically inert cortisone to biologically active cortisol 11-beta hsd2 uses the cofactor nad+ to convert cortisol to cortisone overall, the net effect is that 11-beta hsd1 serves to increase the local concentrations of biologically active cortisol in a given tissue; 11-beta hsd2 serves to decrease local concentrations of biologically active cortisol. if hexose-6-phosphate dehydrogenase (h6pdh) is present, the equilibrium can favor the activity of 11-beta hsd1. h6pdh regenerates nadph, which increases the activity of 11-beta hsd1, and decreases the activity of 11-beta hsd2. an alteration in 11-beta hsd1 has been suggested to play a role in the pathogenesis of obesity, hypertension, and insulin resistance known as metabolic syndrome. an alteration in 11-beta hsd2 has been implicated in essential hypertension and is known to lead to the syndrome of apparent mineralocorticoid excess (same). a-ring reductases (5alpha- and 5beta-reductases) cortisol is also metabolized irreversibly into 5-alpha tetrahydrocortisol (5-alpha thf) and 5-beta tetrahydrocortisol (5-beta thf), reactions for which 5-alpha reductase and 5-beta-reductase are the rate-limiting factors, respectively. 5-beta reductase is also the rate-limiting factor in the conversion of cortisone to tetrahydrocortisone. cytochrome p450, family 3, subfamily a monooxygenases cortisol is also metabolized irreversibly into 6β-hydroxycortisol by cytochrome p450-3a monooxygenases, mainly, cyp3a4. drugs that induce cyp3a4 may accelerate cortisol clearance. chemistry cortisol is a naturally occurring pregnane corticosteroid and is also known as 11β,17α,21-trihydroxypregn-4-ene-3,20-dione. animals in animals, cortisol is often used as an indicator of stress and can be measured in blood, saliva, urine, hair, and faeces.