Synthesis of steroid hormones

the three major classes of steroid hormones are the glucocorticoids the mineralocorticoids and a sex hormones so the major glucocorticoid is cortisol the major mineralocorticoid is aldosterone and the sex hormones are the androgens the estrogens and the progestins now all three classes of steroid hormones can be produced in the outer portion of the adrenal gland we call the adrenal cortex in addition we can also synthesize certain sex hormones outside the adrenal glands in peripheral tissues such as the gonads so in males the gonads or the testes and in females the gonads are the ovaries in addition during embryo logical development and pregnant women we can also actually synthesize specific types of sex hormones in the placenta now all steroid hormones are hydrophobic they don't dissolve very well in water and that's a problem because our blood is predominantly water and so what that means is once we synthesize the steroid hormones to actually move them in the bloodstream to the target location we have to carry them on proteins so as we know albumin is the major protein in the blood and it can do many things and it actually act as a nonspecific carrier for steroid hormones for example it can bind to aldosterone and move it to its target location in addition we also have more specific carrier proteins we have corticosteroid binding globulin also known as trans Courtin which binds which binds cortisol and moves it to its target location and then we have sex hormone binding protein and that can bind and transport sex hormones so let's suppose we synthesize a steroid hormone it's picked up by one of these carrier molecules then what happens well the carrier protein brings it to its target cell whatever that cell may be and then it releases it and because the steroid hormone is hydrophobic it can simply diffuse across the mostly hydrophobic cell membrane and once inside the cell that steroid hormone binds to receptors either in the cytoplasm or in the nucleus either way once bound to the receptor and causes dimerization and it causes the complex to accumulate within the nucleus of the cell now the binding of the hormone to that receptor also exposes a DNA binding domain on that receptor that allows it to interact via a zinc finger motif with the DNA specifically the dimerized complex interacts and binds unto the regulatory DNA sequence known as hormone response element so HR e once bound onto the hormonal response element it increases transcription of target genes and ultimately that builds new proteins and the new proteins elicit that specific physiological response whatever it may be so we'll talk about the specific functions of these steroid hormones towards the end of the lecture so now we know how to transport steroid hormones what the mechanism of action of the steroid hormones is now let's talk about the synthesis of these steroid hormones again the majority of these steroid hormones are produced within the adrenal cortex of the adrenal glands and the precursor molecules to all of these steroid hormones is the same it's a 27 carbon precursor we call cholesterol so cholesterol can either be obtained from our diet or we can synthesize cholesterol from scratch within our liver but whatever the origin of cholesterol is this is what it looks like so we have this hydrocarbon chain on one end we have a hydroxyl group on the other end and in between we have these four rings 1 2 3 4 and then we have a double bond here now what happens is in a multi-step process we essentially reduce the hydrocarbon chain and we can hydroxylate the rings and ultimately cholesterol can be transformed into either aldosterone or cortisol or a variety of different types of sex hormones now the first step is the rate limiting step the first step is catalyzed by an enzyme known as des malaise des malaise is a cytochrome p450 mixed function oxidase enzyme that is located on the inner mitochondrial membrane and it utilized the reducing power of NADPH and oxygen diatomic oxygen to remove six carbons from the from this hydrocarbon chain and an oxygen atom here and move this bond here and so we form we convert a 20-7 cholesterol molecule to a twenty to twenty one carbon atom molecule known as pregnenolone and pregnenolone can then basically go on via these three pathways now the pathway that occurs here depends on where we are within our cortex with a narrowed renal cortex so here is their drillin cortex and we can actually divide it into three different regions we have the outer region we have the middle region and the inner region so this is the outer region this is the middle region and this is the inner region of the cortex the cortex of the adrenal glands now the outer region is also known as zona glomerulosa the middle region is also known as zona fasciculata and the inner region is also known as zona reticularis so gf our zona glomerulosa zona fasciculata zona reticularis now in zona fasciculata this is the pathway that will occur we will form cortisol in zona glomerulosa this is the pathway that will occur we're going to form aldosterone and in zona reticularis this is the pathway that will predominate so this is the zona glomerulosa this is the zone of fascicular da and this is the zona reticularis so let's talk about these pathways individually so first of all pregnant first of all pregnant own is converted into into progesterone by the activity of an enzyme known as 3 beta hydroxy steroid dehydrogenase now all of enzymes shown in red are mixed function oxidases just like des malaise is once we form progesterone let's follow this pathway here so under stressful situations for example because of an underlying infection the brain will activate the hypothalamus to produce a molecule known as CR H known as corticotropin-releasing hormone so under conditions of stress ie infection the hypothalamus releases CR h that travels via the bloodstream into a nearby anterior pituitary gland in which the CR H stimulates the production and release of ACTH adrenocorticotropic hormone ACTH is a peptide hormone it simply diffuses in the blood and it travels to the zona zona fasciculata of the adrenal cortex it binds unto receptors on that cell membrane within these cells and it increases cyclic AMP e production and ultimately what that does is it stimulates the production and release of cortisol the stress hormone and cortisol does a bunch of things again cortisol is picked up in the bloodstream by corticosteroid binding globulin and then it moves to many different types of cells we transported into adipose cells we transported into liver cells we transported to fibroblast and so forth so cortisol does a bunch of things so for one thing cortisol increases lipolysis so cortisol ends up in the adipose tissue and that increases lipolysis with an adipose tissue so that basically redistributes fat in our body and that can cause central obesity in patients it also increases Pro dialysis so it moves to the scale to muscle tissue and increases breakdown of protein it also goes to the liver and increases gluconeogenesis so ultimately we're producing more glucose why well because we have high levels of stress and we want more glucose to basically deal with stress for example II want to deal with that infection in addition cortisol increases the blood pressure how well cortisol increases the expression of alpha one adrenergic receptors on arterioles and that makes those arterioles more sensitive to epinephrine and norepinephrine and that can increase the blood pressure in addition cortisol can also actually bind unto aldosterone receptors and increase the amount of reabsorption of water by the kidneys cortisol also decreases our immune activity and decreases the inflammatory process so it does a bunch of things it decreases the ability of neutrophils to actually bind unto endothelium and so that can increase neutrophils in the blood stream and caused neutrophilia it can also decrease the production of other white blood cells and if you remember cortisol also actually decreases the activity of phospholipase a2 and that decreases production of leukotrienes and a decrease of production of prostaglandins cortisol also decreases the ability of osteoblasts to form bone and so that decreases bone formation and that can cause osteoporosis in the long term and also decrease activity of fibroblasts in the skin and that can cause development of these striations on the skin and it increases insulin resistance so cortisol basically does a bunch of things as a result of a high level of stress now let's talk about the synthesis of cortisol so progesterone is converted into 17 alpha hydroxy progesterone by the activity of 17 alpha hydroxylase then this is converted by the activity of 21 alpha hydroxylase to 11 deoxy cortisol and finally 11 the oxy cortisol is converted to cortisol by the activity of 11 beta hydroxyl a so all of this happens within the zona fasciculata in the middle portion of the cortex then let's move on to the outer portion to the zona glomerulosa so let's suppose in our body we have low levels of sodium and so low levels of sodium end up in the kidneys so this will stimulate the juxtaglomerular apparatus in the kidneys to release rina rina and then goes on and activates the read an angiotensin aldosterone system so greenin causes more production of angiotensin ii and angiotensin ii actually stimulates release and production of aldosterone so in the zona glomerulosa we transform progesterone into eleven deoxy cortisone via the activity of 21 alpha hydroxylase this then is converted into a corticosteroid corticosteroid by the activity of eleven beta hydroxylase and then we have aldosterone synthase converts it into aldosterone and angiotensin ii acts on aldosterone synthase to increase its activity to produce more aldosterone and so aldosterone will act on the distal nephron to increase the reabsorption of sodium and that will allow us to reabsorb more water and that can increase the blood pressure and it also causes secretion of potassium so that can actually cause hypokalemia so level low levels of potassium so again when there is a low level of sodium reaching the kidneys the juxtaglomerular apparatus of the kidneys releases Ranen this ultimately forms more angiotensin ii which stimulates the zona glomerulosa to release more aldosterone by increasing the activity of aldosterone synthase aldosterone acts on the distal nephron to increase sodium reabsorption while decreasing the botas while increasing potassium secretion now I want to come back for a second to ACTH here in the same way that angiotensin 2 increases aldosterone synthase activity ACTH released by the anterior pituitary gland increases production of des malaise or increases the activity of des malaise and that ultimately helps form more cortisol and then we have the zona reticularis so both the zona fasciculata actually and the reticularis can actually produce androgens but predominantly antigens are produced in the zone of vesicular zona reticularis so the two major ones are DHEA which is not shown in this pathway here and andro steamed ion so Andres team diode is converted from a 17 alpha hydroxy progesterone once we form androstenedione it can either be transformed into testosterone within the adrenal cortex or this can move into the bloodstream move into peripheral tissues and be transformed into testosterone testosterone can either carry out its function or we can transform into estradiol or into another molecule called dh8 DHT so we'll come back to this later on so once we form these steroid hormones and once they carry out their function how do we break them down well the breakdown and metabolism of steroid hormones occurs within the liver so the liver is able to modify these steroid hormones for example we can add sulfate out so a sulfate groups we can add glucuronic acid and all of this makes the molecule more water-soluble and it inactivates it about 20 to 30 percent of these metabolized steroid hormones are excreted via the biliary tree into the feces and the remainder 70 to 80 percent are excreted via the kidneys in the urine so essentially and they're being excreted in the urine

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Keywords: steroid hormones, synthesis of steroid hormones, metabolism of steroid hormones, synthesis of aldosterone, synthesis of cortisol, cortisol, aldosterone, adrenal cortex

Id: fAVs90lvEAg

Length: 14min 56sec (896 seconds)

Published: Thu Jun 13 2019