PHY-3.02 Adrenal Physiology (1).pdf

Adrenal Physiology PHY-3.02 BMS 200 Outcomes for today Contrast the histology, regulation, and secretions of the different zones of the adrenal glands. Explain the synthesis of steroid hormones, highlighting significant enzymes involved, as well as their transport and metabolism....

Adrenal Physiology PHY-3.02 BMS 200 Outcomes for today Contrast the histology, regulation, and secretions of the different zones of the adrenal glands. Explain the synthesis of steroid hormones, highlighting significant enzymes involved, as well as their transport and metabolism. Discuss the physiological roles of glucocorticoids, including their impact on carbohydrate, protein, and lipid metabolism, immune system modulation, and responsiveness to the autonomic nervous system and vasopressors. Explain the basic role of mineralocorticoids in sodium handling and fluid homeostasis. Outline General anatomy of the adrenal glands ▪ Microscopic & macroscopic anatomy ▪ Vasculature ▪ Embryology Glucocorticoid: ▪ Synthesis & regulation ▪ Effects Mineralocorticoid ▪ Synthesis & regulation ▪ Effects Catabolism of glucocorticoids & mineralocorticoids Catecholamines ▪ Synthesis & regulation ▪ Effects ▪ catabolism  General Roles of the Adrenal Glands Key components of the endocrine system that are essential to life Four major sets of hormones: ▪ Glucocorticoids regulation of blood sugar and physiologic response to stress ▪ Mineralocorticoids maintain extracellular fluid (ECF) volume, sodium and potassium balance ▪ Weak androgens role in adults is yet to be fully elucidated ▪ Catecholamines: mostly epinephrine with some norepinephrine Adrenal Glands – General Anatomy ~ 3-5cm long, weighs 1.5 – 2.5g 2 components: ▪ cortex - Steroid Hormones Adrenal gland ▪ medulla - Catecholamines Major vasculature: ▪ Suprarenal artery and vein Supplied by abdominal aorta Extremely well-perfused, perhaps the most “vascular” organ in the body In adults, the kidneys and the adrenal glands are surrounded by a large fat pad Image adapted from: Lippincott® Atlas of Anatomy, Chapter 5, 2e, 2020 Adrenal Glands – General Anatomy The adrenal glands, located on top of each kidney, have a rich blood supply. Each gland gets blood from three main sources: 1. Superior suprarenal arteries - These come from the lower part of the diaphragm (the muscle that helps with breathing). 2. Middle suprarenal artery - This comes directly from the abdominal aorta (the main artery that supplies blood to the lower half of the body). 3. Inferior suprarenal arteries - These come from the renal arteries, which also supply the kidneys. Once blood flows into the adrenal gland, it moves through small vessels inside and then leaves through a single central vein. On the right adrenal gland, this vein drains into the inferior vena cava, while on the left side, it drains into the renal vein. Adrenal Glands – General Anatomy continued Image adapted from: Moore’s Clinically Oriented Anatomy, Chapter 5, 9e, 2023  Adrenal Glands - Embryology Adrenal Medulla is Derived from Neural Crest Cells The adrenal medulla, the inner part of the adrenal gland, originates from neural crest cells during embryonic development. Neural crest cells are a group of cells in the embryo that give rise to various structures in the body, including the peripheral nervous system and parts of the adrenal gland. Neural crest cells differentiate into many types of cells, including those that become the chromaffin cells of the adrenal medulla. These chromaffin cells are responsible for producing and releasing catecholamines, such as adrenaline (epinephrine) and noradrenaline (norepinephrine). Because the medulla originates from the neural crest, its function is closely related to the sympathetic nervous system, which also arises from the neural crest. This connection explains why the adrenal medulla acts like a large sympathetic ganglion. Adrenal Glands - Embryology 2. The Medulla Functions as an “Overgrown Sympathetic Ganglion” The adrenal medulla is often described as an "overgrown sympathetic ganglion" because of its relationship with the sympathetic nervous system (SNS), which is responsible for the body's rapid response to stress. In the SNS, sympathetic ganglia are clusters of nerve cells that relay signals from the brain to various organs. The adrenal medulla functions in a similar way but on a much larger scale. Instead of sending signals through nerve fibres to organs, the adrenal medulla directly releases hormones (epinephrine and norepinephrine) into the bloodstream. When the brain detects stress, it activates the adrenal medulla through signals from sympathetic nerves, causing it to release these hormones quickly. This leads to a system-wide response, increasing heart rate, blood pressure, and energy availability, just like the sympathetic nervous system does, but through chemical signals instead of nerve impulses. Adrenal Glands - Embryology Adrenal Cortex is Derived from Mesoderm The outer layer of the adrenal gland, called the adrenal cortex, develops from the mesoderm, one of the three primary germ layers in the embryo. The mesoderm is responsible for forming many structures in the body, including muscles, bones, and the cardiovascular system. The adrenal cortex produces steroid hormones, which are essential for various physiological functions: The zona glomerulosa produces aldosterone, a hormone that regulates blood pressure by controlling sodium and water balance. The zona fasciculata produces cortisol, which helps regulate metabolism, immune responses, and the body's stress response. The zona reticularis produces androgens, which are precursor hormones for sex steroids like testosterone and estrogen. Adrenal Glands - Embryology Since the adrenal cortex arises from the mesoderm, it has a different origin and function compared to the adrenal medulla. The medulla is more closely tied to the nervous system, while the cortex deals with hormonal regulation of various body systems, especially in response to longer-term stress and metabolic demands. Adrenal Glands - Embryology Embryology: Adrenal medulla is derived from neural crest cells ▪ The medulla functions as an “overgrown sympathetic ganglion” Adrenal cortex is derived from mesoderm Adrenal Glands – Functional Histology & Anatomy Four major zones: Cortex: 1. Zona glomerulosa ▪ Smallest zone ▪ Mineralocorticoid secretion 2. Zona fasciculata ▪ Largest zone ▪ Glucocorticoid secretion 3. Zona reticularis ▪ Androgen secretion Adrenal Glands – Functional Histology & Anatomy Four major zones continued: 4. Medulla: Catecholamines ▪ Epinephrine secreted in large quantities (when secretion is stimulated) BMS 100 review of HPA The hypothalamic-pituitary axis (HPA) Hormones released by the hypothalamus regulate hormone release from the anterior pituitary Anterior pituitary hormones regulate the activity of a range of target endocrine glands BMS 100 review of HPA Hypothalamus Releases hormones (like CRH, TRH, GnRH). These hormones travel to the —-> Anterior Pituitary Stimulate the release of pituitary hormones (like ACTH, TSH, LH, FSH). Anterior pituitary hormones then act on target endocrine glands (adrenal cortex, thyroid, gonads) to regulate the production of further hormones (like cortisol, thyroid hormones, sex hormones). Feedback mechanisms ensure that hormone levels remain balanced to avoid over- or underproduction. This system is critical for managing responses to stress, regulating metabolism, controlling reproductive functions, and maintaining overall homeostasis. BMS 100 review of HPA Hormones Released by the Hypothalamus Corticotropin-releasing hormone (CRH): Stimulates the release of adrenocorticotropic hormone (ACTH) from the anterior pituitary. Thyrotropin-releasing hormone (TRH): Stimulates the release of thyroid-stimulating hormone (TSH). Gonadotropin-releasing hormone (GnRH): Stimulates the release of luteinizing hormone (LH) and follicle-stimulating hormone (FSH). Growth hormone-releasing hormone (GHRH): Stimulates the release of growth hormone (GH). Somatostatin (GHIH): Inhibits the release of GH and thyroid- stimulating hormone (TSH). Dopamine (prolactin-inhibiting factor): Inhibits the release of prolactin. BMS 100 review of HPA Hormones Released by the Anterior Pituitary Gland Adrenocorticotropic hormone (ACTH): Stimulates the adrenal cortex to produce cortisol, a key hormone in the stress response and metabolism regulation. Thyroid-stimulating hormone (TSH): Stimulates the thyroid gland to produce thyroid hormones (T3 and T4), which regulate metabolism and energy levels. Luteinizing hormone (LH) and follicle-stimulating hormone (FSH): Target the gonads (testes in males and ovaries in females), regulating reproductive functions and the production of sex hormones (testosterone, estrogen, and progesterone). Growth hormone (GH): Stimulates growth, cell reproduction, and regeneration, targeting bones and muscles primarily. Prolactin: Promotes milk production in the mammary glands. Basic regulation of adrenal hormone secretion Adrenal gland hormone secretion depends on the zone: ▪ Cortisol release is regulated by ACTH from the anterior pituitary gland ▪ Mineralocorticoid release is regulated by: Secretion of angiotensin II Serum K+ levels ▪ Epinephrine release is regulated by the sympathetic nervous system It’s basically a huge sympathetic ganglion FYI – regulation of adrenal androgen secretion is still under investigation Basic regulation of adrenal hormone secretion continued In the case of steroid hormones, secretion is regulated through enzymatic activation alone ▪ The type of steroid hormone that is produced depends on the enzymes expressed by the cell ▪ We don’t need exocytosis for secretion of steroid hormones Why? Steroid hormones are hydrophobic and can cross the cell membrane via simple diffusion In the case of catecholamines, secretion is regulated both by: ▪ a) Enzymatic activation ▪ b) Exocytosis of vesicles containing epinephrine and norepinephrine What does the last slide actually mean? Steroid hormones (like cortisol, aldosterone, and sex hormones such as estrogen and testosterone) are derived from cholesterol. These hormones are not stored in the cells that produce them. Instead, they are made "on demand" when the body needs them. Steroid hormones are lipid-soluble, so they can easily pass through cell membranes, making storage in vesicles difficult. Enzymatic Activation for Hormone Production The production of steroid hormones relies on a series of enzymatic reactions that convert CHOLESTEROL into different hormones. The rate of hormone secretion is controlled by: how active these enzymes are When the body signals a need for more of a specific steroid hormone (e.g., cortisol during stress), the enzymes responsible for synthesizing that hormone become more active, increasing production. Once synthesized, the hormone diffuses out of the cell into the bloodstream, as it cannot be stored. Type of Steroid Hormone Depends on the Enzymes in the Cell Different types of cells express different enzymes, and these enzymes determine which steroid hormones the cell can produce. In the adrenal cortex the zona glomerulosa expresses enzymes that convert cholesterol into aldosterone(which regulates salt and water balance). In the zona fasciculata, other enzymes are expressed that lead to the production of cortisol (which helps regulate metabolism and stress responses). In the gonads (testes or ovaries), enzymes convert cholesterol into testosterone or estrogen (which regulate reproductive functions). Regulation of glucocorticoid secretion - overview Corticotrophin releasing hormone (CRH) is released from hypothalamus CRH stimulates ACTH release from anterior pituitary gland ACTH acts on the adrenal gland to increased synthesis of cortisol in the zona fasciculata. Let’s take a closer look at this step on the next slide Regulation of glucocorticoid secretion ACTH binds to a G-Protein coupled receptor on zona fasciculata cells When ACTH binds it activates a G-protein inside the cell. The G-protein consists of three subunits (α, β, γ), but the most important one here is the α- subunit (Gs) When activated, the α-subunit dissociates and activates an enzyme called adenylyl cyclase. Results in increased cAMP and activation of enzymes that produce cholesterol-derived cortisol Let’s take a look at some of the key steps in this pathway Regulation of glucocorticoid secretion The increased levels of cAMP activate another enzyme called protein kinase A (PKA). PKA is an important regulatory enzyme that phosphorylates (adds a phosphate group to) various target proteins inside the cell. Phosphorylation changes the activity of these proteins, leading to specific cellular responses. Synthesis of adrenal steroids - 1 First off, we need a store of cholesterol: ▪ Most cholesterol used for steroid hormone synthesis comes from LDL uptake (exogenous pathway) rather than intracellular synthesis of cholesterol ▪ Exogenous pathway: cholesterol esters are taken up from LDL/IDL via upregulation of the LDL receptor ▪ Cholesteryl esters are stored in a lipid droplet if not needed Cholesteryl ester hydrolase (CEH) removes the fatty acid Cholesterol is released and can be used for steroid hormone synthesis Synthesis of adrenal steroids - 2 Cholesterol mobilization: PKA stimulates the release of cholesterol from intracellular stores (such as lipid droplets). Cholesterol is transported into the mitochondria, the site where the first steps of steroid hormone production take place. Steroidogenic acute regulatory protein (StAR): PKA enhances the activity of StAR, a crucial protein that helps transport cholesterol into the inner mitochondrial membrane. Synthesis of adrenal steroids - 3 All steroid hormone synthesis begins at the inner membrane of the mitochondria with cleavage of the cholesterol side chain and formation of pregnenolone Enzyme cascade: In the mitochondria, a series of enzymes (such as P450scc, 3β-HSD, 11β-hydroxylase, etc.) convert cholesterol into cortisol through several intermediate steps. The first step involves converting cholesterol into pregnenolone, and through subsequent reactions, it is finally transformed into cortisol. ▪ Enzyme: side-chain cleavage enzyme (SCC) This is the rate limiting step of the synthesis pathway Synthesis of glucocorticoids The remaining steps of glucocorticoid synthesis occur in the inner mitochondrial membrane and smooth endoplasmic reticulum Pregnenolone is eventually converted into cortisol or corticosterone ▪ Cortisol is the more potent glucocorticoid and its production is higher! Glucocorticoid synthesis What were the regulation roles of the SCC enzymes again? Let’s consider how ACTH upregulates steroidogenesis, the synthesis of glucocorticoids in the which is the zona fasciculata process by which cholesterol is ACTH upregulates the following converted into steps: steroid hormones ▪ Increased LDL receptor expression like cortisol, aldosterone, ▪ Increased activity of CEH and StAR estrogen, ▪ Increased activity of the side chain testosterone, and cleavage enzymes others. ACTH also is trophic for the adrenal gland – it makes it grow  Regulation of glucocorticoid synthesis FIGURE 9–6 Fluctuations in plasma ACTH and glucocorticoids (11- OHCS) throughout the day. Note the greater ACTH and glucocorticoid rises in the morning before awakening.  Regulation of glucocorticoid synthesis How are CRH and ACTH release regulated? ▪ Circadian rhythm – we have a “central clock” located in the suprachiasmatic nucleus of the hypothalamus (SCN) that is “calibrated” by melatonin secretion in response to darkness Contributes to regulation of CRH release ▪ Stress – CRH and ACTH are secreted in response to a wide range of (significant) stressors including: Surgery, hypoglycemia, inflammatory cytokines (physiologic stressors) Pain, unpleasant mood (psychologic stressors) ▪ Negative feedback Cortisol negatively feeds back to limit ACTH as well as CRH secretion Effects of glucocorticoids - intracellular Glucocorticoid receptors are found within the cytosol in almost all tissues in a wide range of cells ▪ Cortisol binds to the glucocorticoid receptor ▪ Stimulate transcription at the hormone responsive element (HRE) ▪ Review from BMS100: Binding of cortisol displaces the heat shock protein (HSP) —> Receptor & hormone then form a dimer and translocate the the nucleus —> stimulate transcription at a HRE General effects of glucocorticoids on metabolism and fighting stress Increase energy availability by: ▪ General inhibition of DNA/protein synthesis and acceleration of protein catabolism ▪ Increasing hepatic gluconeogenesis by: Stimulating gluconeogenesis enzymes (PEPCK and G-6- phosphatase) Increased hepatic responsiveness to glucagon ▪ Increasing hepatic & adipose lipolysis More to be available for glycerol for gluconeogenesis Increased free fatty acid release ▪ Can be broken down through which pathway for energy? A: free fatty acids can be broken down in Beta-oxidation ▪ Decreasing glucose uptake in muscle and adipose tissue Chronically this will contribute to increased insulin secretion ▪ Increasing appetite General effects of glucocorticoids on other tissues Fetus ▪ Combinations of glucocorticoids and a wide variety of other hormones are important in the fetal development of the lung and the liver Bone ▪ Physiologic levels of glucocorticoids do not impair bone, but excess glucocorticoids can inhibit bone formation through multiple different pathways: Osteoblast inhibition & overactivation of osteoclasts Potentiation of the effects of parathyroid hormone, reduction of calcium absorption Healing tissue ▪ Physiologic concentration of glucocorticoids can be helpful in healing tissue, but excess glucocorticoids inhibit fibroblasts and impair healing Preview – causing thinned skin and increased bruising General effects of glucocorticoids on other tissues continued Increase effectiveness of catecholamines at peripheral vessels and the heart, and “hypertension-inducing” effects at the kidney ▪ Increasing cardiac output, increasing blood pressure ▪ Also seem to increase salt and water retention at high doses, independently of mineralocorticoids ▪ May also increase the activity of angiotensin II Central nervous system ▪ Physiologic roles not fully understood ▪ Supraphysiologic levels result in euphoria initially and then later an array of mood disturbances: Irritability & emotional lability Depression Rarely psychosis ▪ Low levels invariably result in fatigue and depression General effects of glucocorticoids – the immune system Physiologic, short-term elevations in glucocorticoids increase neutrophil number and activity Physiologic, short-term elevations in glucocorticoids increase the diapedesis of: ▪ Monocytes, eosinophils ▪ Lymphocytes ▪ May also increase the function of innate immune cells, but this is difficult to prove Long-term elevations or supra-physiologic elevations of cortisol result in: ▪ Impaired macrophage activity and healing ▪ Impaired lymphocyte production and antibody production ▪ Decreased migration of cells to damaged sites ▪ Inhibit phospholipase A2 (this decreasing prostaglandin production) General effects of glucocorticoids on other tissues continued Massive number of distributed effects – see FYI table at this link (need to be logged into the library): ▪ https://accessmedicine-mhmedical- com.ccnm.idm.oclc.org/ViewLarge.aspx? figid=166249355&gbosContainerID=0&gbosid=0&gr oupID=0&sectionId=166249274 Synthesis of mineralocorticoids Initial steps are the same as for glucocorticoids ▪ Cholesterol is converted to pregnenolone Enzyme? ▪ Through various steps pregnenolone is converted to corticosterone Corticosterone is converted to aldosterone ▪ Production of aldosterone depends on the presence of aldosterone synthase located on the inner mitochondrial membrane only expressed by cells of the zona glomerulosa Mineralocorticoid secretion regulation Mineralocorticoids are not primarily regulated by ACTH ▪ Although, ACTH can increase the secretion of aldosterone Major regulators of aldosterone secretion are: ▪ Angiotensin II within the renin-angiotensin-aldosterone system (RAAS) ▪ Elevations in serum K+ Signaling in the RAAS – the basics Renin angiotensin aldosterone system ▪ Decreased perfusion to the kidney stimulates renin release --> renin catalyzes the conversion of Angiotensin to Angiotensin I More detail to come in BMS 250! Signaling in the RAAS – the basics ▪ Angiotensin II has multiple effects: ▪ Vasoconstriction ▪ Stimulates secretion of aldosterone ▪ Stimulates secretion of ADH/AVP from posterior pituitary gland ▪ Increases reabsorption of Na+ and secretion of K+ in the kidneys More detail to come in BMS 250! Aldosterone - effects The major effects of aldosterone are: ▪ Increased sodium reabsorption and increased potassium secretion from the kidney Sodium reabsorption causes increase water retention and overall increased ECF volume ▪ Decreased potassium reabsorption from the GI tract ▪ Increased activity of the sodium/potassium pump in many cells Helps to decrease K+ concentrations in the serum to avoid severe electrolyte imbalances (hyperkalemia) Much more limited than the effects of glucocorticoids ▪ Glucocorticoids can also bind to the aldosterone receptor (with low affinity) and also have some “aldosterone-like” effects How are these hydrophobic steroid hormones carried in the circulation? Cortisol and aldosterone will bind somewhat to albumin The majority of cortisol is carried by cortisol binding protein (CBG) Aldosterone circulates in a primarily unbound state, and its clearance is much more rapid than that of cortisol  How are adrenal steroids metabolized? Both cortisol & aldosterone need to be glucuronidated by the liver before being excreted by the kidneys ▪ How does glucuronidation help with excretion? ▪ A: glucuronidation makes the hydrophobic steroid hormones more polar & therefore more easily excreted by the kidney ▪ Metabolites can be measured in the urine Eliminated forms of cortisol are known as 17-hydroxycorticosteroids Aldosterone as 18-glucuronide  Synthesis of catecholamines Catecholamines are synthesized from the amino acids tyrosine. Adrenal medulla is the only tissue that produces epinephrine ▪ how does epinephrine differ from norepinephrine pharmacologically? ▪ Epi stimulates both alpha & Beta receptors. ▪ NE stimulates alpha 1 & 2, Beta 1 but has very little effect on B2 Regulation of catecholamine synthesis Sympathetic stimulation, ACTH, and cortisol all stimulate the synthesis of catecholamines  Catecholamine synthesis Sympathetic Exocytosis of stimulation NE & E ▪ Sympathetic stimulation triggers exocytosis granules containing E & NE  Catecholamine synthesis Stress Response and ACTH-Cortisol Pathway (Chronic Regulation): Sympathetic Stress activates the hypothalamus, which stimulation releases corticotropin-releasing hormone (CRH). CRH stimulates the anterior pituitary to release adrenocorticotropic hormone (ACTH). ACTH targets the adrenal cortex to increase the production of cortisol. Cortisol, produced in the adrenal cortex, reaches the adrenal medulla via the intra- adrenal portal system. Cortisol induces the enzyme phenylethanolamine-N-methyltransferase (PNMT), which converts norepinephrine (NE) into epinephrine (Epi). Chronic regulation refers to how long-term stress or sustained ACTH and cortisol levels affect catecholamine production over time.  Catecholamine synthesis Acute Regulation (Neuron Sympathetic Signaling): stimulation Neurons stimulate the adrenal medulla through the release of acetylcholine. Acetylcholine binds to receptors on chromaffin cells (the cells that produce catecholamines), causing an influx of calcium (Ca²⁺) into the cell. Calcium promotes the exocytosis (release) of catecholamines stored in neurosecretory granules. This mechanism is acute regulation, as it responds to immediate stress or neuronal stimuli, rapidly increasing the release of norepinephrine and epinephrine into the bloodstream.  Catecholamine synthesis Catecholamine Biosynthesis Pathway Sympathetic (Inside Chromaffin Cells): stimulation The process begins with tyrosine, an amino acid that undergoes several enzyme-driven reactions to produce catecholamines: Tyrosine Hydroxylase (TH): Converts tyrosine to L-DOPA. DOPA Decarboxylase (DD): Converts L- DOPA to dopamine (DPN). Dopamine β-hydroxylase (DH): Converts dopamine into norepinephrine (NE). In the presence of cortisol, PNMT converts norepinephrine into epinephrine (Epi). Catecholamines are then stored in neurosecretory granules until they are released in response to neuronal signals. Actions of catecholamines - review Heart ▪ Increased contractile force ▪ Increased heart rate Vessels ▪ Vasoconstriction in skin, visceral tissue ▪ Limited vasoconstriction or vasodilation in skeletal muscle, cardiac muscle Energy metabolism ▪ ↑ blood glucose and “circulating” energy stores Gluconeogenesis, glycogenolysis, ketogenesis in the liver Lipolysis in adipose tissue Lungs ▪ Bronchodilation, decreased mucous production  Catabolism of catecholamines The process by which the body breaks down catecholamines after they have performed their functions. Epinephrine and norepinephrine are excreted in the urine in the form of metanephrine and vanillylmandelic acid (VMA)  Catabolism of catecholamines Key Steps in Catecholamine Breakdown: Enzymes Involved: Monoamine oxidase (MAO): An enzyme that breaks down catecholamines by removing an amine group. Catechol-O-methyltransferase (COMT): Another enzyme that helps by adding a methyl group to catecholamines, making them easier to break down. Main Pathway: Epinephrine and norepinephrine are first degraded by COMT, producing an intermediate called metanephrine (from epinephrine) or **normetanephrine** (from norepinephrine). Then, MAO breaks down these intermediates into vanillylmandelic acid (VMA), which is a final breakdown product. VMA is excreted in the urine.  Catabolism of catecholamines Locations of Breakdown: Catecholamines are broken down primarily in the liver, kidneys, and nerve endings. This process ensures that catecholamines do not remain in the body too long after their effects are no longer needed (like after stress or a fight-or-flight response). Catecholamines like epinephrine and norepinephrine are broken down by the enzymes **MAO** and COMT into byproducts like VMA, which is then excreted in the urine. This prevents overstimulation and keeps hormone levels balanced.