Human Endocrine System
Dr. L K Dwivedi Department of Biomedical Sciences, Bundelkhand University, Jhansi Endocrine and hormone
•Endocrine system communicates to distant tissues through bloodblood""""carriedcarried chemicals. •Organs included in the endocrine system are adrenal, gonads, hypothalamus, pancreas, parathyroid, pituitary, thyroid, etc. Nervous Vs Endocrine system
Nerves in the posterior pituitary release Oxytocin and Antidiuretic hormone, which act on the breast and kidneys, respectively; Nerves release epinephrine from the adrenal medulla, which acts on the heart, skeletal muscle, and the liver; The hypothalamic nerves secrete chemicals (releasing hormones) that act on the anterior pituitary to cause hormone release. Therefore, the definition of the endocrine system should also include such neuroendocrine systems. The hormone
The hormones areareare chemical substances produced bybyby specialized tissues and secreted into blood, ininin which they arearearecarried tototo target organs and triggers specific biological functionsfunctions" """Starling and BaylissBayliss. ... Moreover, AAAhormone isisis aaa chemical nonnon" """nutrient,nutrient, intercellular messenger that isisis effective atatat micromolar concentrations orororless (high efficiency)efficiency). ... Concentration Peptidal hormone ininin animal blood 101010 """12"121212 101010 """10"101010 MMM Steroid hormone ininin animal blood 101010 """10"101010 –––101010 """8"888MMM.M... ENDOCRINE GLAND HORMONES SECRETED TISSUE EFFECT Hypothalamus Corticotropin-releasing hormone (CRH) Stimulates ACTH secretion
Dopamine Inhibits prolactinsecretion Gonadotropin-releasing hormone (GnRH) Stimulates LH and FSH secretion Growth-hormone releasing hormone (GHRH) Stimulates GH secretion Somatostatin Inhibits GH secretion Thyrotropin-releasing hormone (TRH) Stimulates TSH and prolactin Anterior Pituitary Adrenocorticotropic hormone (ACTH) Stimulates synthesis/secretion of cortisol , androgens and aldosterone Anterior Follicle- stimulating hormone (FSH) Stimulates sperm maturation; development of ovarian follicles Growth hormone (GH) Stimulates protein synthesis and growth Luteinizing hormone (LH) Stimulates testosterone, estrogen, progesterone synthesis; stimulates ovulation Melanocyte-stimulating hormone (MSH) Stimulates melanin synthesis
Prolactin Stimulates milk production Thyroid-stimulating hormone (TSH) Stimulates thyroid hormone synthesis/secretion Posterior Pituitary Oxytocin Stimulates milk ejection and uterine contraction ENDOCRINE GLAND HORMONES SECRETED TISSUE EFFECT Posterior Pituitary Antidiuretic hormone (ADH) Stimulates renal water reabsorption Thyroid Triiodothyronine (T3) and Stimulates growth, oxygen consumption, heat production, thyroxine (T4) metabolism Calcitonin Decreases blood Ca concentration
Parathyroid Parathyroid hormone (PTH) Increases blood Ca concentration Adrenal cortex Cortisol Increases glucose synthesis, mediates “stress ” response
Aldosterone Increases renal reabsorption of Na +, secretion of K +, and H+ Androgens Similar to testosterone but weaker Adrenal medulla Epinephrine Stimulates fat and carbohydrate metabolism Pancreas Insulin Decreases blood glucose levels; anabolic effects on lipid and protein metabolism Glucagon Increases blood glucose levels Testes Testosterone Stimulates spermatogenesis and secondary sex characteristics
Ovaries Estradiol Stimulates growth/development of female reproductive system and breasts, follicular phase ofmenstrual cycle,
prolactin secretion, and maintains pregnancy Progesterone Luteal phase of menstrual cycle and maintains pregnancy
Corpus luteum Estradiol and progesterone As above
Placenta) Human chorionic gonadotropin Stimulates estrogen/progesterone synthesis by corpus luteum (hCG Endocrine System Chemical Nature of Hormones
Harmone have paracrine and autocrine functions. Hormones are divided into four groups based on chemical structure:
1. Amines ，(come from the amino acid tyrosine), 2. Peptides ，(less than 20 amino acids), 3. Small proteins ，(more than 20 amino acids), 4. Steroids ，(come from cholesterol).
Hormones act through specific receptors that define tissue selectivity and response.
Receptors for amine, protein, and peptide hormones are located on the cell membrane, while those for steroid and thyroid hormones are within the cell.
Membrane receptors are of four types based on their signaling mechanisms: G protein, tyrosine kinase, guanylyl cyclase, cytokine family.
Steroid and thyroid hormones act through nuclear receptors that stimulate gene expression.
Membrane-receptor mediated hormones elicit rapid (minutes) cellular responses; nuclear-receptor mediated hormones elicit slow (hours), long lasting cellular responses (because of slow protein degradation). Communication of the hormones
Telecrine signals
Neurocrine signals Components of membrane receptors
Carbohydrate group of glycoprotein
Receptor of Outside cell transmembrane 7 times
Cell membrane
Inside cell
Combining position of phosphorylation Membrane receptors consist of three components: (1) an extracellular domain that binds the hormone; (2) a transmembrane domain that anchors it in the membrane; (3) an intracellular domain that couples the receptor to an intracellular signaling system. Receptor Receptor
Enzyme Signal conductive mechanism of G-protein linked membrane receptors
GGG"G"""proteinprotein linked receptors have the characteristic of being linked to an intracellular class of proteins called G proteins.
G proteins are a cluster of three proteins (subunits) that, when activated by hormone binding to the extracellular domain of the receptor, cause stimulation of one of two enzymes, adenylyl cyclase (AC) or phospholipase C...
Activation of AC leads to the formation of cyclic adenosine monophosphate (cyclic AMP, cAMP),,, and activation of phospholipase C
leads to the formation of inositol trisphosphate (IP333))) or diacylglyercerol (DAG or DG),,, or activation of protein kinase C (PKC).
These named second messenger molecules initiate a cascade of events culminating in the hormone response. Theory of the second messengers for G-protein coupled receptor
Cell membrane
Hormone Physiological and Biochemical Functions Hormone Inactive protein Protein phosphorylation AC kinase Glycogen decomposition
Adenylyl cyclase Fat decomposition
Steroid Hormones synthesis Second Active protein Histone-nucleic acid synthesis Hormone Messenger kinase Nuclein-protein synthesis
Membrane protein-membrane permeability AC: Adenylyl cyclase; Canaliculus secreted movement R: regulative part in the receptor; C: part for reaction Principle of hormone acting on membrane receptor Effects of Guanylyl Cyclase (GC) Receptors
The guanylyl kinase receptors (on the membrane, combined with ANP) have the enzyme guanylyl cyclase as a portion of their intracellular domain. Binding of hormone to the extracellular domain leads to activation of guanylyl cyclase and the formation of cyclic guanosine monophosphate (cyclic GMP or cGMPcGMP)))). This second messenger initiates the hormone response. Effects of Tyrosine Kinase (TK) Receptors
The tyrosine kinase receptors are distinguished by having an intracellular domain that phosphorylates proteins on specific tyrosine molecules. These tyrosinetyrosine""""phosphorylatedphosphorylated proteins act as second messengers to initiate a cascade of events leading to hormone response. Mechanisms of hormone acting on membrane receptors (summing-up) Effects of Steroid and Thyroid Hormones
Steroid and thyroid hormones (primarily TTT 333)))signal through intracellular receptors, which actactact solely tototo initiate gene expressionexpression. ...Both hormone types diffuse through thethethe cell membrane tototo actactact ononon their intracellular receptorsreceptors....The receptors areareare protein molecules that bind tototo specific DNA sequences known asasas hormone response elementselementselements.... The hormonehormone- ---receptorreceptor complex activates thethethe HRE, initiating DNA transcription leading tototoprotein synthesissynthesis. ... Mechanism of Steroid Hormones Effect Mechanisms of T3 and T4 Effects Synthesis of hormones
Peptide and protein hormones are synthesized from amino acids as prohormones or preprohormonespreprohormones,, which are subsequently modified and stored in intracellular vesicles
until secreted by exocytosisexocytosis.. (Rough ER) Amine and steroid hormones are synthesized from precursor molecules (tyrosine, cholesterol) present in the blood.
Thyroid and steroid hormones are not stored in secretory vesicles, but the amine hormone epinephrine is. Control of hormone secretion (Common Mechanism)
Humoral regulation
Short feedback
Solid line means positive feedback; Broken line represents negative feedback
Super short feedback
Long feedback
Other mechanisms: biological rhythmic secretion; nervoue regulation, etc. Hormone Transport in the Blood
Amine, peptide, and small protein hormones circulate in a free form in blood because they are water soluble.
Steroid and thyroid hormones are carried in the blood bound to proteins (as carrier, e.g. albumin) because they are water insoluble.
Protein binding reduces hormones loss through the kidney since the proteinprotein--hormonehormone complex cannot be filtered.
Only the free form of the hormone can stimulate tissue receptors because of the capillary endothelium permeability.
Most hormones are removed from the blood by the liver and kidney shortly after being secreted even though their tissue effect continues (half(half--lifelife of hormone). Half-life of hormone in the blood
The rate atatwhich thethe amount ofofhormone inin blood decreases isis called itsits halfhalf--lifelife.. This isis thethetime itit takes thethe concentration ofof ) thethehormone totofall totoone half ofof itsitsprevious level.. level HalfHalf-- HalfHalf--liveslivesvary from plasma plasma µgµg// L L ( life minutes forfor thetheamine
hormones totohours forfor Hormone Hormone concentration concentration steroid and thyroid hormoneshormones.. Endocrine of hypothalamus-pituitary gland
General Organization
Pituitary gland and hypothalamus function in a coordinated manner to integrate many endocrine glands.
Pituitary gland is located just below the hypothalamus at the base of the brain to which it is connected by a short stalk (named the infundibuluminfundibulum))
Pituitary is divided into anterior and posterior portions.
Secretion of anterior pituitary hormones is under the control of hypothalamic releasing hormones.
Posterior pituitary hormones are synthesized in hypothalamic nerves whose axons end in the posterior pituitary where hormone is released into the blood. Relationship of Hypothalamus and Anterior Pituitary Gland Hypothalamic Hormones Influence Anterior Pituitary Hormone Secretion
Many hormones are released from the hypothalamus that control the release of anterior pituitary hormones: TRH, dopamine, GnRH,GnRH , CRH, GHRH, somatostatin,somatostatin , etc. (1) thyrotropinthyrotropin--releasingreleasing hormone (TRH, acts on the thyrotrophs and lactotrophs stimulating TSH and prolactin secretion, respectively. (2) Dopamine inhibits lactotroph secretion of prolactin . (3) Gonadotropin hormonehormone--releasingreleasing hormone ((GnRHGnRH)) stimulates FSH and LH secretion from the gonadotrophsgonadotrophs.. (4) CorticotropinCorticotropin--releasingreleasing hormone (CRH) stimulates corticotroph secretion of ACTH. (5) Growth hormonehormone--releasingreleasing hormone (GHRH) and (6) somatostatin both act on anterior pituitary somatotrophs with GHRH stimulating and somatostatin inhibiting GH secretion. Anterior Pituitary Hormones
Seven hormones are secreted by groups of anterior pituitary cell: TSH, FSH, LH, ACTH, MSH, GH, prolactinprolactin.... Trophic action is the primary effect of anterior pituitarypituitary hormones. Anterior pituitary hormones can be organized into three groups based on chemical and functional similarities: TSH, FSH, LH (same αα"""chain"chain and different ββ"""chain)"chain) ; ACTH and MSH (derived from proopiomelanocortinproopiomelanocortin,, POMC) ; GH and prolactin (straight amino acid chain, about 75% same)same) ... GH is the main regulator of postnatal growth and development, and prolactin is the major hormone responsible for milk production. Growth Hormone (GH)
GH has effects on metabolism that result from the direct action of GH on target tissue and effects on growth through GH release of insulininsulin"""" like growth factor 1 ( IGFIGF""""1)1) primarily from the liver. GH’s metabolic effects include decreased tissue glucose uptake with a consequential increase in blood glucose levels; increased fat metabolism by adipose tissue; and increased tissue amino acid uptake. These metabolic effects lead to an increase in lean body mass and to an elevation in blood insulin levels. IGFIGFIGF"IGF """11 stimulates cell division in many tissues especialespeciallyly bone. Its effect on bone produces linear growth. In addition, IGFIGF""""11 stimulates protein synthesis facilitated by the increased amino acid uptake produced by GH. Given these normal effects, it follows that GH deficiency during early childhood results in a child with a short stature , and excess body fat, while overproduction ((acromegalyacromegalyacromegaly)) results in excess organ and linear growth ((gigantismgigantismgigantism).). The Production and Regulation of GH secretion Prolactin (PRL)
PRL is the major hormone responsible for milk production (lactogenesis) and is involved in breast development. PRL secretion is reciprocally controlled through the stimulatory actions of TRH (and other yet to be identified hormones) and the inhibitory effect of dopamine. In the nonlactating person, the effect of dopamine dominates so blood levels of PRL are low. At puberty in the female, PRL enhances the ability of the elevated levels of estrogen and progesterone to stimulate breast development. During pregnancy: PRL secretion increases, and together with estrogen and progesterone enhance the development of milkmilk""""producingproducing cells in the breast. Despite the high PRL levels, milk production does not occur because the high levels of estrogen and progesterone act on the mammary gland to block the lactogenic effect of PRL. At birth, the mother’s blood levels of PRL, estrogen, and progesterone fall. The act of suckling stimulates TRH (or some other factor) and inhibits dopamine release producing a surge of PRL secretion, which stimulates milk production. Melanocyte-stimulating hormone (MSH) and Trophic Hormones
Propiomelanocortin MSH Stimulate melanocyte forming melanin to deepen skin color. Involved in releasing regulation of GH, aldosteronealdosterone,, CRH, insulin, LH, etc. Controlled by MIF (more) and MRF from hypothalamus MIF: Melanocyte Inhibitory Factor MRF: Melanocyte Releasing Factor Trophic hormones Anterior pituitary also secretes trophic hormone: ThyroidThyroid--stimulatingstimulating hormone (TSH) AAdrenocorticotropicdrenocorticotropic hormone (ACTH) Follicle stimulating hormone (FSH) LLuteinizinguteinizing hormone (LH) Posterior Pituitary Hormones
Posterior pituitary secretes two hormones, oxytocin (OXT) and antidiuretic hormone (ADH), that are synthesized by nerves in the paraventricular and supraoptic nuclei of hypothalamus.
OXT causes milk ejection in response to suckling by stimulating contraction of myoepithelial cells lining the ducts leading to the nipples. Sensory receptors in the nipples signal the brain and hypothalamus causing activation of nerve cells of the PVN and OXT release. In addition, OXT stimulates uterine contraction but its role in parturition is unclear.
ADH increases water reabsorption by increasing the water permeability of the collecting duct of the kidney. Further discussion of its mechanism of action and the control of its release can be found in Renal Physiology. Thyroid gland
Thyroid gland consists of two lobes, one on either side of the trachea just below the cricoid cartilage.
Lobes are composed of spherical follicles formed by a single layer of epithelial cells that surround a lumen filled with a gelgel--likelike substance called colloid composed primarily of thyroglobulin , the precursor of thyroid hormones.
The epithelial cells synthesize and secrete thyroglobulin..thyroglobulin Synthesis of Thyroid Hormone
Blood Follicle Epithelium Colloid MIT+DIT
Thyroid Peroxidase - - I I I2 I2 + T3 Pump Na + TG TG DIT+DIT MIT + Tyrosine DIT -T 3 -T T4 T -T 3 3 4 -T TG -MIT TG 4 + -MIT -DIT T4 -DIT
Synthesis includes steps that occur within the epithelial cells and colloid of the thyroid gland as well as at the target tissue. Iodine uptake and thyroglobulin synthesis occur within epithelial cells.
Iodination of thyroglobulin and synthesis of T 333 and T 444 occur within the colloid.
TTT333, most active form of the hormone, is produced from T 444 at the target tissue. Releases of Thyroid Hormone
Stimulation of hormone secretion by TSH causes the epithelial cells to engulf small globs of colloid and move them into the cell by endocytosisendocytosis.. Within the epithelial cell,
MIT, DIT, T 333, and T 444 are secreted into the blood while MIT and DIT are broken down to II""""and tyrosine molecules for reuse by the epithelial cell.
Most of the secreted T 3 and T 444 are carried in the blood bound to thyroxine bindingbinding
globulin (TBG). TTT333 is more biologically active than T 444, but since T 444 synthesis occurs more rapidly, more T 444 than T 333 is secreted. Target tissues contain an enzyme, 5’5’5’"5’""" iodinasethat converts T4 to T3. Control of Thyroid Hormone Secretion
Secretion is stimulated by TSH, which in turn is stimulated by TRH.
TSH stimulates all aspects of thyroid hormone synthesis and secretion and also has a trophic effect.
Elevated blood levels of T 333 feed back to the anterior pituitary thyrotrophs and reduce TSH secretion. Control of Thyroid Hormone Secretion
TRH isisis release from thethethe hypothalamus which acts ononon thethethe anterior pituitary thyrotrophs stimulating TSHTSHTSH releaserelease. ...TSHTSHTSH acts ononon thethethe thyroid gland stimulating every aspect ofofof thyroid hormone synthesis and secretionsecretion. ... TSHTSHTSHincrease iodide uptake bybyby follicular cells, iodination ofofof thyroglobulin, formation ofofof MIT and DIT, and endocytosis ofofof colloid ...These actions areareare mediated through GGG" G"""proteinprotein coupled membrane TSHTSHTSH receptors ononon thethethe thyroid gland that stimulate thethethe formation ofofof cyclic AMP and aaa cascade ofofof protein phosphorylation stepssteps. ...With sustained TSHTSHTSH release, aaa trophic effect occurs causing thyroid gland enlargementenlargement....
TTT3T333controls itsitsits own release through aaa negative feedback effect ononon thethethe pituitary thyrotrophsthyrotrophs....Increasing blood levels ofofof free TTT3 T333actactact ononon pituitary thyrotrophs tototo decrease their number ofofof TRH receptorsreceptors. ...This makes TRH less effective, decreasing thethethe amount ofofof TSHTSHTSH released and therefore, thethethe amount ofofof thyroid hormone secretedsecreted. ...The netnetnet effect ofofof this feedback process isisis tototo produce aaa relatively constant blood level ofofof thyroid hormones ... Action of Thyroid Hormones
Because T3 acts by inducing DNA transcription, its effects on tissue are the result of protein synthesis, primarily the synthesis of enzymes (particularly the Na-K-ATPase involved in ion transport).
Thyroid hormones are required for normal growth throughout life.
Thyroid hormones affect basal metabolic rate (BMR, raises the cellular oxygen consumption and heat production), metabolism, the cardiovascular system (CO, Ventricular contractility and HR↑), and the nervous system (excitability↑).
Symptoms of thyroid hormone excess or deficiency can be predicted from their normal effect; hyperthyroidism, an autoimmune disease named Graves’ disease or hypothyroidism, also an autoimmune destruction of the thyroid gland, thyroiditis. Cretinism may occur . Hyperthyroidism Vs. Hypothyroidism Cretinism Parathyroid gland, thyroid C cell and VitaminD3
Calcium and phosphate regulation Approximately half of the calcium in the blood is ionized, the biologically active form. Approximately half of the calcium in the blood is bound to albumin or is complexed with anions such as phosphates and sulfates. Blood Ca homeostasis produced through the interaction of bones, kidneys, and small intestine. Parathyroid hormone, calcitonincalcitonin,, and vitamin D are the three hormones of Ca homeostasis. Hypercalcemia (depress nerve excitability) is characterizedcharacterized by constipation, polyuriapolyuria,, and lethargy; hypocalcemia (increase nerve excitability) is characterized by spontaneous muscle twitching, cramps, tingling, and numbness. Parathyroid Gland
Parathyroid gland senses blood Ca levels through cell surface receptors. Parathyroid gland secretes PTH (84 amino acids) in response to reduced blood Ca levels (by cAmpcAmp""""inducedinduced mechanism). PTH stimulates (1) bones dissolutiondissolution,, (2) renal Ca reabsorptionreabsorption,, and (3) intestinal Ca absorption. Vitamin D3
Vitamin D ((cholecalciferolcholecalciferolcholecalciferol)) is a steroid obtained from the diet or synthesized by the skin (from cholesterol under the effect of ultraviolet light).
Active form of vitamin D (1,25 """ dihydroxycholecalciferoldihydroxycholecalciferol)) is formed in the kidneys through the action of 111αα"""hydroxylase."hydroxylase.
Activity of 1 αα"""hydroxylase"hydroxylase is influenced by the blood levels of Ca and PTH.
Vitamin D elevates blood levels of both Ca and phosphate (from DNA levels) through actions on the small intestines, kidneys, and bone. Calcitonin Hormone and its functions
Calcitonin (32 amino acids) is synthesized by parafollicular cells or C cells of the thyroid gland.
Increased blood Ca levels stimulate calcitonin secretion.
Calcitonin inhibits osteoclast bone resorption reducing blood Ca levels.
Its physiological function is not well defined. Pancreas
oo Cells of the endocrine pancreas are organized into clusters called islets of LangerhansLangerhans.... oo Islets of Langerhans are composed of three cell types －alpha, beta, and deltadeltaDDDDthatthat secret glucagonsglucagons,, insulin, and somatostatinsomatostatin,, respectively. oo Blood flow from the beta cells carries insulin past the alpha and delta cells and reduces their secretion of glucagons and somatostatinsomatostatin,, receptively. oo Insulin and somatostatin inhibit, while glucagons stimulates, the secretions of other islet cells. Histology of pancreas Insulin oo Insulin is synthesized by ββ"""cells"cells from a prohormoneprohormone.. oo Insulin is the hormone of plenty and is released when metabolic supply (primarily glucose) exceeds the needs of the body. oo Operating through tyrosine kinase receptors on liver, skeletal muscle, and adiposeadipose cells, insulin conserves glucose and increases fat storage and protein synthesis. oo Insulin also helps maintain a low blood K ion level by stimulating the NaNa""""KKKK""""ATPaseATPase pump. oo Insulin is synthesized from an 86 amino acid prohormoneprohormone by enzymatically removing a central amino acid string and linking the remaining strands with two disulfide bonds. The final hormone looks like two railroad tracks (amino acid chains) held together by two ties (disulfide bonds). This synthesis occurs within storage vesicles of the ββ"""cells."cells. Secretion of Insulin oo In response to a meal, insulin secretion is stimulated. An elevated blood glucose level is the primary stimulus for insulin secretion. oo Glucose binds to its glut 222"2"""transportertransporter on pancreatic ββ"""cells,"cells, which carries it into the cell by facilitated transport. Inside the cell, glucose metabolism leads to increase ATP levels, which in turn open KK""""channelschannels depolarizing the cell and increasing intracellular calcium concentration. oo Elevated Ca induces fusion of the storage vesicles with the cell membrane and stimulates insulin release. Fatty acids and amino acids also stimulate insulin secretion, presumably through a similar mechanism. oo Glucagon stimulates insulin secretion by acting directly through a GG"""" protein linked receptor on ββ"""cells"cells as well as indirectly by elevating blood glucose levels. oo On the other hand, somatostatin inhibits insulin secretion by acting directlydirectly on the ββ"""cells"cells and indirectly by reducing the ability of gluglucagoncagon to stimulate insulin secretion. Mechanism of action of Insulin Functions of Insulin Glucagon
Glucagon is a single chain of 29 amino acids synthesized by αα"""cells."cells.
Glucagon acts primarily on the liver to increase and maintain blood glucose levels.
Glucagons secretion is increased in response to falling blood glucose and increasing blood amino acid levels.
Glucagon secretion is inhibited by insulin acting directly on αα"""cell"cell through the insulininsulin""""receptor.receptor.
Glucagon restores blood glucose levels by stimulating glucose synthesis from amino acids and by stimulating fat metabolism.
Secretion rates of glucagons and insulin change in opposite directions to maintain blood glucose homeostasis. Function of Glucagon
Glucagon elevates blood glucose levels Liver Glucose Synthesis & Fatty bybybystimulating thethethe Acid Metabolism synthesis ofofof newnewnew glucose bybyby thethethe liver Glucose Adipose Tissue from amino acids Amino Acids Fat Breakdown (((gluconeogenesis(gluconeogenesisgluconeogenesis))))....InInIn addition, glucagon Fatty Acids Blood Levels stimulates thethethe liver Glucose Rise tototometabolize fatty Amino Acids Rise acids rather than glucoseglucose.... Correlation between insulin and glucagon Somatostatin
Somatostatin is a peptide hormone released from δδ""" cells.
Somatostatin acts in a paracrine manner to inhibit glucagon and insulin secretion locally.
Somatostatin secretion is increased in response to a meal and, therefore, acts to modulate the response of insulin and glucagon to a meal. Diabetes Mellitus
Diabetes mellitus is a disease of altered insulin function and is in two forms.
Type I is primarily due to the inability of β"""cells"cells to produce and secrete insulin (autoimmune reaction); type II is characterized by marked resistance of target tissues to insulin (obesity, aging, various illnesses).
Metabolic characteristics consist of elevated blood glucose levels, elevated blood amino acid levels, and elevated free fatty acids leading to formation of ketone bodies and acidemia.
Blood level of K ions is also elevated.
Elevated blood glucose levels lead to osmotic diuresis (dehydration, polyuria, thirst ).
Chronic complications of this metabolic disorder affect the eyes, the kidneys, the peripheral nervous system, and the vascular system.
Mechanism is given in next slide
Adrenal gland
The adrenal gland, located above each kidney, is divided into an outer cortex and an inner medulla.
The adrenal cortex secretes three classes of steroid hormones － mineralocorticoids, glucocorticoids and androgens － each form a different cell layer.
The adrenal medulla secretes the catecholamines, epinephrine, and norepinephrine. Hormone synthesis of Adrenal Cortex
Hormones of the cortex are all derived from cholesterol (blood).
Each cortical layer possesses unique enzymes (P450 oxidasesoxidases)) that permit the synthesis of layerlayer""""specificspecific hormones from the common precursor, pregnenolonepregnenolone.... Hormone Synthesis of Adrenal Cortex
Zona Glomerulosa Cholesterol→Pregnenolone→Progesterone→ 11-Deoxycorticosterone→Corticosterone→Aldosterone
Stimulated by ACTH Stimulated by Angiotensin II & K +
Zona Fasciculata Cholesterol→Pregnenolone→17-Hydroxypregnenolone→ 17 -Hydroxyprogesterone→11 -Deoxycortisol→Cortisol
Stimulated by ACTH
Zona Reticularis Cholesterol→Pregnenolone→ 17-Hydroxypregnenolone→Dehyrdroepiandrostrone→Androstenedione Each zone of the adrenal cortex utilizes different enzymes to synthesize specific hormones from cholesterol. ACTH primarily stimulates secretions from the zona fasciculata and reticularis while angiotensin Ⅱand K ions stimulate secretion from the zona glomerulosa. Control of Adrenal Cortex hormone secretion
Secretions of the zona fasciculata and reticularis are under the sole control of the CRHCRH""""ACTHACTH axis.
Cortisol secretion from the zona fasciculata is pulsatile with a diurnal rhythm driven by activity within the brain.
Stress stimulates the hypothalamushypothalamus""""pituitarypituitarypituitary""""adrenaladrenal axis to increase cortisol secretion.
Cortisol secretion is limited by a negative feedback systemsystem at the lever of both the hypothalamus and anterior pituitary.
Secretion of the zona glomerulosa are affected primarily by the action of angiotensin Ⅱand to a lesser extent by K ions and ACTH. Control of Cortisol secretion
(-) Hypothalamus
CRH
(-) Anterior Pituitary (Corticotrophs)
ACTH Negative Feedback Feedback Feedback Feedback Negative Negative Negative Negative Adrenal Cortex (Zona Fasciculata)
Cortisol
Cortisol limits its own secretion at the level of the hypothalamus and anterior pituitary. Circadian Rhythmic changes of plasma cortisol concentration
Cortisol secretion is pulsatile with a diurnal variation driven by rhythmic neural activity in the brain that stimulate pulsatile CRH release. Blood levels of cortisol are highest immediately before waking and shortly thereafter. Stress and other stimuli override this pattern by directly increasing CRH-ACTH-cortisol secretion. Glucocorticoid Action
Glucocorticoids ((CortisolCortisolCortisol)) are essential for life, and without it, wewe cannot survive.
It increases blood glucose levels (especially during starvation, hypoglycemia, stress and trauma), synthesis in the liver and reduces glucose utilization by muscle and fat cells, inhibiting insulin effect, fat redistribution (buffalo hump, moon faciesfacies).).
Glucocorticoids are catabolic and diabetogenic, reduce inflammation, suppress immune responses, stimulate gastric acid secretion and support vascular response to CatecholaminesCatecholamines,, etc.
Stress response, antianti""""shock,shock, antianti""""allergy,allergy, antianti""""poisoning.poisoning.
Increase RBF, GFR and renal water falloff
Widespread use in the clinic. Glucocorticoid Action
Cortisol elevates blood glucose levels by stimulating glucose synthesis in the liver from amino acids and glycerol derived from protein and fat breakdown, respectively. Androgen Action
Adrenal androgens play an important role in the female but not in the male Because it do not contribute significantly to testosterone synthesis. In the female, androgens are responsible for the development of public and axillary hair and for libido. Pathology of Adrenal Cortex
Abnormal adrenocortical secretion can result from alterations in the gland itself, the hypothalamus, or the anterior pituitary. Abnormalities of the adrenal cortex include Addison’s disease , Cushing’s syndrome, and Conn’s syndrome. Abnormalities of the anterior pituitary include Cushing’s disease. Glucocorticoid and Clinic
InInInthethethe hospital Exogenous cortisol used forforfor treatment forforfor long time cannot bebebe stopped atatatonce! Addison’s Disease ( Adrenocortical function deficiency)
Addison’s disease usually results from an autoimmune destruction of all three layers of the adrenal cortex. The symptoms parallel the loss of all adrenocortical hormones and include hypoglycemia and weight loss due to the absence of glucocorticoids as well as increased plasma K and hypotension due to the absence of aldosteronealdosterone.. In the absence of adrenocortical hormones there is no negative feedback inhibition of ACTH release, causing blood ACTH levels to be very high. Because MSH is a part of the ACTH molecule, the high levels of ACTH cause the skin darkening of patients with Addison’s disease. Cushing’s Syndrome and Disease
Cause due tototo excess production ofofof glucocorticoidsglucocorticoids. ... Some ofofof thethethe symptoms include hyperglycemia, muscle wasting, obesity, and hypertensionhypertension. ...ACTH levels will bebebe lowlowlow since there isisis plenty ofofof cortisol tototo inhibit itsitsits releaserelease. ... Cushing’s disease results from oversecretion ofofof ACTH from aaa pituitary tumortumor. ...What distinguishes ititit from Cushing’s syndrome isisis that thethethe ACTH levels areareareelevatedelevated. ...AllAllAll other symptoms areareare thethethe samesame. ... “Full“Full""""moon”moon” face Conn’s syndrome Conn’s syndrome results from excess aldosterone from ananan aldosteronealdosterone" """secretingsecreting tumortumor. ...Symptoms include increase extracellular fluid volume, hypertension, and reduced blood KKK levelslevels. ... Adrenal Medulla
The adrenal medulla is essentially a neuroendocrine organ that is activated by sympathetic preganglionic nerves.
Nerve stimulation results in the release of stored epinephrine (more) and norepinephrine (less) from chromaffin cells (tyrosine).
Catecholamines have widespread effects (through ββ""" adrenergic GG""""proteinprotein linked membrane receptors) on the cardiovascular system, muscle system, and metabolism (blood glucose levels ↑↑).).).
Emergency reaction hypothesis Thank You for Your Attention