Biochemical Endocrinology BCH 560

1. Biochemical EndocrinologyBCH 560 Prof. Omar Al-Attas King Saud University Department of Biochemistry College of Science

2. Endocrinology is the capacity of specialized tissues to function in integral fashion as components of intact organism which is made possible in large by two control mechanism. Nervous system – Neurotransmitters i.e.: Acetylcholine, Dopamine, Serotonin, Gamma Aminobutyric Acid (GABA), Glutamate, Epinephrine and Norepinephrine, Endorphins Endocrine system – Hormones i.e.: ADH, ACTH, Prolactin, Calcitonin ,Parathyroid, Renin, Insulin, Glucagon, CCK, Resistin, Leptin…etc

3. Endocrine versus Nervous Systems • Major communication systems in the body • Integrate stimuli and responses to changes in external and internal environment • Both are crucial to coordinated functions of highly differentiated cells, tissues and organs • Unlike the nervous system, the endocrine system is anatomically discontinuous.

4. Cont… The nervous systemexerts point-to-point control through nerves, similar to sending messages by conventional telephone. • Nervous control is electrical in nature and fast. The endocrine systembroadcasts its hormonal messages to essentially all cells by secretion into blood and extracellular fluid. • Like a radio broadcast, it requires a receiver to get the message – • in the case of endocrine messages, cells must bear a receptor for the hormone being broadcast in order to respond.

5. Endocrinology traditionally defined as the action of hormones and the organs in which the hormones are formed. It is About: • The study of anatomy and physiological function of the major endocrine organs. • The secretory products of these organs. • The mechanism of hormone action. • The clinical manifestation of hormone action

6. The interlocking nature of the nervous and endocrine systems is that there is no sharp distinction between the two systems. Nervous System Endocrine System Regulated Organs or Tissue

7. Endocrine Gland Their products are secreted directly and internally into the blood stream which do not utilize ducts. These ductless glands were termed Endocrine.

8. The Classic Gland Cont… Thyroid and Parathyroid Adrenals Placenta Male and Female Gonads Pancreatic islets Prostaglandin Pituitary

9. Types of Hormones • Products of the ductless gland (Endocrine Hormones) • Work at a relatively short range (Telecrine) • Work at a nearby hormones (Paracrine)- cells secret substances that diffuse into the extracellular fluid and affect neighboring cells. Endocrine and Telecrineglands or specialized cells release hormones into the circulating blood that influence the function of cells at another location in the body. At present, there are about 50 known hormones such as protein, small peptide and steroids.

10. Mechanism of Action of Hormone Hormone are chemical messengers synthesized by organism that initiate biological responses by binding with high affinity and specificity to target cell receptors within the same individual. They are: • Endogenous substance • High affinity and specificity of binding to specific receptors on target cells • Initiates biological response

11. Amine Hormone Derivatives of tyrosine Catecholamines (epinephrine, dopamine) Catecholamines are both neurohormones and neurotransmitters. • These include epinephrine, and norepinephrine • Epinephrine and norepinephrine are produced by the adrenal medulla both are water soluble • Secreted like peptide hormones Thyroid Hormone (dipeptides) are basically a "double" tyrosine with the critical incorporation of 3 or 4 iodine atoms. • Thyroid hormone is produced by the thyroid gland and is lipid soluble • Thyroid hormones are produced by modification of a tyrosine residue contained in thyroglobulin, post-translationally modified to bind iodine, then proteolytically cleaved and released as T4 and T3. T3 and T4 then bind to thyroxin binding globulin for transport in the blood Tryptophan derivative • Melatonin

12. Catecholamines • Molecules with catechol group Hormonal regulators • Dopamine in hypothalamus inhibits prolactin secretion • Epinephrine (adrenaline) – stress reaction • Synthesized from aa phenylalanine or tyrosine in enzymatic reactions

13. Peptide Hormone • Range from 3 amino acids to hundreds of amino acids in size. • Often produced as larger molecular weight precursors that are proteolytically cleaved to the active form of the hormone. • Peptide/protein hormones are water soluble. • Comprise the largest number of hormones– perhaps in thousands

14. Synthesis (peptide Hormone) • By one or two genes e.i.: Insulin from single gene Glycoprotein hormone from two precursors. • Initial ribosomal product called Preprohormonesprohormone hormone • mRNA on ribosomal membrane • Translation of mRNA results in an AA’s sequence at NH2 terminus of nascent polypeptide. • Cleavage occurs at sequence lys – Arg or Arg – Aig in Golgi complex -Transport it to Rough Endoplasmic Reticulum -An energy-requiring process facilitated by activity of cellular microfilaments

15. Release of peptide hormone • Peptide hormones and catecholamine, migrate to control the plasma membrane in microfilament and fuse to membrane by exocytosis • Control by influx of Ca++ . • Secretion at constant rate in pulsetile fashion ( Short Bursts)

16. Storage • After synthesis in rough endoplasmic reticulum • Packed in membrane vesicles to form granules in the Golgi complex as prohormone. • Glands for peptide hormone contain up to one day supply of hormone • Glands for steroids hormone contain longer time

17. Steroid Hormone • All steroid hormones are derived from cholesterol and differ only in the ring structure and side chains attached to it. • All steroid hormones are lipid soluble Types of steroid hormones Glucocorticoids; cortisol is the major representative in most mammals Mineralocorticoids; aldosterone being most prominent Androgens such as testosterone Estrogens, including estradiol and estrone Progestogens (also known a progestins) such as progesterone

18. Facts about steroid hormone • Are not packaged, but synthesized and immediately released • Are all derived from the same parent compound: Cholesterol • Enzymes which produce steroid hormones from cholesterol are located in mitochondria and smooth ER • Steroids are lipid soluble and thus are freely permeable to membranes so are not stored in cells • Steroid hormones are not water soluble so have to be carried in the blood complexed to specific binding globulins. • Corticosteroid binding globulin carries cortisol • Sex steroid binding globulin carries testosterone and estradiol • In some cases a steroid is secreted by one cell and is converted to the active steroid by the target cell: an example is androgen which secreted by the gonad and converted into estrogen in the brain

20. Steroid Hormone (Cholesterol and Lipid Soluble) • From small molecular weight precursors -Cholesterol Sequential cleavage of carbon-carbon bonds - Hydroxylation Site of Synthesis • On the gland tissue • On the Central Nervous System

21. Transport Lipid soluble hormones require transport proteins • albumin and transthyretin (prealbumin) • specific transport molecules (thyroxine-binding globulin) • only unbound hormone can enter the cell. • Steroid and thyroid hormones are 99% attached to special transport proteins i.e. Binding Carrier Circulation in Blood • From seconds (epinephrine) to hours (insulin), to days (reproductive hormone) • Typical resting concentration very low • Under stimulated condition: Peptide hormone: 5-100 folds Catecholamine: 5-100 folds Steroids: 5-1000 folds

22. LH Extracellularlipoprotein Cholesterolpool acetate ATP cAMP cholesterol PKA+ Pregnenolone 3bHSD Progesterone P450c17 Androstenedione 17bHSD TESTOSTERONE

23. Feedback Relationship • Distinguishing characteristics of Endocrine System –Feedback control production. • To maintain homeostatic balance for body fluid and rate of various metabolic process. Example: 1. Increase of parathyroid hormone sensed by (Ca++) level ↑ (Ca++) (-) Feedback ↓ (Ca++) (-) Feedback • (Complex)- Interaction Pituitary- Thyroid hormone Adrenal – Gonads Hormone

24. Type of Feedback • Cation ( Ca++ on PTH) • Metabolites (Glucose on insulin and increase glucagon) • Hormone (Somatostatin on insulin and glucagon) • Osmolality (Vassopressin, renin, aldosterone) Feedback is useful in the assessment of pathological states: Insulin level-Glucose level TSH levels- Serum Thyroxine

26. Function of Hormones Hormonal function involves four Broad domain • Reproduction – Regulate reproductive system • Maintenance of internal environment • Growth and development • Energy production, utilization and storage

27. Cont… Other Function of Hormones • Regulategametogenesis • Control dimorphic, anatomical function and behavioral development • Regulate stability of body fluid and electrolytes, heart rate, acid base balance, body temperature bone mass, muscle and fat. • Mediator for substrate flux, conversion of calories to energy. • Mediator in catabolism – glucagon of glycogen breakdown AA’s and FA’s to glucose • Help regulate circadian rhythms ( Sleep/wake periods)

28. Interaction of Hormones Hormone Different effects on various tissues at different times of life. • Induction of male differentiation of the Wolffian ducts. • Regression of the embryonic breast. • Growth of the male urogenital tract. • Induction of the spermatogenesis. • Growth of the beard and body hair. • Retention of nitrogen • Development of prostatic hyperplasia in aging males of several species. • promotion of muscle growth Testosterone • Explanation: • Binding to a high affinity receptor • Transport of hormone-receptor to nucleus • Binding to DNA to promote synthesis of mRNA

29. Cont… One function of multiple Hormones (Insulin) A classic example is maintenance of plasma glucose within narrow range: high enough to prevent dysfunction of the central on the one hand low enough to prevent the detrimental effects of hyperglycemia on the other hand. Such regulation could not be accomplished smoothly by a single hormone no matter how powerful. Insulin (prevent hyperglycemia) Glucose level Glucagon (prevent hypoglycemia) Catecholamine Cortisol, GH Prevent sever hyperglycemia

30. Mechanism of Steroid Actions Steroid Hormone Cell by diffusion Binding macromolecules protein (receptors) Specific binding sitesin cytoplasm and nucleus of the cell Acceptor protein on the DNA matrix Structure of Steroid Nucleus

31. Signal Modulations These signals or mediators that can modulate the rate and extent of a wide variety of biochemical reaction and metabolic pathways in almost every known cell type. Biochemical Reaction Metabolic Pathways

32. Steroid Receptors Characteristic First, Binding capacity Labeled hormone binding to cells membrane, then measuring the bound receptor and the free hormone receptors High affinity Measured by the physiological response

33. Specificity Biological Response Receptor sites have capacity for recognition to the primer hormone rather for other agonistic or antagonistic. Certain tissue are specific for certain hormone e.g. Sex Steroids for (uterus, vagina) Hormone receptor binding precedes tissue response

34. Control of Hormone Binding By Site Activation Functional Activation Phospohorylation of active site by ATP and protein kinase i.e.,Glucocorticoid receptor Dephosphorylation by phosphatase i.e., estrogen receptors causes the loss of estrogen binding activity Hormone regulation the effective receptor titer: Down rregulation –represent a redubtioninhormone-binding activity. i.e.,progesterone receptor number decreaseswithin 1 hour after progesterone administration. Augment receptor titer Estrogen and estradiol administration causes increase in receptor level Induced fil.

35. Feature of Steroid Receptors Functional Activity of Receptors Presents in a small amount in cells. (0.001%-0.1% of total soluble proteins) Structurally differ form receptor to another High affinity of DNA from hormone Estrogen Receptor binds to DNA after hormone-receptor complex formation. Progesterone receptor A subunit of receptor possesses the DNA binding. Glucocorticoids Receptors should be saturated with the hormone

36. Pancreas

37. Brief History • Herophilus, Greek surgeon first described pancreas. • Wirsung discovered the pancreatic duct in 1642 now called duct of Wirsung. • Pancreas as a secretory gland was investigated by Graaf in 1671. • R. Fitz established pancreatitis as a disease in 1889. • Dr. Whipple performed the first pancreatico-duodenectomy in 1935 and refined it in 1940 now called Whipple procedure.

38. Anatomy of Pancreas

39. H- Head of the PancreasN- Neck of the PancreasB- Body of the PancreasT- Tail of the PancreasUN- Uncinate Head of the Pancreas Neck of the Pancreas Includes uncinate process Flattened structure, 2 – 3 cm thick Attached to the 2nd and 3rd portions of duodenum on the right Emerges into neck on the left Border b/w head & neck is determined by GDA insertion SPDA and IPDAanastamose b/w the duodenum and the rt. lateral border 2.5 cm in length Straddles SMV and PV Antero-superior surface supports the pylorus Superior mesenteric vessels emerge from the inferior border Posteriorly, SMV and splenic vein confluence to form portal vein Posteriorly, mostly no branches to pancreas

40. H- Head of the PancreasN- Neck of the PancreasB- Body of the PancreasT- Tail of the PancreasUN- Uncinate Body of Pancreas Tail of Pancreas Elongated, long structure Anterior surface, separated from stomach by lesser sac Posterior surface, related to aorta, lt. adrenal gland, lt. renal vessels and upper 1/3rd of lt. kidney Splenic vein runs embedded in the post. Surface Inferior surface is covered by tran. mesocolon Narrow, short segment Lies at the level of the 12th thoracic vertebra Ends within the splenichilum Lies in the splenophrenic ligament Anteriorly, related to splenic flexure of colon May be injured during splenectomy (fistula)

41. Histology of Pancreas Exocrine Pancreas Endocrine Pancreas 2 major components – acinar cells and ducts Constitute 80% to 90% of the pancreatic mass Acinar cells secrete the digestive enzymes 20 to 40 acinar cells coalesce into a unit called the acinus Centroacinar cell (2nd cell type in the acinus) is responsible for fluid and electrolyte secretion by the pancreas Ductular system - network of conduits that carry the exocrine secretions into the duodenum Acinus small intercalated ducts  interlobular duct  pancreatic duct Interlobular ducts contribute to fluid and electrolyte secretion along with the centroacinar cells