ENDOCRINOLOGY

1. ENDOCRINOLOGY

2. INTRODUCTION • Endocrinology – study of the endocrine system • Encompasses knowledge of the functions of the endocrine system, endocrine glands, types and functions of hormones especially in the regulation of the physiological activities of the body

3. Functions of the endocrine system • The endocrine and nervous systems are two regulatory systems of the body • Compared to neural activity, the action of hormones is usually slower and prolonged • The endocrine system mainly controls activities that require a longer duration. • Eg: Help in maintaining homeostasis and regulation of activities such as the concentration of chemicals in body fluids and metabolism of lipids, carbohydrates and proteins • Work closely with the nervous system to help the body combat stress • Assist in the regulation of growth and development especially in maturity, sexual development and reproduction

4. The endocrine system is a complex system • One endocrine gland can produce multiple hormones. A single hormone can be produced by more than one endocrine gland. • A single hormone can have more than one type of target cell therefore, more than one effect. Also, a single target cell can be influenced by more than one hormone. • Other factors contribute to the complexity of the system. The rate of secretion of a hormone can vary over time. • The same chemical messenger can be a hormone or neurotransmitter (e.g., norepinephrine). • Some organs have exclusively endocrine functions. Other organs (e.g., testis) have endocrine functions and non-endocrine functions.

5. Hormone • Special chemical substances produced and secreted by endocrine cells/tissues/glands • Effective even in small quantities • Balanced by other hormones • Can act on cells located far away, nearby or on the cell that secretes the hormone • Helps to regulate the rate of biochemical reactions • Is not influenced or changed by the reactions that it controls

6. Hormone Can be categorized by its solubility: 1.   Water soluble (hydrophilic) eg: peptide and protein hormones are transported freely in blood • Fat soluble (lypophilic) eg: steroid hormones and prostaglandins are transported in blood by binding to plasma proteins Can be categorized according to its chemical structure: 1. Acid amino derivatives (amines and secreted by adrenal medulla with the main aa being tyrosine) • Peptide hormones (small peptides, polypeptides, glycoproteins) • Lipid derivatives (steroid hormones and eicosanoids) (steroid hormones are secreted by the adrenal cortex and gonads)

7. Examples of hormones 1. Protein hormones – Growth Hormone (GH), prolactin and insulin 2. Glycoprotein hormones – Follicle Stimulating Hormone (FSH), Luteinizing Hormone (LH), Thyroid Stimulating Hormone (TSH) and Parathyroid Hormone (PTH) 3. Polypeptide hormones – oxytocin, calcitonin, glucagon 4. Acid amino derivative hormones – adrenaline (epinephrine), noradrenaline (norepinephrine), melatonin, dopamine, thyroid hormones 5. Lipid/steroid hormones – testosterone, estrogen, corticosteroids, cortisol 6. Fatty acid hormones/eicosanoids – thromboxane, leucotriene and prostaglandins

8. The mechanisms of hormone synthesis, storage, and secretion vary according to the class of hormone • Peptide hormones have precursors called preprohormones made on ribosomes of the endoplasmic recticulum (ER). Are converted to prohormones and active hormones in the Golgi complex. The Golgi complex concentrates these hormone into secretory vesicles which are then eleased from endocrine cells by exocytosis • Cholesterol is the common precursor for all steroid hormones. A series of enzymatic steps modify this molecule into a different hormone in a specific endocrine cell. Only the precursor (cholesterol) is stored. The lipid-soluble hormone is not stored • The amine hormones are made from tyrosine. These hormones are stored until they are secreted

9. Regulatory feedback mechanisms • Hormones are secreted in a fixed amount to maintain homeostasis, i.e., not secreted continuously • Why? Any changes in the body’s physiology will be detected by the brain (main control center) where actions has to be taken to maintain homeostasis • Therefore secretion of hormones are dependant on a feedback mechanism • This regulatory feedback mechanism is either positive or negative, long loop or short loop • Example of a positive and negative feedback mechanism is the regulation of the functions of the female reproductive system • Example of a long loop and short loop feedback mechanism is the regulation of the body systems under stressful conditions

11. Interactions of hormones with target cells What are target cells? Target cells are: • cells that possess a receptor that is compatible to the hormone and is located either on the plasma membrane surface or in the cytoplasm or nucleus • influenced by certain hormones

12. Hormones that combine with receptors will influence the rate of cell physiological processes • Down regulation is a decrease in the number of receptor molecules in target cells • Up regulation is an increase in receptor molecules of target cells

13. Types of hormone receptors • Receptors that are located on the membrane or membrane surface will bind to hydrophilic hormones or hormones that have a large molecular weight • Receptors that are located intracellular (in the cell) will bind to lypophilic hormones

14. Mechanism of hormone action • Act by binding to special receptors on target organs • A hydrophilic hormone binds to the target cell surface and activates a second-messenger system Eg; Protein hormones will bind to receptors on the surface of the plasma membrane of the target cell • require a messenger i.e., second messenger e.g., cAMP (cyclic adenosine monophosphate) present in the extracellular fluid to trigger a biologic reaction eg., insulin

15. A lipophilic hormone stimulates a gene, promoting protein synthesis Eg;Steroid hormones have a receptor in the cell and can diffuse freely into cells because it is lypophilic • After binding with the cytoplasmic receptors in the target cells, it will trigger a physiological reaction eg., estrogen

16. Mechanism of hormone action for protein hormones (hydrophilic) Hydrophilic hormones secreted by endocrine glands  Travel freely in blood vessels until reach target organs  Bind with receptor on surface of plasma membrane  Hormone-receptor complex stimulates G protein  G protein connects this complex to adenyl cyclase enzyme in the inner surface of the cell

17. Activated adenyl cyclase converts ATP to cAMP  cAMP activates protein kinases  Protein kinases trigger a cascade of enzyme reaction  Causes cells to undergo certain functions i.e., release of energy from hepatic cells  After cells have completed their physiological functions, cAMP is deactivated by phosphodiesterases  Location of receptor on the plasma membrane returns to its origin and ready to receive new hormones

18. Plasma membrane First messenger, usually an extracellular chemical messenger G protein intermediary ECF Adenyl cyclase ICF (Converts) Receptor Second messenger Binding of extracellular messenger to receptor activates a G protein, the a subunit of which shuttles to and activates adenyl cyclase (Activates) (Phosphorylates) (Phosphorylation induces protein to change shape) = phosphate

19. Mechanism of steroid hormones (lypophilic) Lypophilic hormones are secreted  Transported in blood by binding to plasma proteins  Released by plasma proteins on reaching target cells  Diffuses through plasma membrane and binds to receptor inside cytoplasm  Hormone receptor complex enters cell nucleus and binds to cell DNA  Triggers DNA transcription and produces mRNA  Directs protein synthesis eg:breast development under estrogen influence and development of dense muscular mass under testosterone influence

20. Plasma membrane Cytoplasm of target cell Nucleus H = Free lypophilic hormone R = Lypophilic hormone receptor HRE = Hormone response element mRNA = Messenger RNA

21. Hormone excretion • Hormones will be excreted after completing its functions • Hydrophilic hormones have a short life span while lypophilic hormones have a longer life span • Life span of hormones is termed ‘half-life’

22. Rate of hormone excretion • Rate of hormone excretion is dependant on the plasma concentration of that hormone which is regulated by changes in its rate of secretion i.e., • Hormone’s rate of secretion by the endocrine gland (major factor for all hormones) • Its rate of metabolic activation (for a few hormones) • Its extent of binding to plasma proteins (lipophilic hormones) • Its rate of metabolic inactivation and excretion (for all hormones)

23. Types of hormone excretion 1. Rapid excretion – through the kidney into urine or the liver into bile 2. Metabolism - destroyed by enzymes in the blood, liver, kidney, lungs and target cells 3. Active transport – some hormones are transported into cells and reuse as hormone substance or neurotransmitter 4. Conjugation – substances like acid sulphates and glucoronic acids will bind to hormones in the liver and render it less active as a hormone and increase its rate of excretion into urine or bile

24. Plasma Hormone bound to plasma proteins Endocrine gland Binding (lipophilic hormones) Secretion Free, biologically active hormone Activation (some hormones) Metabolism in liver or other tissues Target cells Inactivation Physiologic response Excretion in urine

25. Hormone lifespan Hormone lifespan can be prolong by: • Protection from rapid excretion by binding to plasma proteins eg., lypophilic hormones • Protection from proteolytic enzymes in the circulatory system by having a carbohydrate component in their chemical structure eg., glucoprotein hormones

26. Hormone interactions Four types of interactions exist: • Antagonistic – interaction is opposite each other eg: calcitonin and parathyroid hormone • Synergistic – hormones interact so that the end result will be more meaningful as compared to if only one hormone is functioning/several hormones complement each other and combine effects eg: stimulation of mammary glands development by prolactin, estrogen, progesterone and growth hormone • Permissive – a pattern of interaction whereby one hormone must be present in sufficient amounts for the full effect of another hormone to occur. eg; adrenaline needs thyroid hormones for energy production • Integrative – an interaction whereby many hormones regulate the different body physiological systems eg: calcitriol and PTH effects on tissues involved in calcium metabolism

27. Other hormones • Leukotrienes, together with prostaglandins and other related compounds, are derived from 20 carbon (eicosa) fatty acids that contain double bonds (enoic), hence this group of substances is called the eicosanoids. • The name leukotriene derives from the original discovery of these substances in white blood cells (polymorphonuclear leucocytes) and the fact that they all have in common 4 double bonds (hence the 4 subscript), 3 of which are in a conjugated triene structure. • Leukotrienes do not exist preformed in cells

28. They are formed from the breakdown of arachidonic acid, a polyunsaturated 20 carbon fatty acid. • In its esterified form, arachidonic acid is bound to the phospholipids of the cell membranes • Both immunological and non-immunological stimuli can release arachidonic acid from membrane phospholipids by activating phospholipase A2 • The glucocorticosteroid drugs can inhibit phospholipase A2 and thereby decrease the production of all the leukotrienes and hence leukotriene-mediated responses

29. Endocrine disorders • Due to hyposecretion or hypersecretion of a hormone. • Factors producing hyposecretion include heredity, dietary deficiency, immunologic factors, and disease processes. • Hyposecretion can be primary or secondary (due to the deficiency of the hormone’s tropic hormone). • Replacement therapy of a hormone can often successfully treat the conditions from hyposecretion. • Hypersecretion of a hormone can also be primary or secondary. • Factors producing hypersecretion include tumors on the endocrine gland and immunologic factors. • Endocrine dysfunction can also arise from the unresponsiveness of target cells to a hormone.

30. Hormone release • From hypothalamus to anterior pituitary • ‘releasing’ or ‘inhibiting’ hormones from the hypothalamus are secreted into the HHP tract to the anterior pituitary. Specific hormones from the AP are then secreted into the same blood vessels to be transported to target cells

31. Therefore robust control systems must be present to prevent over or under-secretion of hypothalamic and anterior pituitary hormones. • A prominent mechanism for control of the releasing and inhibiting hormones is negative feedback

32. Hormone release 2. From hypothalamus to posterior pituitary • Neurohormones from posterior pituitary glands are produced by neurosecretory cells whose cell bodies are located in the hypothalamus • These axons from the cell bodies enters the infundibulum of the posterior pituitary gland • Gives rise to a nerve tract called Hypothalamic-Hypophyseal Tract (HH)

33. Hormone release • neurohormones enters axons and are stored in the shape of small secretory vesicles • Action potentials from the neurone cell bodies in the hypothalamus travels down the axons until they reach the axon terminals in the posterior pituitary glands via the HH tract • These action potentials causes neurohormone release • These neurohormones then enters the blood stream

34. Hypothalamic hypophyseal portal veins

35. Pituitary Gland Anatomy of the pituitary gland: • The pituitary gland is as large as a pea, and is located at the base of the brain • The gland is attached to the hypothalamus by nerve fibers • The pituitary gland itself consists of three sections: • the anterior lobe (pars tuberalis) • the intermediate lobe (pars intermedia) • the posterior lobe (pars distalis)

36. Pituitary gland • The anterior pituitary (adenohypophysis) is a classical gland composed predominantly of cells that secrete protein hormones • The posterior pituitary (neurohypophysis) is not really an organ, but an extension of the hypothalamus • Composed largely of the axons of hypothalamic neurons which extend downward as a large bundle behind the anterior pituitary • It also forms the pituitary stalk, which appears to suspend the anterior gland from the hypothalamus

37. Anatomy of the pituitary gland • Each lobe of the pituitary gland produces certain hormones anterior lobe: • growth hormone (GH) (non-tropic hormone) • prolactin (non-tropic hormone) • ACTH (adrenocorticotropic hormone) • TSH (thyroid-stimulating hormone) • FSH (follicle-stimulating hormone) • LH (luteinizing hormone)

38. Anatomy of the pituitary gland intermediate lobe: • melanocyte-stimulating hormone (non-tropic hormones) posterior lobe: • ADH (antidiuretic hormone)/vasopressin • Oxytocin • Tropic hormones – their target cells are other endocrine glands

39. How is it possible for the anterior pituitary gland to produce so many different hormones? • Because the tissues are so specialized • They contain three types of cells which can be distinguished by staining • Red stained cells/acidophils will produce GH and PRL • Blue stained cells/basophils will produce TSH, FSH, LH, MSH and maybe ACTH • Unstained cells/chromophobe) which is a variation of both acidophils and basophils may also produce ACTH

40. Functions of pituitary hormones

41. GROWTH HORMONE (GH) • Somatotropin. Effective on all body sections involved in growth • Have a dramatic effect on the growth rate of children and adolescents where it increases tissue mass and stimulates cell division • Its secretion is controlled by GH-RH and GH-IH from the hypothalamus. This hormone is released in a pulsatile rhythm.

42. Functions of GH: • maintains the epiphyseal discs at long bones • stimulates the rate of growth by increasing RNA development that will promote rate of protein synthesis • decreases protein denaturation • promotes use of fat for energy by storing CHO • changes body composition to have more muscle mass as compared to fat deposition

43. If too much GH is secreted at the end of the adolescent stage, gigantism will occur where the height will reach 7 to 8 feet tall • If less GH is secreted at a young age, then a premature closure at the epiphyseal discs occur and the body will stop growing therefore causing a condition called cretinism or dwarfism • If normal development has stopped but GH is still secreted, then a condition called acromegaly occurs where the bones at the skull, hands and feet thickens • Too much GH secreted will cause hyperglycemia, because the beta cells of the pancreas that secretes insulin are stimulated causing diabetes mellitus

44. Acromegaly

45. Gigantism

46. Adrenocorticotropic hormone (ACTH) • Stimulates the adrenal cortex gland to synthesis and release glucocorticoids • ACTH secretion is regulated by (C-RH) or corticotrophin from hipothalamus. • C-RH is regulated by a feed-back mechanism system that is influenced by stress, the homone insulin, interleukin and other hormones

47. Melanocyte Stimulating Hormone (MSH) • Real function unknown • May play a role in the darkening of skin because skin will look pale without MSH. • MSH release is regulated by two hormones from the hipothalamus that is MSH-RH and MSH-IH • MSH is secreted by the pars intermedia during the fetal stage, during childhood and to pregnant women and also in some diseases. MSH is usually not detected in mature human blood

48. Hyperpigmentation

49. Thyroid stimulating hormone (TSH) • Stimulates the synthesis and secretion of the hormones thyroxine and triiodothreoinine. Goiter occurs when the thyroid gland enlarges due to too much TSH stimulation • TSH secretion is controlled by T-RH from hipothalamus. • T-RH release depends on the concentration of TSH and thyroid hormones in the blood, metabolic rate of the body and the surrounding temperature

50. Anti-diuretic hormone (ADH) • Vasopressin. • Functions in urine production and assist in regulating fluid balance in the body • Target organ is the kidney. • ADH increases kidney tubules permeability to water so > water is reabsorbed into the body and not excreted as urine • If ADH < secreted, a lot of water will be lost up to 23 liters daily causing a condition called diabetes insipidus