Endocrine Physiology

1. Endocrine Physiology Dale Buchanan Hales, PhD Department of Physiology & Biophysics

2. Claude Bernard: the father of endocrinology More than 100 years ago Claude Bernard stated that the endocrine system regulates the internal milieu of an animal. The “internal secretions” or hormones were liberated by one part of the body, traveled via the bloodstream to distant targets cells.

3. Endocrine system maintains homeostasis The concept that hormones acting on distant target cells to maintain the stability of the internal milieu was a major advance in physiological understanding. The secretion of the hormone was evoked by a change in the milieu and the resulting action on the target cell restored the milieu to normal.The desired return to the status quo results in the maintenance of homeostasis

4. Sensing and signaling Endocrine “glands” synthesize and store hormones. These glands have a sensing and signaling system which regulate the duration and magnitude of hormone release via feedback from the target cell.

5. Endocrine vs. Nervous System • 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.

6. Principal functions of the endocrine system • Maintenance of the internal environment in the body (maintaining the optimum biochemical environment). • Integration and regulation of growth and development. • Control, maintenance and instigation of sexual reproduction, including gametogenesis, coitus, fertilization, fetal growth and development and nourishment of the newborn.

7. Hormones travel via the bloodstream to target cells

8. Types of cell-to-cell signaling Classic endocrine hormones travel via bloodstream to target cells; neurohormones are released via synapses and travel via the bloostream; paracrine hormones act on adjacent cells and autocrine hormones are released and act on the cell that secreted them. Also, intracrine hormones act within the cell that produces them.

9. A cell is a target because is has a specific receptor for the hormone

10. Major hormones and systems • Top down organization of endocrine system. • Hypothalamus produces releasing factors that stimulate production of anterior pituitary hormone which act on peripheral endocrine gland to stimulate release of third hormone • Specific examples to follow • Posterior pituitary hormones are synthesized in neuronal cell bodies in the hypothalamus and are released via synapses in posterior pituitary. • Oxytocin and antidiuretic hormone (ADH)

11. Classes of hormones • The hormones fall into two general classes based on their solubility in water. • The water soluble hormones are the catecholamines (epinephrine and norepinephrine) and peptide/protein hormones. • The lipid soluble hormones include thyroid hormone, steroid hormones and Vitamin D3

12. Water soluble hormones • Water soluble hormones are synthesized in endocrine cells and packaged into secretory granules. • These granules fuse with the plasma membrane in an energy dependent process called exocytosis and are released into the extracellular fluid surrounding the cell. • Water soluble hormones are freely soluble in the bloodstream and can travel to their targets without being bound to blood proteins– however, many are associated with binding proteins that modulate their bioavailability

13. Lipid soluble hormones • Lipid soluble hormones are synthesized in endocrine cells but are not packaged in secretory granules. • Lipid soluble hormones passively diffuse out of the endocrine cell and become complexed with blood proteins called globulins. • The hormone protein complex is carried by the blood stream to the target cells where the hormone is released from the protein which enables it to bind to the target cell receptor. • Some lipid soluble proteins don’t have binding proteins, for example, aldosterone.

14. Types of receptors • Receptors for the water soluble hormones are found on the surface of the target cell, on the plasma membrane. • These types of receptors are coupled to various second messenger systems which mediate the action of the hormone in the target cell. • Receptors for the lipid soluble hormones reside in the nucleus (and sometimes the cytoplasm) of the target cell. • Because these hormones can diffuse through the lipid bilayer of the plasma membrane, their receptors are located on the interior of the target cell

15. Hormone Class of hormone Location Amine (epinephrine) Water-soluble Cell surface Amine (thyroid hormone) Lipid soluble Intracellular Peptide/protein Water solube Cell surface Steroids and Vitamin D Lipid Soluble Intracellular Hormones and their receptors

16. Second messenger systems • Receptors for the water soluble hormones are found on the surface of the target cell, on the plasma membrane. These types of receptors are coupled to various second messenger systems which mediate the action of the hormone in the target cell

17. Second messengers for cell-surface receptors • Second messenger systems include: • Adenylate cyclase which catalyzes the conversion of ATP to cyclic AMP; • Guanylate cyclase which catalyzes the conversion of GMP to cyclic GMP (cyclic AMP and cyclic GMP are known collectively as cyclic nucleotides); • Calcium and calmodulin; phospholipase C which catalyzes phosphoinositide turnover producing inositol phosphates and diacyl glycerol.

18. Second messenger systems • Each of these second messenger systems activates a specific protein kinase enzyme. • These include cyclic nucleotide-dependent protein kinases • Calcium/calmodulin-dependent protein kinase, and protein kinase C which depends on diacyl glycerol binding for activation. • Protein kinase C activity is further increased by calcium which is released by the action of inositol phosphates.

19. Second messenger systems • The generation of second messengers and activation of specific protein kinases results in changes in the activity of the target cell which characterizes the response that the hormone evokes. • Changes evoked by the actions of second messengers are usually rapid

20. Cell surface receptor action

21. Receptors for lipid-soluble hormones reside within the cell • Because these hormones can diffuse through the lipid bilayer of the plasma membrane, their receptors are located on the interior of the target cell. • The lipid soluble hormone diffuses into the cell and binds to the receptor which undergoes a conformational change. The receptor-hormone complex is then binds to specific DNA sequences called response elements. • These DNA sequences are in the regulatory regions of genes.

22. Receptors for lipid-soluble hormones reside within the cell • The receptor-hormone complex binds to the regulatory region of the gene and changes the expression of that gene. • In most cases binding of receptor-hormone complex to the gene stimulating the transcription of messenger RNA. • The messenger RNA travels to the cytoplasm where it is translated into protein. The translated proteins that are produced participate in the response that is evoked by the hormone in the target cell

23. Types of hormones-1 • Amine hormones: • Hormones derived from the amino acid tyrosine. • These include epinephrine, norepinephrine and thyroid hormone. • Epinephrine and norepinephrine are produced by the adrenal medulla –water soluble • Thyroid hormone is produced by the thyroid gland –lipid soluble

24. Types of hormones -2 • Peptide/protein hormones: • 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

25. Types of hormones-3 • Steroid hormones: • 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 • 1,25-dihydroxy Vitamin D3 is also derived from cholesterol and is lipid soluble

26. Peptide/protein hormones • Are encoded by a specific gene which is transcribed into mRNA and translated into a protein precursor called a preprohormone • Preprohormones are often post-translationally modified in the ER to contain carbohydrates (glycosylation) • Preprohormones contain signal peptides (hydrophobic amino acids) which targets them to the golgi where signal sequence is removed to form prohormone • Prohormone is processed into active hormone and packaged into secretory vessicles

27. Peptide/protein hormones • Secretory vessicles move to plasma membrane where they await a signal. Then they are exocytosed and secreted into blood stream • In some cases the prohormone is secreted and coverted in the extracellular fluid into the active hormone: an example is angiotensin is secreted by liver and converted into active form by enzymes secreted by kidney and lung

28. Peptide/protein hormone synthesis

29. Steroid hormones • 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

30. Steroid hormones • 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

31. Steroid hormone synthesis All steroid hormones are derived from cholesterol. A series of enzymatic steps in the mitochondria and ER of steroidogenic tissues convert cholesterol into all of the other steroid hormones and intermediates. 1,25-dihydroxy Vitamin D3 is also derived from cholesterol

32. Steroids can be transformed to active steroid in target cell

33. Amine hormones: derived from tyrosine • Epinephrine, norepinephrine and dopamine are water soluble and are synthesized and secreted like peptide hormones • 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

34. Synthesis of catecholamines

35. Thyroid hormones

36. Regulation of hormone secretion • Sensing and signaling: a biological need is sensed, the endocrine system sends out a signal to a target cell whose action addresses the biological need. Key features of this stimulus response system are: ·        receipt of stimulus ·        synthesis and secretion of hormone ·        delivery of hormone to target cell ·        evoking target cell response ·        degradation of hormone

37. Feedback control • Negative feedback is most common: for example, LH from pituitary stimulates the testis to produce testosterone which in turn feeds back and inhibits LH secretion • Positive feedback is less common: examples include LH stimulation of estrogen which stimulates LH surge at ovulation

38. Control of hormonal secretion • Humoral • Neural • Hormonal

39. Regulation of hormone release 1. hormone-hormone 2. substrate-hormone 3. mineral-hormone

40. Substrate-hormone control • glucose and insulin: as glucose increases it stimulates the pancreas to secrete insulin

41. Neural control • Neural input to hypothalamus stimulates synthesis and secretion of releasing factors which stimulate pituitary hormone production and release

42. Inputs to endocrine cells

43. Chronotropic control • Endogenous neuronal rhythmicity • Diurnal rhythms, circadian rhythms (growth hormone and cortisol), Sleep-wake cycle; seasonal rhythm

44. Circadian (chronotropic) control

45. Circadian Clock

46. Negative feedback effects of cortisol

47. Feedback control of insulin by glucose concentrations

48. Hormonal interactions • Permissive • Synergistic • Antagonistic

49. Spare receptors • The "spare receptor" concept is based on this relationship and is states that maximum biological activity is often obtained when only 5 to 10% of the receptors are bound. • When the number of spare receptors are decreased maximum biological activity is achieved at a higher concentration of hormone. Therefore, the greater the number of receptors, the greater the sensitivity of them to hormone