Endocrinology

1. Endocrinology Lecture Notes

2. Endocrinology • The main function of the endocrine system is to maintain the homeostasis of the internal environment. • Hormone: chemical messengers secreted by cells of endocrine glands and tissues that regulate the activity of other cells in the body.

3. Endocrine Glands that function Primarily to Secrete Hormones • Pituitary gland: secretes Anti-diuretic Hormone (ADH), oxytocin and trophic hormones. • Thyroid gland: secretes thyroxin, tri-iodothyronine and calcitonin. • Parathyroid gland: secretes parathyroid hormone. • Adrenal gland: secretes cortisol, aldosterone, epinephrine and androgens. • Pancreas: secretes insulin and glucagon. • Ovaries and testicles: androgens, estrogens and progesterone. • Pineal gland: melatonin. • Thymus gland: thymosine.

4. Other Organs Which Function Secondarily As Endocrine Glands • Heart: secretes atrial natriuretic peptide (ANP) , it is secreted when there is an expansion in blood volume. It causes diuresis, so you lose Na in the urine. By losing Na in the urine water is dragged with it. so the increase in the blood volume is corrected. • Kidney: secretes erythropoietin. This hormone stimulates the bone morrow to produce more red blood cells wherever there is a low RBC mass.

5. Other Organs Which Function Secondarily As Endocrine Glands • Liver: secretes somatomedin which is a growth factor. • Skin: secrets D3 1,25-dihydroxyvitamin D3 which is responsible for calcium homeostasis. • Gastrointestinal tract: secrets gastrin, CCk, and VIP. • Adipose tissue:secrets leptin which plays a role in obesity. • Hypothalamus: releasing and inhibiting hormones.

6. Chemical Classification of Hormones 1- Protein and peptide hormones: • Like insulin. • Usually present as prohormone, they become the active form of the hormone later. • Polar (hydrophilic).

7. Chemical Classification of Hormones 2- Steroid hormones: • Like aldosteron, sex steroids hormones and cortisol. • they all have a back bone of cholesterol. • Non polar, so they cross the cell membrane easily.

8. Chemical Classification of Hormones 3- Tyrosine derivatives: • Like catecholamine and thyroid hormone. • They both have tyrosine backbone • Thyroxin is nonpolar and crosses the cell membrane easily • Epinephrine usually have receptors on the cell membrane.

9. Mechanism of Hormone Action Functional categories of hormones based on the location of their receptor proteins and mechanisms of action: • Hormones that bind to nuclear receptor proteins • Hormones that use second messengers.

10. Hormones That Binds to Nuclear Receptor Proteins Steroids: • Secreted by adrenal cortex, testes and ovaries • Steroid hormones are nonpolar ,hydrophobic (lipophilic), so they need to be carried in the plasma by some sort of protein that will carry them from one place to another. The carrier protein binds to the hormone and carry it to the target call. Once it reaches the target cell the hormone is released. It goes inside the cell to bind to receptors which are present either on the cytoplasm or the nucleus. Once the hormone bind to the receptor it is taken to the nucleus, released and then it binds to a domain on the DNA . This will stimulate transcription and protein synthesis.

11. Hormones That Binds to Nuclear Receptor Proteins Thyroid Hormones: • Secreted by thyroid gland. • Location of receptor proteins is in the nucleus of the target cells. • Very similar to steroids in size, being non-polar and very water insoluble. • Carried mainly by thyroxine-binding globulin (TBG; T4 more than T3

12. Hormones That Use a Second Messengers • Catecholamines (epinephrine and norepinephrine) • Polypeptides • Glycoproteins They are secreted all glands EXCEPT adrenal cortex, gonads and thyroid. Those can’t cross the lipid bilayer of cell membrane. So they need receptors which are present on the outer surface of the cell membrane. Once the hormone binds to the receptor, several changes occur in the cytoplasmic side of the cell membrane which then stimulates a second messenger which can be c-AMP , c-GMP, phospholipase C, Ca2+ and thyrosine kinase.

13. Properties of Different Classifications of Hormones Storage: • Steroids: a very little storage of the hormone, usually they are produced whenever we need them. • Thyroxine: it is usually stored for a much longer period in the thyroid gland, about several weeks. • Peptides, proteins and catecholamines: their storage is very short, can range from one day to several days.

14. Properties of Different Classifications of Hormones Mechanism of secretion: • Steroids: once we need them they are released by diffusion through the plasma membrane. • Thyroxine: it is secreted by proteolysis of thyroglobulin, once we need them we need to breakdown thyroglobulin, by breaking it we will have the release of thyroxine and triiodothyronine. • Peptides, proteins : usually stored in vesicles and once we need them they are secreted by exocytosis. • Catecholamines : usually stored in vesicles and once we need them they are secreted by exocytosis.

15. Properties of Different Classifications of Hormones Binding to plasma proteins: • Steroids: Because they are non-polar, hydrophobic, lipophilic, we rarely find them in the free form in the circulation, so, they need plasma proteins. • Thyroxine: Because they are non-polar, hydrophobic, lipophilic, we rarely find them in the free form in the circulation, so, they need plasma proteins. • Peptides, proteins : Because they are polar, hydrophilic most of them do not need plasma proteins to bind to. Only some may need. • Catecholamines : they do not need any sort of plasma proteins.

16. Properties of Different Classifications of Hormones Mechanism of secretion: • Steroids: once we need them they are released by diffusion through the plasma membrane. • Thyroxine: it is secreted by proteolysis of thyroglobulin, once we need them we need to breakdown thyroglobulin, by breaking it we will have the release of thyroxine and triiodothyronine. • Peptides, proteins : usually stored in vesicles and once we need them they are secreted by exocytosis. • Catecholamines : usually stored in vesicles and once we need them they are secreted by exocytosis.

17. Properties of Different Classifications of Hormones Lifetime in the blood plasma 1/2t: • Steroids: Because the are bound to plasma proteins their half life in the blood is about hours. • Thyroxine: Because the are bound to plasma proteins their half life in the blood is about days. • Peptides, proteins : Because they are rarely bound to plasma proteins or not at all their half life in the blood is about minutes. • Catecholamines : Because they are not bound to plasma proteins their half life in the blood is about seconds.

18. Properties of Different Classifications of Hormones Receptors: • Steroids: either on the cytoplasm or the nucleus. • Thyroxine: on the nucleus. • Peptides, proteins : Because they can not pass the plasma membrane their receptors are on the plasma membrane. • Catecholamines : Because they can not pass the plasma membrane their receptors are on the plasma membrane.

19. Properties of Different Classifications of Hormones Mechanism of action: • Steroids: Receptor-hormone complex controls transcription. • Thyroxine: Receptor-hormone complex controls transcription. • Peptides, proteins : Hormone binding triggers synthesis of cytolic second messengers or protein kinase activity. • Catecholamines : Hormone binding causes change in membrane potential or triggers synthesis of cytolic second mesengers.

20. Hormonal Rhythm It is the pattern of secretion of the hormone Even though hormones have rhythms, the hormone secretion is pulstile. Meaning that the hormone is secreted then stopped, secreted then stopped and so on, just like pulse.

21. Circadian or diurnal Rhythm It means that the hormone is secreted every 24 hours. Examples: • Cortisol: is secreted around 5 am, about 2 hours before waking up. Cortisol secretion depends on what we call light-dark cycle. • Prolactine (PRL): is similar to cortisol. • Growth Hormon (GH): peaks during stages 3 and 4 of sleep wether at night or at day. It is known as the sleep-wake cycle.

22. Ultradian Rhythm It means that the hormone is secreted every ½, one or two hours. Examples: • LH • FSH • Testosterone Infradian Rhythm It means that the hormone is secreted any time more than 24 hours. Examples: • Menstruation or seasonal breeding in animals

23. Methods of Hormone Study Bioassay: measures the potency of a hormone by quantifying a biological effect produced by the hormone. It is not done in clinics on humans. • Example: removing the pituitary gland which produces Growth Hormone from a rat to see the effect of that hormone. Followed by giving the animal that hormone to observe what happens on the animal. Such as the elongation of bones or the changes in blood glucose levels, which are the biological effects of Growth Hormone. Radioimmunoassay (RIA): uses radioactive marker and hormone-specific monoclonal antibodies. Sensitive, specific, precise and convenient. • Example: when taking blood serum from a patient , then adding a radioactive marker to it. The radioactive marker will compete with the hormone tested for the antibody.

24. Methods of Hormone Study Radioreceptor assay: same as RIA except a preparation of hormone-specific receptors instead of hormone-specific antibody. Enzyme-linked Immunoabsorbent assay (ELISA): same as RIA except we use an enzyme instead of a radioactive marker. The enzyme activity is measured so that the amount of hormone can be calculated. High-performance liquid chromatology: separates the hormone from a mixed solution (e.g. plasma) in a fractionating column. The amount of hormone can then be measured. The disadvantages are that it is expensive and slow.

25. Pituitary Gland(Hypophysis) The pituitary gland is connected to the hypothalamus by an infundibulum. It is structurally and functionally divided into 2 lobes: • Anterior hypophysis (Adenohypophysis). • Posterior pituitary or neurohypophysis ( neural of the pituitary; pars distalis).

26. Posterior Pituitary Hormones Posterior pituitary secretes only 2 hormones which are: • Produced in the Paraventricular and supraoptic nuclei of the hypothalamus. • Stored and secreted by the posterior pituitary.

27. Posterior Pituitary Hormones Antidiuretic hormone (ADH): • Also known as arginine vasopressin (AVP) • It stimulates retention of water by the kidneys • At high doses, it causes vasoconstriction of blood vessels. Oxytocin: In females: • It stimulates the contraction of the uterus during labour, required for childbirth • It stimulates milk-ejection reflex in a lactating woman, i.e., contractions of the mammary gland alveoli and ducts. In males: • Secreted during ejaculation, due to its effect on the uterus , it causes the contraction of the female uterus , therefore it will aid in the sperm going up into the fallopian tube to fertilize an egg.

28. Control of ADH & Oxytocin Secretion By Neuro-endocrine reflex Oxytocin secretion: The baby is suckling a mother’s breast  touch receptors located on the nipple send sensory signals to the hypothalamus  oxytocin is released  causes milk ejection. When the baby stops suckling  milk ejection stops

29. Control of ADH & Oxytocin Secretion By Neuro-endocrine reflex Control of ADH secretion: High osmolarity stimulates ADH . When we have high osmolarity  water will leave the osmoreceptors  so they will shrink  this shrinking will stimulate the hypothalamus to produce ADH  that will be secreted from the posterior pituitary. ADH will act on the collecting duct of the kidney to cause water retention and decrease water excretion. That will decrease osmolarity and eventually correct it.

30. Control of ADH & Oxytocin Secretion By Neuro-endocrine reflex Control of ADH secretion: Increased blood volume When we have high an increase in blood volume  it is sensed by receptors present in the left atrium of the heart  it will send signals to the hypothalamus telling it to stop producing ADH. There will be water excretion. There will be an inhibition of ADH.

31. Anterior Pituitary Hormones Secreted by pars distalis of adenohypophysis • Thyroid-stimulating hormone (TSH) • Adrenocorticotropic hormone (ACTH) • Follicle-stimulating hormone (FSH) • Luteinizing hormone (LH) • Prolactine • Growth hormone (GH)

32. Anterior Pituitary Hormones • TSH acts on the thyroid gland to produce T3 and T4. • ACTH acts on the adrenal gland to secret Glucocorticoids (cortisol), mineralocorticoids (aldosterone) and sex steroids. • GH does not have a certain gland to act on . It acts all over the body. • It stimulates the liver to produce IGF-I • It acts on different organs and tissues of the body such as bones, muscle, adipose tissue • GH is anabolic on proteins ,it will increase protein metabolism. • GH is catabolic on carbohydrates and lipids. Meaning that it will increase blood concentration of glucose and free fatty acids. • It has an anti-insulin effect, it stimulates carbohydrates breakdown. • If you have hypersecretion secretion of GH it will cause hyperglycemia.

33. Anterior Pituitary Hormones • Prolactine acts on the breasts. • It stimulates breast development during pregnancy (not during puberty). • In men it facilitates reproductive function. • If men have high levels of prolactin, breasts will develop. These men become infertile because high levels of PRL interfere with the secretion of LH and FSH which are needed for spermatogenesis in males.

34. Anterior Pituitary Hormones • LH: acts on gonads • In females: it stimulates ovulation and conversion of ovulated ovarian follicle into corpus luteum. • In males: it stimulates the secretion of male sex hormones (mainly testosterone) from leydig cells in testes.

35. Anterior Pituitary Hormones • FSH: acts on gonads • In females: it stimulates the growth of ovarian follicle. It acts during the first part of the menstrual cycle. • In males: it stimulates the production of sperms in the testes.

36. Hyposecretion of Growth Hormone • During childhood  Pituitary dwarfism (with normal body proportions) • During adulthood  Simmonds’ disease • Hypersecretion of Growth Hormone • During childhood  Gigantism (longitudinal growth of the bone because the epiphyseal plate has not fused) • During adulthood  Acromegaly (no further growth but person’s appearance changes as a result of thickening of bones, growth of soft tissues as in face, hand and feet.

37. Control of Secretion of Anterior Pituitary Hormones 1- hypothalamic control: achieved through hormonal control. 2- Feedback control: by hormones secreted from target glands.

38. Hypothalamic control (Endocrine control) of anterior pituitary hormones. • Control is hormonal. • Hypothalamic releasing and inhibiting hormones pass through the hypothalamo-hypophyseal portal system and regulate secretions of anterior pituitary.

39. Thyrotropin-releasing hormone (TRH) stimulates the secretion of TSH. • Corticotropin-releasing hormone (CRH) stimulates the secretion of ACTH. • Gonadotropin-releasing hormone (GnRH) stimulates the secretion of LH and FSH • Growth hormone releasing hormone (GHRH) stimulates GH secretion. • Somatostanin (SS) inhibits the secretion of Growth hormone. • Prolactin is regulated by hypothalamic inhibitory hormone known as Prolactin-inhibiting hormone (PIH).

40. When cutting the connection between the hypothalamus and the anterior pituitary there will be a decrease in all hormones except prolactine.

41. Feedback control of anterior pituitary Secretion of ACTH, FSH, LH and TSH is controlled by negative feedback inhibition: • Target gland hormones  hypothalamus • Target gland hormones  anterior pituitary • Anterior pituitary  hypothalamus

42. Long loop negative feedback • Target gland hormones  anterior pituitary  hypothalamus Short loop negative feedback • Anterior pituitary  hypothalamus Ultrashort negative feedback • hypothalamus hypothalamus

43. End of The First Lecture