1. “Basics of Endocrinology” Dietary Cancer Prevention Course Rebecca B. Riggins, Ph.D. rbr7@georgetown.edu 202-687-7451 February 12 th, 2009

2. Lecture Outline What is endocrinology? What are hormones? – Key types of hormones – Where are hormones made? – How are hormones measured? – What do hormones do? Why are hormones important to Dietary Cancer Prevention? – obesity/diabetes/cancer – breast cancer items highlighted in red are important! Many figures are taken from Lehninger’s Principles of Biochemistry, 4 th Edition, Chapter 23 – Dr. Ganganna has an electronic (PDF) copy of this if you would like to read more

3. Endocrinology The study of the endocrine system and its secreted products (hormones) endocrine is Greek; “endo” = within, “krinein” = to release, separate The endocrine system is a collaborative system of (small) organs

4. Organs of the Endocrine System Classification of adipose (fat) tissue as an endocrine organ is recent We will focus later on the ovaries and pancreas

5. Endocrine System Control The endocrine system is controlled by the nervous system Nerve impulses travel to a target cell, tissue, or organ, and stimulate hormone release Hormones are released into and carried around the body to their targets via the bloodstream

6. Definition of a Hormone Hormones are the messengers of the endocrine system 3 common sub-classifications of hormones by location of action – Endocrine: act at a distance; released far from where they act – Paracrine: act nearby; released next to where they act – Autocrine: act on the same cell/tissue/organ from which they were released

7. Classification of Hormones by Type

8. Hormone Receptors Receptors are SPECIFIC for each hormone The presence/absence of a receptor (“expression”) or its function (“activity”) dictates the effect of any hormone on a tissue Peptide/amine hormones act faster than steroid hormones Peptide/Amine Steroid

9. Hormone Synthesis

10. Peptide Hormone: Insulin Primary Structure = “beads on a string” Quaternary Structure = specific folding creates domains, or “units” of the protein Peptides, or proteins, are chains of amino acids

11. Peptide Hormone: Insulin Proteolysis, or cleavage/digestion of peptide bonds, produces active insulin

12. Amine Hormones fight-or-flight response Tyrosine can be made by the body (from phenylalanine) Also found in nuts/seeds, meats, dairy

13. Eicosanoid Hormones inflammatory/immune responses can be made from omega-3 or omega-6 fatty acids Aspirin, Tylenol, Advil prevent eicosanoid hormone synthesis

14. Steroid Hormones cholesterol is made by the body, or obtained by eating any animal fats

15. Vitamin D Vitamin D made by your body begins with a form of cholesterol Alternatively, vitamin D is obtained by eating fortified foods (milk, bread, orange juice, etc.)

16. Other Hormones

17. Focus on Insulin and Steroid Hormones Insulin: regulation of metabolism Steroids: sex determination (estrogen, androgen)

19. Insulin is produced in the pancreas

20. Physiology and Blood Glucose Levels fasting blood glucose

21. Glucose regulates insulin production by the pancreas close open Glucose enters the bloodstream after food is digested Insulin triggers glucose uptake by important tissues: liver, muscle, and adipose (fat)

22. Physiology and Blood Insulin feeding response of blood insulin levels Why/how does this happen?

23. Glucose, Insulin, and Glucagon When you eat, glucose is released following digestion Insulin is secreted to lower, or counter-act, high blood glucose Glucagon is another peptide hormone that is released to lower insulin levels When this system is functioning, energy intake roughly equals energy output; weight maintenance glucoseinsulinglucagon 1. 2. 3. 4.

24. Obesity, Type II Diabetes, and Insulin Resistance More than 65% of adult Americans are overweight or obese Determined by body mass index (BMI) Insulin resistance: high, unregulated insulin levels Chronic high insulin + high blood glucose = type II diabetes glucoseinsulinglucagon 1. 2. 3. 4.

25. Cancer Being overweight or obese increases your cancer risk: endometrial, breast, and colon Insulin resistance/high insulin is also linked to breast cancer risk On February 26 th – Dr. Hilakivi-Clarke will lecture on “obesity and cancer risk”

26. Breast Cancer Second-leading cause of cancer death in women – ~40,000 in 2008 >140,000 women in the U.S. were diagnosed with breast cancer in 2008 – ~1000 men were diagnosed with breast cancer in 2008 too!

27. Breast Cancer Histology I Invasive D Ductal C Carcinoma (IDC) I Invasive L Lobular C Carcinoma (ILC) Normal Cancer

28. Different types of Breast Cancer Most common (~70%) are estrogen receptor positive (ER+)

29. Estrogen in Pre- vs. Post- Menopausal Women Major site of pre-menopausal estrogen synthesis Major site of post-menopausal estrogen synthesis Most active form of estrogen = 17-β-estradiol (E2)

30. The Estrogen Receptor Active, E2-bound ER forms a dimer

31. Inhibiting the Estrogen Receptor Selective estrogen receptor modulators – SERMs Tamoxifen – competes with estrogen for binding to the receptor, preventing its activation Aromatase inhibitors = AIs Letrozole, Anastrazole – block estrogen synthesis in post-menopausal women

32. Inhibition of Breast Cancer Growth X SERMs X AIs Breast Cancer Cell

33. Estrogen Mimics On March 5 th, Dr. Warri will lecture on “ Soy and Cancer Risk” – Genistein is a component of soy On April 16 th, Dr. Hilakivi-Clarke will lecture on endocrine disruptors – Cadmium, BPA, others