MCB 135K Discussion

1. MCB 135K Discussion April 13, 2005

2. Topics • Hypothalamo-Pituitary-Adrenal Axis • Homeostasis and Allostasis • Hormone Replacement Therapy

5. Table 10.1 Factors Influencing Evaluation of Endocrine Function in Aging Physiologic Factors Metabolic rate, body composition, dietary regimen, physical exercise, exposure to stress (environmental and psychosocial) Relations with other endocrines and body systems Secretory cells and their rates of secretion Transport of the hormones to target cells • Metabolism of the secreted hormones • Metabolites may be more or less biologically active than the • secreted hormones (e.g. more active, conversion of T to DHT) Number and affinity of hormone receptors Intracellular postreceptor molecular events Occurrence of disease and use of medications

6. Gene expression & new protein synthesis • Relatively long latency of onset • Medium & long term cell program • Organization of cell networks for complex functions • Activation/repression of pre-existing cell proteins • Rapid onset of action • Rapid adaptation to changes in the milieu • Dynamic modifications of long term cell programs

8. Changes with Aging in the Hypothalamo-Pituitary-Adrenal Axis No significant changes in healthy, non-stressed, elderly The few changes that occur are rapidly compensated for (e.g. decreased secretion of GCs from the adrenal cortex) but also less rapid metabolism in the liver & less urine excretion Therefore the circulating levels remain constant Also, normal ACTH & cortisol responses to CRH administration Some alterations of the circadian rhythm

9. Exposure to Stress Generates: • Specific responses: vary with the stimulus (specialized responses) and generate different responses with each different stimulus. • Nonspecific responses: (also called non- specialized) are always the same • regardless of the stimulus • mediated through stimulation of neural, endocrine, and immune axis

10. HomeostasisFrom Walter B. Cannon (1871-1945)Wisdom of the Body, 1932 From Greek: homeo “the same” stasis “state” Indicates that for optimal function of the organism, a steady state (or equilibrium) must be achieved This “constancy” of the internal environment allows survival despite continuing changes in the external environment (stress)

11. Homeodynamics A constant environment obtained through a series of dynamic adjustments This continual need for adjustment is implicated in the term “allostasis” (From Greek allo “different” stasis “state”) Emphasizes the dynamism of adaptive responses to stress This adaptation to stress is often achieved with a price -- a declining ability to adapt and/or an increased pathology and disease *Prof. T. Seeman, Geriatrics, UCLA (UCB alumna)

12. Table 10.6 glucagon secretion

13. Table 10.6

14. Hormone Replacement Therapy • Loss of a body constituent • Metabolite, hormone, enzyme, vitamin, etc. • Constituent is necessary for the organisms survival and normal function • Involves the attempt to replace, or substitute, the lost constituent with a similar exogenous substance with comparable properties and actions • Dose, duration, metabolism, target cells, and side effects

15. Replacement Therapy Problems in Aging • Complexity of endocrine system • Loss or insufficiency of endogenous hormones • Target cells for hormones are themselves aging and this may effect their responsiveness • Changes in hormones and their targets due to disease and degenerative processes

16. Dihydroepiandrosterone (DHEA) • DHEA is the principal adrenal androgen • *Note-Does not bind androgen receptor • DHEA(S) concentrations change throughout the human life • DHEA(S) levels are lower in women than men • Increased mortality is associated in men with a lower DHEA(S) baseline, but not in women

17. DHEA is regulated by ACTH via the H-P-A axis • DHEA(S)  DHEA is necessary for downstream conversion to sex steroids • Ability of ACTH to induce DHEA(S) is reduced with age

18. Epidemiological Evidence Increased overall mortality and cardiovascular mortality in male subjects with lowest DHEA(S) levels Low levels found in severe diseases: systemic lupus erythematosus Dementia Breast cancer Rheumatoid Arthritis DHEA(S) levels may be indicative of a severe disease or predictive of a future disease DHEA Replacement Adrenal Insufficiency 25-50mg oral DHEA Improves: androstendione and testosterone levels, depression, anxiety, and sexual function Healthy Elderly 50 mg DHEA No increase in well being, cognition, nor sexuality Elderly with impaired mood, cognition and sexual function 50-100mg DHEA Similar results to adrenal insufficiency study DHEA and Aging

19. Growth Hormone and Aging • Study in 1990 demonstrated in small group of elderly men that GH and IGF I levels were reduced: • 12 out of 21 men injected with hGH over a 6 month period showed small increases in muscle mass and bone density (10-14%) • Suggests that GH might be responsible in part for decreased muscle and bone in elderly

20. Effects of GH Treatment • 1998 study of ICU patients found: • Mortality increased from 19% to 44% in patients having GH therapy for 7-14 days • Length of hospital stay was prolonged by GH therapy • Attributed to: • Decreased immune function • Increased insulin resistance • Multi-Organ Failure

21. Menopausal Hormone Use • Also referred to as: • Hormone Replacement Therapy (HRT) • Postmenopausal Hormone Use • Estrogen Replacement Therapy (ERT) • Conjugated Estrogen + Progestin Replacement Therapy (HT) • Prescribed to treat some of the problems associated with menopause

22. Estrogens Used alone or in combination with progestin Approximately doubles the level of menopausal estrogen Optimal dose is the lowest dose to treat symptoms over the shortest duration Progestins Initially used in conjunction with Estrogen to reduce risk of endometrial cancer In 2002 the WHI stopped a trial using Estrogen + Progestin finding the risks outweighed the benefits Types of Hormones Used

23. Risks of HT • Estrogen + Progestin • Increases Risk of: • Breast Cancer • Heart Disease • Stroke • Blood Clots • Dementia • Decreased Risk of: • Hip Fractures (Osteoporosis) • Colon Cancer

24. Risks of ERT • Estrogen Alone • Only given to women that have had a hysterectomy • E alone is a risk factor for endometrial cancer • Does not improve long-term health • Decreases risk of fractures (osteoporosis) • Increases risk of stroke • May increase risk of ovarian cancer • Does not significantly effect coronary heart disease • Does not significantly alter breast cancer incidence

25. Alternatives to Hormone Therapy?(Recommendations from the Mayo Clinic) • Maintain a Healthy Heart: • Don't smoke. • Be physically active. • Eat a low-fat, high-fiber diet, plentiful in fresh fruits and vegetables. • Maintain a healthy weight. • Manage high blood pressure. • Keep cholesterol and triglyceride levels in check. • Control diabetes. • Avoid excess alcohol. • Healthy Bones • Calcium and vitamin D. Make sure you're getting enough of these nutrients in your diet to keep your bones strong. • Exercise. Regular physical activity — especially weight-bearing exercises such as walking or dancing — can help keep your bones strong and healthy.

26. HT Risks Heart Disease Breast Cancer Stroke Blood Clots Dementia ERT Risks Stroke HRT Benefits Improves risk of osteoporosis Effective Treatment for: Hot Flashes Vaginal Discomfort Based on current findings: HRT should only be used as short-term therapy with the lowest possible effective dose Do Not Take for: Memory Loss Heart Disease/Strokes Summary of HRT