1. Menopause "Menopause is a wake-up call to a new phase of your life. A wake-up call most people cannot handle, but what's the choice? You sure can't go back to sleep. So get up and decide what you're doing today—and on into the years ahead." —modified after Marisa Weiss, M.D.

2. What Is Menopause? • Menopause is defined as the cessation of ovarian function, or the cessation of menstrual cycles • Menopause is a natural process, it is not a disease • The mean age for menopause is 51 years • One third of woman’s life occurs after menopause

3. Menopause • Medical • Surgical • “Cold turkey"

4. Menopause • Persistent low (less tan 20 pg/ml) levels of estrogen • Persistent elevated levels of FSH (13–90 milli-international units per milliliter) LH (15–50 mIU/mL). Normal levels of estrogen before menopause peak at 150–300 picograms per milliliter each month (depending on where you are in your menstrual cycle) Lack of negative feedback

5. What Is Perimenopause? • Perimenopause is a transition rather than an event • It is the period of time surrounding menopause when ovarian function is declining, but has not stopped • Onset of perimenopause is usually 3-5 years before the periods stop • Perimenopause and menopause may last 2-10 years

6. Menopause/Aging "Growing old is not for sissies” Other factors then hormones: Empty nest, divorce, widowhood, the dependency of sick parents, the death of a parent or parents, or kids in trouble are all common experiences at this stage of life. Setting aside the hormonal changes that relate to menopause, it's common to feel stress, isolation, and depression.

7. Symptoms of Perimenopause • Hot flashes • Vaginal dryness • Breast Tenderness • Mood disturbances • Sleep disturbances • Urinary tract infections/incontinence • Menstrual changes • Sexual dysfunction

8. Other Physiologic Changes • Slowing of metabolism • Weight gain • Changes in lipids • Increase in heart disease • Osteoporosis

9. Heart Disease • Leading cause of death in women • Higher risk after menopause probably due to changes in cholesterol levels when estrogen levels decline • Elevated “bad” cholesterol (LDL) • Lower “good” cholesterol (HDL) • Elevation in triglycerides (fats)

10. Osteoporosis • 1 out of 2 white women will have an osteoporotic fracture in their lifetime • 24% of patients over age 50 will DIE in the year following an osteoporotic hip fracture • Deaths due to osteoporosis far exceed the numbers of deaths due to breast cancer • Other consequences- physical limitation, chronic pain, depression, poor quality of life

11. Menopause Three factors affect how you age and how you experience menopause: • Hormones — estrogen, progesterone, and others. • Lifestyle — diet, exercise, weight, smoking, environment • Genetic makeup — the genes that come from your parents, the blueprint of your constitution and perhaps your future health

12. Estrogen Replacement Therapy (ERT) or Hormone Replacement Therapy (HRT) • Treats the symptoms of menopause (hot flashes, etc.) • Prevention of heart disease (40-50% reduction in risk) • Prevention and treatment of osteoporosis • May help prevent dementia • May prevent strokes • Lower mortality rates in women who take estrogen

13. Side Effects of HRT • Blood clots (especially in smokers) • Gallbladder disease • May increase risk of breast cancer • Vaginal bleeding • Breast tenderness

14. “Male” Hormones- Can They Help You? • Androgens are produced in the ovaries and the adrenal glands • Known to increase libido • Protects bone mass • Unfavorable effects on cholesterol • Can cause virilization (unwanted hair growth)

15. Complementary Therapies • Most lack scientific proof of efficacy • Large placebo effect • “Dietary supplements”- no regulation by FDA • May be helpful for women who do not choose ERT/HRT or as adjunctive therapy

16. Lifestyle Approaches to Perimenopause • Exercise- aerobic, weight-bearing, strengthening program • High fiber, low fat, soy-rich diet • Maintain regular sexual activity • Relaxation and stress reduction activities • Daily sunlight • Decrease alcohol intake • Stop Smoking

17. Summary • Perimenopause is a process rather than an event • Symptoms are common and most women will seek treatment • ERT/HRT is the best treatment available for symptoms of menopause and to prevent long term consequences of estrogen deficiency • Complementary therapies may be of some short term benefit for symptom control

18. Menopause: Hot Flushes • Sudden, intense, hot feeling on the face and upper body, perhaps preceded or accompanied by a rapid heartbeat and sweating, nausea, dizziness, anxiety, headache, weakness, or a feeling of suffocation. Some women experience an "aura," an uneasy feeling just before the hot flash, that lets them know what is coming. The flash is followed by a flush, leaving the individual reddened and perspiring. Some can have a soaker or merely a moist upper lip. A chill can lead off the episode or be the finale.

19. Menopause: Hot Flushes • Hot flashes are mostly caused by the hormonal changes of menopause, but can also be affected by lifestyle and medications. • A diminished level of estrogen has a direct effect on the hypothalamus that controls body temperature. • Somehow the drop in estrogen confuses the hypothalamus—which is sometimes referred to as the body's "thermostat"—and makes it read "too hot.“

20. Menopause: Hot Flushes • A change in the sensitivity of the “set point” in the thermostat misinforms the hypothalamus about increased body temperature but the response is to dissipate heat • The message is transmitted by the nervous system's chemical messengers, including epinephrine, norepinephrine, prostaglandin, and serotonin. • The response: • elevated heart-rate • vasodilation in the skin to circulate more blood to radiate off the heat • sweat glands release sweat to cool the body off even more.

21. Menopause: Hot FlushesMisconception • Because of the conversion of androstenedione from the adrenal glands into estrone by fat and muscle cells, heavy or muscular women experience less severe hot flashes than thin women. NOT TRUE! • Overweight women have more frequent and more severe hot flushes!!!!!

22. Menopause: Hot Flushes Triggers • Low estrogen levels • Others: • alcohol • caffeine • diet pills • spicy food • hot food • hot tubs • saunas • hot showers • hot beds • hot rooms • hot weather • smoking

23. Hot Flush Therapies • Estrogen • Progestins • Phytoestrogens • Clonidine • SSRI/NRIs: venlafexine (Effexor) • SSRIs: fluoxetine, paroxetine, duloxetine (e.g., Prozac, Paxil, etc.)

24. Median Hot Flash Score Reduction 100 80 Placebo (n=347) Soy (n=66) Clonidine (n=75) Fluoxetine (n=20) 60 Vitamin E (n=57) Median Venlafaxine (n=45) 40 20 Megestrol (n=74) 0 Baseline 1 2 3 4 Week Clinical data on current possible therapies for the treatment of hot flushes (HF) (Loprinzi 2002; breast cancer survivors)

25. Thermoregulatory Center Hypothalamus Potential Vasomotor Pathways serotonin norepinephrine estrogen temperature information from blood progesterone neuropeptides (opioids, neurokinin B) autonomic nervous system brain stem blood vessels in skin vasodilatation or vasoconstriction Heat loss (i.e., hot flush) or preservation

26. Morphine-Dependent OVX Model Direct Temperature Measurement Amplifier TST Thermistor TST=tail skin temperature MacLab

27. 2 Week Post-OVX EE or experimental compound Morphine Implant (chronic dosing) Naloxone (1.0 mg/kg, sc) (2-pellets, 150 mg) 8 0 4 DAY Minutes 95 0 15 35 Ketamine Drug Naloxone End (40 mg/kg) Acute dosing experimental compounds Morphine-Dependent OVX ModelExperimental Paradigm

28. Morphine-Dependent Rat Model * EE chronically abates the naloxone-induced flush

29. Telemetric Temperature Measurement Transmitter Matrix Box Thermistor THERMISTOR IMPLANTED SUBCUTANEOUSLY TST TST=tail skin temperature

30. 2 Week Post-OVX Implant thermistor, sc Chronic: EE (1.0 mg/kg, sc) Start recording Evaluate Therapeutics (continuous daily data acquisition) Surgical Recovery Period BaselineRecording (continuous) 0 7 10 DAY Acute: Clonidine (0.5 mg/kg, sc) OVX-induced change in TSTLong-term monitoring

31. Light Dark 35 OVX 30 TST (oC) Intact 25 Dark phase (active) Light phase (inactive) 20 0 12 24 36 48 60 72 Hours OVX-Induced TST Change Telemetry (Long-Term Monitoring) OVX prevents normal decrease in TST during the active phase

32. Chronic EE dosing (1 mg/kg) 34 SEM OVX+vehicle 32 ± oC) 30 OVX+EE TST ( 28 Intact 26 24 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 Treatment day Effect of Chronic EE on TST Active Phase n=4 Chronic EE treatment restores TST cyclicity in OVXed rats

33. Hot Flush - Gonadotropins HF Finger temperature FSH LH Estrone Estradiol Are hot flushes due to elevated LH levels?

34. Septal application of GnRH facilitates thermoregulatory skin vasodilation. (Hosono et al., 1997)

36. Relative hormone levels during the menstrual cycle

38. Aging-related decline of hormonal systems Decrease in GH results in reduction of IGF-1 production in liver, etc. Decrease in LH and FSH results in reduction of ovarian and testicular hormones: menopause and andropause Decrease in adrenal DHEA contributes to andropause

39. Hormone levels of women and men during aging

40. Serum total testosterone levels in young (21-35 years) and aged (60-80 years) men Serum total testosterone in young men: 18 nM/L (525 ng/dl) Serum total testosterone in old men: 14 nM/L (420 ng/dl)

41. Andropause The effect of testosterone vs placebo on fat mass, lean mass and bone mineral density in older men (65 years of age)

42. Serum testosterone levels in young vs aged men

43. The effect of DHEA in healthy adult, aged men and women on well-being and libido

44. The effect of DHEA on plasma IGF-1 levels and muscle strength in aged men and women

45. Mean 24 hr profiles of plasma Cortisol (A) Thyroid stimulating hormone (B) Melatonin (C) Prolactin (D) Growth Hormone (E) Slow wave sleep (F) Rapid eye movement (REM) (G)

46. GH secretion in Young vs Aged individuals

47. Mean 24 hr GH release in young and old men sampled at every 20 min. Normal diurnal pattern but reduced nocturnal GH peak in older men

48. The relationship between the individual and mean 24 hr integrated GH concentrations and age of normal men and women

49. Gonadotropins and aging

50. “Running out of eggs”