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POSTMENOPAUSAL WOMEN’S HEALTH Barcey T. Levy, M.D., Ph.D. August 23, 2002

POSTMENOPAUSAL WOMEN’S HEALTH Barcey T. Levy, M.D., Ph.D. August 23, 2002. Objectives. Understand major health problems facing postmenopausal women Understand the recent results of the Women’s Health Initiative and how they differ from the observational studies

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POSTMENOPAUSAL WOMEN’S HEALTH Barcey T. Levy, M.D., Ph.D. August 23, 2002

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  1. POSTMENOPAUSALWOMEN’S HEALTHBarcey T. Levy, M.D., Ph.D.August 23, 2002

  2. Objectives • Understand major health problems facing postmenopausal women • Understand the recent results of the Women’s Health Initiative and how they differ from the observational studies • Learn about therapies other than estrogen for post-menopausal women • Through the panel discussion, begin to appreciate women’s concerns regarding menopause and what they expect from their physician

  3. Menopause • Cessation of menstrual periods due to declining estrogen and progesterone production by the ovaries • Refers to the final menstrual period – must be free of periods for one year to be called menopause

  4. Stages of Menopause • Perimenopause – may have erratic cycles, hot flashes, and vaginal dryness; lasts from about 2 years prior to LMP to 2 years after the official “last” LMP. Average age 51 years • Menopause – refers to final last menstrual period • Postmenopausal – from “final” LMP on; women spend about 1/3 of their lives in postmenopausal period

  5. Symptoms of Menopause • Irregular menses • Hot flashes • Vaginal dryness • Urinary incontinence

  6. IrregularMenses • In some women, periods become lighter and less frequent • In others, bleeding may be heavier, with 2 or 3 periods a few weeks apart, and then several months before another period

  7. Hot Flashes • Definition: sudden rush of heat to upper body, followed by sweating and chills • Cause: vasomotor instability triggered by hormonal changes • Affect 50 to 85% women at some point; 15% find them troubling • Treatment: estrogen quickly stops hot flashes • Home remedies: dress in light layers; small fan to cool the face; light bedclothes and cotton blanket; avoid alcohol and caffeine

  8. Estrogen • Estrogen works best for hot flashes • All types and routes of administration equally effective • Markedly improves quality of life for younger postmenopausal women

  9. Vaginal Dryness • Definition: reduced vaginal secretions and thinning of the mucous membranes lining the vagina  dryness and itching and painful intercourse • Cause: declining estrogen levels • Treatment: estrogen; nonprescription lubricant such as Replens • Home remedies: regular sexual activity or non-perfumed oils such as vegetable oils or Vitamin E oil

  10. Urinary Incontinence • Definition: involuntary loss of urine; main types stress or urge incontinence • Cause: declining estrogen levels  thinning of urethra and bladder tissue; anatomical changes in pelvic organs such as cystocele, rectocele or uterine prolapse • Treatment: varies by cause; estrogen therapy may improve bladder control in some postmenopausal women • Home remedies: exercises to tone and strengthen muscles around the bladder (Kegel); avoid caffeine, alcohol and high dose Vitamin C; bladder retraining

  11. Public Health Issues • Heart disease • Osteoporosis • Cancer • Dementia

  12. Heart Disease in Women 32,100,000 women have heart disease 512,902 deaths/year among women Accounts for 1/2.4 deaths among women

  13. Other Public Health Issues in Women Osteoporosis 28,000,000 low bone mass or osteoporosis Cancer (2001) new cases deaths Lung 78,800 67,300 Colon 68,100 29,000 Breast 192,200 42,200 Dementia 4,000,000 total (men and women)

  14. Estrogen and Heart Disease • A healthy 60 year old female has about a 30% lifetime risk of dying of heart disease • Observational studies show a 35 to 50% lower risk of CAD in estrogen users • However, results of recent clinical trials conflict with these findings

  15. Nurses’ Health Study • Largest prospective cohort study in which HRT use and CAD examined (observational) • 70,543 women without prior CAD observed for up to 20 years • Outcome: CAD RRCurrent hormone use 0.60Past hormone use 0.82 • Results were similar for both E users and E+P users

  16. Nurses’ Health StudyRisk of Death Among All Postmenopausal Hormone Users (Never = Referent) Grodstein, NEJM 1997 Hormone Use Cause of Death Current Past All Causes # of Cases 574 1012 adj RR (95% CI) 0.63 (0.56-0.70) 1.03 (0.94-1.12) CAD # of Cases 43 129 adj RR (95% CI) 0.47 (0.32-0.69) 0.99 (0.75-1.30) All Cancer # of Cases 353 529 adj RR 0.71 (0.62-0.81) 1.04 (0.92-1.17) Breast Cancer # of Cases 85 94 adj RR 0.76 (0.56-1.02) 0.83 (0.63-1.09)

  17. Meta-analyses of Observational StudiesCAD -- 10 Prevention RR Current HRT vs. Non-users All Studies 0.53 Prospective Studies 0.60

  18. HERSRCT of HRT for Secondary Prevention of CAD (Hulley, JAMA 1998) • 2763 women with CAD < 80 years, postmenopausal (mean age 66.7 years) • 0.625 mg conjugated estrogen + 2.5 mg MPA qd (n= 1380) or placebo (n= 1383) followed for 4.1 years • Outcome: non-fatal MI or CHD death

  19. HERS Results • No difference in MI or CHD death between groups (RR=0.99) • 11% lower LDL + 10% higher HDL in the hormone group compared with placebo • Time trend with more CHD events in the hormone group in year 1 and fewer in years 4 and 5 • More in the HRT group had venous thromboembolic events (34 vs. 12, RH 2.89) and gallbladder disease (84 vs. 62, RH 1.38) • No difference in total mortality

  20. HERS Conclusions • Treatment with HRT did not reduce the overall rate of CHD events in postmenopausal women • HRT not recommended for secondary prevention

  21. Almost 50% of Undiagnosed Postmenopausal Women Have Low Bone Mass Distribution of T-scores in NORA* • A longitudinal observationalstudy of osteoporosis among previously undiagnosedpostmenopausal women • More than 200,000 women from 4,236 primary care practices participated 7% < -2.5 53% > -1.0 -1.0 to -2.5 40% Data available from Merck & Co., Inc. West Point, PA. DA-FOS65(1). *The National Osteoporosis Risk Assessment (NORA) Study was supported by Merck & Co., Inc.

  22. BMD and Fracture Risk Are Inversely Related Forearm 100 Colles' Spine Vertebrae 4000 Hip Hip and Heel 90 3000 Relative BMD (%) 80 Annual Fracture Incidence 2000 70 1000 60 0 35- 85+ 30 40 50 60 70 80 90 39 Age Age Faulkner, KG. J Clin Densitom. 1998;1:279-285. Cooper C. Baillieres Clin Rheumatol.1993;7:459-477.

  23. Current cigarette smoking Personal history of fracture as an adult Low body weight (<127 lbs) History of fracture infirst-degree relative Estrogen deficiency, including menopause onset <age 45 Alcoholism Caucasian race Low calcium intake (lifelong) Advanced age Impaired eyesight despiteadequate correction Female sex Recurrent falls Dementia Inadequate physical activity Poor health/frailty Poor health/frailty Risk Factors for Osteoporotic Fracture Not Modifiable Potentially Modifiable Gold color denotes risk factors that are key factors for risk of hip fracture, independent of bone density. National Osteoporosis Foundation, Physician’s Guide to Prevention and Treatment of Osteoporosis. Belle Mead, NJ: Excerpta Medica, Inc; 1998.

  24. Hip Fractures Can Lead to Disability, Loss of Independence, and Even Death • Hip fracture is associated with increased risk of: • Disability: 50% never fully recover1,2 • Long-term nursing home care required: 25%2 • Increased mortality within 1 year: up to 24%3 • Lifetime risk of death: comparable to that of breast cancer4 1. Consensus Development Conference. Am J Med. 1993;94:646-650. 2. Riggs BL, Melton LJ III. Bone. 1995;17:505S-511S. 3. Ray NF et al. J Bone Miner Res. 1997;12(1):24-35. 4. Cummings SR et al. Arch Intern Med. 1989;149:2445-2448.

  25. Prevention of Osteoporotic Fractures • Clinical trials show 5 to 7% greater spinal bone density after 2-3 years in women randomized to HRT compared with placebo • OS suggest 50% lower risk of hip and other fractures in HRT users compared with nonusers • In a meta-analysis of 22 small trials, women randomized to HRT had a 27% lower risk of osteoporotic fracture compared with placebo • HERS trial showed no benefit for fracture outcomes after 4 years • Approved by FDA for prevention, but not treatment of osteoporosis

  26. Central DXA Measurement • Measures multipleskeletal sites • Spine • Proximal femur • Forearm • Total body • Office based • Considered theclinical standard

  27. Visualizing a Patient’s T-Score 2 1 0 –1 –2 –3 –4 –5 –6 Peak Bone Mass T-score = Number of standard deviations (SDs) by which the patient’s bone mass falls above or below the mean peak bone mass for normal young adult women = T-score for patient, a 60-year-old woman; here, T = –3.0 Light line: Change in mean bone mass over time for women Heavy line: Mean peak bone mass for young normal adult women SD H T-score = –3.0 20 30 40 50 60 70 80 90 Age (years) H National Osteoporosis Foundation, Physician’s Guide to Prevention and Treatment of Osteoporosis. Belle Mead, NJ: Excerpta Medica, Inc.; 1998

  28. Interpreting BMD Measurement Reports T-Score Is Key • The most clinically relevant value on the BMD report • Describes bone mass compared with the mean peak bone mass of healthy young adult women in terms of Standard Deviation (SD) • Can help confirm the diagnosis of low bone mass or osteoporosis • For every SD below the young adult normal, the risk of fracture doubles

  29. Interpreting BMD Measurement Reports Some BMD Reports Also Include a Z-score • Describes a patient’s bone mass compared with the age-matched and sex-matched mean in terms of SD • Should not be used in the diagnosis of osteoporosis; a patient may have values that compare favorably with age-matched controls, but still be at increased risk for fracture National Osteoporosis Foundation, Physician’s Guide to Prevention and Treatment of Osteoporosis. Belle Mead, NJ: Excerpta Medica, Inc.; 1998

  30. Increased Fracture Risk at T-Score of -2.0 A T-score of -2.0 at the spine or hip represents: • 20% reduction in bone mass (compared with mean BMD of normal young adult women) • 380% increase in fracture at the spine • 480% increase in fracture at the hip

  31. Recommendations for Treatment Based on BMD Testing Results National Osteoporosis Foundation Guidelines for Women T-SCORE ACTION –2.0 or less Initiate therapy –1.5 or less Initiate therapy (with at least 1 additional risk factor) National Osteoporosis Foundation, Physician’s Guide to Prevention and Treatment of Osteoporosis. Belle Mead, NJ: Excerpta Medica, Inc.; 1998

  32. Breast Cancer • Multiple OS have found an  risk of breast cancer among long-term hormone users (30-60%) • No  risk among women who took estrogen for less than 5 years • Until WHI, no RCTs had addressed the risk of breast cancer among estrogen users

  33. Women’s Health Initiative University of Iowa

  34. Components • Preventive Clinical Trial • Hormone Replacement Therapy • Diet Modification • Calcium+Vitamin D Supplementation • Observational Study

  35. WHI Estrogen+Progestin TrialBackground circa 1992 Suspected benefits of hormones: •  risk of CHD •  risk of fracture •  risk of colorectal cancer Suspected risks of hormones: • Possible  risk of breast cancer •  risk of VTE/PE

  36. WHI Estrogen+Progestin TrialSpecific Aims • To test whether E+P reduces the incidence of CHD and other CVD • To test whether E+P reduces the incidence of all osteoporosis-related fractures and hip fractures separately • To assess whether E+P increases the risk of breast cancer

  37. Women’s Health Initiative Trial of Estrogen + Progestin Methods

  38. WHI Estrogen+Progestin TrialRecruitment • National and local area media awareness campaigns • Population-based direct mailings to age-eligible women • Augmented by local recruitment strategies • 3 screening visits

  39. Women’s Health Initiative Clinical Centers • Fred Huthcinson Cancer • Research Center • Univ. of Minnesota Med. Ctr. • Medical College • of Wisconsin • Kaiser Foundation • Research Institute • SUNY • Buffalo • Univ. of Wisconsin • Univ. of Mass • Med. Ctr. • Wayne State Univ. • Albert Einstein • Col. of Med. • Brigham & Women’s Hosp. • Univ. of Iowa • Rush-Presb. • St. Luke’s • Med. Ctr. • Mem. Hosp. of Rhode Is. • Northwestern • Univ. • Univ. of Pittsburgh • Univ. of California, Davis • SUNY, Stony Brook • Univ. of Nevada, Reno • Ohio State Univ. • Univ. of Med. & Dent. • of New Jersey • Kaiser Foundation Research Institute • Univ. of Cincinnati • Medical Center • Leland Stanford Junior University • Medlantic Res. Inst./Howard Univ. • George Washington Univ. • Univ. of California, Los Angeles • Bowman Gray School of Medicine • Univ. of California, Irvine • Univ. of Tennessee • Univ. of North Carolina • Harbor-UCLA Research & Education Inst. • Univ. of California, San Diego • Emory Univ. Sch. of Medicine • Univ. of Alabama • Univ. of Arizona at Tucson • Univ. of Texas Health • Science Ctr., San Antonio • Baylor College of Medicine • Univ. of Florida • Univ. of Miami • Univ. of Hawaii I:\DOCUMENT\GRAPHICS\FIGURES\WHIMAP.PPT

  40. WHI Hormone Program Study Population: Inclusion criteria • Age 50-79 at baseline • Post menopausal, defined as: • No bleeding for >6 months (>12 months for 50-54 years old) • Current / prior use of menopausal hormones • Post hysterectomy with symptoms • Likely to reside in the clinic area for 3 years • Willing to provide written informed consent

  41. WHI Hormone Program Design Conjugated equine estrogen (CEE) 0.625 mg/d YES N= 10,739 Placebo Hysterectomy CEE 0.625 mg/d + medroxyprogesterone acetate 2.5 mg/d NO N= 16,608 Placebo

  42. WHI Estrogen+Progestin TrialBlinding • Treatment assignments unknown to participants, clinic staff and clinic investigators. • Unblinding discouraged unless necessary for safety or clinical management of participants. • When necessary, an unblinding officer provided the clinic gynecologist with treatment assignment. • Unblinding officers and clinic gynecologists were not involved with study outcomes activities.

  43. WHI Estrogen+Progestin TrialReasons for Permanent Discontinuation of Study Medication • Development of breast cancer • Endometrial cancer, atypia or hyperplasia not responsive to treatment • Deep vein thrombosis or PE • Malignant melanoma • Meningioma • Triglyceride level greater than 1000 mg/dL • Prescription of estrogen, testosterone or SERM

  44. WHI outcomes confirmed by hospital records • CHD – MI requiring hospitalization or silent or coronary death • Stroke • Pulmonary embolism/DVT • Cancer • Hip, vertebral, and other osteoporotic fractures

  45. WHI Estrogen+Progestin Trial Global Index • Defined to summarize important aspects of health benefits vs. risks • Defined for each woman as the earliest occurrence of CHD, invasive breast cancer, stroke, PE, endometrial cancer, colorectal cancer, hip fracture or death from other causes

  46. Women’s Health Initiative Trial of Estrogen + Progestin Results

  47. Randomized (N = 16,608) Profile of the Women’s Health Initiative Randomized Trial of Estrogen Plus Progestin in Women With an Intact Uterus Initiated screening (N = 373,092) Provided consent and reportedno hysterectomy (N = 18,845) Estrogen +Progestin (N = 8,506) Placebo (N = 8,102) • Status on 4/30/02 • Alive/outcomes data submitted in last 18 months (n = 7,608) • Unknown vital status (n = 276) • Deceased (n = 218) • Status on 4/30/02 • Alive/outcomes data submitted in last 18 months (n = 7,968) • Unknown vital status (n = 307) • Deceased (n = 231)

  48. Cumulative Drop-out and Drop-in Rates by Randomization Assignment and Follow-up Time Percent

  49. CHD 0.05 0.04 0.03 0.02 0.01 0.0 Time (years) 0 1 2 3 4 5 6 7 Kaplan-Meier Estimates of Cumulative Hazards for CHD The number of women at risk are presented below the horizontal axis for each treatment arm. HR 1.29 nCI (1.02, 1.63) aCI (0.85, 1.97) E+P Placebo E+P 8506 8353 8248 8133 7004 4251 2085 814 Placebo 8102 7999 7899 7789 6639 3948 1756 523

  50. Stroke 0.05 0.04 0.03 0.02 0.01 0.0 Time (years) 0 1 2 3 4 5 6 7 Kaplan-Meier Estimates of Cumulative Hazards for Stroke The number of women at risk are presented below the horizontal axis for each treatment arm. HR 1.41 nCI (1.07, 1.85) aCI (0.86, 2.31) E+P Placebo E+P 8506 8375 8277 8155 7032 4272 2088 814 Placebo 8102 8005 7912 7804 6659 3960 1760 524

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