POSTMENOPAUSAL WOMEN

1
POSTMENOPAUSALWOMENS 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 Womens
  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
  womens 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
Irregular Menses

• 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 EP
  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 lt 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
  (RR0.99)
• 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
7
lt -2.5

• A longitudinal observationalstudy of
  osteoporosis among previously undiagnosedpostmen
  opausal women
• More than 200,000 women from 4,236 primary care
  practices participated

53
gt -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
Cooper C. Baillieres Clin Rheumatol.19937459-477
.
Faulkner, KG. J Clin Densitom. 19981279-285.
23
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,
Physicians 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 252
• Increased mortality within 1 year up to 243
• Lifetime risk of death comparable to that of
  breast cancer4

1. Consensus Development Conference. Am J Med.
199394646-650. 2. Riggs BL, Melton LJ III.
Bone. 199517505S-511S. 3. Ray NF et al. J Bone
Miner Res. 199712(1)24-35. 4. Cummings SR et
al. Arch Intern Med. 19891492445-2448.
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 Patients T-Score
2 1 0 1 2 3 4 5 6
Peak Bone Mass
SD
H
T-score 3.0
20 30 40 50
60 70 80 90
Age (years)

• T-score Number of standard deviations (SDs) by
  which the patients 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

H
National Osteoporosis Foundation, Physicians
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 patients 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, Physicians
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, Physicians
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
Womens Health Initiative
University of Iowa
34
Components

• Preventive Clinical Trial
• Hormone Replacement Therapy
• Diet Modification
• CalciumVitamin D Supplementation
• Observational Study

35
WHI EstrogenProgestin 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 EstrogenProgestin TrialSpecific Aims

• To test whether EP reduces the incidence of CHD
  and other CVD
• To test whether EP reduces the incidence of all
  osteoporosis-related fractures and hip fractures
  separately
• To assess whether EP increases the risk of
  breast cancer

37
Womens Health Initiative Trial of Estrogen
Progestin

• Methods

38
WHI EstrogenProgestin 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
Womens 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.

• Brigham Womens Hosp.

• Albert Einstein
• Col. of Med.

• Univ. of Iowa

• Rush-Presb.
• St. Lukes
• 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 gt6 months (gt12 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 EstrogenProgestin 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 EstrogenProgestin 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 EstrogenProgestin 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
Womens Health Initiative Trial of Estrogen
Progestin

• Results

47
Profile of the Womens 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 7,968)
• Unknown vital status (n 307)
• Deceased (n 231)

• Status on 4/30/02
• Alive/outcomes data submitted in last 18 months
  (n 7,608)
• Unknown vital status (n 276)
• Deceased (n 218)

48
Cumulative Drop-out and Drop-in Rates by
Randomization Assignment and Follow-up Time
Percent
49
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)
EP
Placebo
EP
8506
8353
8248
8133
7004
4251
2085
814
Placebo
8102
7999
7899
7789
6639
3948
1756
523
50
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)
EP
Placebo
EP
8506
8375
8277
8155
7032
4272
2088
814
Placebo
8102
8005
7912
7804
6659
3960
1760
524
51
Kaplan-Meier Estimates of Cumulative Hazards for
PE The number of women at risk are presented
below the horizontal axis for each treatment arm.
52
Kaplan-Meier Estimates of Cumulative Hazards for
Breast Cancer The number of women at risk are
presented below the horizontal axis for each
treatment arm.
53
Kaplan-Meier Estimates of Cumulative Hazards for
Colorectal Cancer The number of women at risk are
presented below the horizontal axis for each
treatment arm.
54
Kaplan-Meier Estimates of Cumulative Hazards for
Hip Fracture The number of women at risk are
presented below the horizontal axis for each
treatment arm.
HR 0.66
nCI (0.45, 0.98)
aCI (0.33, 1.33)
EP
Placebo
EP
8506
8382
8299
8190
7073
4305
2116
826
Placebo
8102
8009
7915
7807
6659
3958
1763
525
55
Kaplan-Meier Estimates of Cumulative Hazards for
Death The number of women at risk are presented
below the horizontal axis for each treatment arm.
56
1.29
2.11
1.26
0.63
1.41
0.67
57
Breast Cancer Outcome (Annualized Percentages) by
Prior Postmenopausal Hormone Use
95
EstrogenProgestin Placebo Hazard
Ratio Nominal CI
Years of Prior Use Never used 114 (0.35) 102 (0.
33) 1.06 (0.81,1.38) lt5 32 (0.39) 15 (0.20) 2.
13 (1.15,3.94) 5 - lt10 11 (0.49) 2 (0.11) 4.61
(1.01,21.02) gt10 9 (0.69) 5 (0.40) 1.81 (0.60,5
.43)
Test for trend, p0.03
58
Sensitivity Analysis of Selected Outcomes to
Actual Use
Hazard Ratio 95 Nominal CI
CHD 1.51 (1.13,2.01) Stroke 1.67 (1.17,2.40) VTE 3
.29 (2.25,4.82) Invasive breast
cancer 1.49 (1.10,2.02)
Censored 6 months after becoming non-adherent
(using lt80, or stopping pills)
59
Attributable Risk Summary

• Excess risk per 10,000 person-years on EP
• 7 more women with CHD
• 8 more women with stroke
• 8 more women with PE
• 8 more women with breast cancer
• Risk reduction per 10,000 person-years on EP
• 6 fewer colorectal cancer
• 5 fewer hip fractures
• Summary 19 additional monitored events per
  10,000 person years on EP

60
WHI EstrogenProgestin TrialSummary

• Treatment with estrogen plus progestin for up to
  5 years is not beneficial overall.
• There is early harm for CHD, continuing harm for
  stroke and VTE, and increasing harm for breast
  cancer.
• This risk-benefit profile is not consistent with
  a viable intervention for primary prevention of
  chronic diseases in postmenopausal women.

61
WHI EstrogenProgestin TrialSummary

• This trial did not address the use of estrogen
  plus progestin for short-term relief of
  menopausal symptoms.

62
WHI EstrogenProgestin TrialLimitations

• Still undetermined is
• Effects of other doses, formulations or routes of
  administration
• Effects of progestin separate from estrogen
• Longer term assessment of risks and benefits
• Rates of discontinuation in the active treatment
  arm may have diluted the observed risks and
  benefits.
• Early stopping limits precision of the results.

63
WHI EstrogenProgestin TrialImplications

• Estrogen plus progestin should not be initiated
  or continued for the primary prevention of CHD.
• The risks for CHD, stroke, PE and breast cancer
  must be weighed against the benefit for fracture
  in selecting from the available agents to prevent
  osteoporosis.

64
HRT
65
Why the Differences Between Observational
Studies and RCTs for CAD?

• OS may produce the wrong answer if there are
  unmeasured differences between hormone users and
  nonusers
• Women who take HRT are generally healthier and
  wealthier than nonusers
• Adherence has been shown to be a strong marker
  for low risk of coronary events, even when
  adherence is to a placebo
• Issue of 1º versus 2º prevention of CAD
• Randomization helps eliminate these and other
  potential biases

66
Clinical Issues Prevention of

• Hot flashes
• Heart disease
• Osteoporosis
• Breast cancer

67
Hot flashes

• Estrogen works!
• Short term use (lt 2 years minimal absolute risk)

68
Other Post-menopausal Prevention Choices

• Alendronate Raloxifene
• Heart disease No effect No effect
• Osteoporotic fx
• Vertebral 0.45 0.50
• Non-vertebral 0.50 0.9
• Breast cancer No effect 0.24
• DVT No effect 3.1
• Rate of hot flashes No effect 30 (worsen)
• Vaginal bleeding None Rare
• not statistically significant

69
Heart Disease Prevention

• In NHS cohort, 82 of CAD cases could be
  eliminated if the population adhered to basic
  behavioral guidelines
• Exercise
• Healthy diet
• Normal weight
• No smoking
• Moderate alcohol consumption

70
Osteoporosis Prevention

• Weight bearing exercise
• 1500 mg calcium daily 400 IU Vit D
• At least normal body weight
• No smoking

71
Summary Healthy lifestyle choices may be the
best medicine