POSTMENOPAUSAL
WOMEN’S HEALTH
Barcey T. Levy, M.D., Ph.D.
August 23, 2002
1
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 postmenopausal women
• Through the panel discussion, begin to appreciate
women’s concerns regarding menopause and what
they expect from their physician
2
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
3
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
4
Symptoms of Menopause
•
•
•
•
Irregular menses
Hot flashes
Vaginal dryness
Urinary incontinence
5
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
6
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
7
Estrogen
• Estrogen works best for hot flashes
• All types and routes of administration equally
effective
• Markedly improves quality of life for younger
postmenopausal women
8
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 nonperfumed oils such as vegetable oils or Vitamin E oil
9
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
10
Public Health Issues
•
•
•
•
Heart disease
Osteoporosis
Cancer
Dementia
11
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
12
Other Public Health Issues in Women
Osteoporosis
28,000,000 low bone mass or
osteoporosis
Cancer (2001) new cases
Lung
78,800
Colon
68,100
Breast
192,200
Dementia
deaths
67,300
29,000
42,200
4,000,000 total (men and women)
13
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
14
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
RR
Current hormone use
0.60
Past hormone use
0.82
• Results were similar for both E users and E+P
users
15
Nurses’ Health Study
Risk of Death Among All Postmenopausal Hormone Users
(Never = Referent)
Grodstein, NEJM 1997
Hormone Use
Cause of Death
All Causes
# of Cases
adj RR (95% CI)
CAD
# of Cases
adj RR (95% CI)
All Cancer
# of Cases
adj RR
Breast Cancer
# of Cases
adj RR
Current
Past
574
0.63 (0.56-0.70)
1012
1.03 (0.94-1.12)
43
0.47 (0.32-0.69)
129
0.99 (0.75-1.30)
353
0.71 (0.62-0.81)
529
1.04 (0.92-1.17)
85
0.76 (0.56-1.02)
94
0.83 (0.63-1.09)
16
Meta-analyses of Observational Studies
CAD -- 10 Prevention
All Studies
Prospective Studies
RR Current HRT
vs. Non-users
0.53
0.60
17
HERS
RCT 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
18
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
19
HERS Conclusions
• Treatment with HRT did not reduce the overall rate
of CHD events in postmenopausal women
• HRT not recommended for secondary prevention
20
Almost 50% of Undiagnosed Postmenopausal
Women Have Low Bone Mass
Distribution of T-scores in NORA*
7%
< -2.5
-1.0 to -2.5
40%
53%
• A longitudinal observational
study of osteoporosis among
previously undiagnosed
postmenopausal women
> -1.0
• More than 200,000 women
from 4,236 primary care
practices participated
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.
Forearm
Relative BMD (%)
100
Spine
Hip and Heel
90
80
70
60
30
40
50
60
70
80
Age
Faulkner, KG. J Clin Densitom. 1998;1:279-285.
90
Annual Fracture Incidence
BMD and Fracture Risk Are Inversely
Related
Colles'
Vertebrae
4000
Hip
3000
2000
1000
0
3539
85+
Age
Cooper C. Baillieres Clin Rheumatol.1993;7:459-477.
Risk Factors for Osteoporotic Fracture
Not Modifiable
Potentially Modifiable
Personal history of fracture
as an adult
Current cigarette smoking
History of fracture in
first-degree relative
Estrogen deficiency, including
menopause onset <age 45
Caucasian race
Alcoholism
Low body weight (<127 lbs)
Low calcium intake (lifelong)
Advanced age
Female sex
Impaired eyesight despite
adequate correction
Recurrent falls
Dementia
Poor health/frailty
Inadequate physical activity
Poor health/frailty
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.
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.
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
25
Central DXA Measurement
• Measures multiple
skeletal sites
–
–
–
–
Spine
Proximal femur
Forearm
Total body
• Office based
• Considered the
clinical standard
Visualizing a Patient’s T-Score
2
1
Peak Bone Mass
SD
0
–1
–2
–3
–4
H
T-score = –3.0
–5
–6
20
30
40
50
60
70
80
90
Age (years)
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
H = 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
National Osteoporosis Foundation, Physician’s Guide to Prevention and Treatment of Osteoporosis. Belle Mead, NJ: Excerpta Medica, Inc.; 1998
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
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
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
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
(with at least 1
additional risk factor)
Initiate therapy
National Osteoporosis Foundation, Physician’s Guide to Prevention and Treatment of Osteoporosis.
Belle Mead, NJ: Excerpta Medica, Inc.; 1998
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
32
Women’s Health Initiative
University of Iowa
33
Components
• Preventive Clinical Trial
– Hormone Replacement Therapy
– Diet Modification
– Calcium+Vitamin D Supplementation
• Observational Study
34
WHI Estrogen+Progestin Trial
Background 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
35
WHI Estrogen+Progestin Trial
Specific 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
36
Women’s Health Initiative Trial of
Estrogen + Progestin
Methods
37
WHI Estrogen+Progestin Trial
Recruitment
• National and local area media awareness
campaigns
• Population-based direct mailings to ageeligible women
• Augmented by local recruitment strategies
• 3 screening visits
38
Women’s Health Initiative Clinical Centers
 Fred Huthcinson Cancer
Research Center
Univ. of Minnesota Med. Ctr.
Medical College
of Wisconsin
 Kaiser Foundation
Research Institute
 Univ. of Wisconsin
Wayne State Univ.
SUNY
Buffalo
Univ. of Mass
Med. Ctr.
Albert Einstein
 Brigham & Women’s Hosp.
Col. of Med.
 Univ. of Iowa
 Mem. Hosp. of Rhode Is.
Univ. of Pittsburgh
Rush-Presb.  Northwestern
 SUNY, Stony Brook
Univ.
St. Luke’s
 Ohio State Univ.
 Univ. of Med. & Dent.
Med. Ctr.
of New Jersey
 Univ. of California, Davis
 Univ. of Nevada, Reno
 Kaiser Foundation Research Institute
 Leland Stanford Junior University
 Medlantic Res. Inst./Howard Univ.
 George Washington Univ.
Univ. of Cincinnati
Medical Center
 Univ. of California, Los Angeles
 Univ. of California, Irvine
 Harbor-UCLA Research & Education Inst.
 Univ. of Tennessee
 Univ. of California, San Diego
 Bowman Gray School of Medicine
 Univ. of North Carolina
 Emory Univ. Sch. of Medicine
 Univ. of Alabama
 Univ. of Arizona at Tucson
Univ. of Texas Health
Science Ctr., San Antonio
 Univ. of Florida
Baylor College of Medicine
 Univ. of Miami
 Univ. of Hawaii
39
I:\DOCUMENT\GRAPHICS\FIGURES\WHIMAP.PPT
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
40
WHI Hormone Program Design
YES
Conjugated equine
estrogen (CEE) 0.625 mg/d
N= 10,739
Placebo
Hysterectomy
NO
N= 16,608
CEE 0.625 mg/d +
medroxyprogesterone
acetate 2.5 mg/d
Placebo
41
WHI Estrogen+Progestin Trial
Blinding
• 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.
42
WHI Estrogen+Progestin Trial
Reasons 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
43
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
44
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
45
Women’s Health Initiative Trial of
Estrogen + Progestin
Results
46
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 reported
no hysterectomy (N = 18,845)
Randomized (N = 16,608)
Estrogen +Progestin
(N = 8,506)
Status on 4/30/02
 Alive/outcomes data
submitted in last 18
months (n = 7,968)
 Unknown vital status
(n = 307)
 Deceased (n = 231)
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)
47
Cumulative Drop-out and Drop-in Rates by
Randomization Assignment and Follow-up Time
40
35
Percent
30
25
Drop-out Estrogen+Progestin
Drop-out Placebo
20
Drop-in Estrogen+Progestin
Drop-in Placebo
15
10
5
0
Year 1
Year 2
Year 3
Year 4
Year 5
Year 6
Year 7
48
Kaplan-Meier Estimates of Cumulative Hazards for CHD
The number of women at risk are presented below the horizontal axis for each treatment arm.
0.05
CHD
0.03
0.04
HR 1.29
nCI (1.02, 1.63)
aCI (0.85, 1.97)
0.0
0.01
0.02
E+P
Placebo
Time (years)
1
2
3
4
5
6
7
E+P
8506
0
8353
8248
8133
7004
4251
2085
814
Placebo
8102
7999
7899
7789
6639
3948
1756
523 49
Kaplan-Meier Estimates of Cumulative Hazards for Stroke
The number of women at risk are presented below the horizontal axis for each treatment arm.
0.05
Stroke
0.03
0.04
HR 1.41
nCI (1.07, 1.85)
aCI (0.86, 2.31)
0.0
0.01
0.02
E+P
Placebo
Time (years)
1
2
3
4
5
6
7
E+P
8506
0
8375
8277
8155
7032
4272
2088
814
Placebo
8102
8005
7912
7804
6659
3960
1760
524 50
Kaplan-Meier Estimates of Cumulative Hazards for PE
The number of women at risk are presented below the horizontal axis for each treatment arm.
0.05
PE
0.03
0.04
HR 2.13
nCI (1.39, 3.25)
aCI (0.99, 4.56)
0.0
0.01
0.02
E+P
Placebo
Time (years)
1
2
3
4
5
6
7
E+P
8506
0
8364
8280
8174
7054
4295
2108
820
Placebo
8102
8013
7924
7825
6679
3973
1770
52651
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.
0.05
Invasive Breast Cancer
0.03
0.04
HR 1.26
nCI (1.00, 1.59)
aCI (0.83, 1.92)
0.0
0.01
0.02
E+P
Placebo
Time (years)
1
2
3
4
5
6
7
E+P
8506
0
8378
8277
8150
7000
4234
2064
801
Placebo
8102
8001
7891
7772
6619
3922
1740
52352
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.
0.05
Colorectal Cancer
0.03
0.04
HR 0.63
nCI (0.43, 0.92)
aCI (0.32, 1.24)
0.0
0.01
0.02
E+P
Placebo
Time (years)
1
2
3
4
5
6
7
E+P
8506
0
8379
8297
8194
7073
4305
2111
825
Placebo
8102
8003
7916
7814
6660
3958
1756
52253
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.
0.05
Hip Fracture
0.03
0.04
HR 0.66
nCI (0.45, 0.98)
aCI (0.33, 1.33)
0.0
0.01
0.02
E+P
Placebo
Time (years)
1
2
3
4
5
6
7
E+P
8506
0
8382
8299
8190
7073
4305
2116
826
Placebo
8102
8009
7915
7807
6659
3958
1763
525 54
Kaplan-Meier Estimates of Cumulative Hazards for Death
The number of women at risk are presented below the horizontal axis for each treatment arm.
0.15
Death
0.10
HR 0.98
nCI (0.82, 1.18)
aCI (0.70, 1.37)
0.0
0.05
E+P
Placebo
Time (years)
1
2
3
4
5
6
7
E+P
8506
0
8388
8313
8214
7095
4320
2121
828
Placebo
8102
8018
7936
7840
6697
3985
1777
53055
1.29
1.26
1.41
2.11
0.63
0.67
56
Breast Cancer Outcome (Annualized Percentages) by Prior
Postmenopausal Hormone Use
Estrogen+Progestin
Placebo
Hazard Ratio
95%
Nominal CI
Years of Prior Use
Never used
114 (0.35%)
102 (0.33%)
1.06
(0.81,1.38)
<5
32 (0.39%)
15 (0.20%)
2.13
(1.15,3.94)
5 - <10
11 (0.49%)
2 (0.11%)
4.61
(1.01,21.02)
5 (0.40%)
1.81
(0.60,5.43)
>10
9
(0.69%)
Test for trend, p=0.03
57
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 <80%, or stopping pills)
58
Attributable Risk Summary
• Excess risk per 10,000 person-years on E+P
– 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 E+P
– 6 fewer colorectal cancer
– 5 fewer hip fractures
• Summary: 19 additional monitored events per 10,000 person
years on E+P
59
WHI Estrogen+Progestin Trial
Summary
• 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.
60
WHI Estrogen+Progestin Trial
Summary
• This trial did not address the use of estrogen plus
progestin for short-term relief of menopausal
symptoms.
61
WHI Estrogen+Progestin Trial
Limitations
• 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.
62
WHI Estrogen+Progestin Trial
Implications
• 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.
63
64
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
65
Clinical Issues – Prevention of:
•
•
•
•
Hot flashes
Heart disease
Osteoporosis
Breast cancer
66
Hot flashes
• Estrogen works!
• Short term use (< 2 years minimal
absolute risk)
67
Other Post-menopausal Prevention Choices
Heart disease
Osteoporotic fx
Vertebral
Non-vertebral
Breast cancer
DVT
Rate of hot flashes
Vaginal bleeding
Alendronate
Raloxifene
No effect
No effect
0.45
0.50
No effect
No effect
No effect
None
0.50
0.9*
0.24
3.1
30% (worsen)
Rare
* not statistically significant
68
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
69
Osteoporosis Prevention
•
•
•
•
Weight bearing exercise
1500 mg calcium daily + 400 IU Vit D
At least normal body weight
No smoking
70
Summary:
Healthy lifestyle choices may be the best medicine
71