1

POSTMENOPAUSALWOMEN’S HEALTH

Barcey 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

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 RR

Current 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

40%40%

53%53%

7%7%

> -1.0-1.0 to -2.5

< -2.5

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.

Almost 50% of Undiagnosed Postmenopausal Women Have Low Bone Mass

• A longitudinal observationalstudy of osteoporosis among

previously undiagnosedpostmenopausal women

• More than 200,000 women from 4,236 primary care practices participated

Distribution of T-scores in NORA*Distribution of T-scores in NORA*

60

70

80

90

100

30 40 50 60 70 80 90

Age

Re

lati

ve

BM

D (

%)

Forearm

Spine

Hip and Heel

0

1000

2000

3000

4000

35-39

85+

Colles'

Vertebrae

Hip

AgeA

nn

ual

Fra

ctu

re In

cid

en

ce

Cooper C. Baillieres Clin Rheumatol.1993;7:459-477.Faulkner, KG. J Clin Densitom. 1998;1:279-285.

BMD and Fracture Risk Are Inversely Related

Risk Factors for Osteoporotic Fracture

Not Modifiable Potentially Modifiable

Personal history of fracture as an adult

History of fracture infirst-degree relative

Caucasian race

Advanced age

Female sex

Dementia

Poor health/frailty

Current cigarette smoking

Low body weight (<127 lbs)

Estrogen deficiency, including menopause onset <age 45

Low calcium intake (lifelong)

Alcoholism

Impaired eyesight despiteadequate correction

Recurrent falls

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.

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.

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

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

Central DXA Measurement

• Measures multipleskeletal sites– Spine– Proximal femur– Forearm– Total body

• Office based• Considered the

clinical standard

SD

Age (years)

2

1

0

–1

–2

–3

–4

–5

–6

20 30 40 50 60 70 80 90

T-score = –3.0

Peak Bone Mass

Visualizing a Patient’s T-Score

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

National Osteoporosis Foundation, Physician’s Guide to Prevention and Treatment of Osteoporosis. Belle Mead, NJ: Excerpta Medica, Inc.; 1998

T-Score Is KeyT-Score Is Key

Interpreting BMD Measurement Reports

• 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

National Osteoporosis Foundation, Physician’s Guide to Prevention and Treatment of Osteoporosis. Belle Mead, NJ: Excerpta Medica, Inc.; 1998

Interpreting BMD Measurement Reports

Some BMD Reports Also Include a 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

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

National Osteoporosis Foundation, Physician’s Guide to Prevention and Treatment of Osteoporosis. Belle Mead, NJ: Excerpta Medica, Inc.; 1998

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 Guidelines for WomenNational Osteoporosis Foundation Guidelines for Women

Recommendations for Treatment Based on BMD Testing Results

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

Fred Huthcinson Cancer Research Center

Kaiser Foundation Research Institute

Univ. of California, Davis Univ. of Nevada, Reno

Kaiser Foundation Research Institute Leland Stanford Junior University

Univ. of California, Los Angeles Univ. of California, Irvine

Harbor-UCLA Research & Education Inst.

Univ. of California, San Diego

Univ. of Arizona at Tucson

Univ. of Texas HealthScience Ctr., San Antonio

Baylor College of Medicine

Univ. of Hawaii

Univ. of Florida

Univ. of Miami

Univ. of Alabama

Emory Univ. Sch. of Medicine

Univ. of Tennessee

Univ. of Minnesota Med. Ctr.Medical Collegeof Wisconsin

Univ. of Wisconsin

Univ. of Iowa Northwestern Univ.

Rush-Presb.St. Luke’sMed. Ctr.

Wayne State Univ.

Ohio State Univ.

Univ. of Pittsburgh

Univ. of CincinnatiMedical Center

Bowman Gray School of Medicine Univ. of North Carolina

SUNYBuffalo

Brigham & Women’s Hosp.

Univ. of MassMed. Ctr.

Mem. Hosp. of Rhode Is. SUNY, Stony Brook

Albert EinsteinCol. of Med.

Univ. of Med. & Dent. of New Jersey

Medlantic Res. Inst./Howard Univ. George Washington Univ.

Women’s Health Initiative Clinical Centers

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

Hysterectomy

Conjugated equine estrogen (CEE) 0.625 mg/d

Placebo

CEE 0.625 mg/d + medroxyprogesterone acetate 2.5 mg/d

N= 16,608

N= 10,739YES

NO

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

• 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

WHI Estrogen+Progestin TrialReasons for Permanent Discontinuation of Study Medication

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

Profile of the Women’s Health Initiative Randomized Trial ofEstrogen Plus Progestin in Women With an Intact Uterus

Provided consent and reportedno hysterectomy (N = 18,845)

Initiated screening (N = 373,092)

Randomized (N = 16,608)

Status on 4/30/02 Alive/outcomes data

submitted in last 18 months (n = 7,968)

Unknown vital status (n = 307)

Deceased (n = 231)

Estrogen +Progestin(N = 8,506)

Status on 4/30/02 Alive/outcomes data

submitted in last 18 months (n = 7,608)

Unknown vital status (n = 276)

Deceased (n = 218)

Placebo(N = 8,102)

48

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

Per

cen

t

49

Kaplan-Meier Estimates of Cumulative Hazards for CHDThe number of women at risk are presented below the horizontal axis for each treatment arm.

CHD0.

00.

010.

020.

030.

040.

05

0 1 2 3 4 5 6 7

Time (years)

E+PPlacebo

E+P 8506 8353 8248 8133 7004 4251 2085 814

Placebo 8102 7999 7899 7789 6639 3948 1756 523

HR 1.29 nCI (1.02, 1.63) aCI (0.85, 1.97)

50

Kaplan-Meier Estimates of Cumulative Hazards for StrokeThe number of women at risk are presented below the horizontal axis for each treatment arm.

Stroke0.

00.

010.

020.

030.

040.

05

0 1 2 3 4 5 6 7

Time (years)

E+PPlacebo

E+P 8506 8375 8277 8155 7032 4272 2088 814

Placebo 8102 8005 7912 7804 6659 3960 1760 524

HR 1.41 nCI (1.07, 1.85) aCI (0.86, 2.31)

51

Kaplan-Meier Estimates of Cumulative Hazards for PEThe number of women at risk are presented below the horizontal axis for each treatment arm.

PE0

.00

.01

0.0

20

.03

0.0

40

.05

0 1 2 3 4 5 6 7

Time (years)

E+PPlacebo

E+P 8506 8364 8280 8174 7054 4295 2108 820

Placebo 8102 8013 7924 7825 6679 3973 1770 526

HR 2.13 nCI (1.39, 3.25) aCI (0.99, 4.56)

52

Kaplan-Meier Estimates of Cumulative Hazards for Breast CancerThe number of women at risk are presented below the horizontal axis for each treatment arm.

Invasive Breast Cancer0

.00

.01

0.0

20

.03

0.0

40

.05

0 1 2 3 4 5 6 7

Time (years)

E+PPlacebo

E+P 8506 8378 8277 8150 7000 4234 2064 801

Placebo 8102 8001 7891 7772 6619 3922 1740 523

HR 1.26 nCI (1.00, 1.59) aCI (0.83, 1.92)

53

Kaplan-Meier Estimates of Cumulative Hazards for Colorectal CancerThe number of women at risk are presented below the horizontal axis for each treatment arm.

Colorectal Cancer0

.00

.01

0.0

20

.03

0.0

40

.05

0 1 2 3 4 5 6 7

Time (years)

E+PPlacebo

E+P 8506 8379 8297 8194 7073 4305 2111 825

Placebo 8102 8003 7916 7814 6660 3958 1756 522

HR 0.63 nCI (0.43, 0.92) aCI (0.32, 1.24)

54

Kaplan-Meier Estimates of Cumulative Hazards for Hip FractureThe number of women at risk are presented below the horizontal axis for each treatment arm.

Hip Fracture0.

00.

010.

020.

030.

040.

05

0 1 2 3 4 5 6 7

Time (years)

E+PPlacebo

E+P 8506 8382 8299 8190 7073 4305 2116 826

Placebo 8102 8009 7915 7807 6659 3958 1763 525

HR 0.66 nCI (0.45, 0.98) aCI (0.33, 1.33)

55

Kaplan-Meier Estimates of Cumulative Hazards for DeathThe number of women at risk are presented below the horizontal axis for each treatment arm.

Death0

.00

.05

0.1

00

.15

0 1 2 3 4 5 6 7

Time (years)

E+PPlacebo

E+P 8506 8388 8313 8214 7095 4320 2121 828

Placebo 8102 8018 7936 7840 6697 3985 1777 530

HR 0.98 nCI (0.82, 1.18) aCI (0.70, 1.37)

56

1.29

1.41

1.26

0.67

0.63

2.11

57

Breast Cancer Outcome (Annualized Percentages) by Prior Postmenopausal Hormone Use

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)

>10 9 (0.69%) 5 (0.40%) 1.81 (0.60,5.43)

Test for trend, p=0.03

95% Estrogen+Progestin PlaceboHazard RatioNominal CI

58

Sensitivity Analysis of Selected Outcomes to Actual Use*

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)

Hazard Ratio 95% Nominal CI

* Censored 6 months after becoming non-adherent (using <80%, or stopping pills)

59

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

60

WHI Estrogen+Progestin 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 Estrogen+Progestin TrialSummary

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

62

WHI Estrogen+Progestin 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 Estrogen+Progestin 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

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 (< 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