The Hormonal Continuum: Benefits to Women from Menarche to Menopause

1
The Hormonal Continuum Benefits to Women from
Menarche to Menopause

• Sponsored by Ortho-McNeil Pharmaceutical, Inc

2
Norgestimate and New Trends in HRT Responses
to the Challenges Faced by Mid-Life Women

• John H. Mattox, MD

3
John H. Mattox, MDChair and Program
DirectorObstetrics and GynecologyGood Samaritan
Regional Medical Center
Professor, Obstetrics, Gynecology and Community
Medicine University of Arizona Phoenix, Arizona,
USA
4
US Women Aged 65 Years
US Bureau of the Census.
5
Top Priority Better Health
Percentage Of Women Indicating Areas Of Life
They Would Most Like To Improve
Health and Fitness
Personal Relationships
Finances
Family Life
Data Source Legato, MJ, et al., Womens
Perceptions of Their General Health, with Special
Reference to Their Risk of Coronary Artery
Disease Results of a National Telephone Survey,
Journal of Womens Health, Vol.,VI, No. 2, 1997.
6
Remaining Life Expectancy and Years of
Independent Living
Paiement GD, Perrier L. Orthopedic Complications
of Menopause. In Lorrain J. et al, eds.
Comprehensive Management of Menopause. 199433
7
Menopause Population Opportunities

• 52 MM women will reach the menopausal
  periodwithin the next decade
• Half will live more than a third of their life
  beyond the age of menopause
• Only 20 of eligible women currently utilize
  combined hormonal therapy (non-hysterectomized
  women) 55 of users do not stay on therapy
  beyond 6 months

US News and World Report, Sept. 2000. Gass MLS et
al. Menopause. 1997419-23. Keating NL et al.
Ann Intern Med. 1999130545-553. Lobo RA. Am J
Obstet Gynecol. 1995173982-989.
8
ERT vs CT SegmentsTotal Contributions

• Rationale
• Gradual decline in hysterectomy

CT41
CT50
ERT59
ERT50
2009
2000
Source IMS NDTI.
9
Evidence-Based Benefits of ERT
Level of Evidence
I II-2 II-2 II-2 II-2 II-2 II-2 II-2 II-2
10
Evidence-Based Hazards of ERT
11
Obstacles to HRT Use

• Fear of breast cancer
• Concerns about progestin-relatedside effects
• Lack of recognition of long-term benefits
• Perception of menopause as natural,medical
  intervention as unnatural
• Misperceptions regarding so-callednatural
  estrogens

12
Mortality From Heart DiseaseUS Women
7000
Heart disease
Breast cancer
6000
Hip fractures
5000
4000
Deaths/100,000
3000
2000
1000
0
25
35
45
55
65
75
85
95
0
Age
Kramarow E et al. Health and Aging Chartbook.
Health, United States, 1999. National Center for
Health Statistics 1999.
13
Women and Cardiovascular Disease
Cardiovascular Disease Mortality Trendsfor Males
and Females
United States 1979-97
520
Females
500
480
Deaths in Thousands
460
Males
440
420
20
0
79
81
83
85
87
89
91
93
95
97
Years
Source CDC/NCHS and the American Heart
Association.
14
Cardiovascular Disease in Postmenopausal Women

• 1 in 2 women will die from cardiovascular disease
• Estrogen exerts beneficial effects on CVsystem
  through
• Direct effect on the vasculature
• Indirect effect on lipid metabolism
• In healthy menopausal women the use of ERT/HRT
  has demonstrated cardiovascular benefit in
  numerous observational studies
• Secondary prevention trials (HERS, ERA) showed no
  effect of ERT/HRT

15
Prevention of CVD in Mid-Life Women Public Health
Issue

• 50 million women in the US have TC gt200 mg/dL
• More than 50 of women (gt55 years old) have TC
  gt240 mg/dL
• The prevalence of CHD in women aged 45-64 is 1 in
  7 and gt65 is 1 in 3
• Deaths from CHD and cancer are equal in younger
  women, but over 65 years old, CHD is the major
  cause of death (more than all cancers combined)

16
Positive Effects of Estrogen on Cardiovascular
Parameters

• Improved lipid profile
• Increases HDL-C
• Decreases LDL-C
• Improves carbohydratemetabolism
• Improve cardiaccontractility andcoronary
  arteryblood flow

• Decreases plateletaggression
• Decreases Lp (a)
• Inhibits LDL oxidation
• Decreases plaqueformation
• Promotes vasodilation

CHD mortality decreased approximately 50 with HRT
Walsh et al. N Engl J Med. 19913251196. Writing
Group for the PEPI Trial. JAMA. 1995. Espeland et
al. Circulation. 199897979. Rosana et al.
Lancet. 1993. Pines et al. Am J Cardiol. 1996.
17
Potential Cardioprotective Mechanisms for Estrogen
Lipid-independent Lipid-dependent Mechanisms
Mechanisms

• HDL
• LDL
• Lp (a)
• LDL oxidation

• Endothelial effects
• Insulin sensitivity
• Vascular dilatation
• Coagulation factors
• Coronary artery LDL uptake

Gerhard, Ganz. Circulation. 1995925 Sullivan.
Br J Obstet Gynaecol. 1996103(suppl)50 Clarkson
, Anthony. In Estrogens and Antiestrogens.
Philadelphia, Pa Lippincott-Raven 199789.
18
Total Cholesterol Levels After Menopause
Menopause
Percent
-24
6
-18
-12
-6
0
Months
8
10
9
9
10
10
8
9
10
10
10
Maturitas 12(1990)321-331.
19
HDL Cholesterol Levels After Menopause
Menopause
Percent
-18
-24
-12
-6
0
6
Months
8
10
9
9
10
10
8
9
10
10
10
Maturitas 12(1990)321-331.
20
LDL Cholesterol Levels After Menopause
Menopause
Percent
-24
6
-18
-12
-6
0
Months
8
10
9
9
10
10
8
9
10
10
10
Maturitas 12(1990)321-331.
21
Triglyceride Levels After Menopause
Menopause
Percent
-24
6
-18
-12
-6
0
Months
8
10
9
9
10
10
8
9
10
10
10
Maturitas 12(1990)321-331.
22
HDL-C Changes PEPI Trial
Percent change from baseline. PEPI Writing
Group. JAMA. 1995273199.
23
Mean Lipoprotein Changes Premenopausal to
Postmenopausal (Over 3 Years) by Hormone Use
Status


Mean Change inLipoprotein Levels (mmol/L)


P?0.05Egeland, GM et al. Obstetrics
Gynecology. 199076776-781.
24
ERT/HRT Prevents Major Cause ofMortality in
Women CVD
Summary of Observational Studies of ERT/HRT and
CVD
Relative Risk
Wilson et al, 1985 Bush et al, 1987 Petitti et
al, 1987 Boysen et al, 1988 Henderson et al,
1988 Van der Giezen et al, 1990 Wolf et al,
1991 Falkenborn et al, 1992 Psaty et al,
1994 Folsom et al, 1995 Grodstein et al, 2000
0
0.5
1.0
2.0
10
25
The HERS Study

• Randomized, double-blind, placebo-controlled
  trial designed to study cardioprotective effects
  of HRT in secondary prevention of CHD
• Postmenopausal women with CHD and intact uterus
  randomized to receive daily either
• CEE (0.625 mg) MPA (2.5 mg) or placebo
• Primary end point nonfatal MI or CHD death

Hulley S et al. JAMA. 1998280605-613.
26
HRT and Cardiovascular Events HERS Trial

• 2,763 women with CHD randomized to CEE and MPA vs
  placebo over about 4 years
• No overall benefit of HRT to reduce CHD
  recurrence
• Increased risk of CHD and VTE in the first year
• Decreased risk of CHD and decline in VTE rate by
  the fourth year
• Time relationships suggest early thrombogenic
  effect and later antiatherogenic effect

Hulley et al. JAMA. 1998280605.
27
Effect of HRT vs Placebo onSecond CHD Events
(HERS)
Placebo
Year
RR
95 CI
70
HRT
1 2 3 45
1.52 1.00 0.87 0.67
1.01-2.29 0.67-1.49 0.55-1.37 0.43-1.04

60
50
Number of Second CHD Events
40
30
20
Year 1
Year 2
Year 3
Year 4 5
P.009, for trend-time analysis. Adapted from
Hulley S et al. JAMA. 1998280605-613.
28
HRT and Cardiovascular Events ERA Trial

• Randomized women with ?30 stenosis in ?1
  coronary artery to 100 to CEE alone, 104 to CEE
  MPA, and 105 to placebo
• After 3.2 years of follow-up, coronary artery
  disease proceeded at same rate in all 3 arms
• Findings persisted when stratified by disease
  severity at baseline

American College of Cardiology Annual Meeting,
Anaheim, Calif April 2000.
29
HRT and Cardiovascular EventsWHI Preliminary
Results

• Over 27,000 average-risk women randomized
• 16,609 with uterus to continuous CEE MPA vs
  placebo 10,739 without uterus to CEE vs placebo
• After 2 years, following trends identified
• Increase in cardiovascular events (MI, stroke,
  VTE) in HRT groups vs placebo
• Actual number of women with CVD events lt1
• Risk perhaps higher with addition of progestin
• Trend diminished over time

NHLBI Press Release, April 3, 2000.
30
Effect of ERT on 10-Year Survival
Women with Normal Coronary Arteries
Women with Moderate CAD
Women withSerious CAD
n64
n53
8
25
11
23
100
100
90
90
n306
117
n789
80
80
40
70
70
260
Still Alive
60
60
50
50
58
40
40
30
30
20
20
10
10
0
0
0
24
48
72
96
120
0
24
48
72
96
120
Months After Catheterization
Stenosis lt 70. Left main stenosis ³ 50 or
other stenosis ? 70. Sullivan JM et al. Arch
Intern Med. 19901502557-2562.
31
Incidence of Death, Nonfatal MI or Nonfatal
Stroke After Angioplasty
60
Estrogen
Control
50
40
Percent with Event
30
20
10
0
0
1
2
3
4
5
6
7
Years
OKeefe JH Jr et al. J Am Coll Cardiol.
1997291-5.
32
Age-Standardized Rates Reinfarction and Death
After First MI
Incidence Rate/1000 Person-Years
No ERT
Past ERT
Current ERT
Reinfarction
Death
Newton KM et al. Am J Epidemiol. 1997145269-277.
33
ERT vs HRT Primary Prevention of Coronary
Artery Atherosclerosis in Monkeys
Adams et al. Arteriosclerosis. 1990101051
Adams et al. Arterioscler Thromb Vasc Biol.
199717217.
34
Reduction of Coronary Artery LDL Degradation and
Atherosclerosis With HRT
P?.05.
Adapted from 1. Wagner et al. Arterioscler
Thromb. 199212717 2. Adams et al.
Atherosclerosis. 1990101051.
35
Effects of ORTHO-PREFEST on Lipid Profile at
Month 12, Compared to 1 mg 17?-E2
Triglyceride
HDL
LDL
TotalCholesterol
45
40
35
29.0
30
25
Mean ChangeFrom Baseline ()
20
12.0
15
9.4
9.7
10
5
1.2
0
-1.9
-5
-4.9
-5.2
-10
E2 1 mg (n36)
E2 1 mg/NGM 90 µg (n31)
-15
Plt0.05 Lobo RA et al. Am J Obstet Gynecol.
200018241-49.
36
Effects of ORTHO-PREFEST on Lipid Profile at
Month 12, Compared to KLIOGEST
LDL
Triglycerides
HDL
Total Cholesterol
10
4.8
5
0
Mean Change FromBaseline ()
-5
-10
-9.2
-12.3
-15
-14.9

-15.9
-20
-17.9

-25
KLIOGEST E2 2 mg/NETA 1 mg (n167)
Significant change from baseline. Plt0.001
between study arms. Ylikorkala O et al. Clin
Ther. 200022622-636.
ORTHO-PREFEST E2 1 mg/NGM 90 µg (n178)
37
Effects of PREMPRO on Lipid Profile at Month 12
Triglycerides
HDL
LDL
35
30
25
20
15
ChangeFrom Baseline
10
5
0
-5
-10
-15
-20
PREMPRO 0.625 mg/2.5 mg
-25
PREMPRO package insert, 2000.
38
Effects of Low Dose PREMPRO on Lipid Profile at
Month 12
Triglycerides
HDL
LDL
35
30
24.8
25
20
ChangeFrom Baseline
15
10
5
0
-5
-10
-15
Low Dose PREMPRO 0.45 mg/1.5 mg
Lobo RA et al. Fertil Stenl. 200176(1)13-24.
39
Effects of femhrt on Lipid Profile at Month
24, Compared to Placebo
Triglycerides
HDL
LDL
35
30
25
20
15
10
ChangeFrom Baseline
5
0
-5
-6.7
-10
-15
-20
femhrt
-25
femhrt package insert, 2000.
40
Effects of ACTIVELLA on Lipid Profile at Month
12, Compared to Placebo
Triglycerides
HDL
LDL
35
30
25
20
15
10
ChangeFrom Baseline
2.2
5
0
-5
-10
-10.8
-12.4
-15
-20
ACTIVELLA
-25
Activella package insert, 2000.
41
Contrasting HRT Lipid Impact
Non-Comparative Data
HDL
LDL
TG
ORTHO-PREFEST
?
?
?
PREMPRO
?
?
?
femhrt
?
?
?
ACTIVELLA
?
?
?
ORTHO-PREFEST package insert 2000.
PREMPRO package insert, 2000. femhrt
package insert, 2000. Activella package
insert, 2000. Data from Kliogest Study
42
Lipid Results ( Change)
ORTHO-PREFEST,12 Months data,N167
PEPI Trial, 36 Months data, N180 per Group
P lt.05 vs baseline. The Writing Group for the
PEPI Trial. JAMA. 1995273199-208. Ylikorkala O
et al. Clin Ther. 200022622-636.
43
NCEP Lipid-Level Guidelines
Postmenopausal Women With One or MoreRisk
Factors for Cardiovascular Disease
Not currently on hormone replacement
therapy. LDL-Clt100 mg/dL is recommended for
women who already have heart disease.
44
Summary

• Menopause has an adverse effect on lipids
• Effects of estrogen on lipids
• HDL
• LDL
• Triglycerides
• Various progestins attenuate the effects of
  estrogen differently and may exertvariations in
  clinical effects

45
HRT Selection Lipid Considerations

• For women with undesirable lipid levels needing
  combination therapy, consider the type and
  doseof progestin
• When selecting HRT options for all women,
  consider the impact on lipids as well as
  theirdirect effect on the vascular system

46
What Is Currently Known About C-Reactive Protein
and Homocysteine as Markers for CVD and What Is
Known About the Effect of HRT?
47
Predictors of Risk of CV Events

• C-reactive protein a marker of inflammation
• ? C-reactive protein is associated with? risk of
  CV events
• The clinical significance of ? C-reactive protein
  levels with ERT/HRT needs to be further studied
• Homocysteine
• Increased levels are associated with ? riskof
  CAD, peripheral arterial disease, stroke,and VTE

48
Any CV Events Among Healthy Women After 3 Years
Follow-Up by Baseline C-Reactive Protein (CRP)
Concentration
6

Any CV Event P for trend 0.001
5

4

Relative Risk
3
2
1
0
Quartile of CRPCRP Range
1lt1.5 mg/L
21.5-3.7 mg/L
33.8-7.3 mg/L
4gt7.3 mg/L
Models are age- and smoking-matched and
controlled for body mass index,
diabetes,hypertension, hypercholesterolemia,
exercise, family history, and treatment
assignment CI do not include 1.0 Ridker PM et
al. Circulation. 199898731-733.
49
Relative Risk of Cardiovascular Events in 366
Postmenopausal Women from Womens Health Study
Adjusted for OtherPlasma Markers
Adjusted for Other PlasmaMarkers and Risk
Factors
Variable
Relative Risk(95 CI)
Relative Risk (95 CI)
P Value
P Value
0.01 0.02 0.2
Ratio of total cholesterolto HDL
cholesterol High-sensitivityC-reactive
protein Homocysteine
1.4 (1.1-1.7) 1.4 (1.1-1.9) 1.1 (0.9-1.4)
1.4 (1.1-1.9) 1.5 (1.1-2.1) 1.1 (0.8-1.4)
0.02 0.02 0.6
Subjects were matched according to age and
smoking status. Adjusted for body-mass index,
hypertension, diabetes and a parental history of
myocardial infarction. Associated with an
increase of one quartile in the concentration of
each plasma marker.
Ridker PM et al. N Engl J Med. 2000342836-843.
50
Distribution of C-Reactive Protein of
Postmenopausal Women (N493)
1.2
1.0
0.8
Median CRP (mg/dL)
0.6
0.4
0.2
0.0
WomenNo HRT
Any HRT
EstrogenAlone
Estrogen PlusProgesterone
Ridker PM et al. Circulation. 1999100713-716.
51
C-Reactive Protein PEPI Trial
CEE
3
2.5
Estimated Mean Level ofC-Reactive Protein (mg/L)
2
1.5
1
P0.0001
0
12
36
0
Time (Months)
Cushman M et al. Circulation. 1999100717-722.
52
C-Reactive Protein (CRP) Clinical Significance

• Increase in CRP associated with increasein CV
  events
• ERT/HRT use associated with increasein CRP
• Estrogen has cardiovascular protective effect
• Studies on effect of hormone mediatedchanges in
  CRP on risk of subsequentCV events are needed to
  assess if causal relation exists

53
Changes in Serum Homocysteine Concentration in
Postmenopausal Women (N390)
6
4
2
0
-2
Median Percent Change inHomocysteine Baseline to
6 Months
-4
-6
-8
-10
-12
P
CEE/MPA
raloxifene 60
raloxifene 120
Percent change
0.0
-8.0
-5.7
-6.6
Absolute change (µmol/L)
0.0
-1.0
-0.6
-0.7
Plt0.001 compared with baseline. Plt0.001
compared with placebo. Walsh BW et al. J Clin
Endocrinol Metab. 200085214-218.
54
AHA Recommendationson HRT and CVD

• Secondary Prevention
• HRT should not be initiated for women with
  existing heart disease
• Primary Prevention
• Insufficient data to suggest that HRT should be
  initiated for the sole purpose of primary
  prevention of CVD
• HRT initiation and continuation should be based
  on
• Established noncoronary benefits and risks
• Possible coronary benefits and risks
• Patient preference

55
Patient Management Guidelines

• To manage high LDL levels, initiate therapy with
  a statin and treat to target levels (NCEP-ATP
  III, JAMA May 2001)
• Type, dose and route of delivery of both estrogen
  and progestin (HRT) have different effects on the
  lipoprotein profile
• In selecting type of HRT, consideration should be
  given to its effect on lipid profiles