Transcript Menopause Narrated Powerpoint

Hormones,
Hot Flashes,
&
Highlights in
Women’s Health
Laura Davisson, MD
Assistant Professor, Section of General Internal Medicine
Clinical Care Co-Director, Center of Excellence in Women’s
Health
History of
Women’s Health
History of Women’s Health
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1941: Diethylstilbestrol (DES) approved by FDA
1953: Study published showing ineffectiveness at
preventing miscarriage
Until 1971: Continued to be aggressively marketed and
routinely prescribed
1971: Identified as cause of vaginal clear cell
adenocarcinoma in DES daughters
1971: FDA advised physicians to stop prescribing to
pregnant women and national effort begun to find
women prescribed DES while pregnant
History of Women’s Health
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Such tragedies in pregnant women led to fear of using
women of childbearing age in trials
1970s: regulations restricted testing in women of
reproductive age
Ultimately led to widespread exclusion of women from
trials
Throughout most of 20th century: treatments tested
solely on men
1990: GAO report brought to light underrepresentation of women in federally funded trials
History of Women’s Health
Now…
 Several Federal agencies have changed policies to
promote inclusion of women in studies
 Learning that women affected by some diseases at
different rates than men
 Learning that women can present differently than
men
 There is emerging body of gender-specific
research to guide practice in women’s health
Today’s Goals
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Review literature regarding several important
women’s health topics
Increase awareness of emerging discipline of
women’s health
Outline
 Hormones
 Hot
flashes
 Highlights
Preferred Terminology
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ET: estrogen therapy
EPT: combined estrogen-progestogen therapy
HT: Hormone therapy (encompasses both ET
and EPT)
Note: hormone therapy (HT) as opposed to
hormone replacement therapy
Progestogen encompasses both progesterone
and progestin
North American Menopause Society (NAMS),
2007 Position Statement
1990’s Recommendations
based on observational studies
“Women who have coronary heart disease or who are at
increased risk of coronary heart disease are likely to benefit
from hormone therapy”
American College of Physicians, 1992
“Probable beneficial effect of estrogen on heart disease”
American College of Obstetricians and
Gynecologists, 1992
“Estrogen replacement therapy does look promising as a longterm protection against heart attack”
American Heart Association, 1996
Heart and
Estrogen/Progestin
Replacement
Study
(HERS)
1998
HERS
Purpose:
To evaluate secondary prevention of CHD with
hormone therapy (HT) in postmenopausal
women with known coronary disease
HERS
Methods:
 Randomized, double blinded, placebo-controlled trial
 Over 2700 women with CHD and intact uteri
 Mean age 67
 Average follow-up: 4.1 years
 Hormone formulation: conjugated equine estrogen
(CEE) 0.625mg + medroxyprogesterone acetate (MPA)
2.5 mg daily
HERS
Results:
No significant differences in CHD found in
treatment vs. placebo groups
HERS II (2002)
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Subsequent unblinded follow-up of HERS
subjects
Looked at long-term outcomes for 2.7 more
years
Confirmed HERS findings that HT did NOT
decrease risk of CHD in women with known
history of CHD
HERS I and II
Interpretation of HERS trials:
HT not effective in secondary prevention of
CHD
WHI
Women’s Health
Initiative
WHI
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Observational Study
Clinical Trials:
Hormone Therapy
 Dietary Modification
 Calcium/Vitamin D
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Some of the 100+ WHI papers:
Estrogen plus progestin and the risk of coronary heart
disease. NEJM, 2003
Effect of estrogen plus progestin on stroke in
postmenopausal women. The women’s health
initiative: a randomized trial. JAMA, 2003
Estrogen plus progestin and colorectal cancer in
postmenopausal women. NEJM, 2004
Estrogen plus progestin and risk of venous
thrombosis. JAMA, 2004
Conjugated equine estrogens and coronary heart
disease: the women’s health initiative. Arch Intern
Med, 2006
Venous thrombosis and conjugated equine estrogen in
women without a uterus. Arch Intern Med, 2006
WHI
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Multi-million dollar, 15-year project sponsored
by NIH, NHLBI
Over 160,000 women aged 50-79
40 Clinical Centers across US
One of most definitive, far-reaching clinical
trials of post-menopausal women's health ever
done
WHI Hormone Therapy Trial
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Long-term study to evaluate HT’s effects on
CHD, osteoporotic fractures, and breast cancer
in postmenopausal women
Two arms:
Estrogen plus Progestin (E+P)
 Estrogen Alone (E Alone)
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WHI Hormone Therapy Trial:
E+P arm
WHI: E+P arm
Methods:
 Over 16,000 women with intact uteri
 Randomly assigned to E+P vs. placebo for 5
years (planned duration 8.5 years)
 Hormone formulation: CEE 0.625mg plus MPA
2.5mg daily
WHI: E+P arm
Results:
 Trial halted early--July 2002
 Overall harm found in treatment group
WHI: E+P arm
Decreased risk of:
Colorectal cancer (34%)
 Hip fractures (34%)
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Outweighed by increased risk of:
Breast cancer (26%)
 Pulmonary embolism (113%)
 Coronary heart disease (29%)
 Strokes (41%)
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WHI: E+P arm
Absolute excess risks:
 Excess CHD events: 7/10,000 woman-years
 Excess stroke events : 8/10,000 woman-years
 Excess pulmonary emboli: 8/10,000 womanyears
 Excess invasive breast cancer: 8/10,000 womanyears
WHI: E+P arm
Absolute Benefits:
 Fewer colorectal cancers: 6/10,000 womanyears
 Fewer hip fractures: 5/10,000 woman-years
WHI: E+P arm
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Summary of additional adverse events: 19 per
10,000 woman-years
Number needed to harm for 5 years E+P use:
101
WHI Hormone Therapy Trial:
E Alone arm
WHI: E Alone arm
Methods:
 Over 10,000 women aged 50-79 with prior
hysterectomy
 Randomly assigned to 0.625mg CEE vs. placebo
 Followed for average 6.8 years
WHI: E Alone arm
Results:
 Trial halted one year early--February 2004
 Increased risk of stroke among women in
hormone group
WHI: E Alone arm
Results:
 Reduced risk of hip fracture (39%)
 Increased risk of stroke (39%)
 No effect on heart disease, breast cancer,
pulmonary embolus, colorectal cancer, total
mortality, or global index
 No overall benefit
WHI: E Alone arm
Major Clinical Outcomes
RR
Hip fracture 0.61*
Breast
cancer
CHD
0.77
Total
Mortality
Colorectal
cancer
CVA
1.04
0.91
1.08
1.39*
WHI Hormone Therapy Trial
Relative Risks and Absolute Risk
Differences among Women 50-54
Outcome
E+P RR (95%
CI)
CHD
E Alone RR (95%
CI)
Absolute Risk
Difference
1.29 (1.02-1.63) 0.26
0.91 (0.75-1.12)
---
CVA
1.41 (1.07-1.85) 0.20
1.39 (1.10-1.77)
0.20
Pulmonary
embolism
2.13 (1.39-3.25) 0.45
1.34 (0.87-2.06)
---
Breast cancer
1.26 (1.00-1.59) 0.93
0.77 (0.59-1.01)
---
Colon Cancer
0.63 (0.43-0.92) -0.18
1.08 (0.75-1.55)
---
Hip fracture
0.66 (0.45-0.98) -0.10
0.61 (0.41-0.91)
-0.12
Net outcomes
per 1000
women years
Absolute Risk
Difference
1.56
Adapted from N Engl J Med 2006;355:2338-2347
0.08
WHI Hormone Therapy Trial:
Divergent results
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Heart disease
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Pulmonary embolism
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Increased: E+P
Neutral: E Alone
Increased: E+P
Neutral: E Alone
Breast cancer
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Increased: E+P
Neutral: E Alone
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Colorectal cancer
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Decreased: E+P
Neutral: E Alone
Global index
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Increased: E+P
Neutral: E Alone
WHI Hormone Therapy Trial:
Concordant results
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Increased:
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Decreased:
 Fractures
 Vasomotor symptoms
 Diabetes
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Neutral:
 HRQOL
Strokes
 Dementia (>65)
 Gallstones
 Urinary incontinence
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WHI Hormone Therapy Trial
Limitations:
 Only tested CEE and MPA hormone regimens
 Early termination of trials can lead to bias
 Average age mid-60’s, not typical 50 year-old
women seeking relief from menopausal
symptoms
 Possible that recently menopausal women with
low baseline risk of heart disease may have
more favorable balance of benefits and risks
WHI Hormone Therapy Trial
Conclusions:
 HT should not be recommended for chronic disease
prevention in postmenopausal women
 Rate of adverse events was higher with E+P than
E Alone
 Possible that progestins exacerbate risks
 Possible that other formulations, routes of
administration, or lower doses might be associated
with fewer adverse events (little supportive
evidence)
Divergence of clinical trials from
observational studies
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Highlights importance of randomized controlled
clinical trials
Confounding may explain lower heart disease rates in
hormone users in observational studies because they
were:
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Leaner
Less likely to smoke
More physically active
More likely to see doctors regularly
More highly educated
Another possible explanation for discrepancy:
timing of initiation of HT
Timing of initiation of HT
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Emerging data suggests disparities may be related
to timing of initiation of HT in relation to
proximity of menopause
On average, women in WHI and HERS initiated
HT more than a decade after menopause
Insufficient numbers of younger, symptomatic,
newly postmenopausal women to determine
whether similar patterns apply to them
Trial results should be extrapolated to recently
postmenopausal women only with caution
Meta-analysis:
Mortality by treatment assignment and age group
Group
All ages
Odds Ratio (95% CI) for
Mortality
0.98 (0.87-1.18)
<60 years
0.61 (0.39-0.95)
>60 years
1.03 (0.90-1.18)
Adapted from J Gen Intern Med 2004;19:791-804
Rossouw, JE, et al. JAMA. Apr 4, 2007;297:1465-1477
Timing of initiation of HT
Purpose:
To explore whether the effects of HT on risk of
cardiovascular disease vary by age or years since
menopause began
JAMA. Apr, 2007;297:1465-1477
Timing of initiation of HT
Methods:
 Secondary analysis of WHI HT trial results
 Combined data from the two trial arms to
improve statistical power to be able to examine
trends across categories of age and years since
menopause
 Main outcome: CHD
 Other outcomes: mortality and a global index
JAMA. Apr, 2007;297:1465-1477
Timing of initiation of HT
Results:
 Trend for reduced CHD risk in women closer
to menopause but no subgroup met statistical
significance
 Nonsignificant tendency for total mortality to
be reduced among younger women (50-59)
 Risk of stroke did not vary by age or time
since menopause
JAMA. Apr, 2007;297:1465-1477
Timing of initiation of HT
Conclusions:
 Offers reassurance that HT a reasonable option
for short-term treatment of menopausal
symptoms
 Raises the question of whether there may be a
protective effect against CHD in younger,
recently postmenopausal women
JAMA. Apr, 2007;297:1465-1477
Decrease in HT and Breast Cancer—
Coincidence?
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After WHI (in 2002), HT use decreased by about 30%
Breast cancer incidence dropped 7% from 2002-2003
It is suspected that the decreased use of HT may have led
to decreased breast cancer incidence but causality cannot
be determined from this data
Could also be from decreased mammography rates
leading to decreased detection (mammography rates
decreased 1% between 2000 and 2003)
Ravdin PM, Cronin KA, Howlander N, Chlebowski RT, Berry DA.
29th Annual San Antonio Breast Cancer Symposium, Dec. 2006.
Hormone Therapy (HT):
Current Guidelines
HT: current guidelines
Indications by current labeling:
 Treatment of moderate-severe vasomotor
symptoms
 Treatment of moderate-severe urogenital
symptoms
 Prevention of osteoporosis (not treatment) in
women at significant risk
HT: current guidelines
Per NAMS position statements:
 Limit use to short term menopausal symptom relief
 Lowest dose, shortest duration possible
 Avoid in women with history of breast cancer, uterine
cancer, or thromboembolic disease
 Must add progestin if patient has uterus
 Do not initiate or continue to prevent CHD
 2007 revision: benefits of short-term HT for
treatment of perimenopausal symptoms likely
outweigh risks for younger women
Outline
 Hormones
 Hot
flashes
 Highlights
Definition of natural menopause
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Retrospectively defined: no menstrual period
for 12 months
Average age: 51-52 years
Perimenopause
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Around ages 42-52 years
Irregular cycles: shorter or longer; heavier or
lighter; missed completely
Vasomotor symptoms: hot flashes, night sweats
Urogenital symptoms: dryness, itching,
dyspareunia, incontinence, increased bladder
infections
FSH rises (often normal range during
perimenopause)
Perimenopause
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Many vasomotor symptoms will improve
within several months
Most will resolve within 4-5 years
Substantial minority (10-15%) continue to have
troublesome symptoms for years
Treatment of vasomotor symptoms
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Data to guide therapy is lacking
Studies complicated by high rate of placebo
effect (around 25%)
Trials have been small and brief, providing little
information about long-term efficacy and risks
Treatment of vasomotor
symptoms:
Estrogen
Treatment of vasomotor symptoms:
estrogen
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Multiple randomized trials have demonstrated its
efficacy
All types and routes of administration markedly
improve frequency and severity of hot flashes
Dose-related improvement
Efficacy of Treatment of Hot Flushes with Various Doses
of Estrogen, as Compared with Placebo
Type/dose of estrogen
% Reduction in hot flash
frequency
Oral conjugated equine estrogen 0.625mg
94
Oral conjugated equine estrogen 0.45mg
78
Oral conjugated equine estrogen 0.3mg
78
Oral 17 Beta-Estradiol 2 mg
96
Oral 17 Beta-Estradiol 1 mg
89
Oral 17 Beta-Estradiol 0.5 mg
79
Oral 17 Beta-Estradiol 0.25 mg
59
Transdermal 17 Beta-Estradiol 0.1mg
96
Transdermal 17 Beta-Estradiol 0.05 mg
96
Transdermal 17 Beta-Estradiol 0.025 mg
86
Adapted from N Engl J Med 2006;355:2338-2347
Nelson, HD, Vesco KK, Haney E, et al.
Nonhormonal therapies for menopausal hot
flashes: Systematic review and meta-analysis.
JAMA. 2006;295:2057-2071
Methods
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10 trials of antidepressants (SSRI’s or SNRI’s)
10 trials of clonidine
6 trials of other prescribed medications
17 trials of isoflavone extracts
JAMA. 2006;295:2057-2071
Results and Conclusions
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Isoflavone extracts: no definite evidence of
benefit
SSRI’s, SNRI’s, clonidine, gabapentin: some
evidence of efficacy but less than estrogen
Few trials of non-hormonal therapies have been
published
Most have methodological deficiencies
Generalizability limited
JAMA. 2006;295:2057-2071
Evidence of Efficacy of Non-hormonal
Prescription Drugs for Treatment of Hot
Flashes from Randomized, Controlled Clinical
Trials
Treatment
MPA
Megestrol
Evidence of Benefit
Yes
Yes
Gabapentin
Clonidine
Methyldopa
Yes
Mixed
No
Citalopram
Fluoxetine
Paroxetine
No
Mixed
Yes
Sertraline
No
Venlafaxine
Mixed
Adapted from N
Engl J Med 2006;
355:2338-2347
Nedrow A, Miller J, Walker M, Nygren P, Huffman LH,
Nelson HD. Complementary and alternative therapies
for the management of menopause-related symptoms:
A systematic evidence review. Arch Intern Med.
2006;166:1453-1465
Complementary and Alternative
Therapies
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Systematic review included randomized
controlled trials and meta-analyses
Phytoestrogens: mixed results
Black cohosh: mixed results
Mind-body, energy, manipulative, body-based
therapies and whole medical systems: little
benefit
Data insufficient to support effectiveness of any
therapy in this review
Arch Intern Med. 2006;166:1453-1465
Treatment of vasomotor symptoms:
black cohosh
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2006: longest and largest placebo-controlled,
double-blind trial to date of black cohosh
Showed no improvement in vasomotor
symptoms
In combination with other studies provides
strong evidence that black cohosh ineffective
Ann Intern Med. 2006;145:869-879.
Treatment of vasomotor symptoms
No convincing evidence of efficacy for treatment of
vasomotor symptoms for:
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Evening primrose oil
Ginseng
Wild yam cream
Yoga
Chinese herbs
Dong quai
Kava
Red clover extract
Vitamin E
ANY complementary and alternative therapy
“Bioidentical” hormone replacement
“Bioidentical” hormone replacement
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Term “bioidentical” not defined, has no scientific meaning
These products made by compounding pharmacies
Individualized dosage determined by salivary hormone
levels
Promoted by patient testimonials, often celebrities, as safer
and more effective than conventional therapy
Not produced according to federal Good Manufacturing
Practice, not approved by FDA
No evidence of effectiveness or safety
Cannot be recommended
Practical/behavioral measures
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Paced respirations
Dress in layers
Lower ambient temperature
Avoid turtlenecks, down comforters, alcohol,
spicy foods, bright lights
Summary of Treatment Options for
Vasomotor Symptoms
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Practical/behavioral measures—first line for mild symptoms
HT for moderate to severe symptoms—most effective
Topical treatment if urogenital symptoms only
Non-hormonal drugs can be tried if want to avoid estrogens
(off-label):
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Antidepressants including venlafaxine, fluoxetine, paroxetine
Gabapentin
Clonidine
Treatment of vasomotor symptoms—if
HT used:
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Follow NAMS guidelines (avoid use in patients
with contraindications, use low doses/short
durations)
Reasonable to try discontinuing every 6-12
months since vasomotor symptoms are usually
temporary
Possible that women will have recurrence of
symptoms after stopping
If symptoms recur, try gradually tapering dose or
number of days per week used (no guidelines)
Outline
 Hormones
 Hot
flashes
 Highlights
Low-Fat Dietary Pattern and Risk of
Colorectal Cancer
Low-Fat Dietary Pattern and Risk of
Invasive Breast Cancer
The Women’s Health Initiative
Randomized Controlled Dietary
Modification Trial
JAMA, February 8, 2006;295
WHI Dietary Modification Trial
Background:
 Observational data suggests association of
dietary fat intake with breast cancer,
cardiovascular disease, and colorectal cancer
 Purpose: to evaluate effectiveness of low-fat diet
WHI Dietary Modification Trial
Methods:
 Over 48,000 women, aged 50-79
 Subjects randomized to low-fat/high fruit,
vegetable, grain diet vs. usual eating pattern
 Followed for mean of 8.1 years
WHI Dietary Modification Trial
Results--no significant reduced risk of any outcome:
 Breast cancer
 Colorectal cancer
 Stroke
 CHD
WHI Dietary Modification Trial
Limitations:
 Did not specify types fats--potential for benefit of diet
lower in saturated and trans fat
 Few met target of 20% calories from fat--may have
been underpowered to detect difference
 Positive trend toward decreased coronary heart
disease, breast cancer, and colon polyps as trial
progressed—did not reach statistical significance
 Health implications of diet may take years to be fully
realized--benefits may show up in future follow-up
Women’s Intervention Nutrition
Study (WINS)
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Randomized, prospective, multicenter clinical trial
Tested dietary intervention for reducing recurrence of
breast cancer
Intervention: decrease fat intake to 15% of calories (30%
at baseline)
Over 2000 women with resected, early-stage breast
cancer receiving conventional cancer management
Analysis performed after median follow-up of 60 months
J Natl Cancer Inst. 2006 Dec 20;98(24):1767-76
Women’s Intervention Nutrition
Study (WINS)
Results:
 Intervention group achieved fat intake of 20% of
calories (29% in control group)
 Intervention group weighed 6 pounds less than control
group (same at baseline)
 24% risk reduction for relapse in intervention group
 Number needed to treat: 38
 Subgroup analysis suggested most benefit in hormone
receptor negative cancers (not statistically significant)
J Natl Cancer Inst. 2006 Dec 20;98(24):1767-76
Women’s Intervention Nutrition
Study (WINS)
Limitations:
 Effect could have been from weight loss rather
than the dietary fat on its own
 Generalizability of benefit of low fat diet is
limited: only studied recurrence of breast cancer
in women with previous breast cancer history
J Natl Cancer Inst. 2006 Dec 20;98(24):1767-76
Interpretation of these trials: Should
women bother eating a low-fat diet?
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Studies need to be interpreted with caution because
conducting clinical trials of lifestyle changes is difficult
WINS study suggests that reduced dietary fat intake
with influence on weight may benefit breast cancer
patients
WHI Dietary Modification trial did not show benefit,
but experts are not recommending change in current
recommendations
Longer follow-up of these trials will answer more
questions about its benefit
Low-fat diet still recommended for overall health
Conclusions
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Hormones
HT trials
 Limited role for HT
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Hot flashes
Menopause/perimenopause
 Limited options for vasomotor symptoms
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Highlights
Low-fat diet trials
 Several recent trials have changed treatment of women
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