Back to the Future:
Applying New Evidence
in Menopause
Management
Michael Policar, MD, MPH
www.PolicarLectures.com
Topics To Be Discussed
 New information from the WHI
 The expanding range of treatments for
managing menopausal symptoms
– Which treatments are available to your patient?
 Practice Recommendations
– How can your patient use these treatments safely,
effectively, and conveniently?
NAMS Definitions
 Progestogen
 ET
 EPT
 HT
 CC-EPT
 CS-EPT
Progesterone or progestin (P)
Estrogen (E) therapy
Combined E+P therapy
Hormone therapy (ET and EPT)
Continuous-combined E+P therapy
- E+P given every day
Continuous-sequential E+P therapy
- E daily with P added on set
sequence
NAMS position statement. Menopause 2007.
Act 1
Let’s Get This
Out of the Way….
The WHI Re-analyzed
Background: HRT 1960-1980s
 Menopause seen as endocrine deficiency
requiring hormone replacement therapy
 1960s: successful oral contraceptive introduction
– “The Pill” freed women from fear of pregnancy
– HRT offered women freedom from fear of aging
 1972: Forever Feminine by Robert A. Wilson, MD
 1980s: Expanding uses of HRT
– Initially used to treat hot flashes, vaginal sxs
– Later uses…protection of bone and heart
Background: Late 1980s
 In 40 retrospective observational studies, both EPT and
ET reduced the risk of heart attack by 50%
– Most studies included women in their 50s
– Women were self-selected for hormone use (or not);
studies were subject to selection bias
 Conventional wisdom
– All women should use HT for heart protection,
unless there was a reason not to do so
– Women with CVD risk factors, especially previous
MI, stroke, HTN or diabetes, should use HT
Background:1990s
 1990: Wyeth requested that FDA add labeling to
HT products that included cardioprotection
 FDA insisted that RCTs be performed to prove
that HT improved CVD outcomes vs. placebo
 Two RCTs initiated to evaluate cardioprotection
– HERS: secondary prevention trial
– WHI: primary prevention trial
HERS Study: 1998
 Does EPT reduce MIs in women with CHD?
 2,763 women randomized to CC-EPT or placebo
– Entry: MI, CABG, balloon angioplasty, + angiogram
– Menopausal, intact uterus, 44-80 years of age
– Average follow up: 4.1 years
 Study findings
– EPT had no value in reduction of MIs or CHD deaths
»More deaths in year 1; neutral thru year 8
»Not seen in prior observational studies
– 3-fold increased risk of VTE events
Hulley, JAMA 1998:280:605
Women’s Health Initiative (WHI): 2002
 1993-2005: RCT with 17,000 women
 Postmenopausal women 50-79 years old
– 33%: 50-59 yrs old; 45%: 60-69 yo; 22% 70-79 yo
– Average age: 64 years old
 End points
– Primary prevention of MI and stroke
– Hip fracture, various cancers
 Treatment arms
– If uterus: CC-EPT (CEE+MPA) vs. placebo
– If no uterus: ET (CEE) vs. placebo
WHI: EPT Arm Study Results
Released July 2002: Findings after 5.2 years
Event
RR Risk/10K/yr Benefit/10K/yr
Heart attack
1.29
7
Stroke
1.41
8
Breast cancer
1.26
8
TE event
2.11
18
Colorectal CA
0.63
6
Hip fractures
0.66
5
 Discontinued early, as “risks greater than benefits”
WHI : ET-Only Study Arm
Released 2004: Findings after 7 years
Outcome
Coronary heart disease
Breast cancer
Stroke
Hip fractures
Dementia, cognitive
Change (> 65 years old)
Change vs. Placebo
No difference in risk
No difference in risk
Increased risk
Decreased risk
Trend toward increased
risk
WHI and HERS:
The 2004 Take Home Message
 HT does not protect women from heart
attacks over the long term
…and actually may increase the risk of
MI in the first year of HT use
 The rest is “specialty-specific” perception
of benefit and risk
Was the WHI designed to evaluate the
safety and efficacy of EPT in treating
menopausal changes?
The Women’s Health Initiative
 Was not a menopause study
 Was a drug study of the effect of hormones
on CVD, cancer, fractures, and memory in
older women (average 64 year old)
How Different Were WHI Findings
Compared to Earlier Studies?
Manson JE, Menopause 2006;13:139
WHI: HT and Risk of CV Disease by
Age and Years Since Menopause
Roussow JE. JAMA. 2007: Combined secondary analysis
Age at HT initiation
Heart attack
Stroke
Death from
any cause
50–59 years
↓ 7%
↑ 13%
↓ 30%
60–69 years
↓ 2%
↑ 50%
↑ 5%
70–79 years
↑ 26%
↑ 21%
↑ 14%
“Women who initiated HT closer to menopause tended to have reduced CHD risk
compared with the increase in CHD risk among women more distant from
menopause, but this trend test did not meet our criterion* for statistical
significance.”
*Statistically significant defined as p<0.01.
WHI (EPT arm) Re-analyses
Age vs. Years Since Menopause
Age (years)
50–59
1.27
1.05
60–69
70–79
1.44
Years Since Menopause
<10
0.89
10–19
1.22
20
1.71
0.5
1.0
1.5
2.0
Hazard Ratio for CHD
Manson JE, et al. N Engl J Med. 2003;349:523-34
2.5
WHI: Estrogen and Major Health Outcomes
in Women Under 60 Years of Age
Total mortality
Coronary heart
disease
Stroke
New onset DM
Fracture
Breast cancer
VTE
% difference in
relative risk
-29 (0.46-1.11
-37 (0.36-1.09)
Events/ 10,000 WY
of CEE therapy
-11
-11
-11 (0.47-1.69
-12 (0.77-1.01)
-30 (0.59-0.83)
-18 (0.65-1.04)
+37 (0.70-2.68)
-2
-14
-56
-8
+4
Hodis HN, Mack WJ. Menopause Management 2008
The Unified
Hypothesis
2005
WHI
Phillips LS, Langer RD,
Postmenopausal hormone
therapy: critical reappraisal
and a unified hypothesis.
Fertility and Sterility 2005;
83:558-66
Clinical Implications: Unified Hypothesis
 Mild cardioprotection
– Women in their early-mid 50s, who
– Initiate HT soon after menopause, with
– Few or no heart disease or stroke risk factors
– And who use estrogen-only regimens
 Increased heart disease risk
– Women in their mid-60s or later, who
– Initiate HT long after menopause, who have
– Heart disease or stroke risk factors
– And who use estrogen and progestin regimens
Benchmark HT Cardioprotection Studies
Primary Prevention Secondary Prevention
“Healthy women”
Observational
Studies
•Nurses Health
Study
Randomized
Clinical Trials
•WHI
•KEEPS
Women with known
heart disease
Various small studies
•HERS
Key Points:
NAMS March 2007
Position Statement
on Hormone Therapy
The North American Menopause Society.
Estrogen and progestogen use in peri- and
postmenopausal women: March 2007 position
statement of The North American Menopause
Society. Menopause 2007
Copyright 2007
HT and Coronary Heart Disease
 ET/EPT not recommended as single or
primary indication for coronary
protection in women of any age
 Data do not currently support EPT
in secondary prevention of CHD
NAMS position statement. Menopause 2007.
HT and Stroke
 Both ET and EPT appear to increase the risk
of ischemic stroke in postmenopausal women
 No HT regimen should be used for the
primary or secondary prevention of stroke
 HT should be avoided for women who have
elevated baseline risk of stroke
NAMS position statement. Menopause 2007.
HT and Venous Thromboembolism
 Significant increase in VTE risk in




postmenopausal women using systemic HT
Risk increased with both EPT and ET
VTE risk appears during first 1-2 years after
therapy initiation and decreases over time
Transdermal 17ß-estradiol and oral therapies may
have different risk
Lower doses of oral estrogens may be safer than
higher doses
NAMS position statement. Menopause 2007.
EPT and Breast Cancer Risk
 Breast cancer risk increases with EPT use
beyond 5 years
 Increased absolute risk in WHI is viewed as
rare (4-6 additional invasive cancers/10,000
women/year when use EPT used for ≥ 5 yrs)
 Not clear whether risk differs between CC-EPT
and CS-EPT
NAMS position statement. Menopause 2007.
ET and Breast Cancer Risk (cont’d)
 Women in WHI’s ET arm had 8 fewer cases of
invasive breast cancer/10,000 women/yr of ET use
 Available evidence suggests ET for < 5 years has
little breast cancer risk impact
 Limited observational data suggest ET given
longer than 15 years may increase risk
NAMS position statement. Menopause 2007.
Act 2
Therapeutic Interventions
Non-Hormonal
General Health Recommendations
 Exercise: aerobic + strength training
– Reduction in hot flashes in some women
– Healthier heart; stronger bones
 National Osteoporosis Foundation (NOF) Feb 2008
– Adults under age 50 need, per day
»1,000 mg of calcium*
»400-800 IU of vitamin D3
– Adults 50 and over need, per day
»1,200 mg of calcium*
»800-1,000 IU of vitamin D3
* In divided doses, preferably with meals
Hot Flashes: Lifestyle Changes







Exercise routinely, at least 3-4 days/week
Cool room temperature, especially at night
Dress in layers (remove outer layers if warm)
Avoid hot and spicy foods
Relaxing activities
Avoid cigarettes
Minimize alcohol
North American Menopause Society. Menopause. 2004;11:11-33; Kronenberg F, Fugh-Berman A. Ann Intern Med.
2002;137:805-13; Huntley AL, Ernst E. Menopause. 2003;10:465-76.
Botanicals and PhytoSERMs
Probably better than placebo
 Black cohosh
No evidence of efficacy
 Soy isoflavones
 Red clover isoflavones
 Evening primrose oil
 Dong quai
 Ginseng
 Vitamin E
 Chasteberry (Vitex)
Not better than pbo
Not better than pbo
Not better than pbo
Not better (as monotx)
Not better than pbo
Not better than pbo
No studies
Botanicals: Black Cohosh
 Total of 14 trials reported, including 4 randomized
trials using placebo and/or estrogen treatment arm
– 3 of 4 RCTs found black cohosh to be beneficial
– 12 of 14 trials reported some benefit
– Currently, longest trial is 6 months
 NIH-funded, large, randomized, prospective,
2-year trial ongoing
– Preliminary data fail to show binding to E receptors
– Binding to serotonin receptor noted
Botanicals: Black Cohosh
 Available as Remifemin,
Estroven, or other single or
combination products
 Dosage: 40-80 mg daily
 Adverse effects: headaches,
stomach discomfort,
heaviness in legs
Non-hormonal Hot Flash Therapies
Drug
Hot Flash Reduction
Antidepressants
•Paroxetine
62-65%
•Venlafaxine
38-60%
•Fluoxetine
20%
Anticonvulsants
•Gabapentin
45%
Antihypertensives
•Methyldopa
•Clonidine
65%
38%
Menopause 2004;
11(1): 11-33
ACOG Task Force on HT
Obstet Gynecol 2004;
104:106s-17s.
Act 2
Therapeutic Interventions:
Hormonal Medications
Prescription HT Options: ET and EPT
Oral
ET
• Micronized estradiol
• Conjugated equine
estrogens (CEE)
• Synthetic conjugated
estrogens
• Esterified estrogens
• Estropipate
• Estradiol acetate
EPT • CC-EPT
• CS-EPT
Med Lett Drugs Ther 2004; 46:98.
Transdermal
•
•
•
•
Patches
Gels
Emulsion
Spray
• E+P
(combination)
patches
Intravaginal
• Creams
• Intravaginal
tablet
• Rings
HT Regimens
Month 1
Month 2
Estrogen Therapy (ET)
Estrogen
Continuous combined (CC) EPT
Estrogen
Progestin
Continuous-sequential (CS) EPT
Estrogen
Progestin 14d
Off for 14 d
Continuous-pulsed (CP) EPT
3d
Off for 14 d
Choice of HT Regimen
 If no uterus: estrogen only
 If uterus present
– Goal is to avoid vaginal bleeding entirely, or, at
least, to make it predictable
 Endometrial activity predicts bleeding pattern
– Recent spontaneous or induced bleeding
»Continuous sequential
– No bleeding for >2-3 cycles
»Continuous combined
ET Oral Tablets
Product
Estropipate
Micronized E2
Brand
Ogen
Ortho-est
Generic
Estrace
Generic
Estradiol acetate Femtrace
Standard
dose
Low dose
0.625 m
none
1.0 mg
0.5 mg
0.9 mg
0.45 mg
ET Transdermal: Patch*
Brand name
Mg/24 hr
Use/ wk
Alora
0.025, 0.05, 0.075, 0.1
2
Esclim
0.025, 0.0375, 0.05, 0.075, 0.1
2
Estraderm
0.05, 0.1
2
Vivelle
0.05, 0.1
2
Vivelle-Dot
0.025, 0.0375, 0.05, 0.075, 0.1
2
Climara
0.025, 0.0375,0.05, 0.06, 0.075, 0.1
1
Menostar
0.014 ☼
1
* All contain 17B- estradiol only
☼ Indicated only for prevention of osteoporosis
ET Transdermal:
Gels, Emulsions, Sprays*
Brand
name
Type
mg/24 hr
Use
Divigel
Gel
0.25, 0.5, 1 mg/
packet
Elestrin
Gel
0.87 gm pump
1 pump daily
EstroGel
Gel
1.25 gm pump
1 pump daily
Estrasorb
Emulsion
1.74 gm/ pouch
2 pouches daily
Evamist
Spray
1.53 mg/ spray
1 spray daily
* All contain 17B- estradiol only
1 packet daily
Choice of Estrogens
 Start low dose transdermal or oral estrogen
 If suboptimal response, modify by:
– Change the estrogen dose (upward)
– Change the estrogen preparation
– Change delivery systems (oral
transdermal)
– Consider an estrogen-androgen combination
 Injectable estrogen not recommended
– Dosage equivalencies are not known
– Estrogen cannot be discontinued easily
Route of Administration
 Non-oral routes of ET/EPT administration may
offer advantages and disadvantages vs oral routes,
but the long-term risk-benefit ratio has not been
demonstrated
 Possible lower risk of deep venous thrombosis
(DVT) with non-oral route
 Similar increased breast cancer risks with oral and
transdermal estrogens, per large observational study
NAMS position statement. Menopause 2007.
Adjusted Odds Ratio (95% CI)
Oral vs. TD-E: The Risk of VTE
The ESTHER Study
OR = 4.0 (1.9-8.3)
5
3.5
4
(1.8-6.8)
3
2
0.9
1.0
(0.5-1.6)
1
0
Nonusers
Scarabin P-Y, et al. Lancet. 2003;362:428-432
Oral estrogen
users
Transdermal
estrogen users
“First Line” Use of
Transdermal Estrogen
 Underlying medical conditions
– History of DVT or PTE
– High triglyceride levels
– Gall bladder disease
 Need for “steady state” drug release
– Daily mood swings (especially while on oral HT)
– Migraine headaches
 Inability to use oral tablets
– Stomach upset due to oral estrogen intake
– Problems with taking a daily pill
Lower HT Doses
 Provide nearly equivalent vasomotor and genital
skin symptom relief and preservation of BMD
compared to standard doses
 Additional local ET may be required for
persistent vaginal symptoms
 Lower HT doses better tolerated and may have a
better risk-benefit ratio than standard doses
(cont’d)
NAMS position statement. Menopause 2007.
Lower HT Doses (cont’d)
 Lower-than-standard ET/EPT doses should be
considered, such as daily doses of
– 0.3 mg oral conjugated estrogens
– 0.25-0.5 mg oral micronized 17β-estradiol
– 0.025 mg transdermal 17β-estradiol patch
– or the equivalent
NAMS position statement. Menopause 2007.
Progestogen Indication
 Primary menopause-related indication is
endometrial protection from unopposed ET
 Adequate progestogen (as CC-EPT or CS-EPT)
recommended with intact uterus
 Progestogen not generally indicated with ET
post-hysterectomy
NAMS position statement. Menopause 2007.
Progesterone/ Progestin Products
Oral Progestin
MPA
Micronized
progesterone
Drospirenone
Norethindrone
acetate
Norethindrone
Norgestimate
Norgestrel
Equiv dose
5-10 mg
200-300 mg
Available doses
1.2, 2.5, 5, 10 mg
100, 200 mg
0.5 mg/d
1.0 mg/d
0.5 mg/d
0.5, 1.0 mg/d
0.7-1.0 mg/d
0.09 mg
150 mcg/d
0.35 mg
0.09 mg
150 mcg/d
EPT Oral Tablets
Activella
Estrogen
17-E2 1 mg
Progestin
NETA 0.5 mg
Angeliq
17-E2 1 mg
FemHRT
EE 5 g
EE 2.5 g
Drosperinone
0.5 mg
NETA 1 mg
NETA 0.5 mg
Prefest
Premphase
14 active
14 placebo
Prempro
28 active
Dosing
Once daily oral
Once daily oral
Once daily oral
E (alone) 3 days
E+P 3 days
CEE 0.625 mg
Micronized
NGM 0.09 mg
MPA 5 mg
CEE
0.625 mg
0.45 mg
0.3 mg
MPA
5.0 mg; 2.5 mg
2.5 mg
1.5 mg
Once daily oral
(CC-EPT)
17- E2 1 mg
Once daily oral
(CS-EPT)
EPT Transdermal Patches
Estrogen
17-E2
CombiPatch 0.05 mg
0.05 mg
Progestin
NETA
0.14
0.25 mg
17-E2
Climara Pro
0.045 mg
LNG
0.015 mg
Dosing
Twice weekly
Once weekly
Off-Label EPT Uses
 Insufficient endometrial safety evidence to
recommend off-label use of
– Long-cycle progestogen (ie, P every 3-6 months
for 12-14 days)
– Vaginal administration of progesterone
– Levonorgestrel intrauterine system (Mirena)
– Low-dose estrogen without progestogen
 Close endometrial surveillance recommended with
these approaches
NAMS position statement. Menopause 2007.
Compounded Bioidentical
Hormones
“Then, suddenly, the Seven
Dwarfs of Menopause arrived at
my door without warning: Bitchy,
Sweaty, Sleepy, Bloated,
Forgetful, and All-DriedUp….What was it that sent those
wretched dwarfs packing?
Natural bioidentical hormones.”
Somers S. The Sexy Years: Discover the Hormone Connection:
The Secret to Fabulous Sex, Great Health, and Vitality for Women and Men.
Front Matter. 2004 Random House, Crown Publishing, NY.
Compounded Hormone Therapy
 The marketing of compounded hormonal therapy
– Only bioidentical hormones are used
– Combination of 2 or 3 estrogens is more “natural”
– Dosage is tailored to the individual
– More “pure” than commercial products
– Safer delivery systems (no dyes, etc)
 The reality
– The same hormones are used in commercial and
compounded 17b-E2 and progesterone
Sources of Exogenous Hormones
Compounded Hormone Therapy
Compounded hormones will probably work, but…
 Salivary hormone levels are not useful
 The value of adding E1 + E3 has not been evaluated
 Progesterone skin cream is not absorbed
 Compounded hormone doses are not standardized
 FDA-approved HT products will offer
– Bioidentical hormones
– Choice of delivery systems
– Formulary coverage/ lower out-of-pocket costs
http://www.fda.gov/consumer/updates/bioidenticals010908.pdf
Act 3
Practice Guidelines
How can your patient use these
treatments safely, effectively, and
conveniently?
Treatment of Hot Flashes
 If mild sxs, try exercise, black cohosh + phytoSERM
 Initiate low dose HT if
– Moderate or severe symptoms
– Non-hormonal treatments have failed
– No interest in non-hormonal therapy
 Titrate estrogen dosage upward if needed
 When estrogen can’t be used, offer
– SSRI or SNRI
– Gabapentin, clonidine, a-methyldopa,
– MPA or Megesterol (Megace)
 Attempt discontinuation after 1-2 years
Treatment of Sleep/ Irritability Sxs
 If mild symptoms
– Lifestyle change, black cohosh, phytoSERMs
 If severe symptoms or no response to above
– Low dose HT, then titrate upward
– If mood swings, transdermal E preferred
 Depression component, or no response to HT
– SNRI or SSRI
HT and Vaginal Atrophy
 When HT is considered solely for this
indication, local (not systemic) vaginal ET is
generally recommended
 Progestogen generally not indicated with lowdose, local vaginal ET
 Vaginal lubricants often improve vaginal
dryness and painful intercourse
NAMS position statement. Menopause 2007.
Vaginal Estrogen Therapies
Product
Conjugated
estrogen cream
Brand
Dosage
Premarin
0.625 mg/ gram
cream
0.01%
Estradiol cream Estrace
(0.1 mg/ gm)
Estradiol vaginal
Vagifem 25 micrograms
tablet
Estradiol ring
Estradiol ring*
Dose
Daily, then 1-3
time/wk
Daily, then 1-3
time/wk
Daily for 2 wks,
BIW
Estring
7.5 mcg/ 24 hrs Every 90 days
Femring
0.05 mg/d
0.1 mg/d
*Intended to be used as systemic HT
Every 3 months
Vaginal ET: Endometrial Surveillance?
 There are insufficient data to recommend annual
endometrial surveillance in asymptomatic women
using low-dose, local vaginal ET
 Closer surveillance may be required if a
woman is
– At high risk for endometrial cancer
– Using a greater dose of vaginal ET
– Having symptoms such as spotting,
breakthrough bleeding
NAMS position statement. Menopause 2007.
HT and Cognition
 Initiating EPT after age 65 not recommended for
primary prevention of dementia or cognitive
decline
 Insufficient evidence to support ET/EPT for
primary prevention of dementia when therapy is
initiated during perimenopause or early
postmenopause
 ET does not appear to convey direct benefit or
harm for treatment of Alzheimer’s disease
NAMS position statement. Menopause 2007.
HT and Cognition
 Many women experience worsening of short term
memory with onset of menopause
 9 RCTs and 8 cohort studies
– HT does not improve cognitive performance in
women without symptoms
– If symptoms, HT improved verbal memory,
reasoning, and motor speed tests
 Reasonable to provide HT to lessen cognitive
changes in symptomatic menopausal women
Hormone Therapy and
Fracture Prevention
Pros
 Good data on fracture prevention (mainly 2o prevention)
 Relatively lower cost than boisphosphonates
 Less concern of adverse effects with ET alone (vs EPT)
Cons
 Requires long term use and surveillance
 Post-menopausal bleeding can be troublesome
 Increased risk of breast cancer after 5 years of use
Utility
 Fracture prophylaxis if using HT for another indication
 Otherwise, consider bisphosphonates as first line
HT and “Quality of Life”
 RCTs and retrospective studies show that HT has no
effect on “quality of life” measures
 Many woman who wean from HT state that they “feel
worse”…even after 20 years after menopause!
 Conventional wisdom
– In women who “feel better on/ worse off” of HT,
continue low dose HT if few or no risk factors
– When (& how often) to re-attempt wean uncertain
– Don’t start HT for solely for improving QOL
Act 4
The Finale
Discontinuation of HT
 After 2 years, recommend a trial of HT discontinuation
 Is tapering from hormone therapy necessary?
– Grady D, Obstet Gynecol 2003;102:1233
– n= 377 who attempted discontinuation of HT
– 74% successfully stopped; 26% resumed
– 71% stopped abruptly; 29% tapered: equal success
 “Rebound” hot flashes occur in some women and can
last up to 3 months…many experts recommend a taper
 Taper hormone therapy over 8-12 weeks
– Reduce dose or extend intervals (every 2, then 3 days)
– Cut patches in half
If what I just said
sounded unusually
clear, then you
must have
misunderstood me
Alan Greenspan