Menopause
Robert F Casper
Menopause
• Occurs on average around age 51
• Etiology is genetically programmed loss of
growing ovarian follicles
• Result is absence of menstrual periods and
symptoms of low estrogen
– Hot flashes
– Insomnia
– Vaginal dryness
• Confirmation is elevated FSH (>40 IU/L)
Premature Menopause
• Now called premature ovarian insufficiency
(POI)
• Menopausal diagnosis under the age of 40
• Etiologies include:
–
–
–
–
Turner’s syndrome or mosaic
Fragile X (FMR1) gene pre-mutation
Iatrogenic (surgery, chemotherapy, radiation)
Most are unexplained
Menopause Management
• Treatment of symptoms by lifestyle
modification
• Discussion of pros and cons of hormonal
therapy
After WHI Study (2002)
• HT causes heart attacks and strokes!
• HT causes breast cancer!
• HT shouldn’t be prescribed for menopausal
women!
Women’s Health Initiative (WHI)
• Large (16,000) prospective study funded by NIH
• Stopped early after interim analysis
demonstrated increased cardiovascular
morbidity, slight increase in breast cancer, and
an increase in DVT in HT users vs placebo
• A third arm of estrogen only in women with
previous hysterectomies was continued because
adverse events did not offset beneficial effects
JAMA 2002;288:321-32
WHI Study Population
• Absence of symptoms (hot flushes)
• Mean age 63.5 years
• Not typical of women who generally start
HT
• Mean BMI 28.5 (overweight)
• One third of women had BMI > 30 (obese)
• 50% past or current cigarette smokers
• Received CEE and MPA
WHI Study
• Venous Thromboembolic Disease
– HR 2.11 (95% CI, 1.58 – 2.82)
• Stroke
– HR 1.41 (95% CI, 1.07 – 1.85)
• Coronary Heart Disease
– HR 1.29 (95% CI, 1.02 – 1.63)
HRT and Coagulation
• CEE known to increase the risk of coagulation
• An increased risk of DVT (2 to 4-fold) also in
menopausal women women taking CEE in the
HERS study
• Natural E2 transdermally has a favorable impact
on blood clotting
• Recent study of oral HT (2 mg E2 and 1 mg
NETA /day) no increased coagulation and
improved fibrinolytic activity
Vascular Effects of Estrogen
• Estrogen inhibits oxidation of LDL
• Estrogen prevents oxLDL deposition in
vascular wall
• Estrogen promotes vasodilatation
• In primate studies, prevented atherosclerosis
(Clarkson and Adams)
Vascular Pathophysiology
Nature 420: 868–874, 2002
Estrogen and Atherosclerosis
• Atherosclerotic
plaque has a core of
lipid covered by a
fibrous cap
• Prevents contact of
the lipid core with
blood
Nature 420: 868–874, 2002
Estrogen and Atherosclerosis
• E  MMP-9
• Dissolves shoulder
regions of the fibrous cap
• Exposes lipid core to the
circulation
• Release of vasoactive
cytokines, tissue factor
• Platelet aggregation and
thrombosis
Nature 420: 868–874, 2002
Estrogen and Atherosclerosis
• Result is acute MI, or
healed ruptured
plaque in which
smooth muscle and
collagen
accumulation allows
evolution of a fatty
lesion to a more
fibrous one
Nature 420: 868–874, 2002
Progestin Component of HT
• Adverse CVD effects of MPA in primate studies
(Adams et al 1997)
• Blocked direct beneficial effects of estrogen
(decreased LDL deposition in the blood vessel
wall)
• Antagonized the vasodilatory effects of estrogens
• MPA binds to glucocorticoid receptors with high
affinity
• May promote smooth muscle contraction and
vasoconstriction (Minshall et al, 1998)
Progestin Component of HT
• Natural progesterone did not antagonize the
beneficial effects of estrogen on blood
vessels
• New third generation progestins with little
if any androgen receptor activity
• Like natural progesterone, they have no
negative impact on HDL cholesterol
Women’s Health Initiative
(WHI)
• Increased risk of breast cancer (HR 1.26, CI
1.0 – 1.59)
• Consistent with previous observational
studies
• Continuous combined CEE and MPA
• No increased risk in the CEE only arm
Breast Changes in the Menstrual Cycle
• In normal breast tissue, ER are not
downregulated by progesterone or progestins
• Supported by continuing proliferation of breast
tissue in the luteal phase
Main “Media Message” about HT
and Breast Cancer Risk from the
WHI
“Hormone therapy resulted in a 26%
increase in breast cancer risk”
What did the WHI study actually find:
• No increased risk in women using estrogen alone
• No increased risk for E&P in the 74% of women
using MHT for first time (HR 1.0 CI0.81-1.38)
• No risk evident for total population with Kaplan
Meier analysis until year 5
How Should we Express the Risk
of Breast Cancer for Women
Considering HT ?
• In the WHI the overall breast cancer
incidence was: 30/10,000 placebo users and
38/10,000 HT users
• This is 8 more breast cancers per 10,000
women using combined E&P per year
• Can be described as the “Attributable” risk
– 8 cancers per 10,000 women = 0.08% per year
• This is considered a “rare” risk by the
World health organization
Perspectives on HT and Breast
Cancer Risk
• Hormone Therapy
• increased risk <1% per year
• Delayed menopause
– increased risk 2.3% per year (JA Collins, 1999)
• Alcohol consumption (2 drinks per day)
– increased risk 1-2% per year
• Light exposure at night (shift work)
– Increased risk 1-3% per year
• Dense breasts on mammogram
– Increased risk 3.5-8% per year
Scary Headlines
from 2002
Risks Exceeded Benefits So Study
Stopped Prematurely
Many Doctors, Fearful of Hormone
Effects, Advised Women to Stop HT
Complementary and Alternative Medicine
Where’s the Evidence?
• Six systematic reviews…..
“Although individual trials suggest benefits
from certain therapies, data are insufficient to
support the effectiveness of any
complementary and alternative therapy in the
management of menopausal symptoms.”
Nedrow et al . Arch Intern Med 2006; 166(14): 1453-1465
HT and SSRI Reciprocal
since 2002
McIntyre RS, Konarski JZ, Grigoriadis S, Fan NC, Mancini DA, Fulton KA, Stewart
DE, Kennedy SE. Hormone replacement therapy and antidepressant
prescription patterns: a reciprocal relationship. CMAJ 2005; 172 (1):57-59
HT and SSRI Reciprocal
“The simultaneous increase in prescriptions
of serotonergic antidepressants (after the
WHI publications) suggests that
antidepressants are being prescribed for
symptoms (psychological, physical)
previously controlled with the use of HRT”
59
R S McIntyre et al, CMAJ 2005;172:57-
Rossouw JE et al.
Postmenopausal hormone therapy and
risk of cardiovascular disease by age
and years since menopause.
JAMA. 2007;297:1465-77
Benefits of HRT
• Significant reductions in risks of fracture
and colon cancer (WHI study)
• Improved quality of life
– Hot Flushes
– Sleep Disturbances
– Urogenital Atrophy
– Increased Skin Thickness
Consensus
Development
NAMS Recommendations (2012)
• Based on reanalysis of WHI
• HT an acceptable option for symptomatic
menopausal women up to age 59 or within
10 years of menopause
• HT most effective treatment for hot flushes
and vaginal atrophy
NAMS Recommendations (2012)
• No difference in clotting risk between low
dose oral estrogen or transdermal estrogen
• Evidence lacking that custom compounded
bioidentical HT is safe or effective
NAMS Recommendations (2012)
• E2 increases risk of VTE but risk is rare in
50 to 59 year olds
• Increased risk of breast cancer with 5 or
more years of continuous use of HT
• Less than 5 years recommended for HT but
needs to be individualized
• Lack of safety data regarding use of ERT or
HT in breast cancer survivors
NAMS Recommendations (2012)
Endorsed by:
• American Academy of Family Physicians
• Society of Obstetricians & Gynaecologists
of Canada
• American Association of Clinical
Endocrinologists
• SIGMA Canadian Menopause Society
• National Osteoporosis Society
Media Impact
• “Unfortunately the media has pervasive
impact on public perceptions of risk
• Research has shown that strong beliefs
about risk, once formed, change very
slowly and are extraordinarily persistent
in the face of contrary evidence”
Vincent Convello,
Centre for Risk Communication,
Columbia University
WHI Positive Findings Largely
Ignored by the Media
The contrasting results of the estrogen-alone trial
- no increase in breast cancer, a lower rate of
coronary events including revascularization
in women aged 50 – 59 years
were largely ignored because of the negative
perspective surrounding HRT by that time.
RD Langer JA Manson, MA Allison. Climacteric 2012; 15: 206-212
Likelihood of Death from Different
Causes in Next Decade
Woloshin S et al J Natl Cancer Inst 2008;100: 845 – 853
SSRIs instead of HT at What Cost?
Increased Fracture Rates since 2002
Islam S, Liu Q, Chines A, Helzner E. Trend in incidence of osteoporosis-related fractures among 40- to
69-year-old women: analysis of a large insurance claims database, 2000-2005. Menopause 2009;
16(1): 77-83
Osteoporosis Prevention in
Symptomatic Women
• “ Hormone therapy should be
considered as first-line therapy for
preventing bone loss and fractures in
early postmenopausal women who are
symptomatic”
Gallagher JC, Levine JP. Preventing osteoporosis in symptomatic
postmenopausal women. Menopause 2011;18(1):109-118
Breast Cancer Risk
•
•
•
•
•
•
•
•
•
•
HT use > 5 yrs
Early menarche
Delayed menopause 1.4
Alcohol use
Shift work
Late 1st pregnancy
Menopausal obesity
Increased breast density
Age >65
BRCA gene mutation
1.3
1.3
1.2
1.5
1.8
1.2
2.4
5.8
200
Modified from Singletary S.E. Ann Surg 2003;237:474
Incidence Of Breast Cancer
Breast Tissue Estradiol Levels
ns
Estradiol fmol/mg
30
20
10
0
HT
No HT
Pre
menopausal
BREAST ESTROGEN EXPOSURE
100
90
80
70
Pre-menopausal
60
50
40
30
20
10
0
Relative Estrogen Exposure
Relative Estrogen Exposure
100
90
80
70
Post-Menopausal
60
50
40
30
20
10
0
Local
Blood
Local
Blood
Hypothesis
• A combination of an aromatase inhibitor
and HT may decrease breast cancer risk
• The AI reduces local estrogen exposure in
the breast
• The HT prevents hypoestrogenic symptoms
related to AI
• Long-term use of the combination should be
safe and free of adverse effects
New Hormone Replacement
• Natural estrogen and low dose progestin
PLUS
• an aromatase inhibitor to prevent local
breast estrogen production
BREAST ESTROGEN EXPOSURE
90
80
70
100
60
50
Pre-menopausal
40
30
20
10
0
Relative Estrogen Exposure
100
90
80
Relative Estrogen Exposure
Relative Estrogen Exposure
100
90
80
70
60
50
40
HRT plus
Aromatase Inhibitor
30
20
10
0
70
Local
60
50
40
Post-Menopausal
30
20
10
0
Local
Blood
Blood
Pilot Study
• 23 PMP women on HT for several years
• At least 2 annual mammograms prior to
study
• Started on letrozole 2.5 mg on Monday,
Wednesday and Friday
• Control group of 22 age matched women on
HT only
Mousa et al, Menopause 2008
Analysis
• Study group had at least two mammograms
one year apart for comparison
• Addition of letrozole for at least one year
• Control group breast density compared on
two mammograms, the same interval of
time apart, to rule out an age effect on
density
Mousa et al, Menopause 2008
Analysis
• Mammograms for each subject digitized
• Breast density pre- and post-AI
• Image analysis software (Image Quant and
Image J)
Lost density
Mousa et al, Menopause 2008
Conclusion
• Addition of AI to HT significantly reduced
mammographic breast density without
hypoestrogenic side effects
• May reduce risk of breast cancer in postmenopausal women
Mousa et al, Menopause 2008
AIs vs SERMs
• Unlike SERMs, AIs directly prevent estrogen
synthesis in the breast
• Carcinogenic impact of estrogen not only through
ER
• May also be associated with genotoxic
metabolites of estrogen (catecholestrogens)
• Preventive advantage of AIs over tamoxifen
Conclusions HT
• HT use for menopausal symptom relief
accepted as safe for up to 5 years
• Slight increase risk in breast ca associated
with HT but not with E only
• Dosing should be lowest that will relieve
symptoms (usually 1 mg E2 orally or 50
mcg/day transdermally)
• HT use past 5 years should be considered
on an individual basis